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1
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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Nishimura, Jun-ichi, Antoine Soubret, Simon Buatois, Jean-Eric Charoin, Sasha Sreckovic, Christoph Bucher, Jules Hernández-Sánchez, et al. "An Optimized Crovalimab Dose and Regimen Reduced the Formation of Drug-Target-Drug Complexes in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Phase I/II COMPOSER Trial." Blood 136, Supplement 1 (November 5, 2020): 2–3. http://dx.doi.org/10.1182/blood-2020-136265.
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Introduction Crovalimab is a novel anti-complement component 5 (C5) monoclonal antibody engineered with the Sequential Monoclonal Antibody Recycling Technology (SMART-Ig; Fukuzawa et al, Sci Rep. 2017) to extend half-life and enable infrequent, subcutaneous (SC) self-administration in C5-mediated diseases. Crovalimab is being investigated as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a disease for which C5 inhibition is the standard of care. The Phase I/II COMPOSER trial (NCT03157635; Röth, et al. Blood. 2020) is a global, open-label, multicenter study of crovalimab consisting of 4 sequential parts. Parts 1, 2, and 3 assessed the pharmacokinetics (PK) and safety of crovalimab in healthy volunteers, C5 inhibitor-naive patients, and patients switched from eculizumab, respectively. Part 4 assessed an optimized crovalimab dose and regimen in naive and switched patients with PNH. Because eculizumab and crovalimab bind to different C5 epitopes, drug-target-drug complexes (DTDCs) consisting of eculizumab, C5, and crovalimab motifs can temporarily form in the circulation of patients who switch treatments. DTDCs can form in a range of sizes, from single crovalimab-C5-eculizumab motif to larger complexes with multiple motifs. Larger DTDCs are a concern because they take longer to clear and may be more likely to induce type III hypersensitivity reactions. Objectives Describe the impact of DTDC formation on the safety, PK, and pharmacodynamics of crovalimab in patients with PNH who switched from eculizumab to crovalimab and to describe the effect of crovalimab dose on DTDC size distribution and kinetics. Study Design and Methods Using data from COMPOSER Parts 1-3, a biochemical mathematical model was developed to investigate the kinetics of the formation and dissociation of DTDCs under the assumption that larger complexes are formed by the reversible binding of smaller complexes. The model was calibrated using concentration-time profiles of total C5, total crovalimab, and the concentration of eculizumab at the time of crovalimab initiation. DTDC size distributions were measured using size-exclusion chromatography coupled to enzyme-linked immunosorbent assay. Using model-based simulations, an optimized crovalimab dosing strategy was identified to reduce the formation of large DTDCs while maintaining serum concentration of crovalimab above the target level of ≈ 100 μg/mL. The optimized dose and regimen were a loading series of 1000 mg intravenously on day 1 and 340 mg SC on days 2, 8, 15, and 22, followed by maintenance dosing of 680 mg SC every 4 weeks starting on day 29. The loading dose series increased the total crovalimab dose received during the first month of treatment to reduce the formation of larger DTDCs, in line with the lattice theory of complex formation. This optimized dosing strategy was investigated in Part 4 patients who switched from eculizumab. Results In COMPOSER, 19 patients with PNH were enrolled in Part 3 and switched from eculizumab to crovalimab. DTDCs were observed in all patients from Part 3 (Figure; larger DTDCs are found in fractions 1-4 and smaller crovalimab-containing complexes, such as single motifs and single crovalimab molecules, are found in fractions 5 and 6). Two Part 3 patients experienced clinical manifestations compatible with type III hypersensitivity reactions that were ascribed to DTDCs. The DTDC size distribution in Part 4 patients, who received the optimized dosing strategy, evolved differently than in Part 3 patients, consistent with model predictions. In the switched patients from Part 4, large DTDC levels started to decrease on day 8 and continued to decrease, in contrast to Part 3, in which they started to decrease on day 15. On day 22, the mean percentage of the largest DTDCs was reduced by 56% in patients in Part 4 relative to patients in Part 3. Part 4 patients achieved and maintained serum crovalimab concentrations above ≈ 100 µg/mL throughout follow-up. Despite DTDCs being observed in all Part 4 patients who switched from eculizumab, no adverse events suggestive of a type III hypersensitivity reaction occurred. Conclusions The optimized crovalimab regimen resulted in lower concentrations of large DTDCs than in patients who received the Part 3 regimen and reduced the persistence of DTDCs in patients who switched treatment. This regimen is now being evaluated in the Phase III COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092) studies. Figure Disclosures Nishimura: F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Alexion: Honoraria, Research Funding; Chugai: Consultancy. Soubret:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Buatois:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Charoin:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Bucher:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; ANAVEON AG: Current Employment. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Jordan:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Genentech, Inc: Current Employment, Other: Received fellowship support from Genentech, Inc.. Arase:Osaka University: Current Employment; Chugai: Consultancy; Alexion: Research Funding; F. Hoffmann-La Roche. Ltd.: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Hotta:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Isaka:Osaka University: Current Employment; Chugai: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ito:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kanakura:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Chugai Pharmaceutical: Consultancy. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Kinoshita:Alexion: Honoraria; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Morii:F. Hoffmann-La Roche Ltd: Honoraria, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Chugai: Honoraria, Research Funding. Panse:Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: 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; Chugai: Speakers Bureau; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault De Latour:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: 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, Speakers Bureau; Amgen: Research Funding. Röth:Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Takamori:Alexion: Research Funding; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ueda:Chugai: Research Funding; Novartis: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Sanofi: Consultancy, Honoraria. Yoon:Kyowahako Kirin: Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Amgen: Consultancy, Honoraria. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland..
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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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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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Li, Chi-Chung, Brendan Bender, Shen Yin, Zao Li, Cindy Zhang, Genevive Hernandez, Antonia Kwan, et al. "Exposure-Response Analyses Indicate a Promising Benefit/Risk Profile of Mosunetuzumab in Relapsed and Refractory Non-Hodgkin Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 1285. http://dx.doi.org/10.1182/blood-2019-123961.
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Introduction: Mosunetuzumab (M; RG7828) 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). Clinical data from GO29781 (NCT02500407), a Phase I/Ib study in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts, indicate that M has promising efficacy and safety (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report the characterization of exposure-response (E-R) relationships for safety and efficacy to inform clinical dose/regimen finding. Methods: DATA: Data from Group A (0.05 to 2.8mg q3w dosing) and Group B (0.4/1/2.8 to 1/2/27mg Cycle 1 Day 1/8/15 step-up dosing, followed by q3w dosing) were analyzed. E-R for safety was assessed in 142 evaluable pts by dosing Group. E-R for efficacy was assessed in 130 evaluable pts by aggressive (a) (n=83, primarily DLBCL and transformed FL) and indolent (i) (n=47, primarily FL) NHL histologies. PHARMACOKINETIC (PK) ENDPOINTS: Pt-specific PK exposure metrics, including AUC and Cmax, were derived using a preliminary two-compartment population PK model with time-dependent clearance. Due to the presence of residual rituximab (R) at baseline from prior treatments, an additional exposure metric of average CD20 receptor occupancy (RO%) of M was derived based on the serum PK and binding affinity (KD) of both agents to assess the impact of target binding competition over time. E-R ANALYSES: Objective response rate (ORR), complete response rate (CRR), and adverse event (AE) rates, including cytokine release syndrome (CRS) and neurological AEs (NAE), were summarized by exposure-tertiles and the E-R relationships modeled by logistic regression (linear or Emax models). Response rates and E-R were further assessed in subgroups by RO% tertiles and baseline factors, such as the number of prior lines of therapy, refractory status, lactate dehydrogenase level, and tumor burden, and modeled by multivariate logistic regression. Results: R was present at modest levels at baseline in aNHL pts (median, 3 µg/ml, 33% of pts below quantitation limit [BQL] of 0.5µg/ml) but minimally in iNHL pts (median, <BQL). SAFETY: No statistically significant E-R relationships were found, although a visual trend of E-R for NAE was observed after fixed dosing, but not step-up dosing (Figure 1). EFFICACY: In aNHL pts, E-R analysis indicated that RO%, rather than Cmax or AUC, was strongly correlated with clinical response (Figure 2). The relevance of RO% was supported by strong correlations with pharmacodynamic biomarkers, such as T-cell activation and IFN-γ (Hernandez et al. ASH 2019). Pt baseline factors were balanced across RO% tertiles, except for time since last R dose, as expected per definition of RO%. Maximal clinical responses were achieved with greater RO%, reflected by the E-R plateau and described by an Emax logistic regression model. The observed ORR and CRR among pts in the top RO% tertile was 64% (18/28 pts) and 43% (12/28), respectively (Figure 2), denoting favorable therapeutic potential of M in R/R aNHL. The E-R relationship was statistically significant on top of evaluated baseline pt factors, reflected by positive E-R trends in all pt subgroups. Clinical responses were observed at 20mg even in the presence of high residual R levels (20-40µg/ml) in pts who had recently received R (within 3 months). Further dose escalation is expected to enhance efficacy by increasing the proportion of pts achieving sufficient target engagement. For iNHL pts, AUC correlated well with ORR and CRR, with no clinically meaningful interference from R due to the indolent nature of the disease. The observed ORR and CRR in pts in the top AUC tertile was 75% (12/26 pts) and 44% (7/16), respectively. M was active at dose levels (1.2-27 mg) that translated to a RO% of 0.2-10% (far below receptor saturation), consistent with its mechanism as an agonist of T-cell activation. Conclusions: E-R analyses indicate promising therapeutic benefit/risk of M in R/R NHL pts. Step-up dosing mitigated CRS-related toxicities, resulting in a broad therapeutic window of M that enables further dose escalation to maximize efficacy. The lack of E-R for safety was contrasted by a steep E-R for efficacy whereby higher M exposures overcome target binding competition in pts with residual R. Our analyses provide useful guidance for the dosing strategy of CD20-targeting T-cell bispecifics. Disclosures Li: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bender:Genentech, Inc.: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Li:Pro Unlimited - Genentech, Inc. contractor: Employment; F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Zhang:Genentech, Inc., SSF: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Sun:Harpoon Therapeutics: Employment, Equity Ownership; F. Hoffmann-La Roche Ltd / Genentech, Inc.: Employment. Adamkewicz:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Wang:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lim:Genentech, Inc.: Employment. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Sehn:Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Genentech, Inc.: Research Funding; MSD: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Li:Genentech, Inc. / F. Hoffmann-La Roche Ltd: Employment. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. OffLabel Disclosure: Mosunetuzumab (RG7828) 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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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.
Full textAbstract:
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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Grether, Uwe, and Julie Blaising. "MAGL inhibition: A novel treatment option for combating inflammatory disease?" Open Access Government 41, no. 1 (January 19, 2024): 48–49. http://dx.doi.org/10.56367/oag-041-11209.
Full textAbstract:
MAGL inhibition: A novel treatment option for combating inflammatory disease? Pharma researchers Uwe Grether and Julie Blaising from F. 48-La Roche Ltd. highlight the vast therapeutic potential of MAGL inhibition for central and peripheral diseases. The endocannabinoid system (ECS) is an important lipid signalling system that is highly conserved among vertebrates. It plays a key role in many human health and disease states.(1) Key components of the ECS are the endocannabinoids (eCBs), in particular 2-arachidonylglycerol (2-AG) and N-arachidonoylethanolamine (AEA). The eCBs bind to and activate the type-1 and type-2 cannabinoid receptors (CB1R and CB2R, respectively), which are highly important targets for treating multiple human diseases ranging from metabolic indications to neurodegenerative disorders.(2)
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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.
Full textAbstract:
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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Négrier, Claude, Johnny Mahlangu, Michaela Lehle, Pratima Chowdary, Olivier Catalani, Víctor Jiménez-Yuste, Benjamin M. Beckermann, et al. "Emicizumab Prophylaxis in Persons with Mild or Moderate Hemophilia A: Results from the Interim Analysis of the HAVEN 6 Study." Blood 138, Supplement 1 (November 5, 2021): 343. http://dx.doi.org/10.1182/blood-2021-146009.
Full textAbstract:
Abstract Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F)IX and FX, substituting for the function of missing activated FVIII in persons with hemophilia A (HA). The HAVEN 6 study (NCT04158648) aims to assess the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of emicizumab prophylaxis in persons with mild or moderate HA without FVIII inhibitors. Here we report the results of the interim analysis (IA). Methods: HAVEN 6 is a Phase III, multicenter, open-label study of emicizumab in persons with mild (FVIII level >5%-<40%) or moderate (FVIII level ≥1%-≤5%) HA without FVIII inhibitors, who warrant prophylaxis as assessed by the treating physician. Participants received loading doses of emicizumab 3 mg/kg once per week (QW) for 4 weeks, followed by maintenance doses of either 1.5 mg/kg QW, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety endpoints include adverse events (AEs), serious AEs (SAEs), and AEs of special interest, including thromboembolic events (TEs) and thrombotic microangiopathies (TMAs). Efficacy endpoints include negative binomial-regression model estimates of annualized bleed rate (ABR) for treated bleeds, all bleeds, and joint/target joint/spontaneous bleeds; change from baseline in Hemophilia Joint Health Score 2.1 (HJHS); health-related quality of life using the Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH); and treatment preference as measured by the Emicizumab Preference (EmiPref) questionnaire. PK, PD, and immunogenicity are evaluated. The IA was conducted after ≥50 participants with moderate HA completed ≥24 weeks on study or withdrew. Results: Of the 72 participants enrolled, 71 received emicizumab and were included in the analysis. Median (range) follow-up period was 27.5 (6.7-61.7) weeks. Participants (69 males; 2 females) had a median (range) age of 23.0 (2-71) years (Table 1). Twenty participants (28.2%) had mild and 51 (71.8%) moderate HA; 37 participants (52.1%) were on FVIII prophylaxis at baseline. Participants had a median (range) of 2.0 (0-60) bleeds in the 24 weeks prior to emicizumab prophylaxis; 24 participants (33.8%) had target joints at baseline. Forty-nine participants (69.0%) had ≥1 AE (Table 2); headache was the most common (14.1%). The majority of AEs (84.5%) were not emicizumab-related. Local injection-site reactions were reported for nine participants (12.7%); all were emicizumab-related. One participant (1.4%) experienced two Grade ≥3 AEs, neither emicizumab-related. Four participants (5.6%) reported a total of six SAEs; none were considered emicizumab-related by the investigator. There were no deaths, AEs leading to treatment withdrawal/modification/interruption, TEs, or TMAs. The model-based ABR (95% confidence interval [CI]) for treated bleeds was 0.8 (0.41-1.46; Table 3). ABR (95% CI) for all bleeds was 2.3 (1.63-3.10), for treated joint bleeds 0.3 (0.12-0.65), and for treated spontaneous bleeds 0.1 (0.02-0.23). Calculated median ABRs were zero for all bleed categories except 'all bleeds'. Zero bleeds were reported for 80.3% (treated bleeds), 46.5% (all bleeds), 90.1% (treated joint bleeds), 95.8% (treated spontaneous bleeds), and 94.4% (treated target joint bleeds) of participants. Two participants (2.8%) had anti-drug antibodies (ADAs), one of these had ADAs that were neutralizing in vitro; however, no clinical impact or impact on emicizumab PK was observed. Emicizumab trough concentrations were 10%-15% higher compared with HAVEN 1-4 (Callaghan, et al. Blood 2021). A mean (standard deviation) improvement in HJHS total score from baseline of -1.77 (2.94) was observed at Week 25 (n=47). The trend for improvement from baseline in the treatment burden domain for CATCH was consistent across age groups (8-17 and >18 years). Except for a small improvement in 'social activity risk perception' among adolescents, the remaining CATCH domains were stable. Improvements were observed in 'treatment burden' and 'preoccupation' domains among caregivers, but due to small sample number, trends should be interpreted with caution. Overall, 48/50 (96.0%) EmiPref respondents preferred emicizumab over their previous HA therapy. Conclusions: Data at the IA of the HAVEN 6 study indicate that emicizumab has a favorable safety profile and is efficacious in bleed prevention for persons with mild or moderate HA, which is in line with results from the HAVEN/STASEY studies. Figure 1 Figure 1. Disclosures Négrier: Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Mahlangu: Univeristy of the Witwatersrand: Current Employment; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Catalyst Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Spark: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Unique: Research Funding; Sanofi: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; WFH: Speakers Bureau; ISTH: Speakers Bureau; Springer: Speakers Bureau. Lehle: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chowdary: Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Freeline: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Chugai: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Sanofi: Honoraria; Spark: Honoraria. Catalani: F. Hoffmann-La Roche Ltd: Current Employment. Jiménez-Yuste: NovoNordisk: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding. Beckermann: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Schmitt: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company; Co-inventor: Patents & Royalties: Co-inventor of a patent relating to an anti-FIXa/FX bispecific antibody. Hermans: Cliniques Universitaires Saint-Luc: Current Employment; Bayer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Takeda: Research Funding. Ventriglia: F. Hoffmann-La Roche Ltd: Current Employment, Other: Holds stocks. Windyga: Alfasigma: Honoraria; Aspen: Honoraria; Bayer AG: Honoraria; Octapharma: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Swixx BioPharma: Honoraria; Werfen: Honoraria; Alnylam Pharmaceuticals: Research Funding; Sanofi/Genzyme: Honoraria, Research Funding; Alexion: Honoraria; Takeda: Honoraria, Research Funding; Shire: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; CSL Behring: Honoraria; Baxalta: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Rigel Pharmaceuticals: Research Funding. Kiialainen: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. d'Oiron: Shire/Takeda: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; LFB: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Biomarin: Honoraria, Research Funding; Sobi/Sanofi: Honoraria, Research Funding; Uniqure: Honoraria; Spark: Honoraria. Moorehead: Roche Canada: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Teodoro: F. Hoffmann-La Roche Ltd: Current Employment. Shapiro: Sangamo: Other: Advisory board fees, Research Funding; Prometric BioTherapeutics: Research Funding; Pfizer: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; OPKO: Research Funding; Octapharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Agios: Research Funding; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding. Oldenburg: University Clinic Bonn AöR: Current Employment; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen Idec: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy, Honoraria, Speakers Bureau; Biotest: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Freeline: Consultancy, Honoraria, Speakers Bureau; Grifols: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Sparks: Consultancy, Honoraria, Speakers Bureau; Swedish Orphan Biovitrum: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gesellschaft für Thrombose- und Hämostaseforschung e.V.: Membership on an entity's Board of Directors or advisory committees.
