Journal articles: 'Hoffman-La Roche AG'

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Pott, Christiane, Eva Hoster, Britta Kehden, Michael Unterhalt, Michael Herold, Richard van der Jagt, Ann Janssens, et al. "Minimal Residual Disease Response at End of Induction and during Maintenance Correlates with Updated Outcome in the Phase III GALLIUM Study of Obinutuzumab- or Rituximab-Based Immunochemotherapy in Previously Untreated Follicular Lymphoma Patients." Blood 132, Supplement 1 (November 29, 2018): 396. http://dx.doi.org/10.1182/blood-2018-99-115930.

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Abstract Introduction: Minimal residual disease (MRD) status reflects depth of response and informs prognosis after first-line therapy in patients (pts) with follicular lymphoma (FL). In the GALLIUM study (NCT01332968), the primary endpoint of investigator (INV)-assessed progression-free survival (PFS) in previously untreated FL pts was significantly improved with obinutuzumab (GA101; G)- versus rituximab (R)-based immunochemotherapy treatment. We previously reported consistently higher MRD response rates with G- versus R-based treatment at the end of induction (EOI) (92% vs 85%, respectively; p=0.0041; Pott et al. ASH 2016). Here we report the correlation of MRD response at EOI with updated PFS data and the results of MRD response assessment during maintenance treatment and follow-up. We also assessed MRD responses and outcome in pts who remained MRD-positive at EOI. Methods: Previously untreated pts aged ≥18 years with FL requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg IV on days [D] 1, 8, and 15 of cycle [C] 1 and D1 of C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemotherapy (CHOP, CVP, or bendamustine). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. MRD status was assessed by real-time quantitative (RQ)-PCR assays at mid-induction (MI) in peripheral blood (PB), at EOI in PB and bone marrow, at 4-monthly intervals during maintenance in PB, and at 6-monthly intervals during follow-up in PB, and was defined as negative (MRD response) if RQ-PCR and subsequent nested PCR were negative in all samples analyzed at the respective time point. INV-assessed PFS was estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Pts were included in the various analyses if they had evaluable MRD data and achieved a complete or partial response at EOI. Results: After 57 months' median follow-up, MRD evaluable pts (n=634/1202 randomized FL pts) who had a MRD-negative response at EOI (n=564) continued to have a longer PFS than those who had a MRD-positive response at EOI (n=70; hazard ratio 0.38; 95% confidence interval 0.26, 0.56; p<0.0001; Figure 1), which was irrespective of treatment arm (Figure 2). Of the MRD evaluable pts who continued on maintenance treatment, a MRD-negative response was observed at EOI in 300/324 (92.6%) pts in the G arm versus 264/310 (85.2%) in the R arm (p=0.0034). The majority of the MRD-negative pts remained negative during maintenance. No difference in the MRD relapse rate (conversion to MRD positivity) was observed between pts treated with G or R maintenance (6.3% vs 6.1%, respectively). Two-thirds of MRD-negative responses were sustained throughout the maintenance period (G, 67.0%; R, 63.2%), with a rate of disease progression or death of 11.4% in the G arm and 15.5% in the R arm. Twenty-four pts in the G-chemo arm and 46 pts in the R-chemo arm were MRD positive at EOI but eligible for maintenance treatment based on clinical (CT-based) response. Of these, 22 (92%) pts in the G-chemo arm (18 within the first 4 months of maintenance treatment) and 36 (78%) pts in the R-chemo arm (27 within the first 4 months) achieved MRD negativity during maintenance. Of the 12 pts who never achieved an MRD response, 8 progressed or died within 7 months of EOI, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until D1348 and D1709. Conclusions: These data confirm the prognostic value of MRD status at EOI in previously untreated FL pts receiving immunochemotherapy. Analysis of MRD kinetics revealed that most of the pts who achieved MRD negativity at EOI sustained their responses during maintenance. The majority of pts who were MRD positive at EOI achieved MRD negativity during the first 4 months of maintenance. While this is likely to be indicative of the efficacy of continued treatment, it also suggests that response kinetics can be slower than in those pts who have an early MRD response at MI, and that responses that are beyond the sensitivity of the MRD assay may be less deep. Importantly, pts who failed to achieve MRD negativity at EOI or during early maintenance had a high chance of experiencing early progression or death. These data demonstrate the prognostic value of MRD response assessments in previously untreated FL pts receiving immunochemotherapy. Disclosures Hoster: F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. van der Jagt:F. Hoffman-La Roche Ltd: Employment, Honoraria, Research Funding. Janssens:Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Mayer:Affimed: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding; Novartis: Research Funding. Pocock:Kent & Canterbury Hospital: Employment. Knapp:Roche: Employment. Danesi:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Mundt:Roche: Employment, Other: Ownership interests PLC. Marcus:Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees . Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Schmidt, Christian, Anna-Katharina Zoellner, Vindi Jurinovic, Martin Sökler, Roswitha Forstpointner, Sascha Haubner, Christian Buske, et al. "Chemotherapy-Free Combination of Obinutuzumab and Ibrutinib in First LINE Treatment of Follicular Lymphoma. the Alternative Study By the German Low Grade Lymphoma Study Group (GLSG)." Blood 132, Supplement 1 (November 29, 2018): 448. http://dx.doi.org/10.1182/blood-2018-99-111692.

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Abstract Background: The clinical course of follicular lymphoma (FL) is characterized by a slow progression over years with continuous relapses despite good response to initial treatment. The median overall survival is 10 to more than 15 years. Standard therapy for patients requiring treatment consists of an anti-CD 20 antibody combined with chemotherapy followed by antibody maintenance. With this combination a 1-year-PFS of 93% was seen in the GLSG-2000 trial (Hiddemann et al, Blood 2005). Because of the substantial side effects of chemotherapy such as infections, secondary malignancies and impairment of the stem cell reserve novel "chemotherapy-free" treatment approaches could substantially improve the treatment tolerability in FL. The BTK-inhibitor ibrutinib has demonstrated promising activity in patients with iNHL, CLL and MCL. Anticipating the recent reports on a superior activity of obinutuzumab as compared to rituximab in the GALLIUM trial (Marcus et al., NEJM 2017), the GLSG initiated a phase II study combining ibrutinib and obinutuzumab to explore the efficacy and safety of this "chemotherapy-free" alternative. Methods: ALTERNATIVE is a prospective multicenter single-arm phase 2 study of the combination of ibrutinib and obinutuzumab in 98 patients with previously untreated FL and a high tumor burden (defined by modified GELF criteria) in need of treatment. Induction comprises 6 cycles of obinutuzumab at a dose of 1000 mg by intravenous infusion on days 1, 8, 15 of cycle 1 and on day 1 of cycles 2-6 to be given every 21 days. Ibrutinib is administered orally at a dose of 560 mg once daily throughout all 6 cycles. In patients with at least partial response (defined by Cheson Response Criteria 2007) after the end of induction, maintenance with obinutuzumab (1000mg every 8 weeks) plus ibrutinib (560mg daily) is given for an additional 24 months. In patients remaining MRD positive at 30 months ibrutinib is continued for another 12 months in an extended maintenance setting without obinutuzumab. The primary efficacy endpoint is the rate of investigator-assessed PFS one year after registration. Response rates at end of induction, after one year and after end of maintenance, duration of response, percentage of progression during induction and maintenance, time to treatment failure, overall survival, duration of molecular remission in MRD negative patients and safety are key secondary endpoints. Results: 98 patients with advanced stage FL were included, The median age was 59 years (29-81), 60% were male and 40% had a high risk FLIPI, 90% stage III/IV disease and 10% were stage II with a high tumor burden. Response to in induction was 90% (87/97) with 85% (82/97) PR and 5% (5/97) CR. 5 patients (5%) progressed during induction. Of the 82 patients with PR after end of induction, 8 patients achieved a CR during the first 6 months of maintenance treatment. 95 patients were evaluable for the primary endpoint of 1-year-PFS and 76 patients (80%) remained alive and free of progression at this timepoint. 18 patients progressed in the first year, two of whom died due to progressive disease. One additional death was caused by a non-lymphoma related event. An MRD-marker was found in 65 patients. MRD at the end of induction was evaluable for 63 patients. 44 patients (70%) were MRD negative after induction treatment. Of the 42 patients with follow-up MRD peripheral blood or bone marrow samples, 35 (83%) were MRD negative one year after registration. Therapy was generally well tolerated. Most common adverse events were diarrhea in 30% of patients, rash in 25% and fatigue and nasopharyngitis (common cold) in 23% and 20%, respectively. Concerning hematotoxicity grade 3-4 neutropenia and thrombopenia were seen in 8% and 4% of patients, respectively. Severe (>=grade 3) infectious complications were rare (6% pneumonia/bronchitis, 2% sepsis, 7% other infections). Conclusions: The chemotherapy - free combination of ibrutinib and obinutuzumab showed high anti-lymyphoma activity with high overall response rates and a high proportion of MRD negativity at one year. While the combination of ibrutinib and obinutuzumab was associated with a low toxicity profile, the combination was inferior to the published results of conventional immunochemotherapies in terms of the primary efficacy endpoint (1-year-PFS). Further evaluations might demonstrate whether subgroups exist which particularly benefit clinically from this low toxicity regime. Figure Figure. Disclosures Schmidt: Celgene: Honoraria; Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Buske:Bayer: Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Viardot:Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Keller:BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; MSD: Consultancy; Celgene: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Hänel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Liersch:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Dürig:Celgene: Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Hoster:Roche Pharma AG: Other: Travel support, Research Funding; F. Hoffman-La Roche: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

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Bezombes, Christine, Emilie Decaup, Pauline Gravelle, Christine Jean, Camille Laurent, Christian Klein, Nathalie Varoqueaux, Ariel Savina, Jean-Jacques Fournié, and Guy Laurent. "Multicellular Aggregates Of Lymphoma Cells (MALC): An Invaluable Model For Studying Follicular Lymphoma Biology and Mechanisms Of Action Of Therapeutic Drugs Such As Anti-CD20 Antibodies." Blood 122, no. 21 (November 15, 2013): 4410. http://dx.doi.org/10.1182/blood.v122.21.4410.4410.

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Follicular lymphoma (FL) is the second most common type of B non-Hodgkin’s lymphomas (NHL) and makes up 40% of all adult lymphomas. Like most carcinomas, NHL grow as spherical tumors. Based on carcinoma 3D models (often described as spheroids) it is acknowledged that spatial organization may profoundly affect tumor cell behavior since important functions are dictated by the collective properties of a cell population rather than those of a single cell. These include growth, metastasis, cell-to-matrix and cell-to-cell interaction, as well as intracellular signaling and resistance to anti-tumor agents or even immune escape. Spatial organization can exert these effects in cancer cells by affecting gene expression profiles or influencing major signaling pathways such as those driven by MAPK, Akt and oncogenic products such as HER-2. More importantly, spatial organization is known to influence the response to antibodies such as Trastuzumab or Pertuzumab. Conventional 2D NHL cell culture models do not reflect the true effects of antibodies as they occur in vivo and may be of limited use. Thus, we recently created a NHL 3D culture system, the so-called Multicellular Aggregates of Lymphoma Cells (MALC) model, using a modification of the “hanging drop” method. This model is not only useful for studying FL biology, but also for evaluating tumor sensitivity to antibodies since diffusion/distribution is different within a solid 3D tumor. In this study, we present transcriptomic and extracellular matrix proteins expression profiles in 2D, 3D FL cell cultures and patients biopsies, and observed that MALC, but not 2D cultures, display similarities to patients samples. Indeed, we observe an upregulation of genes involved in the response to hypoxia, activation of NFκB pathway and negative regulation of cell cycle promoting the emergence of chemoresistant quiescent cells. Moreover, MALC, in contrast to 2D cultures but as observed in biopsies, exhibit higher expression of fibronectin, laminin, vitronectin and collagen. Recently, we showed that spatial organization also influence response to anti-CD20 monoclonal antibodies such as Rituximab and Obinutuzumab. Here, we investigate the antibody-dependant cell cytotoxicity induced by these two monoclonal anti-CD20 antibodies in the MALC model: cell cytotoxicity, effector and target cells signaling, and spatial localization are presented. Thus, we present an invaluable model for further investigation of FL biology, and also for the development/screening of new genotoxic drugs and therapeutic monoclonal antibodies in lymphoma. Disclosures: Bezombes: Roche: Research Funding. Decaup:Institut de Recherche Roche: Employment. Klein:Roche Glycart AG: Employment. Varoqueaux:F. Hoffman-La Roche AG: Employment. Savina:Roche S.A.S: Employment.

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Alig, Stefan, Alessandro Pastore, Vindi Jurinovic, Sarah Häbe, Deepak Bararia, Verena Passerini, William Keay, et al. "Clinicogenetic Risk Models in Patients Randomized to Receive Consolidative Autologous Stem-Cell Transplantation after Frontline R-CHOP for Advanced Follicular Lymphoma: An Analysis from the GLSG2000 Trial." Blood 132, Supplement 1 (November 29, 2018): 4096. http://dx.doi.org/10.1182/blood-2018-99-118000.

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Abstract Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore whether HDT/ASCT is an effective frontline therapy for patients identified to be high-risk by clinical (i.e., FLIPI) or clinicogenetic risk models (i.e., m7-FLIPI, POD24-PI). Methods: We performed targeted DNA deep-sequencing of >150 genes in available diagnostic FL biopsies from 165 patients ≤60 years with advanced FL from the GLSG2000 trial who uniformly received R-CHOP as frontline treatment. Of these, 87 patients (53%) were randomized to receive consolidative HDT/ASCT, 78 (47%) were randomized to interferon maintenance. We performed intention-to-treat (ITT) survival and regression analyses to explore whether known clinical and clinicogenetic risk factors can be overcome by ASCT. Results: The HDT/ASCT and no-HDT/ASCT cohorts were balanced regarding age (48 vs 50 years), sex (49% vs 64% male patients), high-risk FL International Prognostic Index (FLIPI; 25% vs 29%), Eastern Cooperative Oncology Group Performance Score >1 (6% vs 5%) and mutation status of EZH2 (23% vs 18%) and TP53 (3% vs 3%). The incidence of POD24 was not significantly lower in the HDT/ASCT cohort (8% vs 14%, p=0.32). After a median follow-up of 7.5 years, 5-year failure-free survival (FFS) rates in the HDT/ASCT and no-HDT/ASCT cohorts were 77% and 69% (HR 0.7, p=0.16), 5-year OS rates were 95% and 90% (HR 0.6, p=0.21), respectively. The high-risk cohorts identified by FLIPI, m7-FLIPI, and POD24-PI comprised 27% (n=45), 18% (n=29) and 22% (n=37) of patients, respectively (Fig. A). The m7-FLIPI reclassified 10% (n=16) of patients from high-risk FLIPI to low-risk m7-FLIPI. The POD24-PI reclassified 5% (n=9) of patients from high-risk FLIPI to low-risk POD24-PI; one patient was reclassified from low-risk FLIPI to high-risk POD24-PI. Patients identified to be high-risk by all three indices had shorter FFS (FLIPI: HR 2.8, p=0.0002; m7-FLIPI: HR 3.0, p=0.0003; POD24-PI: HR 2.5, p=0.0013), but OS was not different (FLIPI: HR 1.4, p=0.47; m7-FLIPI: HR 1.5, p=0.45; POD24-PI: HR 1.5, p=0.47). The risk to develop POD24 was increased in high-risk patients (FLIPI: OR 4.4, p=0.007; m7-FLIPI: OR 4.8, p=0.005; POD24-PI: OR 4.3, p=0.008). Consolidative HDT/ASCT did not prolong FFS in high-risk patients as defined by FLIPI (HR 1.2, p=0.67), m7-FLIPI (HR 1.2, p=0.70; Fig. B) and POD24-PI (HR 1.3, p=0.63; Fig. B). Similarly, OS was not significantly improved in all three high-risk cohorts (FLIPI: HR 0.2, p=0.13; m7-FLIPI: HR n/a, p>0.99; and POD24-PI: HR 0.3, p=0.22). In low-risk patients, HDT/ASCT was associated with a non-significant trend towards prolonged FFS (FLIPI: HR 0.5, p=0.061; m7-FLIPI: HR 0.6, p=0.16; POD24-PI: HR 0.5, p=0.068; Fig. B), but again OS was not significantly different (FLIPI: HR 0.8, p=0.69; m7-FLIPI: HR 0.8, p=0.66; and POD24-PI: HR 0.7, p=0.52). Conclusions: Our ITT-analysis confirms that consolidative HDT/ASCT should not be offered to unselected cohorts of patients with previously untreated, advanced FL after R-CHOP. Also, our current clinicogenetic risk models are not optimized to select high-risk patients who may benefit from frontline HDT/ASCT. The fraction of patients identified to be high-risk by FLIPI, m7-FLIPI and POD24-PI is low when applied to younger, medically fit patients. Moreover, the fraction of patients being reclassified by integrating gene mutation data is low in this patient cohort. Therefore, we are developing specific stratification algorithms for younger, medically fit patients who are eligible for dose-intensified approaches. Figure. Figure. Disclosures Klapper: F.Hoffman-La Roche: Honoraria, Research Funding; HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Dreyling:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Hoster:F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Weigert:Roche: Research Funding; Novartis: Research Funding.

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Versmold, Katharina, Ferras Alashkar, Carina Raiser, Richard Ofori-Asenso, Tao Xu, Yutong Liu, Pablo Katz, Aijing Shang, and Alexander Roeth. "Clinical Profile and Long-Term Outcomes of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab in a Real-World Setting: High Frequency of Anemia Despite Decreased Intravascular Hemolysis." Blood 138, Supplement 1 (November 5, 2021): 4314. http://dx.doi.org/10.1182/blood-2021-147162.

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Abstract Background: Eculizumab, an anti-C5 antibody, was approved for the treatment of patients (pts) with symptomatic paroxysmal nocturnal hemoglobinuria (PNH) in 2007 and has been the standard of care for over a decade. However, published data on real-world outcomes of eculizumab-treated pts with PNH are limited. The aim of this study was to describe the clinical profile of pts with PNH treated with eculizumab by characterizing their short- and long-term laboratory and clinical outcomes. Methods: This retrospective study (Versmold et al, Blood 2020) used preexisting medical records of eculizumab-treated pts with PNH (treatment duration ≥24 weeks [wks]) treated at the University Hospital Essen, Germany prior to April 2018. Anonymized data were collected via electronic case report forms. Laboratory data were extracted from the hospital computer system. Lactate dehydrogenase (LDH), hemoglobin, absolute reticulocyte count (ARC), and bilirubin profiles were assessed at baseline (12 months before treatment) and during the treatment phase (up to 13.2 years [yrs] follow-up). Breakthrough hemolysis (BTH) was defined as ≥1 new symptom or sign of intravascular hemolysis (including fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction in the presence of elevated LDH [≥2 × the upper limit of normal (ULN)] after reduction of LDH to ≤1.5 × ULN). Extravascular hemolysis was defined as persistence of reticulocytes >100 × 10 9/L with bilirubin >1 × ULN and positive direct Coombs test or reticulocytes >100 × 10 9/L with bilirubin >1 × ULN and ≥1 positive C3c or C3d test. Complete hematologic response was zero blood transfusions with hemoglobin ≥12 g/dL and LDH ≤1.5 × ULN and major hematologic response was zero blood transfusions with hemoglobin ≥12 g/dL and LDH >1.5 × ULN within any 24-wk window (Risitano et al, Front Immunol 2019). Transfusion-dependence was ≥2 blood transfusions within any 24-wk period. Pts transferred from other centers or within 24 wks of treatment were excluded due to missing baseline data. Results: The study included 56 pts with PNH (mean age: 42.9 yrs [± 17.6]; 46.4% female) treated with eculizumab for ≥24 wks (mean follow-up: 5.24 yrs [± 3.25]) during the study period. The median duration from diagnosis to starting eculizumab was 1.57 yrs. Overall, 18 pts (32.1%) had aplastic anemia at diagnosis, 10 (17.9%) had symptoms of high disease activity, and 34 (60.7%) had a blood transfusion in the prior 12 months. The most reported disease-related symptoms at baseline were anemia (28.6%), fatigue (26.8%), thrombosis (21.4%), dyspnea (17.9%), dysphagia (10.7%), erectile dysfunction (10.0%), kidney complications (8.9%), abdominal pain (8.9%), and hemoglobinuria (7.1%). Mean hemoglobin (n=44) was 9.67 g/dL [± 2.06] and LDH in the past 12 months (n=47) was 1480 U/L [± 1010]. During the first 24-wk treatment phase, 37% (20/54) of pts had LDH >1.5 × ULN, 31% (14/45) had ARC >1.5 × ULN, and 17% (8/47) had hemoglobin ≥12 g/dL (Figure). Among pts with response data, 15% (7/47) had complete hematologic response and 2% (1/47) had major hematologic response within 24 wks. Documented BTH with symptoms occurred in 11% (6/56). Moreover, 23% (13/56) of pts were transfusion-dependent, increasing to 39% (22/56) when including pts who had ≥1 transfusion during the first 24 wks of treatment. Six pts (11%) received a higher-than-labeled dose (600 mg intravenous [IV] weekly for 4 wks, 900 mg IV 1 wk later, then 900 mg IV every 2 wks thereafter) of eculizumab. Over the long term (ie, between 25 and 246 wks), 11.1-34.7% of pts received blood transfusions and 7.0-21.7% had LDH >1.5 × ULN in any 24-wk window; whereas 36.1-72.7% had ARC >1.5 × ULN (Figure). Moreover, 65.8-77.3% of pts had hemoglobin <12 g/dL within any 24-wk period and 69.0-77.2% did not meet the criteria for major or complete hematologic response during any 24-wk period from wks 25 to 246. During the treatment phase, no meningococcal infections were reported. Conclusions: In this long-term real-world study, a considerable proportion of pts with PNH treated with eculizumab did not achieve optimal clinical outcomes with an ongoing burden of disease (ie, low hemoglobin level with high reticulocyte count due to extravascular hemolysis, BTH, etc.). Future exploration of other therapies that improve pt outcomes could help to address remaining unmet medical needs. Figure 1 Figure 1. Disclosures Alashkar: Alexion: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria; Bluebird Bio: Honoraria. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Xu: F. Hoffmann-La Roche AG: Current Employment. Liu: Genesis Research: Current Employment. Katz: F. Hoffman-La Roche Ltd: Current Employment. Shang: F. Hoffman-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Roeth: Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bioverativ, a Sanofi company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Kira: Consultancy, Honoraria.

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Seymour, John F., Thomas J. Kipps, Barbara F. Eichhorst, Peter Hillmen, James D'Rozario, Sarit Assouline, Carolyn Owen, et al. "Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)." Blood 134, Supplement_1 (November 13, 2019): 355. http://dx.doi.org/10.1182/blood-2019-123930.

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Introduction: Venetoclax (Ven) is a highly selective oral inhibitor of key apoptosis regulator BCL-2, which is overexpressed in CLL. MURANO (a randomized Phase III study) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. The superior progression-free survival (PFS) of VenR versus BR was established in the first pre-planned analysis (Seymour et al. N Engl J Med 2018); continued PFS benefit was seen with longer follow-up and after all patients (pts) had completed therapy (Kater et al. J Clin Oncol 2019). We now present data from a further analysis (median follow-up 48 months) when all pts had been off Ven treatment for median 22 months. Methods: As previously published, pts were randomized to 6 cycles of VenR then Ven 400mg once daily for 2 years in total, or 6 cycles of BR. PFS status was based on investigator assessment. Central analysis of minimal residual disease (MRD) status in peripheral blood (PB) was performed at Cycle 4, end of combination treatment (EOCT) then every 3-6 months. Pts were categorized as undetectable MRD (uMRD; <1 CLL cell/10,000 leukocytes [<10-4]), low-MRD (≥10-4 - <10-2), or high-MRD (≥10-2) status. All p-values are descriptive. Safety data collected for the current analysis period were pre-specified adverse events (AEs) of concern, serious AEs (SAEs) related to study drug, and development of a second primary malignancy. Results: 389 pts were enrolled: VenR (n=194), BR (n=195). At data cutoff (May 8, 2019), all pts were off treatment and with a median follow-up from enrolment of 48 months. With a median follow-up period of 22 months since Ven completion (1-35 months), the PFS benefit of VenR over BR was sustained (HR, 0.19 [95% CI 0.14, 0.25]; p<0.0001; Figure 1). The 4-year PFS estimates were 57.3% (95% CI 49.4, 65.3) versus 4.6% (95% CI, 0.1, 9.2), respectively. For the pts who completed 2 years of Ven (n=130), the 18- and 24-month post-treatment cessation PFS estimates were 75.5% (95% CI 67.4, 83.7) and 68.0% (95% CI 57.6, 78.4), respectively. Thirty-five of 130 pts had developed progressive disease (PD, defined by International Workshop on Chronic Lymphocytic Leukemia criteria) after completion of Ven. Sustained overall survival (OS) benefit was demonstrated with VenR over BR (HR, 0.41 [95% CI 0.26, 0.65]; p<0.0001; 4-year rate: 85.3% vs 66.8%; Figure 2). This OS benefit was seen despite 103/142 (73%) BR pts receiving treatment after progression; 81/103 (79%) pts in the BR arm received novel targeted agents (Bruton tyrosine kinase inhibitors [BTKis; n=60], PI3K inhibitors [PI3Kis; n=9], BH3-only mimetics [n=10] or investigational medicinal products [IMPs; n=2]). The response rate to novel targeted agents in the BR arm was 47/81 (58%; Figure 3). Forty-two of 64 (66%) pts in the VenR arm received anti-CLL therapy after PD. Of these, 28 received novel targeted therapies (BTKis, n=12; PI3Kis, n=1; BH3-only mimetics, n=14; IMPs, n=1) and the response rate to these treatments was 9/28 (32%; Figure 3). Fourteen of the VenR arm pts with PD subsequently received Ven or were re-treated with VenR, producing an overall response rate of 2/14 (14%); 10/14 pts (71%) were without an evaluable or available response. Updated response data for these pts will be presented. In both treatment arms, the previously reported association between uMRD in PB at the EOCT response visit with improved PFS was maintained with this extended follow-up (Figure 4A). In the VenR cohort, improved PFS was observed for pts who were uMRD at end of treatment (EOT; Figure 4B). Among VenR pts who had detectable PB MRD at the EOCT response visit and at EOT, low-MRD pts continued to show improved PFS versus high-MRD pts. There were no new SAEs considered related to study drug. Excluding non-melanoma skin malignancies, 3 second primary malignancies were detected (1 who received BR [melanoma] and 2 who received VenR [melanoma and breast cancer]) since the previous update. There were no new reported events of Richter's transformation. Conclusions: Four-year data from MURANO demonstrate sustained PFS and OS benefits with VenR versus BR. 24-month post-treatment cessation PFS was 68.0% in pts completing 2 years of Ven, and pts who attained PB uMRD showed particularly durable responses. These follow-up data provide further support for the application of time-limited VenR in R/R CLL. Disclosures Seymour: Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Janssen: Consultancy, Research Funding. Kipps:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Owen:AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Teva: Honoraria; Merck: Honoraria; Acerta: Research Funding. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. de la Serna:Roche, AbbVie, Janssen, Gilead: Speakers Bureau; Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria; Roche, Celgene: Consultancy. Montillo:Versatem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Kim:AbbVie: Employment, Other: Stock or options. Wu:Genentech, Inc.: Employment, Equity Ownership, Other: Stock options. Jiang:F. Hoffman-La Roche: Equity Ownership; Genentech: Employment, Equity Ownership. Wang:Genentech, Inc.: Employment; Roche: Equity Ownership. Lefebure:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Kater:Genentech: Research Funding; Roche: Other: Travel funding, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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Phillips, Tycel J., Adam J. Olszewski, Javier Munoz, Tae Min Kim, Dok Hyun Yoon, Richard Greil, Jason Westin, et al. "Mosunetuzumab, a Novel CD20/CD3 Bispecific Antibody, in Combination with CHOP Confers High Response Rates in Patients with Diffuse Large B-Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 37–38. http://dx.doi.org/10.1182/blood-2020-136295.