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Khair, Kate, Francis Nissen, Mariabeth Silkey, Tom Burke, Aijing Shang, Martynas Aizenas, Oliver Meier, Jamie O'Hara, and Declan Noone. "Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis." Blood 136, Supplement 1 (November 5, 2020): 43–45. http://dx.doi.org/10.1182/blood-2020-134658.
Full textAbstract:
Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey:Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone:Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.
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Caglayan, Caglar, Jesse Dixon, Anna Wall, Gilles A. Salles, Eva Hoster, Wolfgang Hiddemann, Michael Herold, et al. "A Multistate Survival Analysis for Patients with Follicular Lymphoma (FL) Using 13 First-Line Randomized Trials from FL Analysis of Surrogate Hypothesis (FLASH) Group." Blood 134, Supplement_1 (November 13, 2019): 2812. http://dx.doi.org/10.1182/blood-2019-122328.
Full textAbstract:
Introduction: Most patients with newly diagnosed FL treated with rituximab (R) alone or R + chemotherapy will experience prolonged progression-free survival and overall survival (OS), but it remains unclear what factors have the greatest influence on FL-associated and other causes of death in this patient population. We utilized individual patient data from 13 first-line randomized clinical trials from the FLASH database to perform a comprehensive multistate survival analysis to examine and quantify the relationships between clinical characteristics, treatment response, and early, intermediate, and late FL outcomes. Methods: The multistate survival analysis model defined states for "Alive after beginning Induction Treatment (TX)", "Alive after beginning Maintenance TX", "Death due to FL", and "Death from Other Causes" (Figure 1). We used the Aalen-Johansen estimator, a generalization of the Kaplan-Meier estimator, to calculate the likelihood of being in each model state and estimate the course of FL over time. Making no assumptions on the probability distributions and capable of coping with censored observations, the Aalen-Johansen estimator is a convenient and reliable nonparametric estimator for clinical data. Results: Among 7,465 FL patients with median age 56 (range 18-90) years, 49.2% were female; 28.7% Stage I-III, 71.3% Stage IV, and FLIPI was 0-1 (20.0%), 2 (36.8%), ≥ 3 (43.2%). Following initiation of induction treatment, 2-, 5- and 10-year death rates were 1.7%, 3.8%, and 5.8% due to FL, and 0.7%, 2.1%, and 4.8% from other causes (Figure 2). Death rates at 2, 5, and 10 years due to FL and other causes for subgroups based on clinical characteristics and treatment response are shown in Table 1. Notably, patients > 70 years and patients with FLIPI ≥ 3 had worse outcomes and patients achieving CR at 18, 24, and 30 months experienced improved outcomes. Conclusion: This is the largest study using data from randomized trials to quantify the impact of clinical factors on early, intermediate and late mortality by cause of death. We demonstrated that age > 70 years and FLIPI ≥ 3 were linked to increased FL-associated death and response to TX distinguished patients with favorable and poor outcomes. Future analyses should quantify the impact of predictors on the rate/time of FL outcomes in multivariable models. Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support. Hiddemann:Bayer: Research Funding; Gilead: Consultancy, Honoraria; Vector Therapeutics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Herold:Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Honoraria. Morschhauser:Servier: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Roche/Genentech: Consultancy; BMS: Honoraria; Celgene: Honoraria. Rummel:Roche Pharma AG: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Kimby:AbbVie,: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: educational lectures. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gyan:Pfizer: Honoraria. Ladetto:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Sandoz: Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Flowers:AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; V Foundation: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding; Bayer: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding; National Cancer Institute: Research Funding; Millenium/Takeda: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum: Consultancy;
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Hutchings, Martin, Fritz C. Offner, Francesc Bosch, Giuseppe Gritti, Carmelo Carlo-Stella, Harriet Walter, William Townsend, et al. "Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 16–17. http://dx.doi.org/10.1182/blood-2020-136571.
Full textAbstract:
Background: Up to 50% of patients suffering from Non-Hodgkin`s lymphoma (NHL) become refractory to or relapse after treatment (M. Crump, Blood 2017). With this, the lack of curative outcomes for patients with both indolent and aggressive NHL subtypes remains an unmet medical need. The CD20 CD3 T cell bispecific antibody glofitamab induces specific T-cell activation and has demonstrated significant single agent activity in r/r NHL patients (NP30179 study, M. Dickinson, EHA 2020, Abstract S241). RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti-tumor activity when combined with glofitamab in preclinical models (fig 1). RO7227166 is a bispecific antibody-like fusion protein composed of a split trimeric 4-1BB ligand, a tumor antigen-targeting moiety recognizing CD19, and a silent Fc part preventing Fc-mediated toxicity. 4-1BB is an inducible co-stimulatory molecule expressed by activated T-cells or NK cells. Through CD19-binding, the 4-1BB ligand moiety can deliver co-stimulatory signals to activated T- and NK-cell subsets in the tumor. The expected mode of action (MoA) for this molecule is to deliver a costimulatory signal 2 to enhance the effector function of tumor-infiltrating T cells or NK cells upon their activation (signal 1) by a T-cell bispecific antibody (e.g. glofitamab, RO7082859) or a tumor-targeted ADCC antibody (e.g. obinutuzumab). By delivering direct T-cell-target cell engagement followed by costimulatory activation the aim is to offer a highly active off-the-shelf immunotherapy combination. Methods: RO7227166 is being developed in combination with glofitamab and obinutuzumab in a phase I, open-label, dose-escalation study BP41072 (NCT04077723). The study is designed to evaluate the combination maximum tolerated dose (MTD), safety, tolerability, pharmacokinetic (PK), and/or pharmacodynamic (PD) profile of escalating doses of RO7227166, and to evaluate preliminary anti-tumor activity in participants with r/r NHL. The dose escalation stage is divided into Part I (combination with obinutuzumab) and Part II (combination with glofitamab) followed by an expansion stage (Part III). During Part I patients receive 1000mg obinutuzumab intravenously (IV) at a q3w schedule in combination with CD19 4-1BBL IV. During part II glofitamab is given in a q3w schedule with RO7227166 introduced at C2D8 and administered concomitantly from C3D1 onwards. A fixed dose of obinutuzumab (Gpt; pre-treatment) is administered seven days prior to the first administration of RO7227166 and seven days prior to the first administration of glofitamab (M. Bacac, Clin Cancer Res 2018; M. Dickinson, EHA 2020, Abstract S241). Patients will initially be recruited into part I of the study only using single-participant cohorts, where a rule-based dose-escalation is implemented, with dosing initiated at 5 μg (flat dose). As doses of RO7227166 increase, multiple participant cohorts will be recruited and dose-escalation will be guided by the mCRM-EWOC design for overdose control. Commencement of Part II including decision on the RO7227166 starting dose will be guided by safety and PK data from Part I. Patients with r/r NHL meeting standard organ function criteria and with adequate blood counts will be eligible. The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2. Disclosures Hutchings: Takeda: Honoraria; Takeda: Research Funding; Genmab: Honoraria; Roche: Honoraria; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sankyo: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sanofi: Research Funding. Bosch:Hoffmann-La Roche: Research Funding. Gritti:Italfarmaco: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria; Jannsen: Other: Travel Support; Autolus: Consultancy; IQVIA: Consultancy; Kite: Consultancy; Takeda: Honoraria; Amgen: Honoraria. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy. Townsend:Roche, Gilead: Consultancy, Honoraria. Morschhauser:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Janssen: Honoraria; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy. Cartron:Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Gilead: Honoraria. Ghesquieres:CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. de Guibert:Gilead Sciences: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Herter:Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Korfi:Roche Diagnostics GmbH: Consultancy. Craine:Roche: Current Employment. Mycroft:Roche: Current Employment. Whayman:Roche: Current Employment. Mueller:Roche: Current Employment. Dimier:Roche: Current Employment. Moore:Roche: Current Employment. Belli:Roche Pharma: Current Employment. Kornacker:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner:Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Dickinson:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Skinner, Mark W., Gillian Hanson, Tao Xu, Richard Ofori-Asenso, Richard H. Ko, Emily Cibelli, Francis Nissen, Michelle Witkop, Fabian Sanabria, and Amy D. Shapiro. "A Novel Methodology for Building Longitudinal, Patient-Centric Real World Datasets in Hemophilia A." Blood 138, Supplement 1 (November 5, 2021): 594. http://dx.doi.org/10.1182/blood-2021-146160.
Full textAbstract:
Abstract Background: There are limited real-world data (RWD) available on the unmet needs of people with mild or moderate hemophilia A (PwHA). This population accounts for 40-52% of all PwHA, including nearly all women with hemophilia A (HA), and is under-represented in scientific literature (Michele, et al. Haemophilia 2014; Benson, et al. Blood Transfus 2018; Peyvandi, et al. Haemophilia 2019). Available claims data from payer databases are confined to billing codes, and lack key information on outcomes and disease characterization (e.g. severity, treatment response.) (Tyree, et al. Am J Med Qual 2006). Registry datasets can require resource-intensive data entry and potentially miss key information about care received at outside facilities, at home, or after patients switch providers (Gliklich, et al. Registries for Evaluating Patient Outcomes: A User's Guide. 2014). To address these data gaps, we developed a novel, patient-centered approach to create a longitudinal healthcare database from individuals with mild and moderate HA in the United States. This study assessed the feasibility of this approach, which integrates medical record data collected during routine clinical care along with patient-reported outcomes (PROs) to provide needed insights into this under-represented population. Methods: Recruitment began in June 2020 via a broad strategy of social media outreach, healthcare provider partnerships, and patient advocacy groups. Eligibility was confined to mild or moderate PwHA, confirmed via physician report within provider notes in combination with baseline factor VIII levels (>5-50% mild, 1-5% moderate.) This study received research ethics board approval and abides by the guiding principles of the Declaration of Helsinki. PwHA enrolled via an online record management platform, PicnicHealth. After signing authorization forms for collection of their electronic health records (EHR) and informed consent to share their de-identified data for research, participants were prompted to enter information on their care providers. Records were gathered from all providers, across any facility, retrospectively as records were available. (Figure 1) All records obtained were made available to the participants via a medical timeline. Records were translated to text via optical character recognition with human review. Data elements from structured text as well as disease-specific elements from narrative text were captured using natural language processing and supervised machine learning. All elements, including visit metadata, conditions, measurements, drugs, and procedures were mapped to standardized medical ontologies and reviewed by a team of nurses. (Table 1) Quality control was assessed via inter-abstractor agreement on outputs with physician review. Patient-reported bleed, treatment, and pain data were collected via online questionnaire for a subset of PwHA, with participants prompted to enter data every 2 weeks. Abstracted EHR data was linked to PRO responses in a de-identified dataset. Cohort and abstraction characteristics were summarized descriptively. Results: From June 1, 2020 to June 30, 2021, 104 PwHA met eligibility criteria for enrollment (65 [62.5%] mild; 39 [37.5%] moderate). Participants saw providers across 34 states in the US, 22.1% (23/104) were female, and 20.6% (14/68) of those with known race/ethnicity status were from minority groups. Records were gathered from a median of six care sites and 16 providers per participant. A median of 50 (IQR [21-93]) clinical documents from 11 years were processed for each PwHA. (Table 2) Inter-abstractor agreement to assess abstraction quality averaged 95.9% for condition, 99.5% for drug name, and 95.4% for drug start date. As of June 2021, the average PRO response rate was 90.3% (150/166 of all requests) and continues prospectively. Conclusions: The patient-centric data collection methods implemented in this study provide a novel approach to build longitudinal real-world data sets. Technology-enabled data abstraction showed consistent high quality when processing the heterogeneous clinical records across disparate providers and care sites, and direct engagement with patients complements potential gaps in the clinical record. Additionally, this approach provides needed data on groups under-represented in RWD and traditional PwHA cohorts, including those with mild and moderate disease and women with HA. Figure 1 Figure 1. Disclosures Skinner: ICER: Membership on an entity's Board of Directors or advisory committees; Spark (DMC): Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Pfizer (DMC): Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; uniQure: Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Freeline: Research Funding; BioMarin: Honoraria, Research Funding; IPA Ltd.: Current holder of individual stocks in a privately-held company; National Hemophilia Foundation: Consultancy; Institute for Policy Advancement Ltd: Current Employment; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Xu: F. Hoffmann-La Roche AG: Current Employment. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Witkop: Roche Advisory Panel: Consultancy; National Hemophilia Foundation: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding.
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Castaman, Giancarlo, Jerzy Windyga, Hazza Alzahrani, Susan Robson, Fabian Sanabria, Monet Howard, and Víctor Jiménez-Yuste. "Surgical Experience from the Phase III STASEY Trial of Emicizumab Prophylaxis in Persons with Hemophilia A with FVIII Inhibitors: Final Analysis." Blood 138, Supplement 1 (November 5, 2021): 344. http://dx.doi.org/10.1182/blood-2021-145890.
Full textAbstract:
Abstract Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, replacing the function of missing activated FVIII in persons with hemophilia A (PwHA). The Phase IIIb, multicenter, single-arm STASEY study (NCT03191799) assessed the safety and efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors. Surgical experiences in STASEY are reported here. Methods: Following informed consent and ethics committee approval, PwHA aged ≥12 years with FVIII inhibitors received 3 mg/kg/week emicizumab for 4 weeks (loading dose), then 1.5 mg/kg/week for the remaining 2-year treatment period. Minor and major surgeries were managed per the investigators' discretion. The type and number of procedures performed, additional prophylaxis, and frequency and management of postoperative bleeds were analyzed. Surgeries occurring up to 28 days after the last dose of emicizumab were included, due to emicizumab's ~28-day half-life (Emicizumab Prescribing Information, United States Food and Drug Administration, 2017). Surgeries were documented using an electronic case report form by the treating physicians and classified as minor or major based on manual medical review (Santagostino, et al. Haemophilia, 2015). Bleed and prophylactic hemophilia medication data were recorded in the electronic Bleed Medication Questionnaire by participants. Case narratives were provided by trial investigators. Results: Overall, 46 patients reported ≥1 on-study surgery. Thirty-seven patients had 56 minor surgeries (central venous access device [CVAD], n=9; dental, n=20; joint, n=4; other, n=23) (Figure), one of which (skin laceration and suture insertion on Day 9) was performed during the loading phase. Twenty-four surgeries (42.9%) were managed with additional prophylactic medications (Table). Of these, 11/24 (45.8%) resulted in postoperative bleeds, of which 6/11 were treated (54.5%). Of surgeries managed without additional prophylactic medications, 15/32 (46.9%) resulted in postoperative bleeds, of which 5/15 (33.3%) were treated. A total of 13 patients had 22 major on-study surgeries (arthroplasty, n=13; other, n=9). 'Other' included hemorrhoid operations, coronarography, sigmoidectomy, colostomy, laparotomy and polypectomy. Eighteen (81.8%) major surgeries, including all arthroplasties, were managed with additional prophylactic medications (Table). Of these, 12/18 (66.7%) resulted in postoperative bleeds (including 10/13 arthroplasties), of which six (50.0%) were treated (all arthroplasties). Four (18.2%) major surgeries were managed without additional prophylactic medication, including three hemorrhoid operations in one patient, and a coronarography in a patient with acute myocardial infarction. One hemorrhoid operation resulted in a postoperative treated bleed. Major surgeries included a 55-year-old male with Grade 4 device dislocation of left knee prosthesis on Day 7, who was diagnosed with recurrent infection and prosthesis misalignment on Day 62. Amputation of the left leg above the knee was performed, with treatment including tranexamic acid and rFVIIa. A 61-year-old male with left knee prosthesis infection underwent left knee arthrodesis on Day 457, vacuum-assisted closure therapy on Day 495, skin grafting on Day 512, and left knee arthrodesis with skin flap placement on Day 527. Throughout these surgeries, the individual experienced recurrent joint bleeding and received rFVIIa. Neither of these individuals had a change in their study treatment due to these events. No thrombotic events (TEs) or thrombotic microangiopathies (TMAs) related to surgeries were observed. Conclusions: In the STASEY study of PwHA with FVIII inhibitors receiving emicizumab prophylaxis, most minor surgical procedures were performed without additional prophylactic coagulation factor and did not result in postoperative treated bleeds. Therefore, emicizumab alone provided adequate hemostatic coverage for some PwHA undergoing certain types of minor surgery, such as tooth extraction and CVAD removal. Major surgeries were safely performed with additional coagulation prophylaxis. Management of surgeries with rFVIIa did not result in TE or TMA. In case of bleeds, a bleed management plan should be in place. Effects of emicizumab on coagulation and assays may persist for up to 6 months after the last dose, which may be relevant when planning postoperative treatment. Figure 1 Figure 1. Disclosures Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Windyga: Swixx BioPharma: Honoraria; Octapharma: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Werfen: Honoraria; Bayer AG: Honoraria; Aspen: Honoraria; Alfasigma: Honoraria; Takeda: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Alnylam Pharmaceuticals: Research Funding; Sanofi/Genzyme: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Alexion: Honoraria; CSL Behring: Honoraria; Rigel Pharmaceuticals: Research Funding; Novo Nordisk: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. Alzahrani: Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; King Faisal Specialist Hospital and Research Centre: Current Employment. Robson: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.
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Witkop, Michelle, Tao Xu, Gillian Hanson, Richard Ofori-Asenso, Richard H. Ko, Emily Cibelli, Martynas Aizenas, Mark W. Skinner, Fabian Sanabria, and Amy D. Shapiro. "Characterizing Mild and Moderate Hemophilia A Patients in the Real World: A Patient-Centric Approach." Blood 138, Supplement 1 (November 5, 2021): 2107. http://dx.doi.org/10.1182/blood-2021-146543.
Full textAbstract:
Abstract Background: Persons with mild or moderate hemophilia A (HA) account for 40-52% of all persons with HA (PwHA) but are under-represented in scientific literature. To address this gap, we utilized a novel, patient-centric approach developed by PicnicHealth to create a longitudinal healthcare database from persons with mild or moderate HA in the United States (US). This study integrates data collected during routine clinical care from various providers and sites along with patient-reported outcomes (PROs) on an online record management platform to provide an in-depth characterization of patients' disease journey. Methods: PicnicHealth HA study recruitment commenced in June 2020. Eligible PwHA had a documented HA diagnosis. Severity status was confirmed based on physician-reported severity in provider notes or reported baseline factor (F)VIII level (>5-50% mild, 1-5% moderate); the lowest FVIII value was used if notes and baseline levels were inconsistent. Data elements from structured text (e.g. medication lists) as well as disease-specific elements from narrative text were captured from patients' electronic health records and linked to self-reported data. PROs were collected biweekly via an online questionnaire for a subset of PwHA. Ethics approval was obtained. Further details on the PicnicHealth platform will be reported separately. Quality control was assessed via inter-abstractor agreement on outputs with physician review. Descriptive analyses were performed to summarize cohort characteristics and demonstrate the breadth and completeness of the data. Cohort characteristics were compared with mild and moderate PwHA data from the Center for Disease Control and Prevention (CDC) Community Counts, a public health monitoring program for people with bleeding disorders. Results: As of June 2021, 143 PwHA had signed up to the study, of whom 104 (65 [62.5%] with mild HA; 39 [37.5%] with moderate HA) met the eligibility criteria for enrollment. PwHA were recruited from 32 US states. Among those enrolled, 22.1% (23/104) were female. Median age at enrollment was 29 years (interquartile range [IQR]: 22-42). Age at diagnosis was available for 55 (52.9%) PwHA; the median was 3 years (IQR 0-12). Notably, males were diagnosed at a younger age (2 [0-10] years) than females (18 [5-35] years). Among PwHA aged ≥20 years (n=83), 59 had valid body mass index (BMI) measures, of whom 44 were obese (n=28, 47.4%) or overweight (n=16, 27.1%). These cohort characteristics were generally in line with those reported by the CDC's Community Counts, e.g. by age, BMI and ethnicity distributions, except for the higher proportion of female PwHA recruited in the present study (Table). Medical records were available over a median (IQR) of 6.3 (3.7-11.1) years from 16 (8-28) healthcare providers of six (3-10) care sites for the cohort before the enrollment dates (Table). In total, data were collected from 588 care sites and 1963 providers, including 234 hematology and 1729 non-hematology providers, with specialties including radiology, family medicine, pediatrics, and orthopedics. In the year before enrollment, 83 PwHA had outpatient visits, with a median of three visits for the cohort; 20 PwHA had inpatient admissions (Table). Inpatient admission and outpatient visit frequencies in the year before enrollment were lowest in the 20-44 years age group (median [IQR] 1 [1-3]) (Figure). PROs were collected prospectively via biweekly requests in 25 PwHA starting from Feb 25, 2021 with the latest data collected in June 2021. On average, the response rate was 90.3% (150/166 requests). Of the 25, 10 (40.0%) responded to all questions at the expected time, nine (36.0%) missed one response, and six (24.0%) had more than one response missing. Conclusions: The patient-centric data collection methods implemented in this study provide a new approach to building cohorts for observational studies for PwHA. PicnicHealth combines routine clinical care data and PROs, and preliminary results suggest validity when compared with an existing data set. Participants have access to all records collected, organized in a medical timeline and shareable with care providers, potentially alleviating the burden of care coordination for the patient. The result is a patient-centric approach to data that benefits participants while providing needed data on groups traditionally under-represented in real-word evidence and traditional PwHA cohorts. Figure 1 Figure 1. Disclosures Witkop: National Hemophilia Foundation: Current Employment; Roche Advisory Panel: Consultancy. Xu: F. Hoffmann-La Roche AG: Current Employment. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Aizenas: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Skinner: Institute for Policy Advancement Ltd: Current Employment; National Hemophilia Foundation: Consultancy; IPA Ltd.: Current holder of individual stocks in a privately-held company; BioMarin: Honoraria, Research Funding; Freeline: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Takeda: Honoraria, Research Funding; uniQure: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer (DMC): Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Sanofi: Honoraria; Spark (DMC): Honoraria; ICER: Membership on an entity's Board of Directors or advisory committees; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Pfizer: Research Funding; OPKO: Research Funding; Octapharma: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Takeda: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Prometric BioTherapeutics: Research Funding; Agios: Research Funding.
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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.
Full textAbstract:
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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Jiráčková, Jana, Radomir Hyšpler, Sumaya Alkanderi, Ladislava Pavlíková, Vladimir Palicka, and John A. Sayer. "Novel CYP24A1 Mutation in a Young Male Patient with Nephrolithiasis: Case Report." Kidney and Blood Pressure Research 44, no. 4 (2019): 870–77. http://dx.doi.org/10.1159/000500922.
Full textAbstract:
Background/Aims: The CYP24A1 gene encodes the vitamin D 24-hydroxylase enzyme, which hydroxylates active forms of vitamin D into inactive forms. Biallelic mutations in the CYP24A1 gene can lead to elevated levels of active vitamin D metabolites and, consequently, to hypercalcemia, hypercalciuria, nephrocalcinosis, and nephrolithiasis; however, monoallelic mutations have been associated only with milder phenotypes. In the present manuscript, we report the case of a young male patient who presented hypercalcemia and nephrolithiasis, suppressed parathormone, and elevated 1,25 dihydroxy vitamin D levels. Methods: Biochemical analyses were performed on Cobas 8000, F. Hoffmann-La Roche AG, Basel, Switzerland. The proband was initially evaluated for occult malignancies by body imaging, serum electrophoresis, and tumor markers, which did not reveal any pathology. DNA samples of the proband and his sibling were then examined using Sanger sequencing. Results: Genetic analysis revealed 2 compound heterozygous CYP24A1 mutations (p.L148P and p.R223*). The novel nonsense CYP24A1 mutation, p.R223*, was also found heterozygously in other family members with a medical history of nephrolithiasis. Conclusions: The identification of this gene mutation causing hypercalcemia, hypercalciuria, and renal stones allows the specific management of endogenous vitamin D production.
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Jurinovic, Vindi, Verena Passerini, Mikkel Z. Oestergaard, Andrea Knapp, Kirsten Mundt, Shamzah Araf, Julia Richter, et al. "Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma Treated within the Gallium Trial: EZH2 mutation Status May be a Predictive Marker for Differential Efficacy of Chemotherapy." Blood 134, Supplement_1 (November 13, 2019): 122. http://dx.doi.org/10.1182/blood-2019-130208.
Full textAbstract:
Introduction : We have previously shown that a clinicogenetic risk model called the m7- Follicular Lymphoma (FL) International Prognostic Index (m7-FLIPI), which includes the mutation status of 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FLIPI, and the ECOG performance status improves risk stratification in patients with advanced stage FL receiving frontline immunochemotherapy (Pastore, 2015). The m7-FLIPI was trained on a group of patients treated with R-CHOP and validated on an independent cohort treated with R-CVP. The aim of this study was to test the prognostic utility of the m7-FLIPI in patients treated within the GALLIUM trial. The GALLIUM trial enrolled 1202 patients with FL randomized to either receive Rituximab (R)- or Obinutuzumab (GA101, G)-based frontline treatment (Marcus, 2017). The chemotherapy consisted either of CHOP, CVP or Bendamustine and was allocated by the treating study center. All patients had previously untreated FL, advanced stage disease (stage III/IV or stage II with bulky disease) and ECOG performance status 0-2. All patients required treatment according to the GELF criteria. Methods: We performed targeted DNA sequencing of recurrently mutated genes, including the m7-FLIPI genes from diagnostic FL biopsies. We excluded cases with no available biopsies, insufficient DNA quantity/quality, or if patients did not sign informed consent for molecular studies. 418 patients were available for evaluation of the m7-FLIPI. The m7-FLIPI was calculated as previously described (http://www.glsg.de/m7-flipi/). Investigator-assessed progression-free survival (PFS), the primary endpoint in the GALLIUM trial, was the primary endpoint of this analysis. We performed Kaplan-Meier estimation and Cox proportional hazards regression to test the prognostic utility of the m7-FLIPI. The median follow up in the evaluable cohort was 4.7 years. 283 patients (68%) received Bendamustine (140 R, 143 G), 111 (27%) received CHOP (52 R, 59 G), and 24 (6%) received CVP (12 R, 12 G). Results : 104 patients (25%) had high-risk m7-FLIPI. 90 out of 194 patients with high-risk FLIPI (46%) were reclassified as low-risk by the m7-FLIPI. High-risk m7-FLIPI was associated with shorter PFS in the overall cohort (HR 1.52, P=0.030). Likewise, the m7-FLIPI was prognostic in patients treated with R-based regimens (HR 1.67, P=0.037). However, it was not prognostic in patients treated with G-based regimens (HR 1.24, P=0.49). When analyzed by different chemotherapy regimens, the m7-FLIPI was prognostic in patients receiving CHOP/CVP-based treatment (HR 2.05, P=0.013), validating the results from our original publication. The m7-FLIPI outperformed the FLIPI (HR 1.34, P=0.31) and had a significantly higher C-index (m7-FLIPI C=0.69, FLIPI C=0.57, P=0.021). However, the m7-FLIPI was not prognostic in patients receiving Bendamustine-based treatment (HR 1.23, P=0.42). Within the m7-FLIPI, mutations in EZH2 have the highest weight of all gene mutations. In this study, we found EZH2 mutations in 93 cases (22%). EZH2 mutations were associated with longer PFS (HR 0.25, P=0.0036) in CHOP/CVP-treated patients, but not in Bendamustine-treated patients (HR 1.11, P=0.71). Interaction analysis between the chemotherapy regimen and EZH2 mutation status showed a significant interaction term of 1.49 (P=0.011) for EZH2 mutations and Bendamustine. This increased the previously favorable HR in EZH2 unmutated patients (HR 0.55 for Bendamustine vs CHOP/CVP) to an unfavorable HR of 2.42 in EZH2 mutated patients. Overall, patients with EZH2 mutant FL appeared to benefit more from CHOP/CVP, whereas patients without EZH2 mutations had longer PFS with Bendamustine-based regimens, regardless whether chemotherapy was combined with R or G (see Figure). Conclusions: Here, we validated the prognostic utility of the m7-FLIPI for patients treated with R-CHOP/CVP. However, the m7-FLIPI was not prognostic in patients treated with Bendamustine-based regimens. While EZH2 mutation status was associated with longer PFS in patients receiving CHOP/CVP regimens (with either R or G), it did not impact treatment outcome of patients treated with Bendamustine, suggesting that EZH2 mutation status is a predictive marker for differential efficacy of the chemotherapy regimen. If confirmed, the EZH2 mutation status might be a highly useful biomarker to guide the selection of the preferred upfront chemotherapy. Figure Disclosures Oestergaard: F. Hoffmann-La Roche: Employment. Knapp:F. Hoffmann-La Roche Ltd: Employment. Mundt:F. Hoffmann-La Roche: Employment. Fitzgibbon:Gilead: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Marcus:Roche / Genentech: Honoraria, Speakers Bureau; Gilead: Consultancy. Davies:Karyopharma: 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; Bayer: Research Funding; Acerta Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; GSK: Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Celgene: 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, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding. Herold:Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Honoraria. Hiddemann:F. Hoffmann-La Roche: Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Roche Pharma AG: Other: Travel support; Janssen: Research Funding. Weigert:Novartis: Research Funding; F. Hoffmann-La Roche: Research Funding.