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Introduction: Despite the curative intent of the R-CHOP regimen in the first-line treatment of diffuse large B-cell lymphoma (DLBCL), 35-40% of patients who received R-CHOP will eventually succumb to their disease (Coiffier, et al. Blood 2010; Sarkozy and Sehn. Ann Lymphoma 2019). As such, improved treatments are needed. Mosunetuzumab (Mosun) is a T-cell-engaging bispecific antibody that redirects T cells to eliminate malignant B cells by binding to CD3 on T cells and CD20 on B cells. Mosun monotherapy has a manageable safety profile and promising efficacy, including durable complete responses (CR), in patients (pts) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL) (Schuster, et al. ASH 2019). This is the first report describing the safety and efficacy of Mosun plus CHOP (M-CHOP) in pts with R/R NHL and newly diagnosed DLBCL in the ongoing GO40515 (NCT03677141) study. Methods: Pts with R/R NHL and with newly diagnosed DLBCL received six 21-day cycles of M-CHOP. In Cycle (C) 1, Mosun was administered in step-up doses on Day (D) 1 (1mg), D8 (2mg), and D15 (13.5mg and 30mg in R/R NHL; 30mg in newly diagnosed DLBCL) to mitigate cytokine release syndrome (CRS). Full dose Mosun (C1D15 dose) was given on D1 of subsequent cycles in addition to CHOP. Interim and primary response assessments were obtained after C4 and C6, respectively. Primary prophylaxis with granulocyte colony-stimulating factor was mandatory for all pts. Pts with a partial response or stable disease at the end of C6 could continue Mosun monotherapy for up to 11 additional cycles. Response rates were based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014). Results: As of June 3, 2020, 43 pts had received M-CHOP: seven patients with R/R NHL, and 36 pts with newly diagnosed DLBCL. Pts with disease stage II-IV were enrolled, with a median IPI score of 3 (range: 2-4) and ECOG performance status between 0 and 2. Median age was 66 (range: 39-87) and 17 pts (42%) were female. In pts with R/R NHL treated with M-CHOP (n=7), the overall response rate (ORR) was 86%, with 71% of pts achieving a CR. Twenty-seven out of 36 pts with previously untreated DLBCL started treatment at least three months prior to data cut-off date; in these pts the ORR was 96%, with a CR rate of 85% (Table). Grade (Gr) ≥3 adverse events (AEs) occurred in 37 pts (86%) and serious AEs in 19 pts (44%). Two pts (29%) with R/R NHL experienced CRS (one with Gr 1 and one with Gr 2; ASTCT grading, Lee et al. Biol Blood Marrow Transplant 2019); one pt received tocilizumab. Nineteen pts (53%) with previously untreated DLBCL had CRS events (14 with Gr 1, five with Gr2); one pt received tocilizumab. No pts required vasopressors or high-flow oxygen. All CRS events occurred in C1, resolved without sequelae, and did not result in discontinuation or delay in treatment. No immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed. Neutropenia occurred in two pts with R/R NHL (29%; Gr 4 n=2) and 23 pts with newly diagnosed DLBCL (64%; Gr 3 n=3, Gr 4 n=20). Febrile neutropenia occurred in two pts (29%) with R/R NHL, and six pts (17%) with newly diagnosed DLBCL. Gr 5 AEs, excluding disease progression, were reported in two pts: one due to Pneumocystis jirovecii pneumonia in a pt with R/R NHL, and one due to pneumonia in a pt with newly diagnosed DLBCL. All pts with R/R NHL have completed treatment. Among pts with newly diagnosed DLBCL, four have completed treatment and 29 remain on treatment; one pt died on-study (Gr 5 pneumonia), and two withdrew from the study treatment due to AEs (one due to treatment-unrelated esophageal perforation; one due to treatment-related pneumonitis). Linear pharmacokinetics (PK) were observed for Mosun. No differences were seen in Mosun exposure for pts with R/R NHL and previously untreated DLBCL. Similar PK characteristics were seen with M-CHOP as with Mosun monotherapy, indicating no impact when co-administered with CHOP. Conclusions: Preliminary data show that Mosun, a novel CD20/CD3 bispecific antibody, when combined with CHOP confers high response rates and a manageable safety profile in pts with R/R NHL and previously untreated DLBCL. End of treatment response rate data for pts with previously untreated DLBCL, and correlative studies of T-cell response, will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy; BMS: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding. Munoz:Alexion: Consultancy; Portola: Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Verastem: Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Incyte: Research Funding; Millenium: Research Funding. Kim:AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Greil:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Westin:Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Infinity: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; Karyopharm: Honoraria; Gilead: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding. Canales:Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, F. Hoffmann-La Roche, Sandoz: Honoraria; Janssen, F. Hoffmann-La Roche, Sandoz, Takeda: Speakers Bureau. Chen:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol-Myer Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Janssen Pharmaceuticals: Current equity holder in publicly-traded company. Althaus:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Negricea:F. Hoffmann-La Roche: Current Employment. Xie:F. Hoffmann-La Roche: Current Employment. McCord:Genentech, Inc.: Current Employment; F. Hoffman-La Roche: Current equity holder in publicly-traded company. Purev:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Vallurupalli:Received Research funding to University of Kansas to conduct the ongoing GO40515 clinical trial for which the abstract is being submitted.: Research Funding; On Kite speaker Bureau but do not receive any honorarium.: Speakers Bureau. OffLabel Disclosure: Mosunetuzumab (RG7828; CD20-TDB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

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Zeng, Zhihong, Natalia Baran, Sergej Konoplev, Antonio Cavazos, Qi Zhang, Vinitha Mary Kuruvilla, Philip Lorenzi, et al. "Targeting DHODH with AG-636 Induces Apoptosis and Differentiation and Inhibits Mitochondrial Function in AML, Translating into Anti-Tumor Efficacy in Vitro and in Vivo." Blood 134, Supplement_1 (November 13, 2019): 3911. http://dx.doi.org/10.1182/blood-2019-125469.

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Background: Acute myeloid leukemia (AML) is a devastating hematopoietic malignancy caused by differentiation arrest and suppression of apoptosis of immature myeloid cells. The long-term survival of AML under the established therapies remains poor. Differentiation therapy has been developed to promote the normal process of hematopoietic maturation from self-renewing progenitors to terminally differentiated effector cells. The recent discovery of a novel target, the enzyme dihydroorotate dehydrogenase (DHODH), offers differentiation-promoting therapy for the majority of AML (Sykes, D.B., et al.Cell, 2016). DHODH is the rate-limiting enzyme in the pyrimidine biosynthesis pathway. DHODH inhibition was reported to efficiently relieve the differentiation block caused by HoxA9 overexpression in 70% of AML, making this discovery potentially universally applicable for AML patients with diverse genomic alterations. AG-636 is a novel, potent, selective DHODH inhibitor developed by Agios Pharmaceuticals. This small molecule inhibitor has favorable pharmacokinetic properties and is in dose-finding Phase I clinical trials in lymphoma patients (NCT03834584) and is ready to enter a Phase I study in acute leukemia and myeloid dysplasia syndrome. Here, we investigated single agent activity of AG-636 in pre-clinical AML models. Results: AG-636 inhibited cell proliferation, induced apoptosis in AML cell lines, primary blasts and CD34+ leukemic stem/progenitor cells from AML patients with various genomic alterations cultured under physiologic conditions of stromal support (Fig. 1A). Flow cytometry and multi-parametric mass cytometry (CyTOF) analysis demonstrated that AG-636 reduced bulk AML and facilitated emergence of the differentiated myelo-monocytic cell subset co-expressing CD11b, CD11c and CD14 (Fig. 1B). Both cytotoxic and differentiating effects were rescued by supplementing the DHO downstream metabolite uridine, supporting on-target activity of AG-636 through DHODH inhibition and dependency of AML survival and stemness on the pyrimidine biosynthesis (Fig 1A top). Mass spectrometric analysis of 166 metabolites confirmed that targeting DHODH by AG-636 resulted in accumulation of the upstream L-dihydroorotic acid and ureidosuccinic acid, and depletion of the downstream metabolites, such as uridine 5'-diphsophate, uridine 5'-monophsophate, CDP and dCMP in pyrimidine biosynthesis pathway. Metabolic profiling further demonstrated the depletion of 5'-phosphoribosyl-N-formylglycinamide in treated cells, indicating the sequential effect of AG-636 on purine biosynthesis and metabolism. Seahorse-based metabolic assay showed inhibition of basal oxygen consumption and ATP generation in AG-636-treated cells, suggesting a contribution of DHODH in coupling of the mitochondria function. Proteomic profiling and immunoblots analysis revealed that AG-636 triggered AMPK activation in response to metabolic stress, and upregulated the expression of TP53, PUMA and NOXA known to regulate mitochondrial integrity. A role for DHODH inhibition in impairment of mitochondria function is of note given the key metabolic dependence of AML cells on OXPHOS/mitochondria function as shown by us and others (Molina J.R. et al. Nat Med, 2018). In vivo, twice daily administration of AG-636 significantly extended survival in a xenograft MOLM13-GFP-luciferase mouse model (Fig. 1C). Flow cytometry and CyTOF analysis demonstrated that AG-636 induced differentiation of CD11b+CD14+ and CD11b+CD11c+CD14+ monocytes in the bone marrow of treated mice (Fig. 1D). Administration of AG-636 significantly reduced tumor burden, induced differentiation and delayed leukemia progression in two AML patient-derived xenograft mouse models, one harboring mutations EZH2, NRAS and TET3, the other with mutations in ASXL1, BCOR and U2AF1. Daily treatment of AG-636 was well tolerated in all xenograft AML models tested, with a minimal effect on body weight and no significant toxicity recorded over the course of regimen. Conclusions: Our preliminary findings demonstrate that AG-636 is highly active against ex-vivo stroma-supported AML and AML stem/progenitor cells and in the in vivo AML xenograft models with diverse genetic subtypes. The significant monotherapy efficacy observed in pre-clinical studies provides the strong rationale for a clinical evaluation of AG-636 in myeloid malignancies. Disclosures Kuruvilla: The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. DiNardo:celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria. Murtie:Agios Pharmaceuticals, Inc.: Employment. Ulanet:Agios: Employment, Equity Ownership. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding.

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Schuster, Michael W., Miguel A. Canales, Jason Westin, Josée M. Zijlstra, George A. Follows, Reem Karmali, Nagesh Kalakonda, et al. "Selinexor Efficacy and Safety Are Independent of Renal Function in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis from the Pivotal Phase 2b Sadal Study." Blood 136, Supplement 1 (November 5, 2020): 34–35. http://dx.doi.org/10.1182/blood-2020-137025.

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Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl >60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl >60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl <60 mL/min) compared to those with normal (CrCl ≥60 mL/min) renal function. No dose adjustments are required in patients with renal dysfunction and DLBCL who are treated with selinexor. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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Thom, Howard Z., Jason Shafrin, Edna Keeney, Lauren M. Zhao, George J. Joseph, Menaka Bhor, Avery A. Rizio, Lanetta Bronté-Hall, and Nirmish Shah. "Relationship between Vaso-Occlusive Crisis and Quality of Life: An Analysis of Patients with Sickle Cell Disease in the United States." Blood 134, Supplement_1 (November 13, 2019): 4700. http://dx.doi.org/10.1182/blood-2019-124132.

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Introduction: Sickle cell disease (SCD) affects approximately 100,000 people in the United States (US) today. SCD can lead to painful vaso-occlusive crises (VOCs), damage to major organs, increased vulnerability to severe infections, and as such, affects a patient's health-related quality of life (HRQoL). The objective of this study was to quantify how disease severity and the presence of VOCs affects patient quality of life, as measured by the economic metric of patient utilities. While previous studies (Anie et al. 2012) have measured utilities among patients with SCD in the United Kingdom (UK), this is the first US study to evaluate utilities in patients with SCD during and outside the experience of a VOC. Methods: This study was a non-interventional, cross-sectional, online survey of patients with SCD. Individuals were recruited through SCD patient advocacy groups and a market research group. In this analysis, the outcome of interest was health utility values derived from the EuroQoL Five Dimension 5 level (EQ-5D) scale. Utility is a continuous measure of health status, where a utility of 1 represents perfect health, and a utility of 0 represents death. The EQ-5D survey responses were converted to EQ-5D health utilities using the United States EuroQoL value set, and EQ-5D health utility values (mean and 95% confidence intervals [CI]) were estimated. Respondents completed the EQ-5D question twice: once in reference to their health status when they were not experiencing a VOC and once in reference to their health status when experiencing a VOC. We estimated EQ-5D for both these measures. For EQ-5D not during VOC we estimated EQ-5D stratified by three classes of disease severity. These classes were informed by clinical expert severity. Respondents were classified as Severity Class I if they had no history of VOC requiring treatment by health care providers in the past year; Class II if they had ≥1 emergency department (ED) visit or hospital admission in the past year without organ damage; and Class III if they had long term organ damage (such as stroke or renal disease). Results: 326 individuals were screened and 299 individuals were included in the final analytic sample. Among these individuals, the average age was 34.3 years (range 18 - 72); 219 (73.2%) were female and 1 (0.3%) was non-binary. Based on self-report of VOC, as well as presence of complications and organ damage of individuals, 79.6% (238/299) were Severity Class III, 12.0% (36/299) were Class II, and 8.4% (25/299) Class I. The estimated health utility value derived from EQ-5D during VOC was 0.311 (95% CI: 0.286, 0.337). The estimated health utility values not during a VOC derived from EQ-5D was 0.733 (0.713, 0.753) for Severity Class III and 0.775 (0.725, 0.826) for Severity Class II. This result suggests >5% worse health status utility in Class III than Class II disease severity, although a Wald t-test for difference in means did not suggest evidence of a statistically significant difference in utility (p-value 0.13). Conclusion: The presence of VOC had a more severe impact on HRQoL for patients with SCD than previously estimated. When not experiencing a crisis, patients with Severity Class III, indicated by presence of organ damage, had >5% worse HRQoL than those with Severity Class II. Disclosures Thom: Novartis Pharma AG: Consultancy; Pfizer: Consultancy; Hoffman-La Roche: Consultancy; Bayer AG: Consultancy. Shafrin:Precision Health Economics, part of Precision Medicine Group: Employment, Equity Ownership. Keeney:Novartis Pharma AG: Consultancy; Pfizer: Consultancy. Zhao:Precision Health Economics, part of Precision Medicine Group: Employment. Joseph:Cigna: Equity Ownership; Pfizer: Equity Ownership; Amgen: Equity Ownership; Novartis: Employment, Equity Ownership. Bhor:Novartis: Employment, Equity Ownership. Rizio:Optum: Employment. Bronté-Hall:bluebird bio: Research Funding. Shah:GBT: Research Funding; Alexion: Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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Jaeger, Ulrich, Michael R. Bishop, Gilles Salles, Stephen J. Schuster, Richard T. Maziarz, Xia Han, Alexander Savchenko, et al. "Myc Expression and Tumor-Infiltrating T Cells Are Associated with Response in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel in the Juliet Trial." Blood 136, Supplement 1 (November 5, 2020): 48–49. http://dx.doi.org/10.1182/blood-2020-137045.

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Background: Tisagenlecleucel (tisa-cel; autologous anti-CD19 CAR-T cell therapy) has demonstrated durable responses and a manageable safety profile in adult pts with r/r DLBCL in the JULIET trial. Here we report updated efficacy results with a 40 month median follow-up and associations with baseline Myc overexpression in tumor and tumor microenvironment (TME) characteristics. Methods: JULIET is a global, phase 2 trial of tisa-cel in adult pts with r/r DLBCL. The relationship between Myc overexpression (Myc+: >40% by immunohistochemistry [IHC]), TME characteristics (including CD3+ T-cell infiltration, myeloid-derived suppressor cells [MDSCs], and LAG3 expression by fluorescent IHC) with efficacy outcomes (Month 3 [M3] response, duration of response [DOR], progression-free survival [PFS], and overall survival [OS]), and genomic mutation profile with M3 response were assessed. Results: As of February 20, 2020 (median follow-up of 40.3 mo), 115 pts received tisa-cel infusion. Among the 61 pts with a response, the relapse-free probability was 60.4% at 24 and 30 mo; median DOR was not reached (95% CI, 10-not estimable [NE]). Median OS among all 115 infused pts was 11.1 months (95% CI, 6.6-23.9). Survival probability at 12, 24, and 36 months was 48.2%, 40.4%, and 36.2%, respectively. Median OS of pts with CR (n=37) or PR (n=7) at M3 was not reached; 80% of CR pts had an OS benefit of 20 months or longer. No new safety signals were detected. Of the 23 pts with ongoing CR and B-cell count available, 11 had CD19+ B cells recovered back to normal after 1 year, with similar patterns observed for CD20+ and CD22+ B cells. Of 111 pts whose baseline archival tumor biopsies were tested for baseline Myc expression, 73 were Myc+ and 38 were Myc−. Baseline Myc− status was associated with improved outcomes compared with Myc+ pts, including longer median DOR (not reached vs 19 months [95% CI, 3.4-NE]), PFS (6.2 months [95% CI, 2.9-NE] vs 2.5 months [95% CI, 1.7-3.0]; Fig.1A), and OS (21 months [95% CI, 10-NE] vs 7.8 months [95% CI, 4.6-18]). In the TME analysis of baseline biopsy, lack or low frequency of tumor-infiltrating CD3+ T cells (cutoff of ≤3%; n=16) was associated with shorter median PFS (2.2 months [95% CI, 0.92-2.8] vs 4.2 months [95% CI, 2.6-21]; Fig.1B) and OS (7 months [95% CI, 1.8-12] vs 21 months [95% CI, 6.7-NE]) compared with pts with >3% CD3+ T cells (n=64). Interrogation of checkpoint molecule expression on tumor-infiltrating CD3+ cells revealed that pts with the highest frequency of LAG3+CD3+ cells out of entire CD3+ T cell population (cutoff of >20%; n=12) at baseline had decreased median PFS (2.1 [95% CI, 0.82-3.1] vs 4.2 months [95% CI, 2.4-21]) and OS (4.3 [95% CI, 2.7-10] vs 21 months [95% CI, 10-NE]) compared with pts with ≤20% LAG3+CD3+ T cells (n=68). No differences in baseline clinical characteristics were observed in subgroups by Myc, CD3+, and LAG3+CD3+ expression. Additionally, in a small dataset, pts with the highest frequency of CD11b+HLA-DR− cells that represent MDSC phenotype at baseline were enriched with nonresponders. In a survival tree analysis including infiltrating T cells, LAG3+ CD3+ cells, Myc, and LDH, pts with Myc− status and normal pre-infusion LDH levels (n=16) had longer PFS compared with normal LDH and Myc+, and pts with LDH 1- to 2-fold or >2-fold above the upper limit of normal, with the latter group having a poor PFS. Whole exome sequencing of 46 baseline tumor samples was performed. No significant association with response was observed in mutations at the single-gene level. The correlation between molecular subtypes and M3 response was also investigated. Samples grouped into newly identified DLBCL subtypes (Chapuy et al. Nat Med. 2018; Schmitz et al. N Engl J Med. 2018; Wright et al. Cancer Cell. 2020) did not reveal an association with response, although the small sample size may limit interpretation. Conclusions: Updated long-term data with 40 months median follow-up from the JULIET trial demonstrate sustained benefit in responding pts; in particular 80% of CR pts had a long-term OS (≥20 months). Taken together, the results suggest that Myc overexpression, or an unfavorable immunosuppressive TME with restricted T-cell response, may impact CAR-T cell efficacy in pts with DLBCL. Disclosures Jaeger: AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding. Bishop:Incyte: Honoraria, Speakers Bureau; CRSPPR Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Maziarz:Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding; Novartis and Athersys: Other: DSMB participant; Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Athersys: Patents & Royalties. Han:Novartis Pharmaceuticals Corporation: Current Employment. Savchenko:Novartis Pharmaceuticals Corporation: Current Employment. Roscoe:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Current Employment. Orlando:Novartis Institutes for BioMedical Research: Current Employment. Knoblock:Novartis Pharmaceuticals Corporation: Current Employment. Tiwari:Novartis: Current Employment. Bubuteishvili Pacaud:Novartis: Current Employment. Corradini:Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for.

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Simpson, Ewurabena, Robert J. Klaassen, Pranesh Chakraborty, Beth Potter, Melanie Ann Kirby-Allen, Isaac Odame, Suzan Williams, et al. "Increasing Incidence and Prevalence of Pathologic Hemoglobinopathies Among Children in Ontario, Canada from 1991-2013." Blood 132, Supplement 1 (November 29, 2018): 4698. http://dx.doi.org/10.1182/blood-2018-99-110468.

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Abstract Background: In Ontario, Canada's largest province, population-based health administrative data represents an accessible and useful tool for population surveillance of people with chronic diseases. While hemoglobinopathies can be identified using data from universal hemoglobinopathy screening, which was implemented in November 2006, these data would not contain information on affected immigrants (21.9% of the population). We validated algorithms using provincial health administrative data and newborn screening data to identify children with hemoglobinopathies whether or not they were born in Ontario, thereby creating a population-based surveillance cohort. Objectives: (1) Validate algorithms to identify children with sickle cell disease, thalassemia and other hemoglobinopathies from within health administrative data; and (2) Determine incidence and prevalence of hemoglobinopathies in Ontario children. Methods: For the validation study, a positive reference cohort was established using lists of known hemoglobinopathy patients who were followed at five pediatric hemoglobinopathy treatment sites in Ontario and born between November 24, 2006 and March 31, 2013. Health card numbers of these patients were linked deterministically to unique identification numbers in administrative data, which included data on hospitalizations, physician claims, sociodemographic characteristics, immigration records and cause of death. The negative reference cohort included all children residing in Ontario cities who had never been seen at a hemoglobinopathy centre, and therefore assumed not to have disease. Various combinations of administrative data codes were tested for their ability to identify children <18 years of age with hemoglobinopathies from within the databases, and we selected the algorithms with the highest positive predictive value, while maintaining sensitivity >80%. Using two validated algorithms, we identified all children with hemoglobinopathies born between April 1, 1991 and March 31, 2013. We described the crude incidence and prevalence per 100,000 patient-years (PYs). Results: Two algorithms functioned best to identify incident and prevalent hemoglobinopathy cases (see Table). Among children born between April 1, 1991 to March 31, 2013, 1526 incident hemoglobinopathy patients were identified using Algorithm 1 (crude incidence of 4.85 per 100,000 PYs) and 1660 new hemoglobinopathy patients were identified using Algorithm 2 (crude incidence 5.28 per 100,000 PYs, 95% CI 3.51 to 3.92). In 2013, the overall prevalence of children <18 years living with hemoglobinopathies was 1215-1325 cases. Conclusion: Through an innovative approach using provincial health administrative, immigration and demographic data, this study identified a rising incidence and prevalence of hemoglobinopathies among Ontario children <18 years of age between April 1, 1991 and March 31, 2013, potentially due to increased immigration rates. These findings could be used to inform health services distribution. This surveillance cohort will be used to understand the impact of immigration status on health care inequality for hemoglobinopathy-related health services delivery, as well as to assess outcomes in this important group of chronic diseases. Disclosures Klaassen: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Octapharma AG: Consultancy, Honoraria; Agios Pharmaceuticals Inc.: Consultancy; Novartis: Research Funding; Hoffman-La Roche: Consultancy; Shire: Consultancy; Cangene: Research Funding. Jardine:Pfizer: Other: Advisory board; Bayer: Other: Advisory board; Baxalta: Other: Advisory board.

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Shafrin, Jason, Howard Z. Thom, Daisy Gaunt, Lauren M. Zhao, George J. Joseph, Menaka Bhor, Avery A. Rizio, Lanetta Bronté-Hall, and Nirmish Shah. "How Does Sickle Cell Disease Severity Affect Patient Collection of Disability Insurance and Income: An Analysis of US Survey Data." Blood 134, Supplement_1 (November 13, 2019): 5781. http://dx.doi.org/10.1182/blood-2019-122774.

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Introduction: Sickle cell disease (SCD) is a complex genetic disease with a multifactorial pathophysiology including multi-cell adhesion between red blood cells, white blood cells, platelets and endothelial cells, ultimately resulting in vaso-occlusive crises (VOCs). VOCs are the hallmark of SCD and are the primary cause for hospitalization. These recurrent episodes induce severe pain, decrease quality of life, can cause life-threatening complications, and are associated with increased risk of organ damage and mortality. While the clinical burden of SCD is well-documented, less evidence exists surrounding how the severity of SCD affects patients economically. The number of VOCs and other complications not only affect the likelihood of patients being able to work on a given day, but may also affect their long-term economic prospects. This analysis aims to better understand the association between SCD disease severity and its impact on the likelihood of collecting Supplemental Security Income (SSI) and patient income. Methods: A web-based survey was administered to adult patients (≥18 years) living in the United States with a self-reported diagnosis of SCD. The outcomes of interest for this analysis were Social Security Income (SSI) receipt and self-reported total household annual income. These outcomes were stratified by SCD disease severity. Our first measure of disease severity was the number of self-reported VOCs in the prior year. Our second measure of disease severity was developed through clinical expert opinion and relied on an algorithm for dividing patients into 3 disease severity classes. Severity Class I was defined as having no VOCs requiring treatment by health care providers in the past year; Severity Class II was defined as ≥1 emergency department visit or hospital admission for a VOC, or complication in the past year without any organ damage; and Severity Class III was defined as long-term organ damage (such as stroke or renal disease). Generalized linear models (GLM) with a binomial link function were used to analyze the association between SCD disease severity and SSI collection (one model used VOC frequency; a second model used severity classes). A linear regression model was used to analyze the relationship between VOC frequency and income level, while an ordered logistic regression model was used to analyze the association between SCD disease severity classes and income level. Results: The final sample was comprised of 303 individuals who completed the survey. The average age was 34.4 years (range 18 - 72) and 221 (72.9%) were female. The probability of SSI collection among patients with SCD varied across VOC frequency in the previous year. The probability of collecting SSI for patients having 0 and ≥4 VOCs in the past year, was 12% (95% confidence interval (CI): 4% to 31%) and 47% (39% to 55%), respectively. A chi-squared p-value of 0.002 indicated a statistically significant association between a greater number of VOCs and probability of SSI collection. The probability of SSI collection among SCD patients with Severity Class II and Severity Class III SCD was 16% (7.5% to 32%), and 39% (32.9% to 45%), respectively. A chi-squared p-value of 0.03 indicated a statistically significant association between SCD disease severity class and SSI collection. The predicted mean income for patients with SCD experiencing 0 and ≥4 VOCs in the past year was $47,488 and $34,569, respectively. A linear association test p-value of 0.06 indicated weak evidence of a lower mean income in relation to number of VOCs experienced. The predicted mean income among patients with class II and class III SCD was $42,443 and $36,842, respectively. There was no evidence of association between SCD severity class and mean income (p=0.29). Conclusion: Among patients with SCD, having more VOCs was strongly associated with the probability of collecting SSI and weakly associated with lower income. Disease severity class was strongly associated with the probability of collecting SSI. Disclosures Shafrin: Precision Health Economics, part of Precision Medicine Group: Employment, Equity Ownership. Thom:Bayer AG: Consultancy; Hoffman-La Roche: Consultancy; Pfizer: Consultancy; Novartis Pharma AG: Consultancy. Gaunt:Novartis Pharma AG: Consultancy. Zhao:Precision Health Economics, part of Precision Medicine Group: Employment. Joseph:Cigna: Equity Ownership; Pfizer: Equity Ownership; Amgen: Equity Ownership; Novartis: Employment, Equity Ownership. Bhor:Novartis: Employment, Equity Ownership. Rizio:Optum: Employment. Bronté-Hall:bluebird bio: Research Funding. Shah:GBT: Research Funding; Alexion: Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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Schuster, Michael W., Miguel A. Canales, Jason Westin, Josée M. Zijlstra, George A. Follows, Reem Karmali, Nagesh Kalakonda, et al. "Effect of Age on the Efficacy and Safety of Single Agent Oral Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Pivotal Study." Blood 136, Supplement 1 (November 5, 2020): 5–6. http://dx.doi.org/10.1182/blood-2020-137020.