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Duncan, Ian, Natalie Danziger, Daniel Duncan, Amanda Hemmerich, Claire Edgerly, Richard Huang, Jo-Anne Vergilio, et al. "Acid-Based Decalcification Methods Compromise Genomic Profiling from DNA and RNA." Blood 134, Supplement_1 (November 13, 2019): 4659. http://dx.doi.org/10.1182/blood-2019-131362.
Full textAbstract:
BACKGROUND: Comprehensive genomic profiling (CGP) performed by next-generation sequencing of DNA detects genomic alterations including point mutations, insertions/deletions, copy number variations, and select gene rearrangements. When RNA sequencing is included in CGP, it allows for expanded detection of gene fusions, which are common in hematologic malignancies and sarcomas. When such tumors involve bone, a decalcification step is frequently employed to soften tissues prior to processing and sectioning. While commonly used acid-based decalcification methods work quickly, the resulting nucleic acid damage can be profound. In this study, we examine the effects of decalcification on DNA and RNA sequencing in the clinical setting. DESIGN: 1711 consecutive formalin-fixed paraffin embedded samples were evaluated by CGP during routine clinical care via DNA and RNA sequencing, using a hybrid-capture next-generation sequencing assay (FoundationOne®Heme). Specimen site [e.g. bone/ bone marrow or soft tissue] and decalcification status were extracted from pathology reports and H&E review. Samples were considered decalcified if reported as such in the pathology report or if visible decalcified bone was present on the H&E. Samples documented to be processed with fixatives other than formalin were excluded. Sequencing failures were defined as samples that failed DNA extraction (DNAx), RNA extraction (RNAx), or library construction (LC) due to insufficient nucleic acid to advance into sequencing. Samples were only evaluated for RNA if DNAx was successful (1594 cases). RESULTS: Specimen site was a strong predictor of sequencing failure, with a significant increase in failure rate from bone/bone marrow samples (n=619) compared to samples from soft tissue sites (n=1092) for both DNA (13.4% vs 4.6%, p=4.7E-9) and RNA (42.5% vs 13.5%, p<2.2E-16). Of the bone/bone marrow samples, 237 of 619 samples were decalcified. Decalcification was associated with significantly higher failure rates than non-decalcified samples for both DNA (29.1% vs 3.7%) and RNA (67.4% vs 30.8%) (Table 2). One method of avoiding decalcification for bone marrow samples is utilization of clot preparations, where aspirates are processed as an FFPE block. Clot preparations fail sequencing significantly less often than decalcified core biopsies (DNA: 3.3% vs 18.8%, p=9.2E-06; RNA: 39.2% vs 70.4%, p=2.5E-03) (Table 3). CONCLUSIONS: CGP of samples acquired from bone and bone marrow sites is challenging, with a lower success rate for DNA and RNA sequencing than soft tissue sites. The higher overall failure rate correlates with use of decalcification agents leading to degradation of nucleic acids and impacts RNA sequencing significantly more than DNA (67.4% vs 30.8% failed). Clot preparations of bone marrow samples performed better than core biopsies for both DNA and RNA. The higher overall RNA sequencing failure rates still observed in in non-decalcified bone/bone marrow are predominantly due to RNA failure of non-decalcified clot preparations. These samples likely have increased failure rates secondary the use of non-standard fixatives (e.g. B+, Bouin's, AZF, etc.) not documented in the pathology report and the frequency of hypocellular clot preparations in conjunction with higher requirements for RNA yield compared to DNA yield. To increase CGP success rates, decalcification should be avoided when possible. Peripheral blood and bone marrow aspirate samples rarely fail sequencing (<1%, data not shown) and are preferable to decalcified samples if adequate tumor is present. Bone marrow clot preparations perform better than bone marrow core biopsies and clot preparations should be fixed with 10% neutral buffered formalin. If decalcification is required for processing, EDTA based decalcification methods and/or minimizing decalcification times is recommended. Disclosures Duncan: Foundation Medicine, Inc.: Employment. Danziger:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Duncan:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Hemmerich:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Edgerly:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc: Employment. Huang:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Vergilio:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Elvin:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. He:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Britt:Foundation Medicine, Inc: Employment. Reddy:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc: Employment. Sathyan:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Alexander:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Ross:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Brown:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Ramkissoon:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Severson:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment.
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Massoth, Lucas R., Yin P. Hung, Judith A. Ferry, Robert P. Hasserjian, Abner Louissaint, Meagan Montesion, Ethan S. Sokol, et al. "Comprehensive Genomic Profiling of 104 Rare Histiocytic and Dendritic Cell Neoplasms Reveals Shared and Distinct Targetable Genomic Alterations." Blood 134, Supplement_1 (November 13, 2019): 2541. http://dx.doi.org/10.1182/blood-2019-123729.
Full textAbstract:
Introduction: Histiocytic and dendritic neoplasms are a diverse group of uncommon hematologic tumors arising from monocytic or dendritic cell lineage. While genomic profiles for the more common entities Langerhans cell histiocytosis and Erdheim-Chester disease are established, less common neoplasms in this broad category are poorly characterized. In the current study, we assessed the genomic landscape of these often aggressive histiocytic and dendritic cell neoplasms to identify distinct mutational signatures for each subtype in the current WHO classification system. Methods: 104 histiocytic and dendritic cell neoplasmswere tested during routine clinical care by hybridization capture of 406 cancer-related genes to detect base substitutions, small indels, amplifications (amp), deletions, and rearrangements. Tumor mutational burden (TMB, mutations/Mb) was determined on ~1.1 Mbp of sequenced DNA. Review of pathology reports, histopathology, and patient clinical data was performed. Cases included 48 follicular dendritic cell sarcoma (FDCS), 37 histiocytic sarcoma (HS), 8 interdigitating dendritic cell sarcoma (IDCS), 5 Langerhans cell sarcoma (LCS), 4 indeterminate cell histiocytosis (ICH), 1 fibroblastic reticular cell tumor (FRCT), and 1 inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma (FDC/FRCS). Results: Pathogenic or likely-pathogenic genomic alterations (GAs) in the four most common sarcoma subgroups are summarized in the Table. CDKN2A and TP53 pathogenic mutations were the most frequent GAs observed in the cohort, present in 27% and 20% of the cases, respectively. Compared to the rest of the cohort, FDCS showed significantly more cases harboring a pathogenic GA in genes involved with NFkB pathway regulation (58% vs. 18%, p<0.0001). Other relevant alterations in FDCS included NTRK1 (2 cases; 1 NTRK1-PDIA3 fusion and 1 amp), NTRK3 (1 case), FGFR3 (1 amp), STAT3 (3 cases) and PTEN (3 cases). Compared to the rest of the cohort, HS showed significantly more cases with pathogenic GAs in the MAPK pathway (59% vs. 19%, p<0.0001), including 3 cases with BRAF fusions. Other relevant alterations in HS included PTEN (3 cases), PDGFRA (2 amp), MET (2 amp), 2 IGH-BCL2 fusions, and 1 IGH-BCL6 fusion. IDCS cases showed pathogenic MAPK GAs in 88% (7/8), and TET2 mutations were identified in 50% (4/8). A single NTRK1-TPR fusion was identified. LCS cases demonstrated GAs in both MAPK and NFkB pathways (4/5 and 3/5 cases, respectively). 2/4 cases of ICH demonstrated NCOA2-ETV3 fusions; TET2 mutations were present in the remaining two cases. The FRCT case contained an NRAS GA, and the FDC/FRCS cases had EBV (HHV-4) sequence reads. Conclusions: Our findings provide a comprehensive view of the shared and distinct genomic features among these rare histiocytic and dendritic cell neoplasms. The frequent inactivation of CDKN2A, which normally encodes an endogenous CDK inhibitor, suggests possible effectiveness of pharmacologic CDK4/6 inhibitors in treatment of this subset of cases. There are significant differences in the molecular profiles of different diseases: 58% of FDCS cases contain at least one pathogenic alteration in the NFkB pathway, while 59% and 88% of HS and IDCS cases contain potentially-actionable MAPK pathway mutations, respectively. LCS cases show frequent mutations in both pathways. Potentially-actionable molecular alterations are identified in 63/104 (61%) histiocytic and dendritic tumors in our cohort. These results illustrate the importance of performing comprehensive genomic profiling to define treatment strategies, including clinical trial "molecular eligibility" and more fully inform personalized therapeutic options. Disclosures Hasserjian: Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Montesion:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Sokol:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Pavlick:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Shah:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Danziger:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Killian:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Severson:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Duncan:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Elvin:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Miller:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Ross:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Vergilio:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Williams:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership.
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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.
Full textAbstract:
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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Sostelly, Alexandre, Simon Buatois, Antoine Soubret, Erica Winter, Barbara Klughammer, Joy C. Hsu, Gregor Jordan, et al. "Exposure-Response Relationship of the SMART-Ig Anti-hC5 Antibody Crovalimab (SKY59): Results from the Umbrella Phase 1/2 Composer Trial in Healthy Volunteers and PNH Patients." Blood 134, Supplement_1 (November 13, 2019): 3745. http://dx.doi.org/10.1182/blood-2019-124258.
Full textAbstract:
Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. We aimed at characterizing the exposure-response relationship of crovalimab used to define the minimum concentration of crovalimab achieving complete terminal inhibition. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1): Part 1: 15 healthy subjects were enrolled. 3 received 75 mg RO7112689 IV, 3 received 125 mg RO7112689 IV, 3 received 100 mg RO7112689 SC, and 6 received placeboPart 2: 10 treatment-naïve PNH patients were enrolled in Part 2 to receive increasing IV doses of 375mg, 500mg, and 1000mg on days 1, 8 and 22, respectively, followed by weekly doses of 170mg SC starting on day 36Part 3: 19 eculizumab pre-treated PNH patients were enrolled in Part 3 to receive 1000mg IV before randomization into 3 different arms: Arm A: 680mg SC Q4W (N=7)Arm B: 340mg SC Q2W (N=6)Arm C: 170mg SC QW (N=6) SC dosing was initiated on day 8 after the IV dose in all the dosing groups. Part 4: 5 eculizumab pre-treated PNH patients and 5 treatment-naïve PNH patients are planned to be enrolled to receive IV dose of 1000mg on Day 1 followed by SC dose of 340mg on Day 2, Day 8, Day 15, Day 22 followed by SC dose of 680mg given Q4W from Day 29 Crovalimab concentrations and free C5 were measured using a validated ELISA. A population PK model was developed using all the available data to describe the crovalimab concentration-time profiles. Crovalimab PD was assessed by evaluating the extent and duration of terminal complement inhibition, quantified using a validated, functional ex vivo liposome immunoassay (LIA) (http://www.wakodiagnostics.com/r_ch50.html). Relationships between crovalimab PK and PD were analyzed using graphical analysis. The PK was best described by a two-compartment open model with first-order elimination and absorption. To describe the PK in eculizumab pre-treated patients, elimination of crovalimab was modeled as a combination of the first-order elimination used for naïve patients and a faster clearance which decreases exponentially over time. Body weight was introduced using allometry on the clearance and volume of the distribution. After SC administration, bioavailability is estimated at 100% and terminal half-life around 30 days. In all PNH patients, complete complement inhibition (defined as LIA <10 U/ml, the LLOQ of the assay) was achieved immediately after end of infusion following the initial dose and maintained across the different dosing intervals investigated in the majority of the patients (Figure 2). Complete inhibition of free C5 (defined as free C5 <0.05μg/mL) was also achieved after end of infusion and maintained throughout the dosing intervals reflecting the LIA profiles. By pooling all the PK and PD data from the 3 parts of the COMPOSER study, crovalimab was shown to induce a concentration-dependent inhibition of serum hemolytic activity and of free C5 which closely correlates with terminal complement inhibition. Collectively, these data indicate that approximately 100μg/mL of crovalimab are required to achieve complement inhibition (Figure 3). At the target concentration of crovalimab between 80-100ug/mL, patients achieve complete terminal complement inhibition. Data collected in the ongoing Part 4 of COMPOSER will be used to confirm the target concentration of crovalimab. Exposure-response characterization demonstrated the potential of crovalimab as an infrequent, subcutaneous therapy for PNH. Disclosures Sostelly: F. Hoffmann-La Roche: Employment. Buatois:F. Hoffmann-La Roche: Employment. Soubret:F. Hoffmann-La Roche: Employment, Equity Ownership. Klughammer:F. Hoffmann-La Roche Ag: Employment, Equity Ownership. Hsu:Roche/Genentech: Employment, Equity Ownership. Jordan:Roche Diagnostics GmbH: Employment; F. Hoffmann-La Roche: Equity Ownership. Bucher:F. Hoffmann-La Roche: Employment. Charoin:F. Hoffmann-La Roche: Employment. Gotanda:Chugai Pharmaceutical Co., Ltd.: Employment. Shinomiya:Chugai Pharmaceutical Co., Ltd.: Employment, Patents & Royalties: (WO2018143266) A PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OR PREVENTION OF A C5-RELATED DISEASE AND A METHOD FOR TREATING OR PREVENTING A C5-RELATED DISEASE. Nagy:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Panse:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Yoon:Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Yuhan Pharma: Research Funding; Janssen: Consultancy. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Röth:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, 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, Research Funding; Bioverativ: Consultancy, Honoraria.
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Severson, Eric A., Ethan S. Sokol, Russell Madison, Daniel Duncan, Amanda Hemmerich, Claire Edgerly, Richard Huang, et al. "Loss of Heterozygosity of FLT3-ITD Is Common in Acute Myeloid Leukemia and May be a More Consistent Prognostic Marker Than FLT3-ITD Allele Frequency." Blood 134, Supplement_1 (November 13, 2019): 1437. http://dx.doi.org/10.1182/blood-2019-131248.