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Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients <65 versus those ≥65 years old. Results: Of the 134 patients enrolled in the study, 52 (39%) were <65 and 82 (61%) were ≥65 years old. In the <65 group, 14% patients had baseline creatine clearance (CrCl) of 30-<60 mL/min compared with 33% in ≥65 group. Patients with transformed DLBCL accounted for 17% and 27% of patients in the <65 and ≥65 groups, respectively. Subtype analysis revealed 43% GCB and 55% non-GCB DLBCL in ≥65 year olds, and 54% GCB and 40% non-GCB in the <65 group. The <65 group had baseline ECOG performance status of 2 in 8% compared with 13% in the ≥65 group. Patients < 65 received numerically higher median doses of selinexor (1360 and 770 mg [p=0.079]) and a longer duration of treatment (13.5 vs. 8.0 weeks [p=0.049]). There was no statistical difference in ORR in patients <65 vs. ≥65 years old: 36.5% vs. 24.4% (p=0.189). The complete response (CR) rates were 17.3% and 11% (p=0.431), respectively. Median DORs were similar at 9.7 months in the <65 compared to 9.2 months in the ≥65 year olds. While the median progression-free survival (PFS) (3.6 and 2.3 months) was similar between groups, the OS was higher in the <65 year olds: 13.7 vs. 7.8 months (p=0.037). The incidence of treatment-related AEs was comparable between both groups: The most common grade ≥3 AEs in <65 versus ≥65 year olds were thrombocytopenia (42.3% vs. 39.0%), nausea (3.8% vs. 7.3%), and fatigue (5.8% vs. 13.4%). Treatment-related serious AEs occurred in 11.5% of patients <65 (n=6) and 26.8% ≥65 (n=22), with general disorders and administration site conditions (n=12) and fatigue (n=6) as the largest contributors in the ≥65 group. Treatment discontinuations due to AEs occurred at a lower incidence in the <65 group compared with >65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those <65 when treated with selinexor, with comparable ORR, CR, PFS, DOR, and safety profile. As expected, younger patients (<65 years old) had a longer overall survival than those ≥65 years old, most likely due to comorbid medical conditions in the patients ≥65 years. These results indicate that selinexor can induce durable responses in younger and older patients with heavily pretreated DLBCL with similar tolerability. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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Al-Sawaf, Othman, Can Zhang, Sandra Robrecht, Anna-Maria Fink, Paula Cramer, Carmen D. Herling, Julia Von Tresckow, et al. "Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials." Blood 136, Supplement 1 (November 5, 2020): 18–19. http://dx.doi.org/10.1182/blood-2020-139242.

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INTRODUCTION Chronic lymphocytic leukemia (CLL) is frequently associated with an impaired humoral and cellular immunity. On a global scale chemoimmunotherapy (CIT) has remained one of the most frequently used treatment option. Thus, patients (pts) may experience further cytopenia, particularly treatment-related neutropenia, increasing the risk of infections. In order to better characterize incidence, characteristics and outcomes of infections during and after therapy, a pooled analysis of phase II and III German CLL Study Group trials was performed. METHODS Data of first line pts from 5 clinical trials (CLL7, pts treated with fludarabine, cyclophosphamide, rituximab [FCR]; CLL8, FC vs FCR; CLL10, FCR vs bendamustine-rituximab [BR]; CLL11, chlorambucil [CLB] vs CLB-R vs CLB-Obinutuzumab [CLB-Ob] and CLL2M, BR) were analyzed. Clinical, laboratory, genetic and event-related data were pooled. Infections defined as severe (CTC grade 3-5) from initiation of therapy until 4 weeks after completion of study treatment were considered related. Due to varying reporting periods for infections of the respective trials later events of infections were not included. Kaplan-Meier curves for landmark overall survival (OS) from completion of study treatment plus 4 weeks were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard regression modelling. RESULTS Data from 2,291 pts receiving at least one dose of CIT were pooled. Median observation time was 71.7 months, ranging between 43.7 months (CLL2M) and 81.0 months (CLL10). Seven-hundred and twenty-seven pts received FCR, 396 pts FC, 395 pts BR, 116 pts CLB, 326 pts CLB-R and 331 pts CLB-Ob. Overall, 274 severe grad 3/4/5 infections were reported in 229 pts (10.0% of 2,291 pts). Of those 189 pts (82.5%) had max. grade 3 infections, 22 (9.6%) pts had grade 4 infections and 18 (7.9%) pts died due to infectious complications. Median time to severe infection from start of treatment was 1.8 months (IQR 0.9-3.6), with a median number of infectious episodes per patient of 1 (range 1-4). Thirty-one (13.5%) of 229 pts had bacterial infections, 35 (15.3%) viral infections, 5 (2.2%) fungal infections and 172 (75.1%) unspecified infections. Higher grade (i.e. ≥ CTC grade 3) leukopenia and/or neutropenia was reported in 121 (52.8%) pts with severe infections. Eighty-eight (12.1%) of FCR treated pts had severe infections, followed by BR 45 (11.4%), CLB 12 (10.3%), FC 35 (8.8%), CLB-Ob 25 (7.6%) and CLB-R 24 (7.4%). Median age was 64 years in the entire cohort; no differences between pts with and without infections were observed with regards to age, sex, ECOG or creatinine clearance. Molecular and cytogenetic characteristics (deletion 17p, deletion 11q, trisomy 12) and IGHV status were similarly distributed between both groups. Median neutrophil count at enrolment was 4.4x10-9/l in both groups, respectively. Prior to therapy, levels of immunoglobulin were comparable between pts with and without infections (median IgG 7.0 vs 7.5 g/L, IgM 0.3 g/L vs 0.3 g/L). Also, pts with at least one episode of ≥ CTC grade 3 leukopenia/neutropenia had comparable rates of severe infections to pts without higher grade leukopenia/neutropenia (147 [53.6%] vs 127 [46.4%] pts). No differences were observed between pts with or without infections regarding the response to first line treatment (183 pts [79.9%] with complete response or partial response to treatment vs 1715 pts [83.2%]) as well as the rate of undetectable minimal residual disease levels (50 [21.8%] vs 477 [23.1%]). Overall survival from 4 weeks after completion of study treatment was significantly shorter in pts with severe infections compared to pts without severe infections (median 73.7 months vs 97.3 months, HR 1.503, 95% CI 1.217-1.856, p < 0.001). CONCLUSION This analysis confirms that prognosis of CLL pts who received first line treatment with (immuno)chemotherapy is influenced by severe infections. This risk does not correlate with the explored cyto- or molecular genetic risk factors, nor with response to treatment, pre-therapeutic levels of immunoglobulins or occurrence of higher grade neutropenia. Pts who experience severe infections have a significantly shorter overall survival compared to pts without severe infections. Due to their vulnerability, careful management of infectious complications in CLL pts is warranted. Figure 1 Disclosures Al-Sawaf: AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: personal fees; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees. Fink:Janssen: Honoraria; Celgene: Research Funding; AbbVie: Other: travel grants. Cramer:F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Beigene: Research Funding; Novartis: Consultancy, Research Funding; Gilead: Other: travel support, Research Funding; AbbVie: Honoraria, Other: travel support. Herling:Roche: Other: Travel support, Research Funding. Von Tresckow:Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Celgene: Other: travel grants; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; AbbVie: Honoraria. Böttcher:Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Dreyling:Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; True North: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Gregor:Roche: Honoraria; Mundipharma: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria. Ritgen:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; Gilead: Other: travel grants. Dürig:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Tausch:AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria. Goede:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Eichhorst:Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding. Langerbeins:AbbVie: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Mundipharma: Honoraria, Other: travel grants, Research Funding.

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Thieblemont, Catherine, Michael Dickinson, Joaquin Martinez-Lopez, Arne Kolstad, Jason P. Butler, Monalisa Ghosh, Leslie L. Popplewell, et al. "Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study." Blood 138, Supplement 1 (November 5, 2021): 131. http://dx.doi.org/10.1182/blood-2021-145025.

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Abstract Background: Follicular lymphoma is an indolent disease with a continuous relapsing pattern and typically requires multiple lines of therapy. Novel therapies such as tisagenlecleucel are being investigated to improve outcomes. Primary analysis of the single-arm, multicenter, Phase II ELARA trial in r/r FL demonstrated that tisagenlecleucel resulted in high overall (ORR) and complete response rates (CRR), and prolonged progression-free survival (PFS) at a median follow-up of 11 months (mo). Here, we report updated efficacy results from the overall population at a median follow-up of 17 mo, and a subgroup analysis of pts with high-risk disease from the ELARA trial (NCT03568461). Methods: Eligible adult pts had histologically confirmed r/r FL (grades 1-3A) after ≥2 lines of therapy or had relapsed after autologous stem cell transplant. Bridging therapy was allowed and was followed by disease evaluation before tisagenlecleucel infusion. Pts received tisagenlecleucel (0.6-6×10 8 CAR+ viable T cells) after lymphodepleting chemotherapy (fludarabine [25 mg/m 2] + cyclophosphamide [250 mg/m 2] QD for 3 d or bendamustine [90 mg/m 2] QD for 2 d). Endpoints included ORR, CRR, PFS, and duration of response (DOR). Descriptive efficacy subanalyses were performed for 9 high-risk subgroups, including prior hematopoietic stem cell transplant (HSCT), ≥5 prior lines of therapy, progression of disease within 24 mo from first immunochemotherapy (POD24), double-refractory disease, high Follicular Lymphoma International Prognostic Index (FLIPI) at study entry, high lactate dehydrogenase at baseline, high C-reactive protein (CRP) prior to infusion, radiological bulky disease (by GELF criteria), and high total metabolic tumor volume (TMTV; >510 cm 3) at baseline (median 155.32 cm 3; range 0.1-2470.4 cm 3). Descriptive subgroup analysis was supported by multivariate analysis to identify factors predictive of worse outcomes. Results: As of March 29, 2021, 97 pts received tisagenlecleucel and 94 were evaluable for primary efficacy analysis (median follow-up 17 mo). High and durable responses were seen in the overall ELARA population (ORR 86.2%, CRR 69.1%, 9-mo DOR 76.0%, and 12-mo PFS 67.0%). In CR pts at 9 mo, PFS was 85.5% and estimated probability of remaining in response was 86.5%. Safety reflected known tisagenlecleucel profile; 48% of pts had CRS (majority were grade 1/2) and 11.3% had neurological events (3% grade ≥3). In the subgroup analysis, pts were stratified into risk groups. Efficacy (ORR, CRR) and durability of response were well maintained in all high-risk subgroups, except for POD24 (n=35), high TMTV (n=20), and ≥5 prior lines of therapy (n=27). Compared with corresponding low-risk subgroups, there was a numerical reduction in CRR for high-risk subgroups (POD24 59.0% vs 87.9%; high TMTV 40.0% vs 76.4%; ≥5 prior lines of therapy 59.3% vs 73.1%) (Figure). A reduction in 12-mo PFS was also identified for pts in these subgroups: POD24 (60.8% vs 77.9%), high baseline TMTV (54.5% vs 68.5%), and ≥5 prior lines of therapy (59.6% vs 69.7%). Evaluating the disease characteristics of the high TMTV subgroup compared with low TMTV, high TMTV was associated with a higher incidence of bulky disease (58.3% vs 90.0%), high FLIPI (54.2% vs 85.0%), and high CRP (45.8% vs 70.0%). In the multivariate analysis of high-risk factors, only POD24 (hazard ratio [HR] 2.34; 95% CI, 1.02- 5.34) and high TMTV (HR 2.53; 95% CI, 1.14-5.65) were associated with shorter PFS. For pts with both POD24 and high TMTV (n=12), the CRR was 16.7% with a 12-mo PFS of 36.0%. These analyses of high-risk subgroups are exploratory in nature and should be validated in a larger study cohort. Conclusions : With 17-mo median follow-up, tisagenlecleucel produced high ORR and CRR and was associated with durable response and promising 12-mo PFS in pts with r/r FL and 2+ prior lines of therapy. Safety was consistent with known tisagenlecleucel profile. POD24 and high TMTV were independently associated with PFS. These results suggest that tisagenlecleucel can induce high rates of durable response, including most pts in the high-risk disease subgroups, who have poor prognosis with current non-CAR-T cell therapies. Figure 1 Figure 1. Disclosures Thieblemont: Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Dickinson: Amgen: Honoraria; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinez-Lopez: Incyte: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Popplewell: Pfizer: Other: Travel; Novartis: Other: Travel; Hoffman La Roche: Other: Food. Chavez: AstraZeneca: Research Funding; Novartis: Consultancy; MorphoSys: Speakers Bureau; Karyopharm Therapeutics: Consultancy; Adaptive: Research Funding; Kite/Gilead: Consultancy; Abbvie: Consultancy; Merck: Research Funding; BeiGene: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Speakers Bureau; Epizyme: Speakers Bureau. Bachy: Roche: Consultancy; Takeda: Consultancy; Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Incyte: Consultancy. Kato: Kyowa Kirin: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Harigae: Novartis Pharma: Honoraria, Research Funding; Chugai Pharma: Honoraria; Janssen Pharma: Honoraria; Ono pharma: Honoraria, Other: Subsidies or Donations; Astellas Pharma: Other: Subsidies or Donations; Kyowakirin: Other: Subsidies or Donations; Bristol Myers Squibb: Honoraria. Kersten: Kite/Gilead: Honoraria, Research Funding; Novartis: Honoraria; Miltenyi Biotech: Honoraria; BMS/Celgene: Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria. Andreadis: GenMAB: Research Funding; Karyopharm: Honoraria; Incyte: Honoraria; BMS/Celgene: Research Funding; Epizyme: Honoraria; Crispr Therapeutics: Research Funding; Atara: Consultancy, Honoraria; Novartis: Research Funding; Kite: Honoraria; Merck: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; TG Therapeutics: Honoraria. Riedell: Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chen: Mesolbast: Honoraria; Morphosys: Honoraria. Nastoupil: MorphoSys: Honoraria; Bayer: Honoraria; Genentech: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Epizyme: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Von Tresckow: Pentixafarm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; MSD: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Kite-Gilead: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Other: Congress and travel support; AstraZeneca: Honoraria, Other: Congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: Congress and travel support; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Teshima: Fuji pharma CO.,Ltd: Research Funding; Astellas Pharma Inc.: Research Funding; TEIJIN PHARMA Limited: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Pfizer Inc.: Honoraria; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Janssen Pharmaceutical K.K.: Other; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol Myers Squibb: Honoraria; Sanofi S.A.: Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy. Patten: ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; NOVARTIS: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding; JANSSEN: Honoraria. McGuirk: Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding. Petzer: AppVie: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Sandoz: Honoraria. Viardot: University Hospital of Ulm: Current Employment; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zinzani: JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; ADC Therap.: Other; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Malladi: Gilead Science: Consultancy; Gilead: Honoraria, Other: Travel support. Lobetti Bodoni: Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: NHS: Ended employment in the past 24 months; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Schuster: Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Alimera Sciences: Consultancy; Merck: Research Funding; Incyte: Research Funding; Acerta Pharma/AstraZeneca: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; TG Theraputics: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Dreyling: Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Genmab: Consultancy; Amgen: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding.

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17

Issa, Jean-Pierre, Marco Gobbi, Patricia L. Kropf, Pierre Fenaux, Gail J. Roboz, Jiri Mayer, Jürgen Krauter, et al. "Progression Free Survival (PFS), and Event Free Survival (EFS) from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 815 Patients with Treatment Naïve (TN) AML Unfit for Intensive Chemotherapy (IC): ASTRAL-1 Study." Blood 134, Supplement_1 (November 13, 2019): 4235. http://dx.doi.org/10.1182/blood-2019-129614.

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Background: Guadecitabine (G) is a next generation subcutaneous hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs TC of azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The ITT results for the primary endpoints of Complete Response (CR), and Overall Survival (OS) were previously presented (Fenaux et al, EHA abstract S879, 2019). There is no consensus on definition of disease progression particularly with HMA treatment which may continue to benefit patients in the absence of objective response. EFS analysis based on end of treatment benefit (treatment discontinuation, or start of an alternative therapy, or death) regardless of progression may offer a simpler way of assessing HMA treatment benefit. We describe here the results of the study based on both PFS and EFS analyses and how they compare with OS analyses in the overall ITT population, and in subgroups of patients based on number of cycles administered. M ethods: TN-AML ineligible for IC due to age ≥ 75 y, or comorbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard regimens. AML diagnosis, and response status by IWG 2003 criteria, were assessed by an independent central pathologist blinded to randomization assignment. CR and OS were co-primary endpoints. PFS was a secondary endpoint calculated from date of randomization to the earliest date of progression by investigators or central assessment, relapse after response, start of an alternative therapy, or death. Since progression date is sometimes difficult to ascertain under HMA treatment, an EFS analysis was conducted post hoc using the concept of time to treatment failure. EFS was therefore calculated from date of randomization to the earliest date of discontinuation of randomized treatment, start of an alternative therapy, or death. PFS, EFS, and OS data are presented for the overall ITT population, and for patients who received at least 4 cycles or 6 cycles, and patients who had an objective response. Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. The majority of patients were randomized to receive an HMA: 759 patients (93%) with only 56 patients (7%) randomized to receive LDAC. In the primary ITT analysis, CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were not significantly different between G and TC. An equal proportion of patients received at least 4 cycles (57.6% for G vs 59.2% for TC), or 6 cycles (45.8% for G vs 46.2% for TC) so there was no obvious bias in terms of adherence to treatment in the 2 study arms. Table shows OS, PFS, and EFS median survival, G/TC HR with 95% CI, and p values for the primary ITT population as well as for patients who received at least 4 cycles (N=476 patients), and those who received at least 6 cycles (N=375 patients). G/TC HR for all analyses favored guadecitabine (HR <1). However only OS, and EFS seemed to significantly favor G in patients who received adequate treatment duration by number of cycles. EFS was also the only analysis to significantly favor G in the overall ITT population suggesting that it may be a better predictor of OS benefit in patients who went on to receive adequate treatment with at least 4 or 6 cycles (Table). In addition, EFS also significantly favored G in patients who achieved an objective response (CR, CRp, CRi, or PR): median EFS for G 17.4 vs 14.6 m for TC, HR 0.68, 95% CI 0.5-0.93, p 0.016. Summary/Conclusions: In a large global 815-patient randomized study of G vs TC (composed mainly of first generation HMAs), EFS analyses that do not rely on progression date which is sometimes difficult to define favored G over TC in the ITT population, and seemed to better predict OS benefit in patients who went on to receive at least 4 or 6 cycles. EFS calculated from date of randomization to the earliest date of randomized treatment discontinuation, start of alternative therapy, or death as conducted here could be a simple surrogate for cessation of treatment benefit particularly for patients treated with HMAs. Table Disclosures Fenaux: Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Roche: Consultancy, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding. Novak:Janssen: Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jedrzejczak:Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Novartis: Research Funding; Takeda: Consultancy; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) . Thomas:ABBVIE: Honoraria; PFIZER: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Chugai: Research Funding; Otsuka: Honoraria. Brandwein:Jazz Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Research Funding. Demeter:Pfizer: Other: Advisory Board; Amgen: Other: Advisory Board; Bristol Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board; Amicus: Other: Advisory Board; Angelini: Other: Advisory Board; Roche: Other: Advisory Board. Griffiths:Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Celgene, Inc: Consultancy, Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Boston Scientific: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding.

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18

Ioannou, Nikolaos, Patrick R. Hagner, Fadi Towfic, Anita K. Gandhi, Kostas Stamatopoulos, Piers E. M. Patten, Anna Vardi, and Alan G. Ramsay. "Eliciting Anti-Tumor T Cell Immunity in Chronic Lymphocytic Leukemia (CLL) with PD-L1/PD-1 Blockade Is Enhanced By Avadomide Immunotherapy through the Triggering of Immunogenic Interferon Signaling." Blood 132, Supplement 1 (November 29, 2018): 237. http://dx.doi.org/10.1182/blood-2018-99-111605.

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Abstract Immune checkpoint blockade has demonstrated potential to reactivate anti-tumor immunity and regress tumors. However, response rates in B-cell non-Hodgkin lymphoma patients have been lower compared to Hodgkin lymphoma, with no activity reported in a recent trial of anti-PD-1 immunotherapy in relapsed CLL. This suggests that certain lymphoma subtypes may harbor non-immunogenic tumor microenvironments (TME). Our preliminary studies revealed that avadomide (CC-122), a cereblon modulator, can enhance T cell immune synapse signaling with autologous CLL cells, resulting in a concomitant increase in PD-1/PD-L1 expression at repaired synapses, indicating that avadomide may represent a complementary treatment partner for checkpoint inhibition. Here, we have extended our pre-clinical studies to investigate how these immunotherapy drugs alter the function and gene signatures of previously exhausted T cells from treatment naïve CLL patients (representing disease heterogeneity). Cytotoxicity assays revealed that treating primary T cells and autologous CLL cells with avadomide (1 μM, 48h) activated anti-tumor T cell killing function (P<.01, n=16), while combining avadomide with anti-PD-1 or anti-PD-L1 treatment significantly enhanced (P<.01) T cell killing function compared to these immunotherapies alone. Notably, anti-PD-1 monotherapy induced comparatively modest improvements of effector function. We next performed RNA sequencing on highly purified T cells from treatment naïve CLL patients, representing extremes of prognosis (n=6 good and n=6 poor including disease harboring TP53 abnormalities), following 18 h treatment with avadomide (100 nM) or anti-PD-1 (nivolumab) or PD-L1 (durvalumab) alone (10 μg/ml) or in combinations. Differential expression pathway analysis revealed that the top functional gene categories common for all the avadomide and combination treated samples (independent of anti-PD-1 or anti-PD-L1 monotherapy) were related to the response to type I and II IFN signaling, as well as inflammatory/stimulatory cytokine TNF-α, proliferative IL-6/JAK/STAT3, and IL-2/STAT5 responses. Type I IFN drives expression of chemokines CXCL10 and CXCL9, which are linked to enhanced tumor-infiltrated lymphocyte recruitment, and these chemoattractant genes were significantly upregulated in the avadomide and combination treated patient samples. In addition to their immunostimulatory roles, type II IFN (IFN-γ) and chronic type I IFN signaling have been linked to T cell resistance/exhaustion. We detected upregulated PD-L1 transcript in avadomide and combination treated T cells - supporting blockade of this inhibitory ligand. To investigate the ability of avadomide to modulate T cell migration, we performed comparative quantitative time-lapse microscopy analysis of pretreated patient T cells (n=12). These assays revealed that avadomide, as well as anti-PD-1 or anti-PD-L1 monotherapies, significantly enhanced (P<.01) T cell migration, and this response was significantly augmented by combination immunotherapy. Luminex protein analysis and cell migration assays confirmed the transcriptome data, highlighting the ability of avadomide and combination immunotherapy to significantly (P<.01) induce the release of CXCL10 (as well as IFN-γ, IL-2, GM-CSF and IL-8) from patient T cells, thereby attracting autologous T cells (CXCR3+). Avadomide as well as its pairing with anti-PD-L1 were also found to increase the proliferation of patient T cells (P<.01, n=6), particularly CD8+ T cells. Patient-derived xenograft models demonstrate that the therapeutic treatment of established tumors (3 weeks post-engraftment) with avadomide treatment (0.5 mg/kg) can activate anti-tumor T cells and significantly reduce disease volume (P<.01) that was associated with increased infiltration of PD-L1+ CD8+ T cells. Pairing avadomide with anti-PD-L1 durvalumab led to maximal activation of anti-tumor T cell immunity. In conclusion, our findings support the concept that PD-L1/PD-1 blockade in CLL could be enhanced when combined with avadomide through the promotion of immunogenic IFN signaling that enhances T cell infiltration and function. We believe these data support the rationale for combination immunotherapy that could convert a non-immunogenic TME into a 'hot' T cell inflamed TME which would be sensitive to checkpoint blockade. Disclosures Hagner: Celgene Corporation: Employment, Equity Ownership. Towfic:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Stamatopoulos:Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Patten:L Hoffman La Roche: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding; AbbVie Inc: Honoraria, Other: travel; Janssen: Honoraria, Other: travel. Vardi:Gilead: Research Funding; Janssen: Honoraria. Ramsay:MedImmune: Research Funding; Roche Glycart AG: Research Funding; Celgene Corporation: Research Funding.

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19

Roboz, Gail J., Hartmut Döhner, Marco Gobbi, Patricia L. Kropf, Jiri Mayer, Jürgen Krauter, Tadeusz Robak, et al. "Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 815 Patients with Treatment Naïve (TN) AML Unfit for Intensive Chemotherapy (IC) ASTRAL-1 Study: Analysis By Number of Cycles." Blood 134, Supplement_1 (November 13, 2019): 2591. http://dx.doi.org/10.1182/blood-2019-127253.

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Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs Treatment Choice (TC) with azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The primary ITT results were previously presented (Fenaux et al, EHA abstract S879, 2019). Clinical guidelines for single agent HMAs recommend a minimum of 4 to 6 treatment cycles for maximum benefit. We describe here the results of the study based on number of treatment cycles administered. M ethods: TN-AML patients ineligible for IC due to age ≥ 75 y, or coexisting morbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard dose/schedule. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. Complete response (CR) and overall survival (OS) were co-primary endpoints. We analyzed patients' characteristics, number of treatment cycles, reasons for treatment discontinuation, CR, and OS including analyses by number of cycles received including prospective subgroups, and OS analyses of responders and non-responders. Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥75 y in 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), and poor risk cytogenetics in 34.3% vs 34.6%. Most patients were assigned to an HMA at randomization (759, 93%) with only 56 patients (7%) randomized to receive LDAC. Both CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were similar and not significantly different between G and TC. Many patients in both arms did not receive the recommended minimum of 4 cycles (42.4% vs 40.8% for G vs TC respectively), or 6 cycles (54.2% vs 53.8% for G vs TC). The proportions were well balanced between the 2 treatment arms. Characteristics of patients who received at least 4 or 6 cycles were also well balanced between the 2 treatment arms for age, PS 2-3, secondary AML, poor risk cytogenetics, BM blasts >30%, and proliferative AML (total white cell count ≥20,000/uL). The primary reasons and proportions for treatment discontinuation were similar for the 2 treatments arms. For patients with <4 and <6 cycles respectively they are, in descending order, early deaths (16.7% and 20.7% of the overall ITT population), progression (7.6% and 11.7%), adverse events (5.8% and 6.9%), and patient decision (5.5% and 7.1%). In patients who received at least 4 cycles more patients achieved CR on G (33.6%) vs TC (28.6%), and median OS was longer on G (15.6 months for G vs 13 for TC, HR 0.78, 95% CI 0.64-0.96, log-rank p 0.02, Fig 1). Similarly, in patients who received at least 6 cycles, there were more CR on G (40.1%) vs TC (36.2%) and median OS was longer on G (19.5 months for G vs 15.0 for TC, HR 0.69, 95% CI 0.54-0.88, log-rank p 0.002, Fig 2). Subgroup analyses of OS in patients who received at least 4 or 6 cycles showed that survival benefit from G over TC was consistent in all prospective subgroups including against each of the 3 TCs (AZA, DEC, and LDAC). OS analyses in patients who received at least 4 or 6 cycles also favored G vs TC in both responders (CR, CRp, CRi, or PR) and non-responders with maximum benefit in patients who received at least 6 cycles (G vs TC OS HR 0.66, 95% CI 0.45-0.96, log-rank p 0.028 for responders, and HR of 0.73, 95% CI 0.53-1.00, log-rank p 0.048 for non-responders). Summary/Conclusions: In a large global 815-patient randomized study of G vs TC composed mainly of first generation HMAs, G was at least as effective as TC based on the primary ITT analysis of CR and the narrow 95% CI of OS HR (0.83-1.14). Analyses of patients by number of treatment cycles showed that those who received at least 4 or 6 cycles achieved longer OS in G vs TC with the largest benefit in those who received at least 6 cycles. The benefit was observed in all subgroups, and in both responders and non-responders. Treatment with single agent guadecitabine should continue as long as the patient can still benefit and for at least 6 cycles to gain the maximum survival benefit. Disclosures Roboz: Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krauter:Pfizer: Honoraria. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding. Novak:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations. Jedrzejczak:Takeda: Consultancy; Amgen: Consultancy, Other: travel support for hematology meetings; Celgene: Other: travel support for hematology meetings; Novartis: Research Funding; Roche: Other: travel support for hematology meetings. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Brandwein:Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Novartis: Consultancy, Honoraria. Demeter:Angelini: Other: Advisory Board; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Bristol Myers Squibb: Other: Advisory Board; Amicus: Other: Advisory Board; Amgen: Other: Advisory Board; Roche: Other: Advisory Board. Griffiths:Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Yee:Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Varughese, Nisha S., Alex Wong, Robert J. Klaassen, Elaine W. Leung, Kathryn Elizabeth Webert, Sylvain Grenier, Sarah Jennings, et al. "Pharmacist Integration into the Hemophilia Treatment Centre: A Canadian Pilot Project to Optimize Treatment and Improve Cost-Savings Using Pharmacokinetic Assessments of Hemophilia Patients." Blood 138, Supplement 1 (November 5, 2021): 832. http://dx.doi.org/10.1182/blood-2021-147813.

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Abstract Context Prophylactic treatment with coagulation factors in patients with hemophilia A and B is associated with significant costs to the health care system. Whether recombinant or plasma-derived therapies, factors are expensive products that follow complicated pharmacokinetic (PK) trajectories and are subject to tremendous inter-individual variation, making their efficient use challenging. Effective management of these products therefore requires tailoring treatment to the patient. To do so, it is essential to systematically assess and interpret the PK profiles of patients. A dedicated pharmacist could greatly assist this process by standardizing the approach and assisting with interpretation. In Canada, pharmacists are not currently part of the comprehensive care team for the hemophilia population. Aim The purpose of this pilot project was to determine whether employment of a pharmacist as part of the Hemophilia Treatment Centre (HTC) would be an effective strategy to reduce costs associated with clotting factor prophylaxis regimens and identify the pharmacist's activities associated with this new role. Methods This project occurred at the Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada, a tertiary pediatric hospital serving 500,000 children and youth. A cost-minimization analysis was conducted to compare the pre-intervention strategy, current model of care without pharmacist involvement, to the post-intervention strategy, model of care that included a pharmacist in the HTC. The analysis was performed from the perspective of the formulary manager, Canadian Blood Services, with a 1-year time horizon. The pharmacist was assigned for the period of 1-year including a 3-month phase-in period during which no interventions were done by the pharmacist, followed by 9 months of specific action on optimization protocols with the goal of achieving cost savings while maintaining best patient care. McMaster's Web-Accessible Population Pharmacokinetic Service (WAPPS-Hemo), which generates PK profiles, served as the basis for therapeutic optimizations. CHEO patients with moderate to severe hemophilia A or B or von Willebrand disease (vWD) receiving prophylactic treatment with recombinant or plasma-derived clotting factor were eligible for a pharmacist assessment. Results The pharmacist performed 18 therapeutic optimizations on 14 patients with moderate to severe hemophilia A or B, and 1 von Willebrand patient, aged 3 to 18 years old. As a result of the pharmacist's intervention (Table 1), clotting factor treatment costs for these patients extrapolated over one year were reduced by 20.5%. This represents a net savings of $225K CAD/year, or $12.5K CAD/optimization/year. The pharmacist not only conducted the PK analyses but also participated in clinics, performed administrative activities, developed practice improvement policies and trained staff (Figure 1). Clinic attendance activities included discussions with families, education on new product administration, and discussions with the multidisciplinary team. Administrative activities consisted of organizing appropriate switch days, coordinating laboratory tests and timing of PK assessments, ensuring entire supply consumption, adverse event reporting and inventory management support. Additionally, a sub-analysis showed that the pharmacist's interventions did not worsen annual bleed rates (ABR). In most cases, the ABRs were improved after their therapy was optimized using pharmacokinetics. Conclusion Substitution of clotting factor products and reduction of doses undertaken by the pharmacist resulted in significant savings. To date, no increase in bleeding frequencies have been observed in patients with optimized therapy, suggesting that patient outcomes are maintained. Thus, our project demonstrated that the addition of a pharmacist to the HTC to manage recombinant and plasma-derived coagulation factors can optimise the treatment plan and significantly reduce the costs of managing patients with hemophilia. Following the success of this pilot project, Canadian Blood Services will provide additional funding to extend the project and expand its scope to include adult hemophilia patients. If the findings in this project continue to be demonstrated, this will be used as a case study to expand to all HTC across Canada. Figure 1 Figure 1. Disclosures Klaassen: Agios Pharmaceuticals: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche: Consultancy; Novo Nordisk: Consultancy; Octapharma AG: Consultancy; Sanofi: Consultancy; Takeda: Consultancy.

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Okwor, Chisom Ifeoma, Robert J. Klaassen, Mary-Ann Harrison, Ken Tang, Isabelle Laforest, Brooke Bowerman, and Ewurabena Simpson. "Predictors of Hydroxyurea Use in Children with Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 4934. http://dx.doi.org/10.1182/blood-2018-99-111377.

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Abstract Background: Since hydroxyurea emerged as an effective therapy for sickle cell disease (SCD), there have been numerous studies that have demonstrated its safety and efficacy in children and adults with SCD. In their 2014 guidelines, the NHLBI recommended that hydroxyurea treatment should be offered to all infants and children with sickle cell anemia (HbSS and HbS/beta0 thalassemia) starting at 9 months of age. However, hydroxyurea is underused among children and adolescents with SCD and to date, there have been no studies that have identified the specific determinants that may predict hydroxyurea adherence in these patients. Objectives: 1. To identify predictors of hydroxyurea adherence in children with SCD. 2. To measure the rate of hydroxyurea use among CHEO patients with SCD who were born between January 1, 2003 and December 31, 2015; and 3. To compare the rates of SCD-related complications between patients who were not prescribed hydroxyurea, patients who were adherent to hydroxyurea and patients who were not adherent to hydroxyurea Methods: We extracted medical chart data to identify patients with SCD who were born between January 1, 2003 and December 31, 2015. Patients were classified as either "Not prescribed hydroxyurea" or "Prescribed hydroxyurea" based on clinical documentation and the presence of at least one hydroxyurea outpatient prescription. For those patients who were prescribed hydroxyurea, hematological indices were collected and analyzed over time to estimate adherence to hydroxyurea. To measure the adherence of children prescribed hydroxyurea, we examined the trends in the patient's hematological indices after their first prescription of hydroxyurea. Adherence was defined as increased hematological indices (from baseline) by greater than or equal to any 2 of the following: Mean corpuscular volume (MCV) by 10 fL; Hemoglobin levels (g/L) by 10 g/L and/or %HbF (fetal hemoglobin) by 10%. We measured the frequency of disease-related complications among CHEO patients with SCD according to their use of hydroxyurea and used multivariate analyses to evaluate immigration status, newborn screening status, SCD subtype, SCD complications, income, age and sex as predictors for hydroxyurea adherence. Results: Children with HbSS were more likely to have been prescribed hydroxyurea compared to children with HbSC (87.8% vs. 9.5%). Canadian citizenship, newborn hemoglobinopathy screening and lower familial income were associated with better hydroxyurea adherence (Table 1). Although the association was not statistically significant, patients were more likely to be prescribed hydroxyurea if they were from a lower income background (61.9% for lowest and second lowest quartiles vs. 38.1% for third and highest quintiles). Patients were also more likely to adhere to hydroxyurea if they did not have private medical insurance for hydroxyurea coverage (Table 1). Finally, hydroxyurea adherence was associated with reduced rates of health care utilization and SCD-related complications (Table 2). Conclusions: In line with previous studies of hydroxyurea for the treatment of SCD, patients who were adherent to hydroxyurea had fewer complications compared to those patients who were either non-adherent to or not prescribed hydroxyurea. Similarly, patients had fewer complications after being prescribed hydroxyurea compared to before they started hydroxyurea with a reduction in the rate of ED visits, acute chest syndromes, complications, transfusions and hospitalizations. Patients from non-immigrant families, patients who were identified through newborn hemoglobinopathy screening and patients from lower income families were more likely to be adherent to hydroxyurea. Although the results of this study were limited by its small sample size, further studies will clarify these determinants of hydroxyurea adherence among SCD patients and enable clinicians to improve hydroxyurea adherence for SCD patients. Disclosures Klaassen: Shire: Consultancy; Novartis: Research Funding; Hoffman-La Roche: Consultancy; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Octapharma AG: Consultancy, Honoraria; Agios Pharmaceuticals Inc.: Consultancy; Cangene: Research Funding.

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Siddiqi, Tanya, Ulrich Jaeger, Olga Moshkovich, Jennifer Devlen, Matthew Miera, Agnes Williams, Jens Hasskarl, Fei Fei Liu, Julia Braverman, and Gilles Salles. "Qualitative Analysis of the Treatment Experience and Well-Being of Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Enrolled in 2 Trials of Lisocabtagene Maraleucel (liso-cel) during the Initial Stages of Therapy." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-137656.

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Background: Chimeric antigen receptor (CAR) T cell therapy is a novel treatment modality for patients with R/R LBCL. Limited information exists regarding patients' views of CAR T cell therapy. Our research aimed to better understand patients' needs by capturing their expectations/concerns, current well-being, and treatment experiences during the beginning stages of CAR T cell therapy in the clinical trial setting. Methods: Patients with R/R LBCL from 2 ongoing trials of the investigational, CD19-directed CAR T cell therapy liso-cel (TRANSCEND WORLD [NCT03484702] or PLATFORM [NCT03310619]) were invited to participate in an optional interview component. Semistructured interviews were conducted to gain insight about patients' experience with CAR T cell therapy in the clinical trials. Interviews of ≤1 hour (in-person or over the phone) were conducted in parallel with screening procedures (interview 1), after leukapheresis (interview 2), and up to 3 days after liso-cel infusion (interview 3). Interviews were audio recorded and transcribed. MAXQDA (VERBI GmbH, Berlin, Germany) qualitative analysis software was used to manage and thematically organize interview transcript data to identify key concepts related to each research objective. Previously reported results of interview 1 showed a high perception of unmet needs, lack of alternative options, and expectations for positive outcomes. The analysis presented here primarily focused on interviews 2 and 3. Denominators shown in the Results vary by question as some patients skipped questions. Results: A total of 75 interviews were analyzed, including 35, 24, and 16 patients at interviews 1, 2, and 3, respectively, across sites in the US (n = 14), Europe (n = 26), and Japan (n = 2). Among 42 patients who completed ≥1 interview, the mean age was 62 years and 69% were male. Treatment Experience: Of 24 patients who completed interview 2, 22 (92%) reported positive experiences during leukapheresis and 16 (67%) reported the procedure was as expected. Patients thought the most difficult part of leukapheresis was the length of the procedure (n = 8/21 [38%]). Of 15 patients who provided feedback on lymphodepleting chemotherapy, a majority reported that it was as expected (n = 8 [53%]) or easier than expected (n = 3 [20%]); when asked about the most difficult part, many patients (n = 7/17 [41%]) discussed side effects (eg, nausea, fatigue, and lack of appetite). Of patients who described liso-cel infusion as different than expected, differences included easier (n = 12/13 [92%]) or quicker (n = 3/12 [25%]) than expected, and 5/12 (42%) reported few/no side effects within 3 days post-infusion. Over half of patients (n = 8/14 [57%]) reported that the infusion, as a whole, was not difficult. Changes over Time: At interviews 1, 2, and 3, respectively, 47% (n = 14/30), 47% (n = 9/19), and 69% (n = 9/13) of patients reported hoping for successful treatment. Similarly, patients generally had fewer concerns later in the process, with 21 (64%) and 11 (33%) of 33 patients reporting side-effect and treatment efficacy concerns, respectively, during interview 1 vs 5 (33%) and 3 (20%) of 15 patients, respectively, during interview 3. At time of enrollment, most patients (n = 21/34 [62%]) were able to function normally or with minimal impact from their lymphoma, although most reported some symptoms like fatigue, pain, or stomach problems. At interview 1, 14 (40%) of 35 patients were employed; most patients reported no changes in their work life at interviews 2 (n = 19/20 [95%]) and 3 (n = 11/12 [92%]). From enrollment to immediately post-infusion, the physical health of most patients remained stable (n = 4/16 [25%]) or deteriorated (n = 9/16 [56%]). However, most patients (n = 14/15 [93%]) reported feeling positive at interview 3. Conclusions: This study provided the unique opportunity to gather feedback directly from patients participating in clinical trials of liso-cel therapy, specifically during the initial treatment stages. The overall impression of the treatment was positive, with most patients reporting that study procedures were easier than expected. The results of this qualitative research provide useful insight into the motivations, expectations, and experiences of patients with R/R LBCL receiving liso-cel therapy, which can inform the design of health care support systems and future clinical trials to better meet patients' needs. Disclosures Siddiqi: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria. Moshkovich:Icon Plc: Current Employment. Devlen:Icon Plc: Current Employment, Current equity holder in publicly-traded company. Miera:Icon Plc: Current Employment. Williams:Icon Plc: Current Employment. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Salles:MorphoSys: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Novartis: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Gilead: Consultancy, Honoraria, Other: Participation in educational events; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Epizyme: Consultancy; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Genmab: Consultancy.

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Bücklein, Veit, Thomas Köhnke, Frauke Schnorfeil, Klaus H. Metzeler, Nikola P. Konstandin, Annika Maria Dufour, Cristina Sauerland, Wolfgang Hiddemann, Karsten Spiekermann, and Marion Subklewe. "Minimal Residual Disease (MRD) Detection By Flow Cytometry Complements Molecular MRD Assessment in AML." Blood 132, Supplement 1 (November 29, 2018): 2753. http://dx.doi.org/10.1182/blood-2018-99-119065.

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Abstract The prognosis of patients with AML is determined by a multitude of recurrent genetic alterations, and treatment algorithms heavily rely on risk stratification by genetic characterization of the disease at the time of diagnosis. However, this a priori risk stratification does not integrate information on treatment susceptibility of the individual patient. Assessment of Minimal Residual Disease (MRD) aims to implement this information in the patient-specific treatment management. AML cells with aberrant phenotypes can be detected at sensitivities below 1:104 by flow cytometry in the majority of patients. Therefore, flow cytometry MRD assessment (flow MRD) enables determination of MRD status in patients without suitable molecular markers (e.g. NPM1, CBFß-MYH11, and RUNX1-RUNX1T1). Here, we validate the role of flow MRD in AML patients receiving intensive chemotherapy with and without available molecular markers. Flow MRD was analyzed in patients with AML (excluding APL) diagnosed between 2012 and 2017 receiving intensive induction chemotherapy (sHAM or 7+3). Flow MRD analysis was performed during aplasia (on day 16 after treatment initiation) as well as post induction. Presence of ≥0.1% Leukemia-associated immunophenotype (LAIP)-positive cells was defined as flow MRD positivity. Molecular MRD was analyzed post induction for NPM1 and CBF, and post consolidation for RUNX1-RUNX1T1. Kaplan-Meier estimators and log-rank tests were used to analyze survival data. Cox's proportional hazards regression model was used to determine the influence of individual factors in multivariate analyses. A total of 161 patients were included. In 5 cases (3.1% of all cases), no LAIP could be identified, and these patients were excluded from further analyses. Flow MRD assessment during aplasia was available in 145 cases. 122 patients had flow MRD assessments available post induction. 114 patients achieving CR or CRi after induction therapy had flow MRD assessments available at both time points. Flow MRD positivity during aplasia was associated with shorter event free survival (EFS, 6.1 months vs. 19.1 months, p<0.001). Similarly, flow MRD positivity post induction was associated with shorter EFS (11.9 months vs. median not reached, p=0.007). For both timepoints, flow MRD was an independent risk factor in multivariate analysis compared to known risk factors such as age, genetic/molecular risk profile as determined by the ELN2017 risk categories as well as early blast clearance by morphology. Persistent flow MRD positivity at both timepoints (combined flow MRD) identified patients with particularly short EFS (8.2 months), whereas patients with flow MRD negativity at both time points had the best outcome in our cohort (median not reached, p=0.002). Combined flow MRD status was an independent predictor of EFS and RFS (HR 1.9 and 1.8, p=0.001 and p=0.007, respectively), whereas blast clearance by morphology had no significant prognostic impact (p>0.05 for all endpoints). 64/161 patients (39%) had molecular MRD assessment available for analysis. In these patients, molecular MRD positivity predicted a significantly shorter EFS (9.3 months vs. median not reached, p=0.01). Indeed, molecular MRD positivity was an independent risk factor for adverse EFS and RFS (HR 1.7 and 1.6, p=0.008 and p=0.018, respectively). In this subgroup, flow MRD was not an independent prognostic factor. However, for patients without available molecular MRD marker (97/161 patients), flow MRD positivity at aplasia (p=0.004), post induction (p=0.015) or as combined status (p=0.004) was associated with a significantly shorter EFS and remained an independent risk factor in multivariate analysis (HR 2.5 and 2.6, p=0.016 and p=0.012 for EFS and RFS, respectively). Taken together, we demonstrate that both flow MRD as well as molecular MRD strongly correlate with survival. While molecular MRD assessment was only available in 39% of patients, MRD assessment by flow cytometry was feasible in >95% of AML patients. Flow MRD positivity both during aplasia and post induction was an independent risk factor, confirming the superiority of flow MRD compared to early morphologic response assessment. In conclusion, molecular and flow cytometric MRD assessment are complementing methods for the estimation of treatment response, and will be integrated in clinical trials to validate their significance for patient-specific treatment management. Disclosures Metzeler: Celgene: Consultancy, Research Funding; Novartis: Consultancy. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Subklewe:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche AG: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Blair, Joanne, Andrew McKay, Colin Ridyard, Keith Thornborough, Emma Bedson, Matthew Peak, Mohammed Didi, et al. "Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT." Health Technology Assessment 22, no. 42 (August 2018): 1–112. http://dx.doi.org/10.3310/hta22420.

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Background The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. Objectives (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. Design A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. Setting Fifteen diabetes clinics in hospitals in England and Wales. Participants Patients aged 7 months to 15 years. Interventions Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. Data sources Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. Outcomes The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. Results A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII – MDI, 2.4 mmol/mol (95% CI –0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (–0.006 QALYs, 95% CI –0.031 to 0.018 QALYs). Limitations Generalisability beyond 12 months is uncertain. Conclusions No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. Future work Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. Trial registration Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

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Livingston, Joel, Melanie Jackson, Ziyad Alrajihi, Catherine McGuire, Robert J. Klaassen, and Melanie Kirby -Allen. "Evaluating the Impact of Thrombopoietin Receptor Agonists Medications on Patient Outcomes and Quality of Life in Pediatric Immune Thrombocytopenia." Blood 138, Supplement 1 (November 5, 2021): 4072. http://dx.doi.org/10.1182/blood-2021-146031.

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Abstract Introduction: The treatment of Immune Thrombocytopenia (ITP) in children has advanced significantly over the last decade with novel therapies and enhanced clinical care guidelines. Recent American Society of Hematology guidelines now recommend the use of thrombopoietin receptor agonist (TPO-RA) medications as the preferred second line therapy for children with ITP. Accompanying this change, recent ASH guidelines also put emphasis on quality of life in managing ITP, acknowledging the detrimental affect ITP and previous managements can have on patient's and family's quality of life. With this change in guidelines, evaluating the impact of these medications on patient reported outcomes outside of clinical trials is important to evaluate the efficacy of therapy. While there is data from adult studies to show that TPO-RAs improve patient's health related quality of life (HRQoL), results were not statistically significant in previous clinical trials in children. Thus, the goal of the present study is to address this gap and describe the real-world experience of using TPO-RAs in pediatric ITP including the impact on patient-reported HRQoL. Methods: We reviewed all children aged 1-18 at our institution with a diagnosis of ITP and started on a TPO-RA medication after March 1, 2017 (date of TPO-RA for pediatric ITP licensure in Canada). A chart review was conducted to collect demographic data (e.g., age, associated diagnoses, previous therapies), TPO-RA data (e.g. dose(s), monitoring, side effects), outcome data (e.g., platelet count, need for emergency treatments). To explore the impact of TPO-RA use on patient-reported HRQoL, semi-structured interviews were conducted by phone with patients over age 7 and/or their guardians with topics including the effects of the TPO-RA on patient symptoms (e.g. bleeding, bruising, need for emergency treatment), activities (e.g. sports, hobbies, social events) mood (e.g. anxiety, stress, fatigue) and financial burden of treatment (e.g. coverage for medication). These interviews were conducted data in parallel to reviewing the Kids ITP Tool (KIT) questionnaire and a qualitative analysis of HRQoL was performed. Results: We identified 25 patients on a TPO-RA medication for pediatric ITP, of these, 3 were on romiplostim, 20 were on eltrombopag and 2 had been on both romiplostim and eltrombopag at different times. The median age at start of TPO-RA was 9 years (range 1 - 16 years). 14/25 responded to TPO-RA medication by meeting platelet count criteria. The average number of treatments per patient in the 6 months prior to commencing a TPO-RA was 3.7 and in the 6 months post commencing a TPO-RA was 0.5. No significant side effects observed with TPO-RA use, although 2 patients had a transient rise in liver enzymes. Of the 25 patients on a TPO-RA, 23 were eligible to participate in the semi-structured interviews (1 family having permanently relocated out of country and was not contactable; one family had a significant language barrier). With interviews ongoing, 11/23 patients and/or families have participated and results to date indicate that the majority (>90%) have seen an improvement in quality of life. All participants interviewed at the time of abstract submission reported improvement in bleeding/bruising symptoms. The majority also noted a reduction in the frequency of emergency treatments and hematology clinic visits. Several participants reported on their ability to resume sports/activities once on a TPO-RA. While there was some reduction in parental stress/worry there was no clear benefit to patient fatigue/mood. Financial concerns about medication costs and duration of therapy were raised, and many parents expressed the cost of medication and source of ongoing funding a significant stressor. There were also concerns related to oral administration for younger children. Discussion: To our knowledge, this is the first post-licensing study to look at the impact of TPO-RA medications on patient-reported HRQoL in children with ITP. At our institution, TPO-RA medications prescribed for pediatric ITP have had a positive impact on patient platelet count and resulted in a reduced need for emergency treatment with minimal noted side effects. There also appears to be a positive impact on patient reported HRQoL reported by the majority of patients and/or families, while issues with medication administration, cost and long-term duration of therapy remain a concern. Disclosures Klaassen: Agios Pharmaceuticals: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche: Consultancy; Novo Nordisk: Consultancy; Octapharma AG: Consultancy; Sanofi: Consultancy; Takeda: Consultancy.

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Ferreri, Andrés J. M., Kate Cwynarski, Elisa Jacobsen Pulczynski, Christopher P. Fox, Elisabeth Schorb, Paul La Rosée, Mascha Binder, et al. "Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial." Blood 128, no. 22 (December 2, 2016): 511. http://dx.doi.org/10.1182/blood.v128.22.511.511.