Full textAbstract:
BACKGROUND: FLT3 alterations in Acute Myeloid Leukemia (AML) occur as either point mutations in the tyrosine kinase domain (TKD) or internal tandem duplications (ITD), both of which result in constitutive activation of FLT3; however, only FLT3-ITD has prognostic value. Per NCCN guidelines, when NPM and FLT3-ITD alterations co-occur, an allele frequency ≥ 0.5 for FLT3-ITD (FLT3-ITDhigh) confers an intermediate prognosis, while allele frequencies < 0.5 (FLT3-ITDlow) confers a favorable prognosis. For allele frequency to be ≥ 0.5, loss of heterozygosity (LOH) or copy number gains at the FLT3 locus are required. In this study, we examined a large cohort of FLT3 mutated AML samples to study LOH at the FLT3 locus. DESIGN: During routine clinical care, 2129 AML samples were evaluated by comprehensive genomic profiling (CGP) for 406 genes via DNAseq for all classes of genomic alterations and 265 genes via RNAseq for rearrangements, using a hybrid-capture next generation sequencing assay (FoundationOne®Heme). Of these samples, 1379 met analytic specifications required for LOH analysis. LOH analysis was performed by first generating copy number models from exon and SNP log ratio and minor allele fractions (maf). LOH was then determined using the modeled copy number, maf, and tumor purity. Samples with low aneuploidy were reviewed manually. RESULTS: The median age of the overall cohort was 60 y (range <1y-88y) with 43.4% females and 56.6% males. Of 1379 samples, 265 (19%) had at least one functional alteration in FLT3. There were 171 (12.4%) samples with FLT3-ITD alteration(s), 115 (8.3%) samples with FLT3 TKD alteration(s), and 21 (1.5%) samples with both FLT3-ITD and TKD alterations. LOH analysis was performed for 236 AML samples with a FLT3 alteration and 224 randomly selected wild-type FLT3 AML samples as controls. Samples with a FLT3 alteration had a significantly higher rate of LOH compared to the control samples (34/236 (14.4%) versus 2/224 (0.9%), p = 9.0x10-9). Samples with a FLT3-ITD were under significantly greater LOH than samples with a point mutation (33/171 (19.3%) versus 4/115 (3.5%), p = 2.8x10-5). Samples with only a point mutation rarely had LOH (1/94, 1.0%), not significantly different than FLT3 wild-type controls. Copy number analysis revealed that FLT3-altered samples had a rate of FLT3 copy number gains not significantly different than control samples (10/236 (4.2%) versus 7/224 (3.1%)). The allele frequency was significantly higher for FLT3-ITD alterations compared to FLT3-TKD alterations (median 0.11 versus 0.24, p < 0.001), and FLT3-ITD alterations under LOH had a higher allele frequency than those not under LOH (median 0.35 versus 0.24, p< 0.01). Only 1/115 FLT3-TKD alterations had an allele frequency > 0.5 versus 7/171 of the FLT3-ITD alterations. Five (of 7) FLT3-ITDhigh samples were under LOH and the remaining 2 samples had FLT3 copy number gains. FLT3-ITD mutated AML has co-occurring genomic alterations of clinical significance; however, with this sample size there were no statistically significant differences in the frequencies between samples with and without LOH at the FLT3 locus (NPM1: 64% vs 43%, DNMT3A: 48% vs 37%, WT1: 36% vs 25%, RUNX1: 12% vs 17%, NRAS: 3% vs 16%). CONCLUSIONS: In AML, the FLT3 locus has increased LOH when a FLT3-ITD is present, compared to FLT3 wild-type controls and samples with FLT3-TKD alterations. Copy number alterations in FLT3 are not different in FLT3-altered vs FLT3 wild type AML. Allele frequencies were higher for FLT3-ITDs compared to FLT3-TKDs and were highest for FLT3-ITDs under LOH. An emerging negative prognostic indicator in AML is FLT3-ITDhigh. Determination of FLT3-ITDhigh status requires high tumor purity, copy number gains, and/or LOH. The requirement of high tumor purity makes FLT3-ITDhigh status dependent on factors other than tumor biology, such as tumor sampling. In our dataset, 33 (19%) FLT3-ITD samples were under LOH but only 5 (4%) were FLT3-ITDhigh. LOH of FLT3-ITDs has also been associated with worse prognosis in AML and further studies are warranted to determine if allele frequency or absence of wild-type FLT3 drives these prognostic correlations. FLT3-ITD LOH is more common than FLT3-ITDhigh and could provide more accurate, sample independent risk stratification for patients with FLT3-ITD+ AML. Disclosures Severson: F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Sokol:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Madison:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Duncan:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Hemmerich:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Edgerly:Foundation Medicine, Inc: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Huang:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Britt:Foundation Medicine, Inc: Employment. Vergilio:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Elvin:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Reddy:Foundation Medicine, Inc: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Sathyan:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Alexander:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Ross:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Ali:Foundation Medicine, Inc: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Ramkissoon:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment.
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Huntington, Scott F., Avyakta Kallam, Frank G. Basile, Danielle Ulanet, Huansheng Xu, Feng Yin, Michelle Mobilia, et al. "AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study." Blood 134, Supplement_1 (November 13, 2019): 1286. http://dx.doi.org/10.1182/blood-2019-123420.
Full textAbstract:
Background: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, key building blocks for RNA and DNA biosynthesis. Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide). Brequinar, a more specific and potent DHODH inhibitor, was evaluated in several phase 1 trials in patients with advanced solid tumors in the 1990s and demonstrated little evidence of antitumor activity; however, patients with hematologic malignancies were not evaluated in those studies. More recent preclinical studies show that cell lines and in vivo models derived from hematologic malignancies are highly sensitive to inhibition of DHODH. AG-636, a novel small molecule DHODH inhibitor, demonstrated strong in vitro and in vivo anti-tumor activity across diverse models of lymphoma and acute leukemia, supporting the evaluation of AG-636 as a treatment for patients with lymphoma and other hematologic malignancies. A phase 1, multicenter, open-label study investigating AG-636 for the treatment of patients with advanced lymphoma began enrollment on May 24, 2019 (NCT03834584). Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-636 and to characterize its dose-limiting toxicities (DLTs) when given to patients with advanced lymphoma. The study includes a dose escalation phase followed by an expansion phase. Approximately 54 adults (42 in the dose escalation phase and 12 in the expansion phase) with advanced lymphoma refractory to standard treatment, will be enrolled at up to 6 centers in the United States. Broad inclusion criteria enable patients with Hodgkin, Diffuse Large B-Cell (DLBCL), Follicular, Peripheral T-Cell, Cutaneous T-Cell, Mantle Cell, and less common subtypes of lymphoma as defined in 2017 by the World Health Organization to enroll. There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy. Patients with active central nervous system disease are excluded. Patients must have an Eastern Cooperative Oncology Group performance status ≤2, an absolute neutrophil count ≥1.0×109/L, a platelet count ≥75×109/L, a serum total bilirubin level ≤1.5×upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels ≤3.0×ULN, and a creatinine clearance ≥30 mL/min (Cockcroft-Gault formula). AG-636 is given as an oral capsule once daily for 2-5 days each week, with 1 cycle of therapy defined as 4 consecutive weeks of treatment. During the dose escalation phase of the study, successive cohorts of patients will be treated with increasing doses of AG-636 to estimate the MTD. The study employs a 2-parameter adaptive Bayesian logistic regression model using escalation with overdose control to guide dose escalation and to estimate the MTD. The MTD is the highest dose that is unlikely (<25% posterior probability) to cause DLTs in ≥ 33% of participants in their first cycle of treatment. Secondary objectives include the safety and tolerability of AG-636, its pharmacokinetics and pharmacodynamics (via measurement of plasma dihydroorotate concentrations), and characterization of any anti-lymphoma activity that may be associated with AG-636 treatment. The dose-expansion phase of the study will treat approximately 12 additional patients at the MTD in order to better characterize the safety, pharmacokinetics, and pharmacodynamics of the dose that may be suggested for future studies. Further expansion may be undertaken if AG-636 shows high activity in specific subtypes of lymphoma, either in the clinic or in preclinical models. The experience in this study with the pharmacokinetics, pharmacodynamics, and safety of AG-636 will inform the optimal starting dose and regimen for evaluation in subsequent studies. Disclosures Huntington: Celgene: Consultancy, Research Funding; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy. Basile:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Ulanet:Agios: Employment, Equity Ownership. Xu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yin:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobilia:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria. Leonard:Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy; AstraZeneca: Consultancy. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.
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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.
Full textAbstract:
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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Jimenez-Yuste, Victor, Midori Shima, Katsuyuki Fukutake, Michaela Lehle, Sammy Chebon, Sylvie Retout, Agnès Portron, and Gallia G. Levy. "Emicizumab Subcutaneous Dosing Every 4 Weeks for the Management of Hemophilia A: Preliminary Data from the Pharmacokinetic Run-in Cohort of a Multicenter, Open-Label, Phase 3 Study (HAVEN 4)." Blood 130, Suppl_1 (December 7, 2017): 86. http://dx.doi.org/10.1182/blood.v130.suppl_1.86.86.
Full textAbstract:
Abstract Introduction Emicizumab is a novel, subcutaneously (SC) administered, recombinant, humanized, bispecific monoclonal antibody that is under investigation for the prevention of bleeds in persons with hemophilia A (PwHA). Emicizumab restores the function of activated coagulation FVIII, which is deficient in PwHA, by bridging activated FIX and FX to enable effective hemostasis. Due to its mechanism of action, emicizumab is not expected to induce or be affected by anti-FVIII antibodies (inhibitors) and is thus being assessed in PwHA both with and without inhibitors. Once-weekly emicizumab prophylaxis was shown to substantially reduce bleed rates by 87% in PwHA with inhibitors compared with no prophylaxis in the Phase 3 HAVEN 1 study (Oldenburg et al. NEJM 2017; July 10: epub). An interim analysis of the HAVEN 2 study showed that once-weekly emicizumab also prevented or reduced bleeds in pediatric PwHA with inhibitors (<12 years of age) (Young et al. RPTH 2017;1 (S2): Abstract OC 24.1). The ongoing HAVEN 3 study (NCT02847637) will assess emicizumab prophylaxis in PwHA without inhibitors. The ongoing multicenter, open-label, Phase 3 HAVEN 4 study (NCT03020160) is assessing emicizumab administered every 4 weeks (Q4W) to PwHA with and without inhibitors; the study consists of a pharmacokinetic (PK) run-in phase followed by an expansion phase. The objective of the PK run-in phase of HAVEN 4 reported here was to investigate the PK and preliminary efficacy and safety outcomes of an emicizumab dose that was previously not assessed in a phase 1 study. Methods Eligible patients in the HAVEN 4 study were aged ≥12 years with congenital hemophilia A with or without inhibitors. In the PK run-in phase, patients must have been receiving episodic (on-demand) treatment with FVIII replacement therapy or bypassing agents with documentation of treatment for ≥24 weeks prior to study entry; the on-study regimen is 6 mg/kg Q4W. The regimen being investigated in the subsequent expansion cohort includes a loading dose of 3 mg/kg SC QW for 4 weeks followed by emicizumab 6 mg/kg Q4W for ≥24 weeks. Results At the data cutoff of April 10, 2017, 7 patients with severe hemophilia A had enrolled into the PK run-in cohort - 4 patients without inhibitors and 3 patients with inhibitors, of which 6 patients were aged ≥18 years of age and followed for a minimum of 6 weeks. Individual observed PK profiles were within the 95% prediction interval computed from a population PK model based on clinical data from a 1.5 mg/kg QW regimen (Figure). Emicizumab PK parameters derived after single SC administration of 6 mg/kg emicizumab (Table) were consistent with values observed in previous studies with emicizumab (Uchida et al. Blood 2016; 127 (13):1633-1641). During the observation period (median, 8 weeks), 14 adverse events (AEs) were reported in 5 patients at the time of data cut-off, including 1 Grade 3 serious AE (worsening of hypertension); no AEs were considered related to study drug. No anti-drug antibodies were detected. Also, 6 of 7 patients had no bleeds while receiving Q4W emicizumab; 1 patient experienced 3 spontaneous nose bleeds on Study Days 12, 14 and 21, which did not require treatment. Conclusions Preliminary data from the HAVEN 4 study showed that Q4W dosing of emicizumab at 6 mg/kg exhibited a PK behavior that was consistent with prior predictions, leading to an expected steady-state concentration average similar to the clinically confirmed dosing regimen (i.e., 1.5 mg/kg/QW). The safety and efficacy results from this PK run-in cohort enabled the opening of the HAVEN 4 expansion cohort, and provided promising support for a Q4W emicizumab prophylaxis regimen for the management of hemophilia A. The HAVEN 4 study is fully enrolled (N=48, including the PK run-in cohort patients). Disclosures Jimenez-Yuste: Roche: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding. Shima: Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Fukutake: EPS: Research Funding; Cimic: Research Funding; Sekisui Medical: Consultancy, Honoraria, Speakers Bureau; Roche Diagnostics: Honoraria, Speakers Bureau; Bioverative: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbott: Honoraria, Speakers Bureau; Kaketsuken: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Pharmaceutical Co., Ltd: Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LSI Medience: Consultancy; SRL Inc: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding; Chuugai: Consultancy, Honoraria, Speakers Bureau; Octapharma AG: Honoraria; Torii Pharmaceutical Co., Ltd: Speakers Bureau. Lehle: F. Hoffmann La Roche: Employment. Chebon: F. Hoffmann-La Roche Ltd: Employment. Retout: F. Hoffmann La Roche: Employment. Portron: F. Hoffmann La Roche: Employment. Levy: Genentech, Inc.: Employment.
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Esatoglu, S. N., B. Tukek, S. S. Taflan, Y. Ozyazgan, D. Ucar, V. Hamuryudan, Y. Ozguler, et al. "POS0816 DRUG SURVIVAL OF INFLIXIMAB IN BEHÇET’S SYNDROME PATIENTS WITH DIFFERENT TYPES OF INVOLVEMENT." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 697.2–698. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3951.