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Abstract Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable disease were randomly assigned to receive 4 courses of MTX-ARAC (arm A); or R-MTX-ARAC (arm B); or MATRix (arm C). ASC were collected after 2nd c. Pts with responsive or stable disease were further randomized between WBRT 36 ± 9 Gy (arm D) and BCNU-thiotepa conditioned/ASCT (arm E). Stratification parameters were induction arm and response . Primary endpoint of the 2ndrandomization was 2-year PFS. To demonstrate a 2-yr PFS improvement from 65% (P0) to 85% (P1), 52 pts/arm (one-sided; α 5%; β 95%) were required. Consolidation arm would be considered effective if ≥40 pts were progression-free survivors at 2 ys. Analyses were performed on an intention-to-treat (ITT) basis. Effects of consolidation treatments on neurocognitive functions and quality of life (QoL) were assessed with the IPCG tests panel and EORTC-QLQ at baseline, after treatment and every 6 months afterwards. Results: 227 pts were enrolled in 52 centers of 5 countries; 219 assessable pts were referred to 1st randomization (arm A 75; B 69; C 75). 167 pts had responsive or stable disease after induction: 49 pts were excluded from 2nd randomization (poor mobilization, poor condition or patients' refusal); 118 pts were thus randomized (59 pts/arm) and constitute the study population (median age 58 ys; range 18-70). 15 (13%) pts had high IELSG risk, 3 pts had ocular disease and 20 pts had meningeal disease; with the exception of a higher male prevalence in arm D, there were no differences in clinical presentation between two arms; There were 6 protocol violations: 4 pts randomly allocated to arm D were treated with ASCT and 2 pts randomly allocated to arm E were treated with WBRT; 5 pts (D 2; E 3) refused consolidation. Therefore, per-protocol (PP) groups consisted of 55 pts treated with WBRT and 58 with ASCT. Both consolidation therapies were well tolerated. Grade 4 toxicity was uncommon (≤5% of pts); as expected, hematological toxicity was more common in arm E (neutropenia 5% vs. 71%; p=0.00001 - thrombocytopenia 2% vs. 72%; p=0.00001). There were 2 toxic deaths (infections), both in arm E. Neuropsychological tests showed a significant impairment of attention/executive functions and a non-significant trend to impaired memory among pts treated with WBRT, whereas pts treated with ASCT exhibited improved functions. Both consolidation therapies were associated with significant improvement in language and QoL. Both WBRT and ASCT were active and resulted in significant improvement in CR rate: from 54% after induction to 95% (95%CI: 90-100) after consolidation in arm D, and from 53% to 93% (95%CI: 87-99) in arm E. After a median follow-up of 40 months (range 24-76), there were 20 events (16 relapses, 2 PDs, 2 off-therapy deaths) in arm D, and 25 events (18 relapses, 2 PDs, 2 toxic deaths, 3 off-therapy deaths) in arm E. Importantly, WBRT and ASCT were both effective, with a number of progression-free survivors at 2 ys equal to the pre-determined efficacy threshold: 40 among both the first 52 arm-D and 52 arm-E pts. There were no significant differences in PFS between WBRT and ASCT; on ITT basis, the 2-yr PFS was 80 ± 5% after WBRT and 70 ± 6% after ASCT; per protocol, the 2-yr PFS was 76 ± 6% and 75 ± 6%, respectively. In multivariate analysis, IELSG risk group, number of lesions and induction arm were independently associated with PFS; gender, CSF cytology status and consolidation arm were not. Forty-two pts randomized to arm D and 37 randomized to arm E are alive, with 2-year OS of 85 ± 5% and 71 ± 6% (p=0.12), respectively. Conclusions: WBRT and ASCT are both feasible, active and effective as consolidation therapies after high-dose-MTX-based chemoimmunotherapy in pts ≤70 ys with PCNSL. Potential impairment of specific neurocognitive functions after WBRT should be considered at the time of therapeutic decision. Disclosures Ferreri: Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding, Speakers Bureau; Italfarmaco: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adienne: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Fox:Adienne: Honoraria, Research Funding; Takeda: Honoraria, Other: travel funding; Gilead: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; AbbVie: Consultancy. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Johnson:Celldex Therapeutics: Research Funding. Linton:Takeda: Research Funding. Hess:Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Celgene: Honoraria; Pfizer: Honoraria. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau. Rummel:Roche Pharma AG: Other: Personal fees, Research Funding; Mundipharma GmbH: Other: Personal fees, Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.

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Ahaneku, Hycienth O., Hagop M. Kantarjian, Graciela M. Nogueras González, Gautam M. Borthakur, Srdan Verstovsek, Tapan M. Kadia, Naveen Pemmaraju, et al. "Outcomes of Patients with Suboptimal /Warning Response to Tyrosine Kinase Inhibitors: A Comparison of the 2009 and 2013 Guidelines of the European Leukemianet." Blood 134, Supplement_1 (November 13, 2019): 2930. http://dx.doi.org/10.1182/blood-2019-129108.

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Introduction Since the advent of tyrosine kinase inhibitors (TKIs) in 2001, the treatment goals in the management of chronic myeloid leukemia (CML) have evolved according to international recommendations. The 2009 European LeukemiaNet (ELN) proposed a category of "suboptimal response". The 2013 recommendations introduced a "warning response" category that saw some "suboptimals" in 2009 becoming failures in 2013. The clinical implications of this intermediate category and the difference in categorizations has not been fully explored. As new recommendations are being prepared, we seek to compare the outcomes of patients with suboptimal/warning using 2009 and 2013 guidelines. Methodology We analyzed 730 patients treated with front-line TKIs in various clinical trials and identified patients who meet the criteria for suboptimal response at 3, 6 and 12 months according to the 2009 ELN guidelines and/or warning criteria according to 2013 ELN criteria. We computed descriptive statistics for patients at each of the above criteria at the 3 time points. Kaplan-Meier product limit method, was used to estimate the median for overall survival (OS), event-free survival (EFS), failure-free survival (FFS) and transformation-free survival (TFS). Results Of the 730 CML patients evaluated, using the 2009 ELN guidelines, 2%, 3% and 5% of the patients met the 3, 6 and 12 months definition of suboptimal response, respectively. Analysis of baseline characteristics show a median age of 44.1, 42.1 and 44.4 years, respectively for the three time lines with a predominantly male and white population. Using the 2013 guidelines 4%, 10% and 17% of the patients met the 3, 6 and 12 months definition of warning, respectively. Patients were again predominantly male and white with a median age at diagnosis of 41.5, 44.1 and 47 years respectively. With regard to achieving complete cytogenetic response (CCyR), a higher percentage of patients achieved CCyR using the 2013 guidelines (55.2%, 80.8% and 98%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (35.3%, 56.5% and 81.1%, respectively). Similarly, for best molecular response, a higher percentage of patients achieved MR4.5 using the 2013 guidelines (10.7%, 20.8% and 44.2%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (13.3%, 4.5% and 24.2%, for suboptimal cohorts respectively). With respect to survival outcomes, patients classified as warning per the 2013 guidelines had better outcomes than those with suboptimal response using the 2009 guidelines. For example, for EFS, median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (29 months vs. 18 months, by 3 months assessment). For FFS, the median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (68 months vs. 11 months, by 6 months assessment). Using the 2013 guidelines median survival could not be reached for most of the survival outcomes. Conclusion Our assessment reveal that survival outcomes were better for the warning cohort using the ELN 2013 recommendations compared to the suboptimal cohort of the 2009 recommendations. This represents a stage migration by moving the subset of patients with the worse outcome away from this intermediate category and into the failure. An important, still unanswered question, is the optimal management of patients in this intermediate category or of those that migrate from one category to the next based on a change in definitions. Disclosures Kantarjian: Ariad: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Novartis: Research Funding. Borthakur:Eli Lilly and Co.: Research Funding; NKarta: Consultancy; PTC Therapeutics: Consultancy; Cyclacel: Research Funding; Eisai: Research Funding; Janssen: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Merck: Research Funding; GSK: Research Funding; Incyte: Research Funding; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Cantargia AB: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding. Verstovsek:Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Novartis: Consultancy, Research Funding. Kadia:BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Pemmaraju:abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding.

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Kadia, Tapan M., Gautam M. Borthakur, Elias Jabbour, Marina Y. Konopleva, Farhad Ravandi, Courtney D. DiNardo, Daniella Zheleva, David Blake, and Judy H. Chiao. "An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS." Blood 134, Supplement_1 (November 13, 2019): 3926. http://dx.doi.org/10.1182/blood-2019-131930.

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Acute myeloid leukemia (AML) is characterized by clonal proliferation of neoplastic myeloid precursor cells resulting in impaired hematopoiesis. Despite initial responses to intensive induction therapy, relapses are frequent and most patients die in less than 5 years (National Cancer Institute 2015). Nucleoside analogues represent an important category of anti-leukemic cytotoxic drugs. Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML. Sapacitabine is a novel, orally bioavailable nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading eventually to production of double-strand DNA breaks and/or G2 cell cycle arrest. In phase 1 and 2 clinical trials, sapacitabine has induced complete remission (CR), CR with incomplete platelet count recovery (CRp), partial remission (PR), and major hematological improvement (HI) in patients with AML and MDS. A subset of these responding patients were previously treated with other nucleoside analogues, suggesting that the anti-leukemic activity of sapacitabine is not limited by resistance to other nucleoside analogues (Kantarjian H et al, JCO, 2010, ASH, 2013). Two clinical studies have demonstrated the synergistic activity of venetoclax in combination with hypomethylating agents or low-dose ara-C in newly diagnosed AML, leading to its recent approval by the FDA for the front-line treatment of this disease. The synergy between venetoclax and cytotoxic therapy in AML models is mediated by combined targeting of the anti-apoptotic BCL2 and MCL1 mechanisms (Teh T-C et al, Leukemia, 2018). Cytotoxic drugs induce apoptosis through genotoxic damage, TP53 activation and increased expression of pro-apoptotic NOXA and PUMA (Villunger A et al, Science, 2003) - features that have also been demonstrated for sapacitabine (Green S et al. Br J Cancer 2010). Although most cytotoxic agents do not directly affect MCL1 levels, increased levels of the pro-apoptotic NOXA and PUMA proteins can inactivate MCL1 to synergize with venetoclax to induce apoptosis. The combination of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411. A synergistic increase in apoptosis induction was observed when CNDAC and ABT737 were combined (Frame S. et al, 14th EHA, 2009, Abs 0761). The above findings support the conduct of a clinical study (NCT01211457) evaluating a combination of sapacitabine with venetoclax in patients with relapsed/refractory AML and MDS. This is an entirely oral treatment regimen. The primary objective is to evaluate the safety and efficacy of two dosing schedules of sapacitabine given concomitantly with venetoclax: twice daily for 5 consecutive days or twice daily for 3 consecutive days per week for 2 weeks. One treatment cycle is 4 weeks. Dose will be escalated in increments of 50 mg twice daily. RP2D is the highest dose level at which ≤2 of 6 patients experience a dose-limiting toxicity during the first 2 treatment cycles. Eligible patients are ≥18 years with previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; adequate bone marrow, renal and liver functions are required. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess responses according to standard criteria. Disclosures Kadia: Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Borthakur:Agensys: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Merck: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arvinas: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.

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Guerra, Veronica A., Yan Yuanqing, Joanne Hsu, Feng Wang, Mansour Alfayez, Kiyomi Morita, Xingzhi Song, et al. "Comprehensive Analysis of Genotype and Prior Exposures in Therapy-Related Myeloid Neoplasms (t-MNs)." Blood 134, Supplement_1 (November 13, 2019): 458. http://dx.doi.org/10.1182/blood-2019-127498.

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Abstract:

Background: Therapy-related myeloid neoplasms (t-MNs) occur after exposures to chemotherapies and/or radiation therapies (CRT). However, true etiological association between CRT exposures and t-MN development is not clearly understood. We and others have recently revealed that selection of preleukemic mutant clones (TP53, PPM1D and others) under the selective pressure of CRT might play an important role in t-MN development (Wong et al. Nature 2014, Takahashi et al. Lancet Oncology 2017, Hsu et al. Cell Stem Cell 2018). For instance, PPM1D-mutated clone exhibited preferential expansion over wild-type clone only when exposed to cisplatin or etoposide, likely due to reduced apoptosis of mutant cells upon exposure to DNA damaging agents. In support of these findings, PPM1D-mutated t-MN patients had significantly frequent prior exposures to platinum and etoposide (Hsu et al. Cell Stem Cell 2018). These data led us to systematically analyze correlations between t-MN genotypes and prior exposures. Methods: We studied 471 patients (pts) with t-MNs (t-AML N = 188 and t-MDS N = 283) whose bone marrow or peripheral blood samples were analyzed by targeted next-generation sequencing. We performed extensive chart review to obtain history of prior exposures and analyzed correlation between CRT exposures and t-MN genotype. Results: Median age at diagnosis was 68 years (IQR:17-91) and the median latency from CRT exposures was 6 years (IQR: 0.1-45). (Table 1). The most frequent prior malignancies were breast cancer (20.8%), non-hodgkin's lymphoma (NHL) (20.3%) and prostate cancer (11.6%). Pts with NHL and multiple myeloma (MM) had significantly increased likelihood of developing t-MDS than t-AML (t-MDS vs. t-AML, 73.4% vs. 28.1%, P = .008 for NHL, 94.2% vs. 5.7%, P = < 0.001 for MM), whereas breast cancer pts developed t-AML more frequently than t-MDS (t-MDS vs. t-AML 43.8% vs. 56.1%, P < 0.001). Two hundred and eight (44.1%) pts had exposures to chemotherapy alone, 185 pts (39.2%) to chemo-radiotherapy, and 78 pts (16.5%) to radiotherapy alone. Eighty (16.9%) pts underwent autologous hematologic stem-cell transplant (auto-SCT). At least 1 driver mutation was detected in 392/471 (83.2%) t-MN pts and TP53 (36.3%), PPM1D (19.4%), TET2 (14.9%) and DNMT3A (14.6%%) were among the most frequently detected mutations. TP53 mutations were significantly more frequent in t-MDS than t-AML (43.8% vs. 25%; P=.000), while FLT3, NPM1, IDH1/2 mutations were more frequent in t-AML (14.9%, 7.4%, 9% respectively) than t-MDS (1.8%, 0%, 5.3%, 3.5% respectively) Correlation analysis of genotype and exposures confirmed previously known associations such as PPM1D mutations and platinum (log odds ratio [OR] 1.1, P = 0.01, false discovery rate [FDR] = 0.10), 11q23 rearrangement and topoisomerase II inhibitors (log OR 0.40, FDR = 0.71), and chromosome 7 abnormalities and alkylating agents (log OR 0.48, FDR =0.08). We found significant associations between TP53 mutations and immunomodulatory imide drugs (IMiDs, log OR = 0.98, , FDR =0.03); negative associations of alkylating agents with TET2 (log OR -0.93, FDR= 0.01) and NPM1 (log OR -3.31, FDR=0.003); and SRSF2 mutations with auto-SCT (log OR -2.24, FDR=0.03) and topoisomerase II inhibitors (log OR -2.42, FDR= 0.02). (Figure 1 Univariate analysis) We adjusted for the confounding effect from multiple exposures by multivariate logistic regression analysis (MLR) with modelbuilding by stepwise AIC or BIC selection criteria. MLR revealed a significant association of TP53 mutations with IMiDs (log OR = 1.07, P = 0.001), platinum (log OR = 0.61, P = 0.02), and vinca alkaloid (log OR = 0.62, P = 0.01). As well as a significant association between EZH2 mutations and vinca alkaloid (Log OR = 1.68, P = 0.009, Table 2). Conclusions: Comprehensive analysis of genotype and prior exposures in a large cohort of t-MNs revealed previously unknown associations, such as EZH2 mutations and vinka alkaloids, and TP53 mutations and IMiDs. The connection between TP53 mutations and IMiDs is consistent with the clonal selection of TP53 mutant clone with lenalidomide in 5q- syndrome (Jädersten et al. JCO 2011). These data provide a rationale for studying the mechanism of clonal selection of TP53-mutant or EZH2-mutant cells under IMiDs or vinka alkaloids. Further, this knowledge might be clinically useful for cancer pts with specific clonal hematopoiesis in reducing the risk of t-MNs by avoiding exposures to certain drugs. Disclosures DiNardo: notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria. Konopleva:Eli Lilly: Research Funding; Ascentage: Research Funding; Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; Astra Zeneca: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Borthakur:Oncoceutics: Research Funding; Novartis: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Eli Lilly and Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

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Pereira-Martins, Diego A., Juan L. Coelho-Silva, Isabel Weinhäuser, Luisa C. A. Koury, Raul Antônio Morais Melo, Rosane Bittencourt, Katia B. Pagnano, et al. "Arsenic Trioxide Abrogate MN1 Mediated RA-Resistance in Acute Promyelocytic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 5166. http://dx.doi.org/10.1182/blood-2019-131595.

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Introduction: Described as a well know marker of worse prognosis in acute myeloid leukemia (AML), MN1 overexpression has been associated with inv(16) or EVI1 overexpression (Heuser et al., Blood 2007). The promoter region of the MN1 gene has Retinoic Acid Response Elements (RAREs), and higher levels of MN1 expression have been associated with decreased response to retinoic acid (RA) in vitro. Nevertheless, in the context of acute promyelocytic leukemia, little is known about MN1 gene expression and functionality in vivo. Aims: Here, we investigated the effects of in vitro treatment with RA plus arsenic trioxide (ATO) in APL cell lines and primary blasts overexpressing MN1. Additionally, we quantified MN1 expression and correlated its levels with treatment outcome in a cohort of patients enrolled in the International Consortium on Acute Leukemia (ICAPL2006) study. Methods: Primary leukemic blasts from hCG-PMLRARα transgenic mice (TM; n=2) and APL patients (age, 36-45y; n=2) were transduced with MN1 or empty vector (EV, control) to evaluate cell proliferation, differentiation and apoptosis. Confirmatory assays were performed using transduced NB4 and NB4R2 (RA-resistant) cell lines. After synchronization using double thymidine block, transduced cells were submitted to proliferation and clonogenic (treated with RA and ATO, as well) assays. To evaluate the apoptotic rate, cells were treated with ATO (1 µM) alone or in combination with RA (1 µM each), for 24, 48 and 72 hours. The granulocytic differentiation in response to RA treatment alone (1 µM) or in combination with ATO (1 µM) was evaluated based on the CD11b and CD11c surface levels. In addition, 116 patients (age, 18-82y; 51% males) with newly diagnosed APL enrolled in the ICAPL2006 study were included. To validate our data, Bootstrap resampling procedure with 1000 repetitions from the original database was performed to assess the model bias. Results: Primary APL cells transduced with MN1 (from TM/APL patients) presented higher proliferation rates compared to controls (P<.05). Similarly, the overexpression of MN1 in APL cell lines was associated with increased proliferation (P=.001) and clonogenicity (P<.05). Furthermore, NB4-MN1 cells are able to form colonies in the presence of RA (1 µM) (P<.01) but not under ATO (1 µM) treatment (P>.05), while NB4R2-MN1 cells were able to form colonies in the presence of ATO (P<.05). To investigate whether MN1 promotes resistance to drug-induced apoptosis, we treated lentivirally transduced cells with RA plus ATO for 72 hours. No differences were founded between the MN1-transduced and the EV cells (P>.05). In accordance with our results using primary APL samples, ATO treatment (alone or in combination with RA) does not modulate the drug-induced apoptosis in a time-dependent manner in NB4 and NB4R2-MN1 cells (P<.05). For NB4 cells, the differentiation rate was lower in MN1-expressing cells under RA alone or in combination with ATO for 48 hours (P<.05), although these effects were abrogated after 72 hours of RA and ATO treatment. In contrast, NB4R2-MN1 cells exhibited decreased differentiation rate at 48 and 72 hours in presence of RA alone or in combination with ATO, in comparison with EV cells (P<.05). In the clinical setting, the retrospective analysis of patients enrolled in the ICAPL2006 study revealed that the baseline characteristics were similar between patients with low and high MN1 levels. According to PETHEMA/GIMEMA criteria for predicting relapse, 34% and 46% of patients assigned to the low- and high-MN1 groups were deemed high-risk patients, respectively (P=.045). High MN1 expression was associated with lower 5-y Disease-Free Survival rates (74%; 95% CI: 69-91%)(HR: 2.61, 95% CI: 0.86-8.36) and Cumulative Incidence of Relapse (25%; 95% CI: 13-34%) (HR: 2.27, 95% CI: 0.75-6. 8). Bootstrap analysis for internal validation resulted in an AUC (0.63, 95% CI: 0.57-0.809) very similar to the original described data. Conclusion: We show that MN1 is relevant for RA-induced differentiation both in vitro and in vivo and may be involved in RA-resistance. Additionally, treatment with ATO circumvented the differentiation blockage in MN1 cells. Disclosures Pagnano: Sandoz: Consultancy; Pint Pharma: Consultancy; Abbvie: Consultancy. Tallman:International Conference in Leukemia: Honoraria; 14th Annual Miami Cancer Meeting: Honoraria; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Mayo Clinic: Honoraria; Rigel: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Oklahoma Medical Center: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy; Danbury Hospital Tumor Board: Honoraria; Hematology Oncology of Indiana: Honoraria. Dillon:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Heuser:Bayer Pharma AG, Berlin: Research Funding; Synimmune: Research Funding. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees.

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Richard-Carpentier, Guillaume, Hagop M. Kantarjian, Guilin Tang, C. Cameron Yin, Joseph D. Khoury, Ghayas C. Issa, Nitin Jain, et al. "Characteristics and Clinical Outcomes of Patients with Acute Lymphoblastic Leukemia with KMT2A (MLL) Rearrangement." Blood 134, Supplement_1 (November 13, 2019): 2582. http://dx.doi.org/10.1182/blood-2019-130864.

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Background: Cytogenetic abnormalities have prognostic implications in acute lymphoblastic leukemia (ALL). High risk cytogenetics include complex karyotype (≥ 5 anomalies), low-hypodiploidy / near-triploidy, 14q32/IGH rearrangements and 11q23/KMT2A rearrangements. The most frequent gene partner involved in KMT2A-rearranged ALL is AFF1 located on chromosome 4q21. ALL with t(4;11)(q21;q23) - KMT2A-AFF1 has a very poor outcome and patients (pts) with this translocation are offered allogeneic stem cell transplantation (HSCT) in first complete remission (CR1). More than 130 gene partners have been described in KMT2A rearrangements. The frequency and prognostic signification of these various gene partners in KMT2A-rearranged ALL is unknown and it is uncertain whether pts harboring these translocations should be offered HSCT in CR1. Methods: We retrospectively reviewed 1102 pts with newly diagnosed ALL treated at our institution between 1984 and 2019 to identify pts with KMT2A rearrangement. Presence of t(11;v)(q23;v) was assessed by conventional cytogenetics with G-banding and/or by fluorescence in situ hybridization (FISH). Clinical and laboratory data were collected retrospectively. We analyzed the pts characteristics at baseline and evaluated remission rates, overall survival (OS) and relapse-free survival (RFS). The survival curves were estimated using the Kaplan-Meier method and differences between groups were evaluated with the log-rank test. Univariate Cox proportional hazard ratio were used for estimation of hazard ratios (HR). HSCT in CR1 was considered as a time-dependent covariate. Results: We identified 51 cases (5%) of ALL with KMT2A rearrangement or amplification. Two cases (4%) were cryptic KMT2A rearrangements identified by FISH, but with a normal karyotype. The most common KMT2A rearrangement was t(4;11)(q21;q23) in 42/51 (82%) pts. Four (8%) pts had t(11;19)(q23;p13) in which KMT2A can be partnered with MLLT1 or ELL, 1 (2%) pt had t(9;11)(p21;q23) - KMT2A-MLLT3, 1 (2%) pt had t(11;15)(q32;q26) with unknown gene partner, 1 (2%) pt had hsr(11)(q23) with KMT2A amplification, and 2 (4%) pts had an unknown gene partner (identification by FISH). Sixteen (31%) pts had additional chromosomal abnormalities, with i(7q) (3/51, 6%) and + X (2/51, 4%) the only identified in more than one case. The pts' clinical characteristics are summarized in table 1. All but one were B-cell ALL. The median age at diagnosis was 45 year-old (range, 18 - 78). The median white blood cell count (WBC) at diagnosis was 107.0 x 109/L (range, 0.5 - 1573.0) and 29/51 (57%) pts had hyperleukocytosis with WBC ≥ 100 x 109/L. None of the cases of B-ALL had CD20 expression, but 32/41 (78%) had CD22 expression (median of 59%; range 0 - 99%). Pts were treated with various regimens, with most pts receiving the Hyper-CVAD regimen (n=35), or one of its variation including addition of anti-CD20 monoclonal antibody (n=2), blinatumomab (n=1), nelarabine for T-cell ALL (n = 1) or dose adjusted regimen with omission of doxorubicin (mini-Hyper-CVD, n = 4). The complete remission rate was 88% (45/51) with 5 (10%) deaths during induction and 1 (2%) refractory disease. The measurable residual disease (MRD) negativity rate was 57% (17/30 evaluable pts). With a median follow-up of 63 months, the median OS and RFS were 14 months (95% confidence interval [CI], 10 - 39] and 10 months (95% CI, 6 - 17), respectively. The 5-year OS and RFS rates were 17% (95% CI, 9 - 35%) and 15% (95% CI, 7 - 33%), respectively. Comparing the 42 pts with t(4;11) and the 9 pts with other KMT2A abnormalities, no difference in OS (HR 0.94, p = 0.89) and RFS (HR 1.00, p = 0.99) were observed (Figure 1A-1B). HSCT in CR1 was associated with a better outcome in terms of OS (HR 0.49, 95% CI 0.24 - 0.99, p = 0.049) and RFS (HR 0.44, 95% CI 0.22 - 0.92). In the 17 (33%) pts who underwent HSCT in CR1 (16 with t(4;11) and 1 with other KMT2A rearrangement), the 5-year OS and RFS rates were 30% (95% CI, 14 - 68%) and 24% (95% CI, 9 - 62%), respectively, versus 10% (95% CI, 3 - 35%) and 9% (95% CI, 3 - 34%), respectively, in the 34 (67%) pts who did not undergo HSCT. The only 2 pts with KMT2A rearrangements other than t(4;11) who remain alive are the only 2 who have undergone HSCT: 1 in CR1 and 1 in CR2. Conclusion: Patients with KMT2A-rearranged ALL have a poor prognosis, which do not differ based on the gene partner involved. These patients benefit from HSCT in CR1. Disclosures Kantarjian: BMS: Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Jain:Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. DiNardo:medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:Xbiotech USA: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cantargia AB: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding. Konopleva:Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Pragmatist: Consultancy; Constellation: Consultancy; Protaganist Therapeutics: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

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Guerra, Veronica A., Jan A. Burger, Gautam M. Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan M. Kadia, Guillermo Garcia-Manero, Hagop M. Kantarjian, Marina Y. Konopleva, and Courtney D. DiNardo. "Interim Analysis of a Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination with Azacitidine in Advanced Myelodysplastic Syndrome (MDS)." Blood 134, Supplement_1 (November 13, 2019): 567. http://dx.doi.org/10.1182/blood-2019-125970.

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Abstract:

Background: Glutaminase (GLS) is an enzyme catalyzing the conversion of glutamine to glutamate, providing key metabolic fuel utilized by tumor cells. GLS is highly expressed in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), particularly in patients (pt) with complex cytogenetics. In preclinical studies, AML cells were dependent on glutamine, and glutaminase inhibition led to reduced cell growth and induced apoptosis. This study was designed to evaluate safety and efficacy of the oral glutaminase inhibitor CB-839 in combination with azacitidine in MDS. Methods: This is a single arm Phase Ib/II trial of CB-839 in combination with azacitidine (AZA) for intermediate and high-risk MDS. Eligible patients included adult pts > 18 years with high-risk MDS (IPSS intermediate-2 or high risk) or intermediate-1 risk with high-risk genomic features including TP53, ASXL1, EZH2, or RUNX1 mutations. Patients with prior hypomethylating therapy were eligible. The primary outcome for the Phase 1 portion was to confirm the safety and recommended Phase 2 dose of CB-839 in combination with AZA. Secondary endpoints evaluate the pharmacokinetic (PK), anti-tumor activity and drug exposure levels, and the efficacy and clinical activity using IWG response criteria. Results: Sixteen pts with MDS were enrolled between December 2017 and April 2019. The Phase I portion was completed confirming CB-839 600 mg BID orally continuously daily with standard AZA. The median age was 69.5 years [49-82]. Twelve pts (75%) were treatment naïve, 4 pts (25%) had prior HMA exposure. Eight pts (50%) were intermediate-2 and 8 pts (50%) intermediate-1 by IPSS with high-risk mutations. Baseline characteristics are listed in Table 1. 6 pts (37.5%) had complex cytogenetics. The most frequent mutations were ASXL1 (n = 9), TET2 (n = 6), TP53 (n = 6) and RUNX1 (n=5). The median time to best response was 1 cycle [1-4 cycles]. With a median follow-up of 8.6 months (mo) (range 1.3-16.5), patients have received a median of 3 cycles [1-9] with a median time between cycles of 29 days [23-137]. Seven pts remain on study. 9 pts discontinued treatment, including 5 pts (41.6%) who proceeded to allogeneic stem cell transplant (HSCT) after 2-4 cycles. (Table 2). Ten pts (62.5%) achieved mCR with or without HI/HI, 5 pts (31.3%) had SD, and 1 pt had NR. The median time to mCR was 2.5 mo [1-4]. One pt progressed to AML after 3 cycles of therapy. The median OS was 10.15 mo (mo, range NR) and EFS 10.42 mo (range 5.1-15.1). For the 12 newly diagnosed (ND) pts, the median OS and EFS have not been reached. (Figure 1) mCR/HI in TP53 mutated pts was 66.6% (4/6), 55.5% in ASXL1 (5/9), 80% in RUNX1 (4/5) and 83.3% in pts with complex cytogenetics (5/6). (Table 3) The most common non-hematological adverse events (AEs) were gastrointestinal AEs of any grade (62.5%), encompassing grade I-II nausea (62.5%), grade I constipation (37.5%), grade III-IV increased ALT (18.7%), and grade I anorexia (18.7%). Grade III-IV infections occurred in 43.7%. Additionally, the most common hematological AE were grade III-IV anemia (12.5%), neutropenia (37.5%) and thrombocytopenia (37.5%). Adverse events are listed in Table 4. Time to blood count recovery are shown in Table 5. Four pts (25%) required dose reduction of CB-839 to 400 mg BID, 1 pt. due to grade III transaminitis and myelosuppression, 2 pts for grade II-III myalgias and 1 pt for recurrent infections. There were a total of 5 deaths, 3 in ND pts (1 pt from disease progression (NR), 2 pts post HSCT) and 2 in pts with prior HMA exposure (1 from transformation to AML and 1 pt from unknown cause in mCR after cycle 6). Conclusions: CB-839 at a dose of 600 mg BID orally continuously daily is safe and well tolerated in combination with azacitidine in pts with advanced MDS with an acceptable safety profile. Preliminarily encouraging response rates include mCR/HI of 62.5%, including 100% in prior HMA exposure, 66.6% in TP53 and 83.3% in patients with complex karyotype. The trial continues to accrue. (NCT0347993) Disclosures Burger: AstraZeneca: Honoraria; Gilead Sciences: Research Funding; BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Aptose Biosciences, Inc: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria. Borthakur:Oncoceutics, Inc.: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy; Arvinas: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; NKarta: Consultancy; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Pemmaraju:incyte: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kantarjian:BMS: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding. Konopleva:Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. DiNardo:celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria.

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Cortes, Jorge, Guillermo Garcia-Manero, Koji Sasaki, Kiran Naqvi, Yesid Alvarado, Tapan M. Kadia, Farhad Ravandi, et al. "Activity of Venetoclax-Based Therapy in Myelodysplastic Syndrome (MDS)." Blood 134, Supplement_1 (November 13, 2019): 1726. http://dx.doi.org/10.1182/blood-2019-126005.

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Abstract:

Background: B-cell leukemia/lymphoma-2 (BCL2), is an antiapoptotic protein commonly overexpressed in hematologic malignancies. Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an efficacious treatment option for patients (pts) with hematologic malignancies. To the best of our knowledge, the outcome of VEN based therapy in MDS pts has not been reported yet. Methods: We retrospectively reviewed MDS pts treated with VEN-based therapy between 2018-2019 including MDS/ myeloproliferative neoplasms (MPN) subtype chronic myelomonocytic leukemia (CMML) pts. Mutation testing was performed using a whole-exome next-generation sequencing panel. Clinical responders were defined by IWG2006 criteria. Pts were stratified according to the Revised International Prognostic Scoring System (IPSS-R). Overall survival (OS) was analyzed with Kaplan-Meier estimators. We analyzed the characteristics of these pts, responses to therapy, and outcomes Results: Twelve MDS pts treated with VEN were identified (9 MDS and 3 MDS/MPN subtype CMML), the median follow up was 12.8 months (range, 0.3 to 40.8). Patient characteristics are shown in Figure 1A. The median age was 68 years (range, 51 to 78), 8 pts were female (66%), and 6 pts (50%) had therapy related MDS. All pts had high risk IPSS-R score (range, 6 to 10). A total of 9 (75%) pts had complex karyotype. The most common identified mutation was TP53 (Figure 1B). The median number of prior treatments was 1 (range, 1 to 3), 10 pts (83%) had relapsed/refractory (R/R) disease all of which had primary failure to hypomethylating agents (HMA), and 3 (25%) underwent allogeneic stem cell transplantation (SCT) with subsequent relapse before receiving VEN. The median dose for VEN was 200 mg (range 100 to 400mg) with median duration of 14 days (range, 7 to 21). VEN was given in combination with: 1) HMA (66%), the number of HMA doses were between 3 to 10 doses in each cycle, 2) Low dose Ara-C (8.5%), 3) Low dose Ara-C+ Cladribine+ Mylotarg (8.5%), 4) Low dose Ara-C+ Cladribine+ Ruxolitinib (8.5%), or 5) CPX-351 + Mylotarg (8.5%). The median number of cycles was 3 (range, 1 to 4). All pts had treatment delays due to slow white count recovery and 2 pts (17%) received G-CSF, 11 pts (92%) had infections and three pts (25%) died from septic shock (VEN doses were 100, and 400 mg). The overall response rate (ORR) was 55%, including one complete remission (CR) (Figure 1C). A total of 3 pts (25%) had subsequent relapse after therapy. The duration of response for pts who relapsed was 6, 8.8 and 15.6 months. Six pts (50%) transformed to acute myeloid leukemia while they were on VEN. One pt underwent allogeneic SCT after receiving VEN. With a median follow up of 12.8, the median OS was 8.6 months (Figure 1D). Conclusion: Combination therapy with venetoclax can have activity in patients with R/R MDS but is associated with prolonged myelosuppresion. Larger studies with longer follow up are needed to determine the role of VEN-based therapy in MDS and identify potential subsets of pts who may benefit from this intervention. Figure 1 Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Daver:Forty-Seven: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; Incyte: Consultancy, Research Funding; Otsuka: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; NOHLA: Research Funding; Celgene: Consultancy; Jazz: Consultancy; Servier: Research Funding; Servier: Research Funding; NOHLA: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Otsuka: Consultancy; BMS: Consultancy, Research Funding; Forty-Seven: Consultancy; Astellas: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Abbvie: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Pfizer: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Borthakur:FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; NKarta: Consultancy; PTC Therapeutics: Consultancy; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; AstraZeneca: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Eli Lilly and Co.: Research Funding. Pemmaraju:incyte: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Cyclacel: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding.

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Sasaki, Koji, Hagop M. Kantarjian, Elias Jabbour, Farhad Ravandi, Marina Y. Konopleva, Gautam M. Borthakur, William G. Wierda, et al. "The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)." Blood 134, Supplement_1 (November 13, 2019): 1642. http://dx.doi.org/10.1182/blood-2019-130148.

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Abstract:

INTRODUCTION: The survival of patients with chronic myeloid leukemia in chronic phase (CML-CP) is approaching that of general population after the approval of tyrosine-kinase inhibitors (TKI), particularly in younger patients who achieve remission. The optimal frontline TKI therapy in older patients in the context of comorbidity remains unknown. The aim of this study is to develop the LEukemia Artificial intelligence Program (LEAP) for treatment recommendations for patients with CML-CP. METHODS: From July 30, 2000 to November 25, 2014, 630 consecutive patients with newly diagnosed CML-CP were enrolled in frontline TKI therapy (imatinib 400 mg/day, imatinib 800 mg/day, nilotinib, dasatinib, and ponatinib). We included 101 social, demographic, clinical, chromosomal, and molecular variables such as the distance from home address to our institution, primary language, the European Treatment and Outcome Study (EUTOS) risk, the EUTOS long-term survival (ELTS) risk, and the severity of comorbidities by Adult Comorbidity Evaluation 27 (ACE-27). We developed an extreme gradient boosting decision tree model through ensemble learning after hyperparameter tuning. Hyperparameter optimization was calculated with Stampede2, a supercomputer located at Texas Advanced Computing Center, which was ranked as the 15th fastest supercomputer in June 2018. The extreme gradient boosting decision tree model was developed for the prediction of overall survival using only the training/validation cohort. We evaluated the final performance with the independent test cohort. A difference in hazard ratios of less than 0.005 between the best treatment option and alternative TKI therapy was considered as the LEAP recommendation. The test cohort was divided into the LEAP recommendation and the LEAP non-recommendation cohort by the LEAP recommendation. To confirm the association and causation of the LEAP recommendation with survival, we performed backward multivariate Cox regression, and inverse probability of treatment weighing (IPTW) to balance baseline difference of covariates. We calculated SHapley Additive exPlanations1 values to interpret the black box of the LEAP recommendation for the evaluation of the significance of variable for prediction. RESULTS: The whole cohort was randomly divided into a training/validation (N=504) cohort and a test cohort (N=126) at a 4:1 ratio (Figure 1). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model. The number of decision trees was 8417, 14659, and 14190 in the first, second, and third cross validation cohort, respectively (Figure 2). The accuracy of prediction at each iteration is shown in Supplemental Figure 1. The area under the curve (AUC) of the training in the first, second, and third cross validation cohort was 0.966, 0.978, and 0.977, respectively; the AUC of the validation in the first, second, and third cross validation cohort was 0.815, 0.832, and 0.742, respectively. The AUC in the test cohort was 0.819. We divided the test cohort (N=126) into the LEAP recommendation (N=94, 75%) and LEAP non-recommendation cohort (N=32, 25%) (Table 1). The LEAP did not recommend one particular TKI (P=0.128). Overall survival did not differ significantly by the type and dose of TKI (P=0.472) (Supplemental Figure 2). Patients in the LEAP recommendation cohort achieved higher rates of overall deep response (Table 2). In the test cohort, treatment consistent with the LEAP recommendation was associated with improved failure-free survival, transformation-free survival, event-free survival, and overall survival (P<0.001; P=0.002; P<0.001; P<0.001) (Figure 3). The median overall survival was 139 months (range, 3.7-216.1), and the median overall survival was 127 months and 148 months in the LEAP recommendation and LEAP non-recommendation cohorts, respectively (P=0.902). Backward multivariate Cox regression analysis and IPTW analysis confirmed the association and causation of improved OS with the LEAP recommendation, respectively (Supplemental Table 1; Supplemental Table 2). The SHAP values identified the presence and degrees of comorbidities and ELTS scores as top three importance for the prediction (Figure 4). Conclusion: The LEAP CML-CP recommendation improves overall survival in patients with CML-CP through higher tolerance, lower rates of progression, and higher rates of deep response. Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Kantarjian:Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Takeda: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Novartis: Research Funding; Immunogen: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Selvita: Research Funding. Konopleva:Agios: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Borthakur:AstraZeneca: Research Funding; Polaris: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Merck: Research Funding; Eli Lilly and Co.: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Arvinas: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Wierda:Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:plexxikon: Research Funding; novartis: Consultancy, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy.

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Rausch, Caitlin R., Courtney D. DiNardo, Abhishek Maiti, Nadya Jammal, Tapan M. Kadia, Kayleigh Marx, Gautam M. Borthakur, et al. "Venetoclax Dosing in Combination with Antifungal Agents: Real World Experience in Patients with Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2640. http://dx.doi.org/10.1182/blood-2019-131988.

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Abstract:

Introduction: Venetoclax (VEN) is approved for the treatment of acute myeloid leukemia (AML) in combination with hypomethylating agents (HMAs) or low-dose cytarabine and commonly used for patients (pts) unfit for intensive chemotherapy. Prophylaxis with triazole antifungals (azoles) during induction treatment in pts with AML has decreased mortality and is the standard of care for pts receiving treatment regimens associated with prolonged myelosuppression (Cornely et al, 2007). Azoles inhibit CYP3A4 (CYP3A4i), the enzyme responsible for the metabolism of VEN, and p-glycoprotein to varying degrees, which VEN is a substrate. Based on this interaction and the results of a small pharmacokinetic study, significant VEN dosage reductions are recommended (Agarwal et al, 2017). Little real-world data exists to demonstrate the tolerability of VEN in combination with azoles during induction treatment with VEN and HMAs. Methods: All pts with newly diagnosed AML treated at our institution with VEN and HMAs from 11/2014-1/2019 were retrospectively reviewed. Pts were treated as standard of care or as part of clinical trial in combination with azacitidine (NCT02203773) or decitabine (NCT03404193; NCT02203773). Pts who received concomitant antifungal for >5 days while also receiving VEN for >7 days were included. VEN 100mg daily with posaconazole or voriconazole (strong CYP3A4i) and VEN 200mg daily with isavuconazole or fluconazole (moderate CYP3A4i) were considered 400mg equivalent dosages. Higher doses of VEN in these combinations were considered >VEN 400mg equivalent. To determine the clinical impact of concomitant azoles, time to absolute neutrophil count (ANC) and platelet (PLT) recovery after induction was analyzed, in addition to response rates, episodes of febrile neutropenia (FN) and documented infections. Results:One-hundred twenty-one pts treated with HMA and VEN were identified (Table 1). The median age was 72 years (48-86) and 35% were > 75 years. Forty pts (33%) had secondary AML, and 10% had therapy-related AML. Most were treated with decitabine 20mg/m2 administered for 10 days (67%) or 5 (22%). VEN was administered for a median of 23 days (7-30) at a 400mg daily dose equivalent in 74 pts (62%) and >400mg dose equivalent in 40 pts (33%). Eighty-nine (74%) received a concomitant azole with VEN including posaconazole (38%), isavuconazole (21%), voriconazole (13%), or fluconazole (2%). Following induction therapy with VEN and HMA, 37% achieved a complete response (CR) and 22% achieved a CR with incomplete blood count recovery (CRi). An additional 10% achieved a morphologic leukemia free state (MLFS) (Table 2). Prior to cycle 2, 55% of pts achieved ANC>500 cells/mm3 and 64% achieved PLT>50,000 cells/mm3 after a median of 34 days and 24 days, respectively. No difference in response was observed based on VEN dosage or duration (Table 3). Pts achieving CR/CRi received VEN for a median of 22 days (7-29), and 38% at the 400mg equivalent VEN dosage with an azole. When analyzing VEN dosage by the use of an azole, duration of neutropenia (ANC<1000 cells/mm3) was 5 days longer in pts receiving an azole compared to those who were not (p>0.05) (Table 4). Number of pts achieving PLT>50,000 cells/mm3 was not affected by concomitant antifungal or VEN dosage, but duration of thrombocytopenia was. Time to PLT>50,000 cells/mm3 was significantly longer for pts receiving VEN 400mg equivalent with an azole (25 vs 20 days, p=0.01) as well as time to PLT>100,000 cells/mm3 (27 vs 22 days, p=0.03). Despite prolonged cytopenias, all pts receiving the VEN 400mg equivalent dosage had similar rates of FN, documented infections, and hospital duration regardless of the use of an azole (Table 4). Those receiving >400mg VEN equivalent had numerically higher rates of FN, infections, and duration of hospitalization. Conclusion: The combination of VEN with HMA is an effective treatment option in pts with newly diagnosed AML. VEN is associated with significant myelosuppression which can be enhanced by concomitant CYP3A4i, such as the azoles. The combination of VEN and azoles resulted in prolonged cytopenias, namely thrombocytopenia, compared to the use of VEN without an azole. This did not result in higher rates of FN, infections, or duration of hospitalization, therefore the concomitant use of VEN and azole appear to provide a clinically safe and effective therapeutic regimen. Higher doses of VEN do not appear to be advantageous in this setting. Disclosures DiNardo: daiichi sankyo: Honoraria; jazz: Honoraria; syros: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria. Maiti:Celgene: Other: research funding. Kadia:Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Arvinas: Research Funding; Oncoceutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Agensys: Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding. Kantarjian:Astex: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Agios: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

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Montalban Bravo, Guillermo, Rashmi Kanagal-Shamanna, Koji Sasaki, Farhad Ravandi, Jorge E. Cortes, Naval G. Daver, Koichi Takahashi, et al. "Outcomes of Patients with Acute Myeloid Leukemia (AML) with Myelodysplasia Related Changes (AML-MRC) Are Dependent on Diagnostic Criteria and Therapy." Blood 134, Supplement_1 (November 13, 2019): 1312. http://dx.doi.org/10.1182/blood-2019-131998.

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INTRODUCTION: AML with myelodysplasia related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, presence of myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. Defining the outcomes within this heterogeneous subgroup of pts is necessary to select optimal therapy. METHODS: We evaluated all pts with AML-MRC diagnosed and treated at our institution from 2013 to 2018. All cases where reviewed by 2 hematopathologists to establish diagnosis of AML-MRC following WHO 2017 criteria. Patients with therapy-related myeloid neoplasms were excluded. Sequencing data was obtained by use of an 81-gene targeted, next generation sequencing (NGS) platform. Pts were classified into 4 categories: 1) AML-MRC was based on cytogenetic abnormalities (AML-MRC-C) in pts with definitory cytogenetic abnormalities; 2) AML-MRC with history of prior MDS or MDS/myeloproliferative neoplasm (MDS/MPN) in 103 (25%) pts (AML-MRC-H); 3) AML-MRC with history of prior therapy for antecedent MDS or MDS/MPN (AML-MRC-S) and 4) AML-MRC with presence of >50% dysplasia in 3 lineages (AML-MRC-M) in pts with compatible morphologic features but none of the prior. We reviewed response and survival outcomes based on subgroup, therapy, and clinic-pathologic factors. RESULTS: A total of 415 pts with AML-MRC where identified. Median age at diagnosis was 70 years (range 18-94). A total of 243 (59%) pts had AML-MRC-C, 47 (11%) had AML-MRC-H, 28 (7%) had AML-MRC-S and 97 (23%) had AML-MRC-M. Among pts with a prior history of MDS or MDS/MPN, 23 (22%) had received therapy with hypomethylating agents, 1 (1%) with lenalidomide and 3 (3%) with ruxolitinib and 1 with 7+3 (1%) (these were categorized as AML-MRC-S). Median bone marrow blast percentage on aspirate was 35% (range 1-97%). Among pts with AML-MRC-C the defining cytogenetic abnormality included: complex karyotype in 186 (77%), monosomy 5 or del(5q) in 14 (6%), monosomy 7 or del(7q) in 38 (16%), concurrent chromosome 5 or 7 abnormalities in 2 (1%), del(13q) in 2 (1%) and i(17) in 1 (0.5%) pt. Data on NGS was available in 95 pts. Identified mutations are shown in Figure 1A. Mutations in TP53 where more commonly observed in pts with AML-MRC-C (p=0.001). Prior publications (Lindsley et al Blood 2015) have shown that secondary-type mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2) identify a subset of pts with AML with worse than expected outcomes. Among evaluable pts, a total of 37 (39%) pts had secondary-type mutations. Based on variant allele frequency of identified mutations, mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. A total of 73 (18%) pts received therapy with single agent hypomethylating agents (HMA), 67 (16%) with HMA in combination with investigational drugs, 86 (21%) with low-dose cytarabine (LDAC) based therapies and 119 (29%) with intensive chemotherapy. Response outcomes on evaluable pts are shown in Figure 1B. With a median follow up of 28.3 months (95% CI 25.7-30.9 months) the median overall survival (OS) was 10.5 months (95% CI 9.1-12.0 months). Pts with AML-MRC-M and AML-MRC-H had significantly better outcomes than those with AML-MRC-C or AML-MRC-S (overall p<0.001, Figure 1C). Among pts with AML-MRC-C those with complex karyotype had significantly worse outcomes than those with other defining cytogenetic abnormalities (p<0.001). Pts treated with intensive chemotherapy had improved OS compared to those treated with other forms of therapy (p=0.002, Figure 1D). However, when evaluating outcomes by AML-MRC subtype, use of intensive therapy was only associated with improved survival on AML-MRC-M (overall p=0.039, Figure 1E) but not in AML-MRC-C or AML-MRC-H (data not shown). No significant differences in OS were observed in pts with secondary-type mutations (p=0.568) but, among pts with AML-MRC-M presence of these mutations was associated with a trend to worse OS (median OS 3.8 months vs NR, p=0.228). CONCLUSION: AML-MRC is a heterogeneous group of AML with diverse mutational abnormalities and outcomes. Selection of therapy should be based on cytogenetic abnormalities and AML-MRC subtype. Figure 1 Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Borthakur:GSK: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding. Konopleva:Calithera: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Astex: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Maiti, Abhishek, Hagop M. Kantarjian, Guillermo Garcia-Manero, Marina Y. Konopleva, Srdan Verstovsek, Michael Andreeff, Gautam M. Borthakur, et al. "Determinants of Outcomes of FLT3mut Acute Myeloid Leukemia with First Salvage Therapy." Blood 134, Supplement_1 (November 13, 2019): 2641. http://dx.doi.org/10.1182/blood-2019-129621.

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Background: Patients (pt) with relapsed or refractory acute myeloid leukemia (R/R AML) with FLT3mut have poor prognosis. FLT3 inhibitors (FLT3i) as single agent, and in combination improve outcomes in FLT3mut AML. However, recent clinical trials of FLT3i have had different inclusion criteria, and determinants of outcomes with FLT3i are not well known. Methods: We conducted a retrospective study to determine factors affecting outcomes in FLT3mut R/R AML with first salvage therapy. We reviewed medical records of R/R FLT3mut AML pts for data regarding prior therapy, salvage regimen and outcomes. Univariate analysis and multivariate Cox analysis were performed to evaluate the association of baseline covariates and outcomes. Evaluated baseline factors included ECOG PS, ELN cytogenetic risk group, FLT-ITD ratio, FLT3-D835 mutation, frontline therapy factors including intensive chemotherapy (IC), hypomethylating agent (HMA), or non-intensive chemotherapy (NIC)-based regimen, anthracycline use, FLT3i use, stem-cell transplantation (SCT), response to frontline therapy, salvage regimen related factors including IC vs. HMA vs NIC-based regimen, FLT3i use, SCT, AML mutations, etc. Efficacy endpoints of interest included CR/CRi per modified IWG criteria for AML, overall survival (OS) and duration of response (DOR). Results: Between June 2002 and July 2019 we identified 202 pts with R/R FLT3mut AML who received first salvage therapy at our institution with or without an FDA-approved or investigational FLT3i. The baseline characteristics are shown in Table 1 and treatment characteristics and outcomes are shown in Table 2. The median follow-up duration was 54 months (mo, 95% CI 46-89) and median OS 7.9 mo (95% CI 6.2-9.8). 53 out of 105 responding pts relapsed and median DOR was 3.6 mo (95% CI 2.7-5.8). Multivariate logistic regression analysis showed higher odds of achieving CR/CRi with salvage IC (OR 2.9), and IC+FLT3i (OR 8.1) compared to HMA, and RUNX1mut was associated with lower odds of achieving CR/CRi compared to RUNX1-WT (OR 0.06, Table 3). Single agent FLT3i as salvage therapy did not have significant association with CR/CRi or OS, as compared to HMA. Similarly, multivariate Cox model for analysis of factors associated with OS showed higher risk of death in pts who had received FLT3i in frontline setting (HR = 2.9) and pts with TET2mut (HR = 2.2, Table 4). Different salvage regimens of IC, NIC, HMA with or without FLT3i, and single agent FLT3i did not show survival benefit compared to HMA alone. Pairwise comparison between salvage regimens for OS censored at SCT (Fig. 1a-f) showed HMA improved OS compared to IC (median OS 10.2 vs 6.4 HR 0.64, 95% CI 0.36-0.99, p=0.046). Addition of FLT3i to HMA or IC did not yield significantly different OS compared to single agent FLT3i (Fig. 1 a-d). On univariate analysis, there was no significant difference in DOR between salvage HMA vs other salvage therapies including IC, NIC, single agent FLT3i, and IC with FLT3i. Covariates not associated with CR/CRi or OS on univariate analysis included ECOG PS, ELN cytogenetic risk group, frontline HMA or IC, prior anthracycline, prior SCT, response to prior regimen, FLT3-ITD ratio, FLT3-D835, and other recurrent AML mutations. Hence, these factors were not included in the multivariate models. Limitations of this study included retrospective nature and small sample sizes in subgroups. Conclusions: This multivariate analysis of a large cohort of R/R FLT3mut AML undergoing first salvage therapy showed association of RUNX1mut with lower odds of achieving CR/CRi, and frontline FLT3i use and TET2mut with worse OS. Both IC, and IC with FLT3i were associated with higher odds of achieving CR/CRi compared to HMAs. However, pairwise comparison of salvage regimens suggested improved OS with HMA compared to IC. Disclosures Maiti: Celgene: Other: research funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding. Garcia-Manero:Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding. Konopleva:Ablynx: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Amgen: Consultancy, Honoraria; Astra Zeneca: Research Funding; Agios: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Genentech: Honoraria, Research Funding. Verstovsek:Pharma Essentia: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Andreeff:AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Aptose: Equity Ownership; Breast Cancer Research Foundation: Research Funding; NIH/NCI: Research Funding; CPRIT: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Borthakur:Strategia Therapeutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cyclacel: Research Funding; Agensys: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; GSK: Research Funding; Eisai: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Polaris: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding. Daver:Abbvie: Consultancy, Research Funding; Agios: Consultancy; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; Servier: Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Agios: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Wierda:Miragen: Research Funding; Cyclcel: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Loxo Oncology Inc.: Research Funding; Oncternal Therapeutics Inc.: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding. Cortes:Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding.

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Pemmaraju, Naveen, Bing Z. Carter, Hagop M. Kantarjian, Jorge E. Cortes, Prithviraj Bose, Tapan M. Kadia, Guillermo Garcia-Manero, et al. "Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis." Blood 134, Supplement_1 (November 13, 2019): 555. http://dx.doi.org/10.1182/blood-2019-130046.