Full textAbstract:
BackgroundInfliximab (IFX) is an effective therapeutic option in the management of severe and refractory manifestations of Behçet’s syndrome (BS).ObjectivesWe aimed to evaluate long term drug survival of IFX in a large cohort of BS patients.MethodsWe reviewed the charts of BS patients who received IFX between 2004 and June 2021 and noted demographic features, reasons for IFX use, IFX duration, and reasons for discontinuation.Results371 patients (290 men, mean age at IFX initiation: 35.5 ± 10 years) received IFX for uveitis (n=164), vascular involvement (n=114), central nervous system (CNS) involvement (n=55), arthritis (n=19), gastrointestinal (GI) involvement (n=15), mucocutaneous involvement (n=10), venous ulcers (n=13), and secondary amyloidosis (n=1). Twenty patients had more than one type of involvement requiring IFX.During a median follow-up of 30 months (IQR: 13-52), 175 (47%) patients were still receiving IFX for a median period of 40 months (IQR: 22-66) while 196 (53%) patients had discontinued IFX after a median follow-up of 19 months (IQR: 8-34).IFX retention rate was 50% for mucocutaneous involvement, 43% for uveitis, 49% for vascular involvement, 58% for CNS involvement, 37% for arthritis, 53% for GI involvement, and 31% for venous ulcer (Table 1).Table 1.Drug survival of infliximab and reasons for infliximab discontinuationMucocutaneous involvement (n=10)Uveitis (n=164)Vascular (n=114)CNS (n=55)Arthritis (n=19)GIS (n=15)Venous ulcer (n=13)Male (n, %)3 (30)127 (77)89 (78)49 (89)14 (74)9 (60)12 (92)Age at infliximab initiation (mean ± SD years)35.8 ± 9.334 ± 9.936 ± 9.136.2 ± 10.439.6 ± 10.743 ± 14.137.4 ± 8.2Number of patients who used concomitant immunosuppressives (n, %)5 (50)108 (66)86 (75)38 (69)5 (26)11 (73)7 (54)Duration of infliximab use (mean ± SD months)33 ± 3845 ± 3828 ± 2337 ± 2837 ± 3526 ± 2625 ± 25Number of patients who discontinued infliximab (n, %)5 (50)93 (57)58 (51)23 (42)12 (63)7 (47)9 (69)Due to remission-30212121Due to primary inefficacy157---5Due to secondary inefficacy212545--Due to adverse event1231211541Due to noncompliance11113--2Due to other reasons-1212311-Reasons for discontinuation were adverse events in 56 (15%), remission in 54 (15%) patients, inefficacy in 45 (12%) (secondary inefficacy in 26 (7%), primary inefficacy in 19 (5%)), and lack of patient compliance in 18 (5%). Other reasons were preparation for surgical operation (n=4), pregnancy (n=4), lack of health insurance (n=4), preferring subcutaneous administration during the pandemic (n=3), due to prison sentence (n=3), willing to get pregnant (n=1), rejecting the treatment (n=1), and death (n=3).Adverse events (n=56) leading to the cessation of IFX were infusion reactions (n=22), infections (n=7), tuberculosis (n=6), malignancy (n=6), palmoplantar psoriasis (n=5), hepatotoxicity (n=4), lichen planus (n=1), drug induced lupus (n=1), auricular chondritis (n=1), macrophage activation syndrome (n=1), splenic infarction (n=1) and a decrease in left ventricular ejection fraction (n=1).At the end of the follow-up, 2 patients had died due to lung adenocarcinoma, 1 patient had died due to pneumosepsis, 1 due to severe parenchymal neurologic involvement and 1 with pulmonary artery involvement due to massive hemorrhage during IFX treatment. Additionally, 7 patients had died 9, 10 months, 3, 3, 4, 7 and 9 years after IFX discontinuation. The causes of death were severe nervous system involvement in 2 patients, right heart failure due to pulmonary hypertension, laryngeal adenocarcinoma, lung adenocarcinoma, sepsis and gastrointestinal bleeding in 1 patient each.ConclusionIFX seems to be effective for the treatment of organ and life-threatening manifestations in the majority of the patients. However, drug retention rate was not optimal, mainly due to adverse events, inefficacy and patient non-compliance.Disclosure of InterestsSinem Nihal Esatoglu Speakers bureau: Sinem Nihal Esatoglu has received honorariums for presentations from UCB Pharma, Roche, Pfizer, and Merck Sharp Dohme, Beyza Tukek: None declared, Sitki Safa Taflan: None declared, Yilmaz Ozyazgan: None declared, Didar Ucar: None declared, Vedat Hamuryudan Speakers bureau: Vedat Hamuryudan has served as a speaker for AbbVie, Celgene, Novartis, and UCB Pharma, Grant/research support from: Vedat Hamuryudan has received grant/research support from Celgene., Yesim Ozguler Speakers bureau: Yesim Ozguler has received honorariums for presentations from UCB Pharma, Novartis, and Pfizer., Emire Seyahi Speakers bureau: Emire Seyahi has received honorariums for presentations from Novartis, Pfizer, AbbVie, and Gliead, Melike Melikoglu: None declared, Ugur Uygunoglu Speakers bureau: Ugur Uygunoglu has received speaker fees from F Hoffmann La-Roche, F Hoffmann La-Roche, Bayer, Merck-Serono, Novartis, Teva, and Biogen Idec/Gen Pharma of Turkey, Consultant of: Ugur Uygunoglu has received advisory board honorariums from F Hoffmann La-Roche, F Hoffmann La-Roche, Bayer, Merck-Serono, Novartis, Teva, and Biogen Idec/Gen Pharma of Turkey, Aksel Siva Speakers bureau: Aksel Siva received honorariums from Teva for speaking engagements., Consultant of: Aksel Siva received honorariums from Bayer-Schering AG, Biogen/Gen Ilac of Turkey, Genzyme, Merck-Serono, and Roche for consulting, fees from Novartis as a consultant and advisory committee member,., Grant/research support from: Aksel Siva received travel and registration reimbursements from Genzyme., Zekayi Kutlubay: None declared, Izzet Fresko: None declared, Sebahattin Yurdakul: None declared, Hasan Yazici: None declared, Gulen Hatemi Speakers bureau: Gulen Hatemi has served as a speaker for AbbVie, Celgene, Novartis, and UCB Pharma., Grant/research support from: Gulen Hatemi has received grant/research support from Celgene.
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Husar, Elisabeth, Maria Solonets, Olaf Kuhlmann, Eginhard Schick, Hanna Piper-Lepoutre, Thomas Singer, and Gaurav Tyagi. "Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans." Toxicologic Pathology 45, no. 5 (July 2017): 676–86. http://dx.doi.org/10.1177/0192623317723539.
Full textAbstract:
Obinutuzumab (GA101, Gazyva™, Gazyvaro®, F. Hoffmann-La Roche AG, Basel, Switzerland) is a humanized, glycoengineered type II antibody targeted against CD20. The preclinical safety evaluation required to support clinical development and marketing authorization of obinutuzumab included repeat-dose toxicity studies in cynomolgus monkeys for up to 6-month dosing with a 9-month recovery period. Results from those studies showed decreases in circulating B cells and corresponding B-cell depletion in lymphoid tissues, consistent with the desired pharmacology of obinutuzumab. Hypersensitivity reactions were noted at all doses in the 6-month study and were attributed to the foreign recognition of the drug construct in cynomolgus monkeys. Findings in monkeys were classified as acute hypersensitivity reactions that were evident immediately after dosing, such as excessive salivation, erythema, pruritus, irregular respiration, or ataxia, or chronic hypersensitivity reactions characterized by glomerulonephritis, arteritis/periarteritis, and inflammation in several tissues including serosal/adventitial inflammation. Immune complex deposits were demonstrated in tissues by immunohistochemistry, immunofluorescence, and electron microscopy. Some of, but not all, the animals that developed these reactions had detectable antidrug antibodies or circulating immune complexes accompanied by loss of drug exposure and pharmacodynamic effect. On the basis of clinical evidence to date, hypersensitivity reactions following obinutuzumab are rare, further supporting the general view that incidence and manifestation of immunogenicity in nonclinical species are generally not predictive for humans.
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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Shima, Midori, Sayaka Nagami, Koichiro Yoneyama, Akira Nomura, Yoshiyuki Ogawa, Kagehiro Amano, and Keiji Nogami. "An Investigational Dosing Algorithm of Emicizumab for Prophylaxis in Acquired Hemophilia a." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-136488.
Full textAbstract:
INTRODUCTION: Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII and is currently indicated for routine prophylaxis of bleeds in patients with congenital hemophilia A (CHA) regardless of factor VIII (FVIII) inhibitor status. Nonclinical investigations suggest that emicizumab would be efficacious for preventing bleeds also in patients with acquired hemophilia A (AHA) (J Thromb Haemost 2020;18:825-33). However, no dedicated investigations have been performed to explore the optimal dosing algorithm of emicizumab for AHA. We present herein a proposed dosing algorithm of emicizumab potentially appropriate for AHA. METHODS: The dose selection for AHA aimed to achieve trough levels of plasma emicizumab concentration (Ctrough) of >30 μg/mL in most patients, at which the effect of emicizumab for preventing bleeds is expected to be almost maximized as in patients with CHA (Res Pract Thromb Haemost 2019;3[Suppl 1]:315). Because the time spent with a high risk of bleeding in AHA is much shorter than in CHA due to the immunosuppressive therapy (IST) given to eradicate FVIII inhibitors (a reported median is 31 days [Blood 2015;125:1091-7]), and because bleeding symptoms in AHA can be severer than in CHA, the loading dose duration of 4 weeks for the current approved subcutaneous dosing regimens of emicizumab for CHA (i.e., 3 mg/kg once weekly [QW] for first 4 weeks [loading dose] followed by 1.5 mg/kg QW, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks from the 5th week onwards [maintenance dose]) was considered too long to maximize the effect of emicizumab in AHA. In addition, the potential risk of hypercoagulation associated with coexistence of emicizumab and FVIII restored as a consequence of successful IST was concerning. Modification of the loading dose together with definition of an appropriate timing for the dosing completion of emicizumab were therefore considered necessary. Exploration of a modified dosing regimen was performed by pharmacokinetic (PK) simulations using a population PK model developed in patients with CHA (Clin Pharmacokinet 2020 Jun 5) with the covariates adjusted for patients with AHA. The given dose per administration was capped at the maximum one approved for CHA. The dosing frequency of the maintenance dose was set to QW, aiming to keep the maximum plasma emicizumab concentration at steady state low for minimizing the potential risk of hypercoagulation after FVIII activity is restored. Development of the dosing completion criteria for emicizumab was addressed by a literature review. RESULTS: A modified subcutaneous dosing regimen of 6 mg/kg and 3 mg/kg on the 1st and 2nd days of the 1st week, respectively (loading dose), followed by 1.5 mg/kg QW from the 2nd week onwards (maintenance dose) was found to meet the defined requirements for AHA. With the modified dosing regimen, the median Ctrough was predicted to achieve >30 μg/mL by the 2nd week and to reach steady state by the 3rd week, which would allow for rapider maximization and stabilization of the effect of emicizumab than with the current approved QW dosing regimen (Figure). However, there remained uncertainty in the PK predictions in association with the older age and severer disease conditions in AHA than in CHA, which may require further adaptation of the dosing regimen in case of insufficient exposure or efficacy. In reference to the lower limit of the normal range of FVIII activity and the definitions of partial remission employed in previous researches, an endogenous FVIII activity of >50 IU/dL measured in the absence of interference by emicizumab was selected for a criterion for guiding the dosing completion of emicizumab. In addition, taking into account a standardized definition of a bleeding event (J Thromb Haemost 2014;12:1935-9) together with the bleeds in AHA possibly occurring even if FVIII is restored, absence of using coagulation factor products for >72 hours after the last episodic use of coagulation factor products was considered as another dosing completion criterion to be met. CONCLUSIONS: A dosing algorithm of emicizumab potentially appropriate for prophylaxis in AHA was proposed leveraging literature information and PK simulations. The appropriateness of the selected dosing regimen together with the developed dosing completion criteria is currently under investigation with possibility of data-driven adaptations in a clinical study (AGEHA; JapicCTI-205151). Disclosures Shima: Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co.: Consultancy; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Honoraria. Nagami:Chugai Pharmaceutical Co., Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Yoneyama:Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Nomura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Ogawa:Chugai Pharmaceutical Co., Ltd.: Consultancy; Bayer AG: Research Funding. Amano:Pfizer Inc.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; F. Hoffmann-La Roche Ltd.: Research Funding; CSL Behring: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Bayer AG: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau. Nogami:Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire Plc: Research Funding, Speakers Bureau; Bioverativ Inc.: Research Funding, Speakers Bureau; Novo Nordisk A/S: Research Funding, Speakers Bureau; Bayer AG: Research Funding, Speakers Bureau. OffLabel Disclosure: Emicizumab for acquired hemophilia A
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Nicklaus, Mr Karl, and Dr Martin Schadt. "Entrepreneur acquires Rolic Ltd from F. Hoffman-La Roche." Liquid Crystals Today 7, no. 2 (June 1997): 10. http://dx.doi.org/10.1080/13583149708047668.
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Wang, Rongrong, Josh Roth, Carmen Ng, Farah Hossain, Jia Li, and Anthony Masaquel. "Cost of Disease Progression after Frontline (1L) R-CHOP in Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 138, Supplement 1 (November 5, 2021): 3002. http://dx.doi.org/10.1182/blood-2021-146802.
Full textAbstract:
Abstract Introduction: While the chemoimmunotherapy combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the standard-of-care in 1L treatment for DLBCL, 30-40% of patients either relapse or are refractory to R-CHOP (Coiffier et al. N Engl J Med 2002). The initiation of subsequent therapies post relapse is integral to relapsed/refractory (R/R) DLBCL management and is associated with substantial treatment cost. Previous studies of treatment costs for R/R DLBCL patients are outdated and exclude novel therapies (e.g. chimeric antigen receptor [CAR-]T therapies). Thus, the cost of disease progression may be underestimated. Using data through 2020, we sought to understand the economic burden associated with disease progression in the DLBCL treatment landscape. Methods: This was a retrospective cohort study using administrative claims data from IQVIA PharMetrics ® Plus (a US commercial claims database). We identified patients ≥18 years, who received 1L R-CHOP treatments between January 1, 2010 and June 30, 2018. Patients were required to have ≥1 inpatient claim or ≥2 outpatient claims with a DLBCL diagnosis from 1 year before to 90 days after initiating R-CHOP. End of therapy was defined as a gap of ≥60 days in the treatment regimen or initiation of new agents (OPTUM 2018). Using this definition as a proxy for progression, patients not receiving second-line (2L) treatment for ≥2 years were assigned to the 'no progression' cohort and those who initiated non-R-CHOP therapy after 1L therapy to the 'progression' cohort. In both cohorts, index date was defined as either 60 days after the end of 1L treatment, or the initiation of 2L treatment, whichever occurred first. All patients had continuous enrollment in medical and pharmacy benefits between R-CHOP initiation and ≥2 years post index date, allowing time for post-1L relapse. Costs per-patient-per-month (PPPM) and 3-year cumulative all-cause costs (2020 USD) were compared between cohorts. Generalized linear models (gamma distribution with log link) were performed to adjust for baseline characteristics, including age and payer type at index, sex, US region, Charlson Comorbidity Index (CCI), and baseline total cost of care 1 year before index date. Results: Overall, 871 patients were identified; 58% were female. The mean (standard deviation [SD]) age and CCI (excluding malignancy) at index date were 58.0 (11.7) years, and 2.5 (3.1) years, respectively. The mean follow-up period was 45 months. Patients in the 'no progression' cohort (N = 725; 83.2%) had similar baseline characteristics to those in the 'progression' cohort (N = 146; 16.8%). About half (N = 76; 52.1%) of the progression cohort had multiple relapse events, with 30.8% receiving ≥4 lines of therapy. Among the progression cohort, 73 (50.0%) and 10 (6.8%) patients received stem-cell transplant (SCT) and CAR-T therapy, respectively. The mean PPPM cost was higher among progressors than non-progressors (unadjusted: $10,163 vs $1,569; adjusted: $10,554 vs $1,561, p < 0.001, Table 1). The major cost driver for disease progression was inpatient costs (41.7% of total costs for progressors vs 19.1% for non-progressors). Cost of progression associated with multiple relapse events was more than twice the cost associated with a single event (unadjusted: $13,934 vs $6,069; adjusted: $14,676 vs $6,216, p < 0.001, Table 1). Compared with no progression, receiving novel treatments after 1L was associated with considerably higher costs (unadjusted: $14,539 [SCT] and $25,032 [CAR-T] vs $1,569; adjusted: $14,306 [SCT/CAR-T] vs $1,549, p < 0.001, Table 2). Similar trends were seen comparing unadjusted 3-year cumulative costs based on month of disease progression in patients in the 'no progression', 'progression' and SCT/CAR-T subgroups (Figure 1). Conclusion: In this analysis of insurance claims through 2020, we systematically selected patients who survived for at least 2 years after the index date; this represented approximately 80% of DLBCL patients treated with 1L R-CHOP. The cost of disease progression in DLBCL is considerable, especially among patients receiving novel treatments as later lines of therapy. The costs for patients experiencing multiple relapse events were more than twice the cost for patients with a single relapse event. Effective frontline treatments for DLBCL are needed to reduce the economic burden associated with disease progression. Figure 1 Figure 1. Disclosures Wang: Aurinia Pharmaceuticals Inc.: Current equity holder in publicly-traded company; Novavax, Inc.: Current equity holder in publicly-traded company; Oragenics, Inc.: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; The SPHERE Institute: Ended employment in the past 24 months; Genentech, Inc.: Current Employment; TG Therapeutics, Inc.: Current equity holder in publicly-traded company. Roth: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Seattle Genetics: Consultancy; Bayer Healthcare: Consultancy; Bristol-Myers Squibb: Consultancy; Epigenomics AG: Consultancy. Ng: Genentech, Inc./F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; Emory University, Rollins School of Public Health: Ended employment in the past 24 months. Hossain: Genentech, Inc.: Current Employment; Legend Biotech: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Li: F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Masaquel: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.
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Sostelly, Alexandre, Antoine Soubret, Christoph Bucher, Simon Buatois, Jean-Eric Charoin, Gregor Jordan, Barbara Klughammer, et al. "Characterizing C5 Inhibition with the SMART-Ig Anti-hC5 Antibody Crovalimab in PNH Patients Using Free Available Paratopes." Blood 134, Supplement_1 (November 13, 2019): 1227. http://dx.doi.org/10.1182/blood-2019-126911.