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Abstract:

Background: Outcomes in patients (pts) with relapsed/refractory (R/R) myelofibrosis (MF) post JAK inhibitor are poor [overall survival (OS) 13-14 months] (Newberry K, Blood 2017; Kuykendall A, Ann Hematol 2018). There are no approved therapies beyond JAK inhibitors for pts with MF. In certain clinical situations, such as severe thrombocytopenia, administration of JAK inhibitors may be difficult or even contraindicated. SMAC mimetics (or IAP antagonists), a novel class of anti-cancer therapeutics, lead to apoptotic cancer cell death through targeting of IAPs. Because these agents are hypothesized to be particularly effective in a TNFα-rich micro-environment, such as in pts with MF, a group known to have markedly increased cytokines including TNFα (Fleischman A Blood 2011; Heaton W, Leukemia 2018; Tefferi A, JCO 2011), we conducted an investigator-initiated phase 2 clinical trial with LCL161 in pts with intermediate to high risk PMF or post-ET/PV MF. Objectives: Primary: overall response rate (ORR) by IWG-MRT 2013; secondary and exploratory: time to response, response duration, safety, improvement in symptom burden by MPN-SAF TSS, measurement of cIAP1/2, XIAP, and mutational profiling via next-generation sequencing. Clinical Trial Design: LCL161 is an oral monovalent SMAC mimetic, administered once weekly, starting dose 1500 mg with 2 dose level reductions (DL-1, 1200mg; DL-2, 900 mg) in pts with MF. One cycle was 28 days. Pts age ≥18, PS 0-2, who were not candidates for, intolerant to, or R/R to JAK inhibitors were eligible. After 3 cycles, bone marrow biopsy/response evaluations were performed. There was no minimum platelet count for eligibility, and prior allogeneic stem cell transplant (SCT) was allowed. Results: The study has completed enrollment. A total of 47 pts were treated with a median age of 72 years [56-85]. The median baseline platelet count was 51 x 109/L [6-1365]. The median baseline spleen size was 12 cm among 28 pts with enlarged spleen at baseline. 70% of the pts had ≥2 prior therapies; 55% had a prior JAK inhibitor, 2 pts had prior SCT. 75% were IPSS high-risk. Driver mutations: 64% JAK2 V167F; 13% CALR; 11% MPL W515L; 5 pts had triple negative MF. Mutation analysis revealed the three most common additional mutations: ASXL1 (23%); TET2 (15%); DNMT3a (11%). ORR was 32% (15/47 pts); 15 pts exhibited a total of 19 objective responses (4 pts met criteria for 2 separate IWG 2013 responses): Clinical improvement (CI) symptoms (n=11); CI anemia (n=6); CI spleen (n=1), cytogenetic response (n=1). At a median follow-up of 21.1 months (mo) [3.9-49.7+], the median number of cycles received was 5 [1-52+], the median time to response was 1.4 mo [0.9-9.1] and median response duration (mo) was 31.5 [3.6-48.8+]. Long-term responders: n=8 for ≥1 year; n=4 for ≥2 years/ongoing. Importantly, median OS is not yet reached on this study (Figure). The most common non-hematologic toxicities (grade 1/2): nausea/vomiting (60%); fatigue syndrome (49%), dizziness/vertigo (32%); non-hematologic Grade 3/4: syncope (n=2); nausea/vomiting (n=1). Hematologic toxicities (grade 3/4): thrombocytopenia n=3 (6%); anemia n=2 (4%). 36% pts had a dose reduction; the most common cause was fatigue (n=10). Overall, 81% pts are now off study [Stable disease/no objective response (n=16); progressive disease (n=9); toxicity (n=5), pt's choice/other (n=6), proceeded to SCT (n=2)]. Correlative analysis: Preliminary analysis demonstrates on-target inhibition of cIAP1 observed in all responding pts analyzed; high levels of XIAP and/or XIAP increases were observed in many pts with resistance/disease progression. Anemia responders: 6 pts achieved CI anemia (n=4 hemoglobin responses, n=2 achievement of transfusion independence). Among these 6 pts: median time to response (mo): 3.1 [0.9-9.1]; median response duration (mo): 8.4 [5.5-28.6]. Conclusion: In an older group of pts with 70% with ≥2 prior therapies (55% JAK inhibitor-exposed), median baseline platelet count of 51, ASXL1-mutated in 23%, we observed a 32% ORR. The median OS has not yet been reached. Oral SMAC mimetics may represent a possible option for older pts, those who have failed prior JAK inhibitor, and those with thrombocytopenia limiting entry onto other trials. Future directions include combination studies with hypomethylating agents and JAK inhibitors for pts with myeloid malignancies. This clinical trial is registered at ClinicalTrials.gov as NCT02098161. Figure Disclosures Pemmaraju: sagerstrong: Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; novartis: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; incyte: Consultancy, Research Funding; affymetrix: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding. Carter:Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding. Cortes:Sun Pharma: Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Merck: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding. Bueso-Ramos:Incyte: Consultancy. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; Tetralogic Pharmaceuticals: Research Funding; GSK: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Cantargia AB: Research Funding; AbbVie: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cyclacel: Research Funding; Polaris: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: LCL161- not yet FDA approved drug; investigational agent = SMAC mimetic /IAP antagonist

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Jain, Nitin, Michael J. Keating, Philip A. Thompson, Jan A. Burger, Alessandra Ferrajoli, Zeev E. Estrov, Gautam M. Borthakur, et al. "Combined Ibrutinib and Venetoclax in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)." Blood 134, Supplement_1 (November 13, 2019): 359. http://dx.doi.org/10.1182/blood-2019-131732.

Full text

Abstract:

Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. The rationale for combining IBR and VEN includes: 1) preclinical models showing synergism, 2) non-overlapping toxicities; 3) non-overlapping mechanisms of action. We recently reported results of the first-line cohort of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019). Here we report results of the 80 pts from the R/R CLL cohort of the trial (NCT02756897). Methods: Pts with R/R CLL meeting 2008 IWCLL treatment criteria were enrolled. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to the 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy stopped both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of combined therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 61.5 yrs (32-79). The baseline characteristics are shown in Table 1. Overall, 30 (38%) pts had a TP53 aberration. The median follow-up for all pts is 22.3 months. Of the 80 pts, 1 pt was later reclassified as splenic marginal zone lymphoma and is excluded from further analyses. Five pts came off study during IBR monotherapy phase (reasons listed below). 74 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. One pt with a prior allo-SCT had no marrow disease at screening and is therefore excluded from serial MRD analyses. After 3 cycles of IBR monotherapy, none of the 73 pts achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 7/68 (10%) achieved BM U-MRD remission. After 6 cycles of the combination, 15/67 (22%) achieved BM U-MRD remission. After 12 cycles of the combination, 29/60 (48%) achieved BM U-MRD remission. After 24 cycles of the combination, 16/24 (67%) achieved BM U-MRD remission. To assess the incremental benefit of the combined IBR and VEN beyond the first 12 cycles, we analyzed the MRD for pts who had received 24 cycles of combined therapy (n=24). Among these 24 pts, 13 were MRD+ at end of 12 cycles; 4/13 (31%) became U-MRD at end of 18 cycles of combination. Similarly, among these 24 pts, 9 were MRD+ at end of 18 cycles of combination; only 1/9 (11%) achieved U-MRD after 24 cycles of combination. PFS and OS are shown in Figure 2. Two pts had CLL progression after completing 24 cycles of combined therapy. 1 pt was in U-MRD remission at 24 cycles and stopped both IBR and VEN per study design; he relapsed 3 months later and responded to IBR monotherapy. The second pt was MRD+ at 24 cycles of combined therapy and continued IBR monotherapy after 2 yrs per study design; he relapsed few months later and is now in remission post CD19 CAR-T. One pt developed Hodgkin's transformation. Two pts died; both due to infectious complications during the IBR monotherapy. One pt developed severe cytopenias during the VEN dose escalation, was non responsive to multiple therapies for worsening cytopenias, then underwent an allogeneic stem cell transplant. One pt, with prior FCR therapy developed MDS. A total of 15 (19%) pts have come off trial; 5 pts came off study during IBR monotherapy (death from infection, n=2; skin rash, n=1; insurance issue, n=1; pt decision, n=1). Three pts came off trial during VEN ramp up (cytopenias, n=2; noncompliance, n=1). Four pts came off trial during the combination phase of IBR and VEN (arthralgia, n=1; Hodgkin's transformation, n=1; renal cancer, n=1; MDS, n=1). Three pts came off trial after completing 24 cycles of combined therapy (CLL progression, n=2; pt decision to continue VEN beyond 24 cycles, n=1). Grade 3-4 neutropenia occurred in 29% pts. Grade 3-4 thrombocytopenia occurred in 3% pts. Atrial fibrillation occurred in 7 (9%) pts. Conclusions: Combined VEN and IBR is an effective well-tolerated chemotherapy-free oral regimen for pts with R/R CLL. Disclosures Jain: Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Thompson:Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Gilead Sciences: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; AstraZeneca: Honoraria. Borthakur:Cyclacel: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eisai: Research Funding; Janssen: Research Funding; GSK: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Bose:Constellation: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Forty-Seven: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; jazz: Honoraria. Pemmaraju:samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

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Jain, Nitin, Michael J. Keating, Philip A. Thompson, Alessandra Ferrajoli, Jan A. Burger, Gautam M. Borthakur, Koichi Takahashi, et al. "Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)." Blood 134, Supplement_1 (November 13, 2019): 34. http://dx.doi.org/10.1182/blood-2019-131847.

Full text

Abstract:

Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. We recently reported results of the first-line cohort (n=80) of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019) (NCT02756897). Here we report updated data for these 80 pts with focus on MRD results. Methods: Pts with previously untreated CLL meeting 2008 IWCLL treatment criteria were enrolled. All pts had at least one of the following features: del(17p), mutated TP53, del(11q), unmutated IGHV, or an age of 65 years or older. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (assessed by multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy will stop both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 65 years (26-83). The baseline characteristics are shown in Table 1. A total of 30% of the pts were 70 years of age or older. Overall, 92% of the pts had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median follow-up for all pts is 22.8 months. Five pts came off study during IBR monotherapy (reasons listed below). 75 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. After 3 cycles of IBR monotherapy, none of the 75 pts had achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 12/74 (16%) achieved BM U-MRD remission. After 6 cycles of the combination, 30/72 (42%) achieved BM U-MRD remission. After 12 cycles of the combination, 45/69 (65%) achieved BM U-MRD remission. After 24 cycles of the combination, 23/29 (79%) achieved BM U-MRD remission. PFS and OS are shown in Figure 2. No pt has had CLL progression. Richter's transformation developed in one pt; this was a 63-year-old man with CLL with high-risk genomics (unmutated IGHV and mutated NOTCH1) in whom back pain developed during dose escalation of venetoclax and who was noted to have DLBCL transformation. Two pts died. One pt was a 60-year-old man who was having headache and numbness on the right side for 1 week before starting ibrutinib. The pt received 1 day of ibrutinib monotherapy, had progressive neurologic symptoms, and was found to have CNS cryptococcal infection. Ibrutinib was discontinued and the pt died 6 months later from complications of disseminated cryptococcal infection. This was deemed unrelated to ibrutinib as the pt had symptoms prior to starting ibrutinib. A second pt received only 2 weeks of ibrutinib and was taken off trial due to development of fungal pneumonia. The pt continued ibrutinib (off trial) and died 2 years later from infectious complications. A total of 12 (15%) pts have come off trial. Five pts came off trial during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Seven pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1]. 54% pts had dose reduction of IBR; 29% had dose reduction of VEN. Conclusions: Combined IBR and VEN is an effective chemotherapy-free oral regimen for pts with high-risk previously untreated CLL. Ongoing randomized studies will further help define the role of this combination approach in CLL. Disclosures Jain: BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding. Thompson:AbbVie: Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria. Borthakur:Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Fowler:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Konopleva:Agios: Research Funding; Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding. Alvarado:Abbott: Honoraria; Jazz Pharmaceuticals: Research Funding. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; medimmune: Honoraria. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wierda:Janssen: Research Funding; Xencor: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

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Kadia, Tapan M., Jorge E. Cortes, Marina Y. Konopleva, Gautam M. Borthakur, Naveen Pemmaraju, Naval G. Daver, Guillermo Montalban Bravo, et al. "Venetoclax Combined with Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Produces High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)." Blood 134, Supplement_1 (November 13, 2019): 2647. http://dx.doi.org/10.1182/blood-2019-122477.

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Abstract:

Treatment of older patients with newly diagnosed AML remains challenging, limited by modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy. We previously reported on a low-intensity backbone of cladribine + LDAC (CLAD/LDAC)alternating with decitabine for older patients with AML, yielding higher rates of CR and improved outcomes compared to historical experience with hypomethylating agents (HMAs) in this setting (Lancet Haematology 2018). Recently, the combination of the BCL-2 inhibitor venetoclax with HMAs demonstrated significant improvements in response rates and survival over experience with HMAs alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients. We designed a phase II clinical trial studying the combination of venetoclax with CLAD/LDAC alternating with 5-azacytidine (AZA) in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of AZA 75 mg/m2 on days 1-7, for up to 18 cycles. Venetoclax was added on days 1-21 of each cycle with dose adjustments (50-400 mg) for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. All patients underwent pre-treatment cytogenetic analysis and mutational testing using a customized 81-gene next generation sequencing panel. MRD was assessed using multiparameter flow cytometry in the marrow at the time of remission. Twenty-six patients have been treated on study, with a median age of 69 yrs (57-84); 11 (42%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. The baseline patient characteristics are summarized in Table 1. Among 24 evaluable pts, 18 (75%) achieved a complete remission (CR), 3 (13%) had a CR with incomplete platelet recovery (CRp), and 1 (4%) had CR with incomplete neutrophil recovery (CRn) for a CR/CRp rate of 88% an overall response rate of 92%. The median number of cycles to response was 1 (1-3) and 83% of pts were negative for MRD by multi-parameter flow cytometry at the time of CR. Among 9 evaluable pts with diploid karyotype, the CR rate was 100% with full count recovery. Rates of CR/CRp/CRn among other genetic subgroups are summarized in Table 2. The regimen was well tolerated, with a 4-week mortality of 0%. The median time between cycle 1 and 2 was 32 days. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=12), lung infection (7), decreased urine output (2), and acute kidney injury (1). Four (18%) of the 22 responding pts went on for allogeneic stem cell transplant, 1 pt (4%) relapsed, 2 (8%) did not respond, and 19 pts continue on treatment. With a median follow-up of 4 months, the median remission duration and overall survival (OS) have not been reached, with an estimated 3- and 6-month OS rate of 95% (Figure). The combination of venetoclax with CLAD/LDAC alternating with AZA is a lower intensity, well-tolerated, and highly effective regimen for older patients with newly diagnosed AML, producing high rates of MRD negative remission and meaningful blood count recovery. Further study of this approach is warranted. Disclosures Kadia: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Agios: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Borthakur:AbbVie: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; Merck: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Eli Lilly and Co.: Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; Arvinas: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; cellectis: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; sagerstrong: Research Funding. Daver:Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; NOHLA: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. DiNardo:abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Andreeff:Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CPRIT: Research Funding; NIH/NCI: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding. Kantarjian:Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Pfizer: Honoraria, Research Funding.

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Short, Nicholas J., Hind Rafei, Naval G. Daver, Hyunsoo Hwang, Jing Ning, Jorge E. Cortes, Jeffrey L. Jorgensen, et al. "Achievement of Complete Remission (CR) with Measurable Residual Disease (MRD) Negativity Is Highly Prognostic in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) Receiving First Salvage Chemotherapy." Blood 134, Supplement_1 (November 13, 2019): 735. http://dx.doi.org/10.1182/blood-2019-122779.

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Abstract:

Background: Achievement of CR with full hematologic recovery and MRD negativity are independently associated with improved survival in pts with AML undergoing frontline treatment. However, in R/R AML, the prognostic impact of these response parameters is not well-established. Methods: We retrospectively analyzed pts with R/R AML who received first salvage with an intermediate- or high-dose cytarabine regimen at our institution between 8/2011 and 7/2018. Only pts who achieved morphological remission, with or without full hematologic recovery, and had MRD measured at the time of best response were included in this analysis. Pts with core-binding factor AML were excluded. MRD was assessed by 8-color multiparameter flow cytometry on bone marrow specimens with a sensitivity of 0.1% or higher. The primary outcomes were cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS). Results: A total of 141 pts met inclusion criteria and were included in the analysis. Table 1 shows the baseline characteristics of the study population. Ninety-five pts (67%) achieved CR, 26 (18%) achieved CR with incomplete hematologic recovery (CRi), and 20 (14%) achieved morphological leukemia-free state (MLFS) as best response. Overall, 86 pts (61%) achieved MRD negativity. MRD negativity rates were similar among response groups (64%, 46%, and 65% for CR, CRi, and MLFS, respectively; P=0.22). The rate of CR was higher in pts with diploid vs. non-diploid karyotype (78% vs. 59%; P=0.02) and in pts with CR1 duration ≥1 year vs. others (87% vs. 57%; P=0.001). The MRD negativity rate was higher in pts with higher baseline bone marrow blasts (median blasts: 35% vs. 26%; P=0.03) and was not associated with any other pretreatment parameter. The median duration of follow-up was 30.5 months. Pts who achieved CR vs. lesser response had lower CIR (P=0.01) and RFS (P=0.004) but not OS (P=0.15); a similar trend was observed in pts who achieved MRD negativity vs. those who were MRD-positive (P=0.01, P=0.05, and P=0.21, respectively). Among MRD-positive pts, level of MRD (i.e. <0.1% vs. 0.1%-1% vs. >1%) did not impact outcomes. Overall, 62 pts (44%) underwent allogeneic HSCT after first salvage therapy, with a median time of 1.4 months between second remission and HSCT. HSCT after first salvage therapy was the strongest prognostic factor for CIR, RFS and OS (P<0.001 for all). HSCT rate was higher in those who achieved CR vs. lesser response (52% vs. 28%; P=0.008) or who were MRD-negative vs. MRD-positive (52% vs. 31%; P=0.01). The relapse rate within 1.4 months following second remission was high in pts who only achieved CRi/MLFS and/or were MRD-positive (16% vs. 3% for pts who achieved CR with MRD negativity; P=0.01) and was a major driver of the inferior outcomes in these groups. In a landmark HSCT analysis, 22 pts who relapsed, died or lost to follow-up within 1.4 months of second remission were excluded. Among the remaining 57 pts who did not undergo HSCT in second remission, stratification of pts into 4 groups by hematologic response (CR vs. CRi/MLFS) and MRD response (positive vs. negative) was associated with significant difference in CIR (P=0.004) and RFS (P=0.008) but not OS (P=0.8). In contrast, among the 62 pts who underwent HSCT, neither hematologic nor MRD response was associated with CIR, RFS or OS. Similarly, MRD status immediately prior to HSCT was also not associated with outcomes. By multivariate analysis including known predictors for outcomes in R/R AML (Breems DA et al. J Clin Oncol 2005) and using HSCT as a time-dependent variable, both CR and MRD negativity were independently associated with lower CIR (P=0.001 and P=0.003, respectively) and better RFS (P<0.001 and P=0.02, respectively) but not with OS. Overall, pts who achieved CR with MRD negativity (n=61) had the best outcomes (2-year CIR: 58% vs. 73%, P=0.004; 2-year RFS: 28% vs. 15%, P=0.008; 2-year OS: 46% vs. 21%, P=0.10; Figure 1A-C). Conclusions: In pts with R/R AML receiving first salvage therapy, CR and achievement of MRD negativity were both independently associated with decreased CIR and longer RFS. The impact of hematologic recovery and MRD response in the salvage setting was largely limited to pts who did not undergo subsequent HSCT, whereas outcomes were similar for those who received HSCT. In the R/R setting, pts who achieve both CR and MRD negativity have the best outcomes, supporting CR with MRD negativity as the optimal response to salvage therapy. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Daver:Servier: Research Funding; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Immunogen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Kadia:Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding. Borthakur:Oncoceutics, Inc.: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics: Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Agensys: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; Arvinas: Research Funding; Polaris: Research Funding; Cantargia AB: Research Funding. Kantarjian:Novartis: Research Funding; Astex: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding.

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Cortes, Jorge, Mansour Alfayez, Tapan M. Kadia, Marina Y. Konopleva, Farhad Ravandi, Jorge E. Cortes, Elias Jabbour, et al. "Activity of Multiple Targetable Therapies in FLT3-Mutated (mu) Acute Myeloid Leukemia (AML) Patients (pts) with Concurrent Isocitrate Dehydrogenase Mutation (IDHm)." Blood 134, Supplement_1 (November 13, 2019): 1447. http://dx.doi.org/10.1182/blood-2019-127257.

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Abstract:

Background: FLT3-mutated (mu) AML pts have poor outcomes. IDH1mutated (IDH1m) and IDH2m co-occur with FLT3 mutations in 15-27% and 8-30% of AML, respectively (Boddu P, et al. Leukemia 2017; 31:2526-2529). FLT3-ITD is a strong risk factor for relapse and since multiple FLT3 inhibitors (FLT3i's) are available, it is important to further determine how the efficacy of these targeted is impacted by concurrent mutation/s. Methods: We reviewed FLT3-mu AML pts with concurrent IDHm's between Jan 2011-Dec 2018 who had received at least one first or second generation FLT3-inhibitor (FLT3i)-based therapy in frontline and/or relapsed/refractory (R/R) setting. We are not discussing IDHi based therapies in double mutant pts this abstract. Mutation testing was performed using a NGS-based analysis for the detection of somatic mutations in the coding sequences of 28 or 81 genes on DNA extracted from BMA, as previously described (33). We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results: Eighty two FLT3, IDH 'double mutated' AML pts were identified. One pt had FLT3-TKD mu and IDH1m, and 2 pts had FLT3-TKD mu and IDH2m and were excluded. We focus here on the 79 pts with concurrent FLT3-ITD mu and IDH1m or IDH2m. 30 pts had concurrent FLT3/IDH1m: 19 (63%) in frontline and 11 (37%) in the R/R setting. 49 had concurrent FLT3/IDH2m: 31 (63%) in frontline and 18 (37%) in the R/R setting. The median follow-up was 8.3 months [1.2 - 115] and 10.5 months [0.3 - 57.8] months for pts with concurrent FLT3/IDH1m and FLT3/IDH2m, respectively. The median number of prior therapies was 2 [1 - 8] in both R/R settings. The most frequent mutations were IR132H (77%) and IR140Q (98%) in pts with FLT3/IDH1m and FLT3/IDH2m, respectively. Patient characteristics are shown in Table 1. As expected, the incidence of adverse cytogenetics in FLT3/IDH mutated pts was low (7/79; 9%). The most common co-occurring mutations in FLT3/IDH1 pts were NPM1 (66%) and DNMT3A (43%). Similarly in FLT3/IDH2: NPM1 (53%) and DNMT3A (31%). FLT3i's were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low intensity therapy (LIT) (hypomethylating agents and low-dose cytarabine) in the frontline or R/R setting (Table 2). CR/CRi rate was highest with CCR with FLT3i, with 83% and 78% of frontline and R/R FLT3/IDH pts achieving CR/CRi with this approach. Among pts who could not receive CCT based therapies, LIT with FLT3i showed encouraging activity with CR/CRi rates of 47% and 40% in frontline and R/R FLT3/IDH pts, respectively. LIT alone was not very effective with CR/CRi rates of 0 and 33% in frontline and R/R FLT3/IDH pts, although numbers are small. Similarly, single agent FLT3 showed modest activity with CR/CRi in 16% of the R/R FLT3/IDH pts. As expected FLT3/IDH2 pts had improved overall survival (OS) and event free survival (EFS) compared with FLT3/IDH1 pts. The median OS was 11.2 and 2.88 in frontline and R/R FLT3/IDH1 pts, respectively. The median OS was 20.6 and 10.3 in frontline and R/R FLT3/IDH2 pts, respectively. The median EFS was 4.98 and 4.27 in frontline FLT3/IDH1 pts who received CCT+FLT3i and LIT+FLT3i, respectively (p=0.10). The median EFS was 14.2 and 8.2 in frontline FLT3/IDH2 pts who received CCT+FLT3i and LIT+FLT3i, respectively (p=0.09). Conclusion:FLT3/IDH2 pts have better EFS and OS than FLT3/IDH1 pts in frontline and R/R setting with FLT3i in combination with CCT or LIT. CCT in combination with FLT3i appears to be optimal therapy for FLT3/IDH co-mutated pts with CR/CRi rates of 83% in frontline, and 78% in R/R setting. In pts unable to tolerate CCT a combination of LIT with FLT3i is a reasonable approach yielding CR/CRi rates of 40-45% in frontline and R/R FLT3/IDH pts. LIT alone and FLT3-inhibitor alone demonstrated lower activity with CR/CRi rates of 14-16% in double mutant pts. Disclosures Kadia: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Agios: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Garcia-Manero:Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Pemmaraju:novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; samus: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Borthakur:Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tetralogic Pharmaceuticals: Research Funding; Janssen: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Agensys: Research Funding; Merck: Research Funding; GSK: Research Funding; Arvinas: Research Funding; Xbiotech USA: Research Funding; Cyclacel: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; Polaris: Research Funding; AbbVie: Research Funding. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Ariad: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria. Daver:Celgene: Consultancy; Glycomimetics: Research Funding; NOHLA: Research Funding; BMS: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Otsuka: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy.

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Montalban-Bravo, Guillermo, Rashmi Kanagal-Shamanna, Koji Sasaki, Farhad Ravandi, Jorge E. Cortes, Naval G. Daver, Koichi Takahashi, et al. "Outcomes of Patients with Acute Myeloid Leukemia with Myelodysplastic Are Dependent on Diagnostic Criteria and Therapy." Blood 134, Supplement_1 (November 13, 2019): 647. http://dx.doi.org/10.1182/blood-2019-129373.