Full textAbstract:
Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1) in healthy volunteers (Part 1), treatment naïve PNH patients (Part 2, Part 4) and in eculizumab pre-treated patients (Part 3, Part 4). The conventional PK metrics to determine optimal target inhibition is drug concentration, however this has some limitations when considering an abundant fluctuating soluble target such as C5. Therefore, we proposed to characterize C5 inhibition by quantifying the level of crovalimab free paratopes (i.e. the concentration of free crovalimab antigen-binding sites not bound to C5) and to illustrate how it can be used to estimate the available binding capacity reserve of crovalimab. Total crovalimab concentration, free C5 and total C5 protein levels (measuring free C5, C5 bound to one crovalimab Fab arm, or two C5s bound to the two crovalimab Fab arms) were measured using validated assays. In assuming steady state conditions at every measurement time for the binding of crovalimab with C5 (due to the rapid binding of C5 with crovalimab), a mathematical model based on law mass action principle was used to describe the equilibrium between free C5, free crovalimab and crovalimab bound to one or two C5 molecules. Available crovalimab free paratope was estimated from the model in using total C5 and total crovalimab concentrations collected in the COMPOSER trial. Paratope level was expressed in C5-binding ability concentration equivalent (i.e. how much additional C5 could be bound). Relationships between total concentration time course, free C5 and available free epitopes were evaluated using graphical analysis. To complement these analyses and using the mathematical model, a sensitivity analysis was performed to identify key antibody properties driving the level of available free crovalimab paratopes. In COMPOSER Part 2, the longitudinal time course of crovalimab free paratope concentration (Figure 2) shows that 170mg SC weekly provided a median reserve of free paratopes that allows binding around 120µg/mL of additional C5 corresponding approximatively to two times the baseline C5 levels observed in Part 2 (i.e. 129µg/mL). Therefore, if the level of C5 in the circulation doubled from baseline, e.g. during infection, there would be a sufficient binding capacity to block the activity of these new C5 molecules at least for 75% of the patients (Figure 2). In COMPOSER Part 3, the observed median reserve of free paratopes was lower during the first 60 days after crovalimab initiation (Figure 2). This is driven by the remaining presence of eculizumab and the binding of both crovalimab and eculizumab to C5. Eculizumab and crovalimab bind different C5 epitopes and switching patients from eculizumab to crovalimab induces formation of drug target drug complexes (DTDC). DTDCs clearance was estimated to be ten times faster than crovalimab-C5 complexes clearance resulting in a drop of free paratope level during the first 60 days. Washout from eculizumab is not feasible in PNH patients. To increase the availability of crovalimab free paratopes after switching, crovalimab dose and regimen was optimized and is currently tested in COMPOSER Part 4 (Figure 1).The sensitivity analysis demonstrated that the main driver of free paratopes availability were the recycling efficiency of free crovalimab after endocytosis and the clearance of crovalimab while the affinity of crovalimab to C5 had little effect. Free paratope concentration enables characterization of available binding reserve of crovalimab. The capacity to adequately control C5 increase due to the SMART-Ig engineering is expected to result in a better control of breakthrough hemolysis in PNH patients compared with an antibody without this technology. For soluble targets, this approach provides more stringent criteria than antibody concentration as it defines the capacity of the drug to bind free target at any time. Therefore, this metric should prove helpful in guiding dose selection for monoclonal antibodies binding a soluble target. Disclosures Sostelly: F. Hoffmann-La Roche: Employment. Soubret:F. Hoffmann-La Roche: Employment, Equity Ownership. Bucher:F. Hoffmann-La Roche: Employment. Buatois:F. Hoffmann-La Roche: Employment. Charoin:F. Hoffmann-La Roche: Employment. Jordan:Roche Diagnostics GmbH: Employment; F. Hoffmann-La Roche: Equity Ownership. Klughammer:F. Hoffmann-La Roche Ag: Employment, Equity Ownership. Dieckmann:F. Hoffmann-La Roche: Employment. Fukuzawa:Chugai Pharmaceutical Co., Ltd.: Employment. Gotanda:Chugai Pharmaceutical Co., Ltd.: Employment. Shinomiya:Chugai Pharmaceutical Co., Ltd.: Employment, Patents & Royalties: (WO2018143266) A PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OR PREVENTION OF A C5-RELATED DISEASE AND A METHOD FOR TREATING OR PREVENTING A C5-RELATED DISEASE. Yoon:Kyowa Hako Kirin: Research Funding; Amgen: Consultancy, Honoraria; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy; Yuhan Pharma: Research Funding; MSD: Consultancy. Panse:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees. Nishimura:Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding. Röth:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Honoraria; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nagy:Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.
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Julia, Edith, Nathan H. Fowler, Emmanuel Bachy, Pierre Feugier, Reda Bouabdallah, Herve Tilly, M. Lia Palomba, et al. "Validation of the PRIMA-Prognostic Index for Patients Treated with Rituximab Plus Chemotherapy and Refinement of Prognostic Parameters for Patients on Rituximab Plus Lenalidomide in the Phase III Relevance Trial." Blood 134, Supplement_1 (November 13, 2019): 1524. http://dx.doi.org/10.1182/blood-2019-129024.
Full textAbstract:
Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level > 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin (<40 g/L) and low hemoglobin (<120 g/L) levels were significantly associated with worse PFS in the R2 arm (p=0.001, and p=0.023), but not in the R-chemo arm. Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: 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; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: 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. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, 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, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, 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.
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Sen, P., N. R, A. Nune, J. B. Lilleker, V. Agarwal, S. Kardes, M. Kim, et al. "POS1260 COVID-19 VACCINATION-RELATED ADVERSE EVENTS AMONG AUTOIMMUNE DISEASE PATIENTS: RESULTS FROM THE COVID-19 VACCINATION IN AUTOIMMUNE DISEASES (COVAD) STUDY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 966–67. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4197.
Full textAbstract:
BackgroundCOVID-19 vaccines have been proven to be safe and effective in the healthy population at large. However, significant gaps remain in the evidence of their safety in patients with systemic autoimmune and inflammatory disorders (SAIDs). Patients and rheumatologists have expressed concerns regarding vaccination triggered allergic reactions, thrombogenic events, and other adverse events (ADEs) contributing to vaccine hesitancy (1)ObjectivesThis study aimed to assess and compare short term COVID-19 vaccination associated ADEs in patients with SAIDs and healthy controls (HC) seven days post-vaccination, as well as between patients with SAIDs receiving different vaccines.MethodsWe developed an comprehensive, patient self-reporting electronic-survey to collect respondent demographics, SAID details, COVID-19 infection history, COVID-19 vaccination details, 7-day post vaccination adverse events and patient reported outcome measures using the PROMIS tool. After pilot testing, validation, translation into 18 languages on the online platform surveymonkey.com, and vetting by international experts, the survey was circulated in early 2021 by a multicenter study group of >110 collaborators in 94 countries. ADEs were categorized as injection site pain, minor ADEs, major ADEs, and hospitalizations. We analyzed data from the baseline survey for descriptive and intergroup comparative statistics based on data distribution and variable type (data as median, IQR).Results10900 respondents [42 (30-55) years, 74% females and 45% Caucasians] were analyzed. 5,867 patients (54%) with SAIDs were compared with 5033 HCs. All respondents included in the final analysis had received a single dose of the vaccine and 69% had received 2 primary doses. Pfizer (39.8%) was the most common vaccine received, followed by Oxford/AstraZeneca (13.4%), and Covishield (10.9%). Baseline demographics differed by an older SAID population (mean age 42 vs. 33 years) and a greater female predominance (M:F= 1:4.7 vs. 1:1.8) compared to HCs.79% had minor and only 3% had major vaccine ADEs requiring urgent medical attention overall. In adjusted analysis, among minor ADEs, abdominal pain [multivariate OR 1.6 (1.14-2.3)], dizziness [multivariate OR 1.3 (1.2-1.5)], and headache [multivariate OR 1.67 (1.3-2.2)], were more frequent in SAIDs than HCs. Overall major ADEs [multivariate OR 1.9 (1.6-2.2)], and throat closure [multivariate OR 5.7 (2.9-11.3)] were more frequent in SAIDs though absolute risk was small (0-4%) and rates of hospitalization were similarly small in both groups, with a small absolute risk (0-4%). Specific minor ADEs frequencies were different among different vaccine types, however, major ADEs and hospitalizations overall were rare (0-4%) and comparable across vaccine types in patients with SAIDs (Figure 1).Figure 1.A. Post Vaccination ADEs in SAIDs compared to HCs. B. Proportions of post COVID-19 vaccination ADEs in SAIDs by vaccine type.ConclusionVaccination against COVID-19 is relatively safe and tolerable in patients with SAIDs. Certain minor vaccine ADEs are more frequent in SAIDs than HCs in this study, though are not severe and do not require urgent medical attention. SAIDs were at a higher risk of major ADEs than HCs, though absolute risk was small, and did not lead to increased hospitalizations. There are small differences in minor ADEs between vaccine types in patients with SAIDs.References[1]Boekel L, Kummer LY, van Dam KPJ, Hooijberg F, van Kempen Z, Vogelzang EH, et al. Adverse events after first COVID-19 vaccination in patients with autoimmune diseases. Lancet Rheumatol. 2021 Aug;3(8):e542–5.AcknowledgementsThe authors thank all members of the COVAD study group for their invaluable role in the collection of data. The authors thank all respondents for filling the questionnaire. The authors thank The Myositis Association, Myositis India, Myositis UK, the Myositis Global Network, Cure JM, Cure IBM, Sjögren’s India Foundation, EULAR PARE, and various other patient support groups and organizations for their invaluable contribution in the dissemination of this survey among patients which made the data collection possible. The authors also thank all members of the COVAD study group.Disclosure of InterestsParikshit Sen: None declared, Naveen R: None declared, Arvind Nune: None declared, James B. Lilleker: None declared, Vishwesh Agarwal: None declared, Sinan Kardes: None declared, Minchul Kim: None declared, Jessica Day Grant/research support from: JD has received research funding from CSL Limited., Marcin Milchert: None declared, Tamer A Gheita: None declared, Babur Salim: None declared, Tsvetelina Velikova: None declared, Abraham Edgar Gracia-Ramos: None declared, Ioannis Parodis Speakers bureau: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Consultant of: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Grant/research support from: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Albert Selva-O’Callaghan: None declared, Elena Nikiphorou Speakers bureau: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Consultant of: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Grant/research support from: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, and holds research grants from Pfizer and Lilly., Tulika Chatterjee: None declared, Ai Lyn Tan Speakers bureau: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB., Consultant of: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB., Grant/research support from: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB., Lorenzo Cavagna: None declared, Miguel A Saavedra: None declared, Samuel Katsuyuki Shinjo: None declared, Nelly Ziade Speakers bureau: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript., Consultant of: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript., Grant/research support from: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript., Johannes Knitza: None declared, Masataka Kuwana: None declared, Oliver Distler Speakers bureau: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Hector Chinoy Speakers bureau: HC has served as a speaker for UCB, Biogen., Consultant of: HC has received consulting fees from Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Grant/research support from: HC has received grant support from Eli Lilly and UCB, Vikas Agarwal: None declared, Rohit Aggarwal Consultant of: RA has/had a consultancy relationship with and/or has received research funding from for the following companies-Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Kyverna, Janssen, Roivant, Boehringer Ingelheim, Argenx, Q32, Alexion, EMD Serono, Jubliant, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant., Grant/research support from: RA has/had a consultancy relationship with and/or has received research funding from for the following companies-Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Kyverna, Janssen, Roivant, Boehringer Ingelheim, Argenx, Q32, Alexion, EMD Serono, Jubliant, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant., Latika Gupta: None declared
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Gupta, L., L. S. Hoff, N. R, P. Sen, S. Katsuyuki Shinjo, J. Day, J. B. Lilleker, et al. "POS0201 COVID-19 SEVERITY AND VACCINE BREAKTHROUGH INFECTIONS IN IDIOPATHIC INFLAMMATORY MYOPATHIES, OTHER SYSTEMIC AUTOIMMUNE AND INFLAMMATORY DISEASES, AND HEALTHY INDIVIDUALS: RESULTS FROM THE COVID-19 VACCINATION IN AUTOIMMUNE DISEASES (COVAD) STUDY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 334–36. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2160.
Full textAbstract:
BackgroundSignificant gaps are present in the evidence of the spectrum and severity of COVID-19 infection in idiopathic inflammatory myopathies (IIM). IIM patients typically require immunosuppressive therapy, may have multiple disease sequelae, and frequent comorbidities, and thus may be more susceptible to severe COVID-19 infection and complications (1). The possibility of attenuated immunogenicity and reduced efficacy of COVID-19 vaccines due to concomitant immunosuppressive medication is a major concern in these patients, and there is little data available on COVID-19 vaccine breakthrough infections (BI) in IIM (2).ObjectivesThis study aimed to compare disease spectrum and severity and COVID-19 BI in patients with IIM, other systemic autoimmune and inflammatory diseases (SAIDs) and healthy controls (HCs).MethodsWe developed an extensive self-reporting electronic-survey (COVAD survey) featuring 36 questions to collect respondent demographics, SAID details, COVID-19 infection history, COVID-19 vaccination details, 7-day post vaccination adverse events and patient reported outcome measures using the PROMIS tool. After pilot testing, validation, translation into 18 languages on the online platform surveymonkey.com, and vetting by international experts, the COVAD survey was circulated in early 2021 by a multicenter study group of >110 collaborators in 94 countries. BI was defined as COVID-19 infection occurring more than 2 weeks after receiving 1st or 2nd dose of a COVID-19 vaccine. We analyzed data from the baseline survey for descriptive and intergroup comparative statistics based on data distribution and variable type.Results10900 respondents [mean age 42 (30-55) years, 74% females and 45% Caucasians] were analyzed. 1,227 (11.2%) had IIM, 4,640 (42.6%) had other SAIDs, and 5,033 (46.2%) were HC. All respondents included in the final analysis had received a single dose of the vaccine and 69% had received 2 primary doses. Pfizer (39.8%) was the most common vaccine received, followed by Oxford/AstraZeneca (13.4%), and Covishield (10.9%). IIM patients were older, had a higher Caucasian representation and higher Pfizer uptake than other SAIDs, and HC. A higher proportion of IIM patients received immunosuppressants than other SAIDs.IIMs were at a lower risk of symptomatic pre-vaccination COVID-19 infection compared to SAIDs [multivariate OR 0.6 (0.4-0.8)] and HCs [multivariate OR 0.39 (0.28-0.54)], yet at a higher risk of hospitalization due to COVID-19 compared to SAIDs [univariate OR 2.3 (1.2-3.5)] and HCs [multivariate OR 2.5 (1.1-5.8)]. BIs were very uncommon in IIM patients, with only 17 (1.4%) reporting BI. IIM patients were at a higher risk of contracting COVID-19 prior to vaccination than ≤2 weeks of vaccination [univariate OR 8 (4.1-15)] or BI [univariate OR 4.6 (2.7-8.0)]. BIs were equally severe compared to when they occurred prior to vaccination in IIMs, and were comparable between IIM, SAIDs, and HC (Figure 1), though BI disease duration was shorter in IIMs than SAIDs (7 vs 11 days, p 0.027). 13/17 IIM patients with BI were on immunosuppressants.ConclusionIIM patients experienced COVID-19 infection less frequently prior to vaccination but were at a higher risk of hospitalization and requirement for oxygen therapy compared with patients with HC. Breakthrough COVID-19 infections were rare (1.4%) in vaccinated IIM patients, and were similar to HC and SAIDs, except for shorter disease duration in IIM.References[1]Brito-Zerón P, Sisó-Almirall A, Flores-Chavez A, Retamozo S, Ramos-Casals M. SARS-CoV-2 infection in patients with systemic autoimmune diseases. Clin Exp Rheumatol. 2021 Jun;39(3):676–87.[2]Wack S, Patton T, Ferris LK. COVID-19 vaccine safety and efficacy in patients with immune-mediated inflammatory disease: Review of available evidence. J Am Acad Dermatol. 2021 Nov;85(5):1274–84.AcknowledgementsThe authors thank all members of the COVAD study group for their invaluable role in the collection of data. The authors thank all respondents for filling the questionnaire. The authors thank The Myositis Association, Myositis India, Myositis UK, the Myositis Global Network, Cure JM, Cure IBM, Sjögren’s India Foundation, EULAR PARE, and various other patient support groups and organizations for their invaluable contribution in the dissemination of this survey among patients which made the data collection possible. The authors also thank all members of the COVAD study group.Disclosure of InterestsLatika Gupta: None declared, Leonardo Santos Hoff: None declared, Naveen R: None declared, Parikshit Sen: None declared, Samuel Katsuyuki Shinjo: None declared, Jessica Day Grant/research support from: JD has received research funding from CSL Limited, James B. Lilleker: None declared, Vishwesh Agarwal: None declared, Sinan Kardes: None declared, Minchul Kim: None declared, Ashima Makol: None declared, Marcin Milchert: None declared, Tamer A Gheita: None declared, Babur Salim: None declared, Tsvetelina Velikova: None declared, Abraham Edgar Gracia-Ramos: None declared, Ioannis Parodis Speakers bureau: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Consultant of: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Grant/research support from: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Albert Selva-O’Callaghan: None declared, Elena Nikiphorou Speakers bureau: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Consultant of: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Grant/research support from: EN holds research grants from Pfizer and Lilly., Tulika Chatterjee: None declared, Ai Lyn Tan Speakers bureau: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB., Consultant of: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB., Arvind Nune: None declared, Lorenzo Cavagna: None declared, Miguel A Saavedra: None declared, Nelly Ziade Speakers bureau: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript, Consultant of: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript, Grant/research support from: NZ has received speaker fees, advisory board fees and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Pierre Fabre; none is related to this manuscript, Johannes Knitza: None declared, Masataka Kuwana: None declared, Oliver Distler Speakers bureau: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: OD has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Hector Chinoy Speakers bureau: HC has been a speaker for UCB, Biogen., Consultant of: HC has received consulting fees from Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Grant/research support from: HC has received grant support from Eli Lilly and UCB, Vikas Agarwal: None declared, Rohit Aggarwal Consultant of: RA has/had a consultancy relationship with and/or has received research funding from the following companies-Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, and Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant., Grant/research support from: RA has/had a consultancy relationship with and/or has received research funding from the following companies-Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, and Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant.