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Abstract:

INTRODUCTION: Acute myeloid leukemia with myelodysplastic related changes (AML-MRC) is a heterogeneous disorder defined by morphologic, cytogenetic and clinical features. Defining the optimal therapy of this subgroup of patients depending on disease features and characteristics is necessary. METHODS:We evaluated all patients (pts) with AML-MRC diagnosed and treated at The University of Texas MD Anderson Cancer Center from 2013 to 2018. All cases where reviewed by two hematopathologists to establish diagnosis of AML-MRC following WHO 2017 criteria. Patients with therapy-related myeloid neoplasms were excluded. Sequencing data was obtained by use of a 81-gene targeted PCR-based next generation sequencing (NGS) platform. Previously described somatic mutations registered at the Catalogue of Somatic Mutations in Cancer (COSMIC: http://cancer.sanger.ac.uk/cosmic) were considered as potential driver mutations. The Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes. RESULTS:A total of 415 pts with AML-MRC where identified. Median age at diagnosis was 70 years (range 18-94). Diagnosis of AML-MRC was based on cytogenetic abnormalities (AML-MRC-C) in 214 (52%) pts, presence of >50% dysplasia in 3 lineages (AML-MRC-M) in 98 (24%) pts and due to history of prior myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) in 103 (25%) pts (AML-MRC-H). Among pts with a prior history of MDS or MDS/MPN, 23 (22%) had received therapy with hypomethylating agents, 1 (1%) with lenalidomide and 3 (3%) with ruxolitinib and 1 with 7+3 (1%). Median bone marrow blast percentage on aspirate was 35% (range 1-97%). Among pts with AML-MRC-C the defining cytogenetic abnormality included: complex karyotype in 162 (76%), monosomy 5 or del(5q) in 14 (7%), monosomy 7 or del(7q) in 34 (16%), concurrent chromosome 5 or 7 abnormalities in 2 (1%), del(13q) in 1 (0.5%) and i(17) in 1 (0.5%) pt. Data on NGS was available in 95 pts. Identified mutations are shown in Figure 1A. Mutations in TP53where more commonly observed in pts with AML-MRC-C (p=0.001). In addition, mutations in RUNX1where more commonly observed in pts with AML-MRC-H (p=0.038). Prior publications (Lindsley et al Blood 2015) have shown that secondary-type mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1and ZRSR2) identify a subset of pts with AML with worse than expected outcomes. Among evaluable pts, a total of 37 (39%) pts had secondary-type mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, andU2AF1tended to appear in dominant clones. A total of 73 (18%) pts received therapy with single agent hypomethylating agents (HMA), 67 (16%) with HMA in combination with investigational drugs, 86 (21%) with intermediate dose chemotherapy and 119 (29%) with intensive chemotherapy. Response outcomes on evaluable pts are shown in Figure 1B. With a median follow up of 28.3 months (95% CI 25.7-30.9 months) the median overall survival (OS) was 10.5 months (95% CI 9.1-12.0 months). Pts with AML-MRC-M had significantly better outcomes than those with AML-MRC-H or AML-MRC-C (median OS 20.8 months vs 18.7 vs 16.9 months, p<0.001) (Figure 1C). Although a trend to worse survival was observed in pts with AML-MRC-H with prior therapy for the antecedent MDS or MDS/MPN this difference was not significant (median OS 5.9 vs 9.9 months, HR 1.5, 95% CI 0.8-2.9, p=0.216). Among pts with AML-MRC-C those with complex karyotype had significantly worse outcomes than those with other defining cytogenetic abnormalities (p<0.001). Pts treated with intensive chemotherapy had improved OS compared to those treated with other forms of therapy (p=0.002, Figure 1D). However, when evaluating outcomes by AML-MRC subtype, use of intensive therapy was only associated with improved survival on AML-MRC-M (p=0.05, Figure 1E) but not in AML-MRC-C or AML-MRC-H. No significant differences in OS were observed in pts with secondary-type mutations (p=0.568) but, among pts with AML-MRC-M presence of these mutations was associated with a trend to worse OS (median OS 3.8 months vs NR, p=0.228). CONCLUSION:AML-MRC is a heterogeneous group of AML with diverse mutational abnormalities and outcomes. Selection of therapy should be based on cytogenetic abnormalities and AML-MRC subtype. Figure 1 Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Daver:Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; NOHLA: Research Funding; Sunesis: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:medimmune: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Borthakur:Incyte: Research Funding; AbbVie: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding. Konopleva:Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Astex: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Ariad: Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Guerra, Veronica A., Hagop M. Kantarjian, Jorge E. Cortes, Guillermo Garcia-Manero, Lucia Masarova, Naveen Pemmaraju, Elias Jabbour, et al. "A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)." Blood 134, Supplement_1 (November 13, 2019): 4237. http://dx.doi.org/10.1182/blood-2019-125974.

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Abstract:

Background: The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) are Philadelphia negative myeloid neoplasms with overlapping clinicopathological features of both MPNs and MDS. Ruxolitinib (RUX), a JAK 1/2 inhibitor is FDA approved for primary myelofibrosis. The hypomethylating agents, azacitidine (AZA) and decitabine, are approved for MDS. The independent activity of RUX and AZA in patients with MPNs and MDS, respectively, and their non-overlapping toxicity profiles suggest that the combination of these two agents administered sequentially and at lower doses may be tolerable and efficacious in patients with MDS/MPNs. Herein we present updated results from a Phase II trial. Methods: This is a single-arm Phase II trial of RUX in combination with AZA for patients (pts) with MDS/MPNs. Eligible pts included adults > 18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MDS/MPNs with intermediate-1, intermediate-2, or high risk according to the DIPSS criteria for PMF. RUX at 15-20 mg orally twice daily was to be given alone in 28 day cycles for the first 3 cycles. AZA was to be added from cycle 4 onward at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the 2015 IWG MDS/MPN response criteria. The secondary objective was to determine the safety and tolerability of the combination therapy. Results: Forty-five pts were enrolled between May 2013 and June 2019. The median age was 68 years; 64% were ≥65 years, 77.7% were int-2 or high risk by DIPPS. Twenty one (46.6%) pts had splenomegaly and 16 (35.5%) pts had EUMNET MF-2 or MF-3. JAK2V617F mutation was present in 16 pts (35.5%). Thirteen pts had pre-therapy BM blasts >5%. The pts. characteristics are in Table 1. Fourty three pts were evaluable for response at the time of this report. AZA was given to 41/45 pts (91.1%), with 26 (63%) pts initiating the AZA before cycle 4 due to increased of bone marrow blast or proliferative disease. After a median follow-up of 30.8 months (mo), 19 pts are still alive. 24 pts (56%) achieved an objective IWG 2015 response. The median time to IWG response was 1.8 mo (0.4-5.5). A ≥50% palpable spleen length reduction was seen in 64% (9/14) of evaluable pts with a median time to response of 1.0 mo. 8/13 (62%) evaluable pts achieved a BM blast reduction to <5%. Specific responses are listed in Table 2. No significant difference in JAK2 mutation status (p=0.215) or frequency of splenomegaly (p=0.298) was noted between responders and non-responders. The most common possibly related non-hematological adverse events were grade I-II constipation (22.2%), nausea (15.5%) and pain (15.5%). Significant possibly related hematological AEs included grade III-IV anemia (35.5%), neutropenia (22.2%) and thrombocytopenia (53.3%), these were usually transient and only 2 pts had to discontinue protocol therapy due to cytopenias. All possibly related adverse events are listed in Table 3. Five pts progressed to AML, with a median time to progression of 13.8 mo. Overall, the median OS was 25.4 mo with 1-year and 3-year OS rates of 86% and 40%. Pts with MDS/MPN-U had a better median OS compared with CMML and aCML (31.8 mo vs. 16 mo vs. 1.5 mo; p=0.009). Figure 1 depicts OS by diagnosis. The 1-year and 3-year OS rates for pts with MDS/MPN-U were 100% and 46%, respectively. The median duration of response was 8.35 mo (range 2.1-14.6 mo).The median OS of 31.8 mo among MDS/MPN-U pts compares favorably to a median OS of 16.1 mo from the previously published historical cohort of MDS/MPN-U patients treated with AZA alone (N = 36) at our institution (DiNardo C et al, Leukemia 2014). Conclusions: RUX in combination with AZA was safe and effective and may be a therapeutic option to consider, especially in pts with MDS/MPN-U. Transient grade III-IV myelosuppression was frequently seen, but only 2 pts (4.4%) required treatment discontinuation, which is similar to discontinuation rates with single agent RUX in MF in COMFORT studies (8-9%). Overall response rate was 56%. Additionally 63% BM remissions were noted among pts with ≥5% blast at baseline. The clinical trial is still recruiting (NCT01787487) and focussed on enrolling MDS/MPN-U pts. Disclosures Kantarjian: BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Astex: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Pemmaraju:novartis: Consultancy, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; cellectis: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Wierda:GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Pharmacyclics LLC: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Ruxolitinib a JAK1/2 is approved for the treatment of MF and PV HMA decitabine and azacitidine are approved for MDS This trial is combining azacitidine and ruxolitinib in MDS/MPNs

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Montalban-Bravo, Guillermo, Rashmi Kanagal-Shamanna, Christopher B. Benton, Caleb Class, Kelly S. Chien, Koji Sasaki, Kiran Naqvi, et al. "Genomic Context and TP53 Allele Frequency Define Prognostic Subgroups and Response Outcomes in TP53 Mutated Myelodysplastic Syndromes." Blood 134, Supplement_1 (November 13, 2019): 1711. http://dx.doi.org/10.1182/blood-2019-124978.

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INTRODUCTION: TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). There is limited data evaluating the impact of the type, number, clonal size and patterns of TP53 mutations in response outcomes and prognosis. METHODS: We evaluated all patients with newly diagnosed myelodysplastic syndromes (MDS) treated at The University of Texas MD Anderson Cancer Center (MDACC) from 2013 to 2018. Genomic DNA was extracted from whole bone marrow aspirate samples and was subject to 28, 53 or 81-gene targeted PCR-based sequencing using a next generation sequencing (NGS) platform. Response assessment was performed following 2006 IWG criteria. The Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes. RESULTS: 938 patients were evaluated including 261 (28%) with detectable TP53 mutations of which 189 (72%) received therapy: chemotherapy-based in 5 (3%) patients, single agent hypomethylating agents in 116 (61%) and hypomethylating agent in combination with novel agents in 65 (34%). Most (n=175, 67%) patients had one TP53 mutation with 75 (29%), 10 (4%) and 1 (0.4%) having 2, 3 and 4, respectively. TP53 dynamics on 18 patients with multiple TP53 mutations and longitudinal sequencing suggested both could present within the same clone in 8 (44%) patients. Median variant allele frequency (VAF) of all TP53 mutations was 39% (range 1-94%). TP53 deletion was more frequent in patients with mutated TP53 (31.8% vs 2.2%, p<0.001). Sixty-three patients (24%) suffered transformation to acute myeloid leukemia with a median transformation-free survival (TFS) of 10.6 months (95% CI 8.8-12.3). By univariate analysis the number of TP53 mutations (HR 2.03, 95% CI 1.3-3.05, p<0.001), TP53 mutation VAF (HR 1.02 increase per 1% VAF increase, 95% CI 1.01-1.02, p<0.001), TP53 deletion (HR 2.10, 95% CI 1.38-3.19, p<0.001) and complex karyotype (HR 2.58, 95% CI 1.70-3.91, p<0.001) were predictors of shorter TFS. By multivariate analysis only TP53 mutation VAF remained an independent predictor of shorter TFS (HR 1.02 increase per 1% VAF increase, 95% CI 1.00-1.03, p=0.005). With a median follow-up of 21.9 months (95% CI 20.3-25.6 months), there were no significant differences in ORR (58% vs 63%, p=0.303) or CR (27% vs 22%, p=0.288) based on the presence of TP53 mutation. Presence of TP53 deletion was associated with lower ORR (OR 0.53, p=0.021). Lower TP53 VAF correlated with higher ORR. Presence of TP53 abnormalities was associated with shorter response duration (HR 2.9, 95% CI 1.64-5.13, p<0.001). Longitudinal sequencing was available in 64 patients. TP53 VAF decreased more among responders (p=0.022) with subsequent increase of VAF at the time of relapse (Figure 1A). Presence of ³2 TP53 abnormalities was associated with shorter survival (HR 1.39, 95% CI 1.03-1.89, p=0.034, Figure 1B). TP53 VAF was associated with worse prognosis (HR 1.02 per 1% VAF increase, 95% CI 1.01-1.03, p<0.001). Patients could be classified into three prognostic groups based on TP53 VAF (Figure 1C). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups (Figure 1D). We developed a multivariable Cox model including TP53 VAF and IPSS-R categories with a corrected concordance index of 0.81 demonstrating a strong model fit. This model was used to generate a nomogram for overall survival (Figure 1E). CONCLUSION: This data suggests that the number and clonal size of TP53 mutations as well as other genomic events may help identify subgroups of patients with MDS with distinct prognosis and clinical outcomes. Figure 1 Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Daver:Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Jazz: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; medimmune: Honoraria; jazz: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Borthakur:Novartis: Research Funding; Merck: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Bayer Healthcare AG: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xbiotech USA: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pemmaraju:cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria. Konopleva:Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Bueso-Ramos:Incyte: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Kantarjian:Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Novartis: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

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Richard-Carpentier, Guillaume, Hagop M. Kantarjian, Jeffrey L. Jorgensen, Sa A. Wang, Joseph D. Khoury, Farhad Ravandi, Nicholas J. Short, et al. "Phase II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (B-ALL) with Positive Measurable Residual Disease (MRD)." Blood 134, Supplement_1 (November 13, 2019): 1299. http://dx.doi.org/10.1182/blood-2019-130283.

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Background: The majority of adult patients (pts) with B-ALL achieve complete remission (CR) with contemporary multi-agent chemotherapy regimens. Persistence or recurrence of measurable residual disease (MRD+) in CR is associated with an increased risk of relapse and lower overall survival (OS) rates. Blinatumomab (blina) is a CD19-CD3 bispecific T-cell engager (BiTE) monoclonal antibody effective in the treatment of relapsed/refractory B-ALL and for the eradication of MRD+. In the BLAST trial, 78% of patients achieved complete MRD response (MRD-) with blina and responders had an improved 4-year OS of 52%. Uncertainty remain whether pts MRD- after blina should undergo allogeneic hematopoietic stem cell transplant (HSCT). In pts with Philadelphia-chromosome positive (Ph+) B-ALL, blina in combination with tyrosine kinase inhibitors (TKI) has not been evaluated for eradication of MRD. The objective of this trial was to evaluate the safety and efficacy of blina in pts with B-ALL and MRD+. Methods: This is an open-label, single-arm, Phase II trial including pts with B-ALL in CR with persistent or recurrent MRD+. Pts in first CR (CR1) or in second CR or beyond (CR2+) were eligible. MRD+ was defined as ≥ 0.01% B-ALL cells by 6-color multiparameter flow cytometry for Ph- B-ALL pts and BCR-ABL1 to ABL1 transcripts ratio of ≥ 0.01% International Scale (IS) by RT-qPCR for pts with Ph+ ALL. Pts received continuous IV infusion of blina 28 µg/day over 4 weeks followed by a 2-week treatment-free interval. For the first cycle, blina was initiated at 9 µg/day for 1 week and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cycles (for a total of 5), and pts could proceed to HSCT at any time. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included the MRD negativity rate, OS, and the safety profile. Results: Between December 2015 and June 2019, 25 patients with B-ALL in CR with MRD+ were enrolled. Baseline characteristics of the patients are shown in Table 1. Ten (40%) pts had Ph+ B-ALL. Eighteen (72%) pts were in CR1 and 7 (28%) were in CR2+. Sixteen (64%) pts had persistent MRD+, and 9 (36%) had MRD+ recurrence after being negative for a median or 20 months (range, 2-36). Pts received a median of 2 cycles (range, 1-5) of blina. For pts with Ph+ B-ALL, blina was combined with ponatinib in 8 pts, bosutinib in 1 pt and dasatinib in 1 pt. The rate of MRD- with blina was 78% (18/23 pts). MRD- was achieved in 6/8 (75%) pts with Ph+ ALL and 12/15 (80%) pts with Ph- ALL (p = 1.00); 11/16 (69%) pts in CR1 vs 7/7 (100%) pts in CR2+ (p = 0.27); and 9/14 (64%) pts with persistent MRD+ vs 9/9 (100%) with recurrent MRD+ (p = 0.12) (Table 2). The median time to MRD- was 1.3 month (range, 1.0 - 5.6); 16/18 (89%) responders achieved MRD- after one cycle. One Ph- ALL pt achieved MRD- after 2 cycles and one Ph+ ALL pt achieved MRD- after 4 cycles. Six of 18 (33%) responding pts proceeded to HSCT after blina (3/11 in CR1 and 3/7 in CR2+), with a median time from treatment start to HSCT of 3.1 months (range, 2.1 - 6.4). Post-HSCT, 1 pt died of transplant-related complications and 5 remain alive in CR. Among 12 responding pts who did not proceed to HSCT, 4 relapsed and 8 are alive in remission. With a median follow-up of 25 months (range, 2 - 43), the median RFS and OS have not been reached. The 2-year RFS and OS were 58% [95% CI, 39 - 85%] and 68% [95% CI, 49 - 93%], respectively (Figure 1A-1B). There was no difference in RFS and OS according of Ph+ status or between pts in CR1 and in CR2+ (Table 2). The 2-year RFS and OS rates for complete MRD responders were 62% [95% CI, 41 - 95%] and 76% [95% CI, 56 - 100%], versus 40% [95% CI, 14 - 100%] and 40% [95% CI, 56 - 100%) for non-responders, respectively (Figure 2A-2B). The 2-year RFS and OS for pts who proceeded to HSCT were both 78% [95% CI, 55 - 100%], versus 37% [95% CI, 15 - 88%] and 56% [95% CI, 31 - 100%) for pts who were not transplanted, respectively. Blinatumomab-related adverse events of any grade were observed in 8/25 pts (32%). Cytokine release syndrome was reported in 3 pts (12%; grade 2, n=2; grade 3, n=1) and neurological adverse events in 4 pts (16%; grade 2; n=3, grade 3, n=1). All events resolved with supportive management and blina could be restarted. Conclusion: Blinatumomab is highly effective for eradication of MRD+ in pts with B-ALL. Pts who achieve MRD- with blina have an excellent outcome. The study continues to accrue patients. Disclosures Kantarjian: Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Khoury:Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AbbVie: Research Funding; PTC Therapeutics: Consultancy; GSK: Research Funding; Incyte: Research Funding; Bayer Healthcare AG: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Cantargia AB: Research Funding; Xbiotech USA: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; NKarta: Consultancy; Polaris: Research Funding. Konopleva:Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Jabbour:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

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Samra, Bachar, Hagop M. Kantarjian, Koji Sasaki, Nicholas J. Short, Rita Khouri, Joseph D. Khoury, Richard E. Champlin, et al. "Outcome of Patients (Pts) with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) without 3-Month Complete Molecular Response (CMR)." Blood 134, Supplement_1 (November 13, 2019): 287. http://dx.doi.org/10.1182/blood-2019-127516.

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Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p<0.001; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.20-0.64), and OS (p=0.001; HR 0.35; 95% CI, 0.19-0.66). In contrast, clonal evolution and transcript type were prognostic for shorter PFS (p=0.03; HR, 2.84; 95% CI, 1.41-5.69, and p=0.005; HR, 2.58; 95% CI, 1.33-4.98, respectively) and OS (p=0.01; HR 2.556; 95% CI, 1.21-5.37, and p=0.014; HR 2.45; 95% CI, 1.19-5.01, respectively). Additionally, older age was predictive for poor OS (p=0.03; HR, 1.02; 95% CI, 1.00-1.04). ASCT was not predictive for PFS nor OS. A 5-month landmark analysis was performed to assess the effect of ASCT on survival by 3-month MMR status. In pts who achieved 3-month MMR, 5-year PFS and OS rates were 60% and 58% (p=0.64) (Figure 2A) and 64% and 64% (p=0.73) (Figure 2B) in pts with and without ASCT, respectively. In contrast, among pts who did not achieve a 3-month MMR, there was a tendency for better PFS (5-PFS, 43% vs 21%; p=0.25) (Figure 2C) and OS (5-year OS, 43% vs. 26%; p=0.57) (Figure 2D) in favor of ASCT. Conclusions: The lack of achievement of MMR at 3 months predicted worse outcomes in Ph+ ALL. Higher survival rates were seen when ASCT was performed in pts who do not achieve 3-month MMR. Innovative targeted strategies aimed to eradicate minimal residual disease are needed to further improve long term outcomes. Disclosures Kantarjian: Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Cortes:Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:AstraZeneca: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; Eisai: Research Funding. Verstovsek:Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding. Daver:Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Immunogen: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding. O'Brien:Eisai: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

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Short, Nicholas J., Hagop M. Kantarjian, Farhad Ravandi, Xuelin Huang, Nitin Jain, Koji Sasaki, Rita Khouri, et al. "Updated Results of a Phase II Study of Reduced-Intensity Chemotherapy with Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 823. http://dx.doi.org/10.1182/blood-2019-125136.

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Abstract:

Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve survival in relapsed or refractory acute lymphoblastic leukemia (ALL) compared to conventional chemotherapy. The combination of INO with reduced-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL is safe and highly effective (Kantarjian H et al, Lancet Oncol 2018;19(2):240-8). The addition of blinatumomab to this regimen may further improve outcomes. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). Results: 64 pts have been treated, 5 of whom were in complete remission (CR) at enrollment. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-81 years); 27 pts (42%) were ≥70 years. 28% were positive for TP53 mutation, 19% were CRLF2 positive, and 27% had adverse-risk karyotype. 33/58 pts (57%) were CD20+ and received rituximab. Among 59 pts evaluable for morphologic response, 58 (98%) responded (CR, n=51; CRp, n=6; CRi, n=1). MRD negativity by 6-color flow cytometry was achieved in 48/62 pts (77%) after 1 cycle and 59/63 pts (94%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 63 pts who achieved remission, 9 (14%) relapsed, 3 (5%) underwent allogeneic SCT in first remission, 30 (48%) remain on treatment or have completed maintenance, and 21 (33%) died in CR/CRp. The rate of death in CR/CRp was higher in pts ≥70 years of age vs. 60-69 years (50% vs. 22%; P=0.02). Causes of death for pts in CR/CRp included: sepsis (n=7; all in pts 70 years and older), VOD (n=3), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1), MDS/AML (n=4; 3 in pts 70 years and older) and unknown causes (n=4). 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/64 (9%) with no difference in VOD in pts who did or did not receive blinatumomab. With a median follow-up of 37 months (range, 2-85 months), 34 pts (53%) were alive, 30 of whom (47%) were in CR and MRD negative status. The 3-year continuous remission and OS rates were 76% and 54%, respectively (Figure 1A). The 3-year continuous remission rate was 69% and 87% for pts age 60-69 and ≥70 years, respectively (P=0.25), and the 3-year OS rate was 63% and 42%, respectively (P=0.13; Figure 1B). The trend for worse survival in the pts ≥70 years was driven predominantly by the increased rate of death in CR/CRp in this older group. The outcomes of pts who did or did not receive blinatumomab were similar. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=77), mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS (54% vs 32%; P=0.007). Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 3-year OS rate of 54%. Further optimization of this regimen with less chemotherapy in patients 70 years and older is warranted to further decrease the rate of death in remission. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Daver:Otsuka: Consultancy; Astellas: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Pemmaraju:sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Konopleva:Ablynx: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Agios: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Merck: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Strategia Therapeutics: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. O'Brien:Astellas: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite: Research Funding; Aptose Biosciences, Inc: Consultancy; Acerta: Research Funding; Verastem: Consultancy; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy. Jabbour:AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. OffLabel Disclosure: The use of inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients with ALL

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Ramos Perez, Jorge M., Tapan M. Kadia, Guillermo Montalban-Bravo, Christopher B. Benton, Stefan Faderl, Koji Sasaki, Kiran Naqvi, et al. "Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Patients with Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)." Blood 134, Supplement_1 (November 13, 2019): 2642. http://dx.doi.org/10.1182/blood-2019-129137.

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INTRODUCTION: The outcome of patients (pts) with relapsed or refractory AML (R/R AML) or MDS after failing hypomethylating agents (HMA) is poor. CPX-351 is a liposomal formulation of cytarabine and daunorubicin, approved by the US Food and Drug Administration (FDA) for advanced secondary AML and AML post-MDS. GO is a humanized immunoglobulin G4 antibody directed against CD33 and conjugated to the DNA toxin calicheamicin, also approved by the FDA for the treatment of newly diagnosed or R/R CD33-positive AML. We have hypothesized that combination of CPX-351 and GO could induce superior antitumor efficacy compared to either agent alone for this pt population. GOALS: To determine the safety and efficacy of CPX-351 in combination with GO in R/R AML and post-HMA failure HR-MDS. METHODS: This is a single institution, pilot study (NCT03672539) enrolling pts with CD33 positive R/R AML, post-HMA failure High-Risk MDS (>10% blasts), and pts with newly diagnosed secondary AML after receiving HMA therapy. Pts received induction cycle CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) administered via intravenous (IV) infusion on days 1, 3 and 5. GO was administered at dose of 3 mg/m2 (always capped at one 4.5 mg vial) IV on day 1. Pts not attaining an IWG-defined complete remission (CR) or CR with incomplete count recovery (CRi) after 1 cycle, could receive a 2nd induction cycle of CPX-351 at the same dose, but only on days 1 and 3 with GO 3 mg/m2 on day 1. Pts attaining response could receive up to 2 consolidation cycles after a minimum of 4 weeks from the start of the last cycle with CPX-351 (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV on days 1 and 3, and GO at 3 mg/m2 on day 1. GO was only administered during the 2nd consolidation cycle if evidence of positive minimal residual disease (MRD). GO could also be administered as a single agent for maintenance treatment on day 1 every 6 weeks only in case of persistent detection of MRD. RESULTS: Twelve pts have been enrolled between November 2018 and July 2019. At the time of data cut off only 10 pts were evaluable for response. Two pts were still too early for assessment after receiving induction cycle. Pt characteristics are summarized on Table 1. Of 10 evaluable pts, 5 pts (50%) achieved an overall response of CR/CRi (4 CR, 1 CRi), including 2 pts with negative MRD at CR. Of note, one pt counted as a responder, had a bone marrow assessment (BMA) on day 21 with 1% blasts and flow cytometry not showing increased blasts but the sample was hypocellular. He was pancytopenic and suffering a grade 3 sinusitis suspicious for an invasive fungal infection. A repeated BMA on day 28 was aparticulate and insufficient for interpretation. Eventually his infection was controlled and his blood counts recovered on day 38 but he was transitioned to a lower intensity regimen given concerns of myelosuppression and infection reactivation. Another BMA upon peripheral blood counts recovery was not obtained. Among the other 4 responders, 1 pt relapsed after 2 consolidation cycles. One of 2 pts in CR with negative MRD was taken out of the study after 2 consolidations at treating physician discretion and the other one is under close protocol surveillance after completing 1 GO maintenance dose. Both are being considered for stem cell transplantation (SCT). The 4th pt is in CR with positive MRD and completed 4 GO maintenance doses. He is also being considered for SCT. Only 1 pt out of 5 not responding received 2 induction cycles and was refractory. Among responders, median time to ANC >0.5 x 109/L was 33 days (range 30-45) and Plt >50 x 109/L was 38 days (range 33-45). Median time to ANC >1 x 109/L was 34 days (range 31-45) and Plt >100 x 109/L was 43 days (range 38-53) after induction. With a median follow up of 6.1 months (mos) (Table 2), median OS has not been reached, and 6 mos OS is 79% (Figure 1). Median CR duration (CRD) has not been reached, with 75% CRD at 6 mos (Table 3, Figure 2). Adverse events regardless of causality are on Table 4. Three pts out of 12 (25%) have died, 2 of progressive disease and 1 of sepsis. Thirty-day mortality rate was 8% (n=1). CONCLUSION: In this preliminary report CPX-351 and GO combination appears to be active with acceptable toxicities in this high-risk disease population. Treatment-related, grade 3-4 non-hematological toxicity have not been observed. There are concerns for significant myelosuppression and infectious complications. Safety and efficacy assessments are ongoing. Therapy may require dose adjustments. Disclosures Kadia: Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Abbvie: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Incyte: Consultancy, Research Funding; Glycomimetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Servier: Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Otsuka: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Novartis: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; Agios: Consultancy. DiNardo:agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; daiichi sankyo: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Borthakur:Xbiotech USA: Research Funding; Eli Lilly and Co.: Research Funding; Polaris: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; NKarta: Consultancy; PTC Therapeutics: Consultancy; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; Incyte: Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics, Inc.: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Al Azzawi:Cyclacel LTD: Research Funding. Pemmaraju:sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding. Konopleva:Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; Calithera: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; CPRIT: Research Funding; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; AstaZeneca: Consultancy; Amgen: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Celgene: Consultancy; Eutropics: Equity Ownership. Kantarjian:BMS: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; Astex: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria.

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