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Tyanova, Stefka, Tao Xu, Mellissa Williamson, Alberto Rocci, Wan-Jen Hong, Huan Jin, Sudeep Karve, James Roose, Ahmed Sawas, and Shaji Kumar. "Lab-Based Response Assessment Algorithm Recapitulates Investigator's Response Assessment in the Phase 3 Bellini Trial." Blood 138, Supplement 1 (November 5, 2021): 4758. http://dx.doi.org/10.1182/blood-2021-147713.
Full textAbstract:
Abstract Background: Real-world data (RWD) derived from electronic health records are becoming increasingly important for deriving insights from clinical practice to complement findings from clinical trials. Response to treatment in multiple myeloma (MM) is assessed using the International Myeloma Working Group (IMWG) response criteria based on MM-specific laboratory measures (i.e. monoclonal [M] protein in serum and urine, free light chain [FLC] levels), as well as radiological images and bone marrow (BM) investigations when appropriate. As healthcare providers do not routinely collect all the information required by the IMWG response criteria, RWD data are often incomplete. Here, we present a derived real-world response (dR) algorithm based on IMWG criteria that accounts for lab measures routinely collected in the clinical care of MM patients and evaluate its ability to accurately assess response to treatment using clinical trial patient-level data. Methods: Treatment response is assessed using a rule-based algorithm integrating longitudinal laboratory measures routinely captured in RWD (Xu et al. Pharmacoepidemiol Drug Saf 2021) as e.g. by the Flatiron MM database. The rules are based on 'relaxed' IMWG criteria, which entail exclusion of BM biopsies data and of imaging results, and reduction in either serum or urine M protein levels (rather than both) to assign partial response. This algorithm was applied to patient-level clinical trial data from the Bellini trial (Kumar et al. Lancet Oncol 2020) with response assignment made by an independent review committee (IRC) in the trial used as the 'ground truth'. Agreement between the IRC's and algorithm's assignments of response was estimated using Cohen's Kappa statistic. Differences in overall response rate (ORR) between treatment and placebo arms were calculated using stratified Cochran-Mantel-Haenszel tests based on strata at randomization with number of prior lines of therapy and previous proteasome inhibitor treatment status variables used for stratification. Results: The Bellini trial is a Phase 3 clinical trial with 2:1 design enrolling 194 and 97 patients in its treatment and placebo arms, respectively (291 patients in total). Regular assessments of M protein and FLC levels were performed (median 13 or 14 measurements), providing detailed trajectory of patient response (Table 1). Comparison between the IRC's and algorithm's assignments of responders classified as Partial Response or better (PR+) resulted in almost perfect agreement with Cohen's Kappa 0.82 (274/291 assignments in agreement). It is worth noting that the Cohen's Kappa between the IRC's and Investigator's assessments is 0.85, indicating that the algorithm's error is within some expected uncertainty. Due to the exclusion of BM information, agreement decreased to 0.56 when depths of response were considered separately as opposed to grouping PR+ patients together with most cases being overestimated as complete response (CR) or stringent CR. In assessing treatment effect, differences in ORR between the intervention and placebo arms in the trial based on IRC's assessment could be accurately recapitulated (68% [66/97] vs 71% [69/97] responders in the placebo arm and 82% [159/194] vs 87% [169/194] in the intervention arm for IRC's and algorithm's assessment, respectively). Based on these results, algorithm response assignment led to consistent conclusions about treatment efficacy in the Bellini trial. Implementation of criteria to characterize very good partial response or better (VGPR+) also led to a conclusion consistent with the Bellini trial IRC's assessment, while implementation of criteria of CR+ resulted in estimates of treatment efficacy that were higher, but directionally consonant (Table 2). Conclusions: We present a fully automated rule-based algorithm for response assessment in MM relying on longitudinal lab measurements during treatment. The algorithm uses 'relaxed' IMWG criteria to account for routine clinical practice settings and demonstrates very high agreement with the assessment of trained clinicians, while reliably reproducing the efficacy analysis in the Bellini trial when ORR and VGPR+ are considered. We envision that, if the concordance observed here is confirmed in other independent cohorts, this algorithm can be used in the assessment of response in RWD and can facilitate response assessment when suboptimal amounts of data are available. Figure 1 Figure 1. Disclosures Tyanova: F. Hoffmann-La Roche: Current Employment. Xu: F. Hoffmann-La Roche AG: Current Employment. Williamson: Amgen: Current equity holder in publicly-traded company; Genentech: Current Employment, Current equity holder in publicly-traded company. Rocci: Novartis: Other: Wife is and employee of Novartis and holds Novartis stocks; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Received travel sponsorship ; Janssen-Cilag Ltd: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Other: Received travel sponsorship ; Owner of 100% stocks of Harlock Healthcare Consulting Ltd (UK privately-held company currently not active).: Current holder of individual stocks in a privately-held company; Roche: Current equity holder in publicly-traded company; Takeda: Consultancy, Honoraria, Other: Received travel sponsorship , Speakers Bureau; Sanofi: Consultancy; NHS: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd.: Current Employment; AbbVie: Other: Received travel sponsorship . Hong: Imago BioSciences: Current Employment; Genentech, Inc.: Ended employment in the past 24 months; Stock options in Imago BioSciences: Current equity holder in publicly-traded company. Jin: Genentech Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Roose: Flatiron Health, Inc.: Current Employment; Roche: Current equity holder in publicly-traded company. Sawas: Seattle Genetics: Honoraria; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flat Iron Health: Current Employment; Acrotech: Honoraria; Daiichi-Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau. Kumar: Antengene: Consultancy, Honoraria; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; KITE: Consultancy, 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; Merck: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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. "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.
Full textAbstract:
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.
40
Xu, Tao, Stefka Tyanova, Mellissa Williamson, Alberto Rocci, Kasra Yousefi, and Shaji Kumar. "Assessment of Associations between Derived Response and Overall Survival in Patients with Multiple Myeloma Using a US-Based Electronic Health Records Database." Blood 138, Supplement 1 (November 5, 2021): 3770. http://dx.doi.org/10.1182/blood-2021-150148.
Full textAbstract:
Abstract Background: Real world data (RWD) is one of the key components to our understanding of the treatment trajectory of patients with multiple myeloma (MM) in clinical practice. However, treatment responses recorded in patients' medical records are not often standardized. We have developed an algorithm to derive real-world response (dR) for MM patients based on the International Myeloma Working Group (IMWG) criteria to overcome issues with missing values (Xu et al. Pharmacoepidemiol Drug Saf 2021). In this study, we evaluate its association with overall survival (OS) in a RWD cohort. Methods: This study included patients diagnosed with MM between Jan 1, 2011 and Jan 31, 2021 from the US-based Flatiron Health electronic health record (EHR)-derived de-identified database. We derived overall response (partial response [PR] or better, e.g. > 50% reduction of serum M-protein from baseline) to 1L treatment in newly diagnosed MM patients based on the IMWG response criteria, taking into account missing data. Associations between dR and OS were evaluated at individual- and treatment-level. At individual-level, associations were assessed using landmark analyses at approximating 3/4/5 cycles of treatment and at 6 months. Patients who died before the landmark were excluded from the analysis. At treatment-level, we stratified the cohort by year of treatment initiation (every two years from 2011-2021). Within each stratum, treatment groups were compared to estimate the hazard ratios (HRs) of OS and odds ratios (ORs) of dR, both adjusted for potential confounding factors (age, ECOG status, cytogenetic risk groups [high vs standard], time between diagnosis and first-line [1L] start date). The association between HRs and ORs was assessed by coefficient of determination (R 2) from a stratum-size weighted linear regression model, where values close to 1 imply a strong correlation and 0 indicates no association. Only significant HRs and ORs (P < 0.05) in the multivariable analysis were used in the analysis. Results: Of 6806 patients in the Flatiron Health MM database, 70% (n=4830) had serum myeloma (M) protein measured by protein electrophoresis within 30 days before the start of 1L treatment, 27% (n=1838) had urine M protein and 57.8% (n=3935) had serum free light chains (FLCs). Patients with at least one serum M protein or FLC measurement were eligible for study entry (n=5609). During 1L treatment, 4727 patients (46% female, mean ± standard deviation age 67.8 ± 10.4 years) had valid laboratory test results for dR assessment (for each patient we required a baseline measurement plus at least one additional measurement after treatment start of the same lab type), of which 71.7% (n=3387) had PR or better. The majority of the patients (n=2188, 46.3%) received a proteasome inhibitor (PI)+steroid+immunomodulatory drug (IMiD) treatment regimen, followed by PI+chemo+steroid (n=639, 13.5%), PI+steroid (n=621, 13.1%), and steroid+IMiD (n=607, 12.8%). Other treatment groups had fewer than 100 patients and were not considered in the treatment-level analysis (Table 1). At the individual-level analysis, dR was significantly associated with OS at all landmarks (HRs 0.80 to 0.81, P < 0.001, Table 2). At treatment-level, the association between dR and OS was R 2=0.67 (P < 0.001, Figure 1). Subgroup analyses were conducted for each pair of treatment groups; however, only PI+IMiD+steroid vs PI+steroid had sufficient sample sizes, which showed R 2 of 0.82 (P = 0.02). Conclusions: In the absence of recorded response data in a patient's EHR, laboratory assessments can successfully be applied using our algorithm to determine, based on part of the IMWG response criteria, the response status for patients with MM. In the RWD cohort, patients who had PR or better to 1L treatment demonstrated longer survival than non-responders. A moderate association was observed at the treatment-level between dR at 1L and OS. However, these associations might be specific to certain treatment groups and the underlying mode of action of the drugs. Further analysis will be needed to validate these results. Figure 1 Figure 1. Disclosures Xu: F. Hoffmann-La Roche AG: Current Employment. Tyanova: F. Hoffmann-La Roche: Current Employment. Williamson: Amgen: Current equity holder in publicly-traded company; Genentech: Current Employment, Current equity holder in publicly-traded company. Rocci: Novartis: Other: Wife is and employee of Novartis and holds Novartis stocks; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Received travel sponsorship ; AbbVie: Other: Received travel sponsorship ; F. Hoffmann-La Roche Ltd.: Current Employment; NHS: Ended employment in the past 24 months; Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Other: Received travel sponsorship , Speakers Bureau; Roche: Current equity holder in publicly-traded company; Owner of 100% stocks of Harlock Healthcare Consulting Ltd (UK privately-held company currently not active).: Current holder of individual stocks in a privately-held company; Celgene: Honoraria, Other: Received travel sponsorship ; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag Ltd: Honoraria, Speakers Bureau. Yousefi: Roche: Current Employment, Current equity holder in publicly-traded company. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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.
Full textAbstract:
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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Andrie, Rachael M., John M. Burke, Christopher R. Flowers, Nathan H. Fowler, Jeff P. Sharman, Timothy A. Quill, Kevin L. Obholz, and Ian W. Flinn. "Analysis of an Online Treatment Decision Tool Reveals Variances in Practice between Experts and Oncology Healthcare Providers for Newly Diagnosed Follicular Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 414. http://dx.doi.org/10.1182/blood-2019-128988.
Full textAbstract:
Background Follicular lymphoma (FL) remains an incurable disease characterized by a persistent risk of relapse and progression. Therefore, to effectively delay progression of disease while maintaining patient quality of life, it is critical that clinicians select therapy for patients with newly diagnosed FL that most optimizes clinical outcomes. To help inform frontline treatment decisions among healthcare providers (HCPs) who care for patients with FL, we have developed an online treatment decision support tool that provides case-specific, individual recommendations from multiple experts. Here we present data from an analysis of self-reported practice trends from HCPs using the tool and compared with corresponding treatment recommendations from FL experts. Methods In May 2018, 5 experts in lymphoma patient care provided specific treatment recommendations for 72 distinct case scenarios of newly diagnosed FL defined by a simplified set of key patient and disease characteristics: disease stage, tumor grade, tumor bulk or burden, presence of symptoms, age and fitness, and patient's primary goal for treatment. Participating HCPs used selection menus to enter specific patient and disease factors along with their intended treatment plan for the case. After completing case entry, individual expert treatment recommendations for that specific patient case were displayed, followed by a short survey designed to determine the impact of the expert recommendations on the HCP's planned course of treatment. Results From August 2018 to July 2019, 311 HCPs (86% MDs) entered 522 patient case scenarios into the online tool. Among the 5 experts, there was a majority consensus in treatment selection for 89% of newly diagnosed FL cases. However, a comparison of expert and HCP treatment choices showed substantial variability for several different patient case scenarios (Table). For example, more than 40% of HCPs recommended chemoimmunotherapy (CIT) for patients with grade 1-3a FL with low tumor burden and no symptoms in contrast to 100% of experts who recommended observation or single-agent rituximab. For patients with grade 1-3a FL, high tumor burden, and a goal to achieve CR or delay PFS, regardless of symptoms, more than 50% of HCPs chose a bendamustine-based CIT regimen in agreement with the experts. However, approximately one third of HCPs chose a more aggressive CHOP-based CIT regimen. For treatment of grade 3b disease or suspected transformation with the intention to achieve CR or delay PFS, more than 25% of HCPs would select a bendamustine-based CIT regimen as compared with 100% of experts who chose R-CHOP. Among the HCPs whose intended treatment plan differed from the consensus expert recommendation, 60% indicated that they would change their initial choice of treatment after viewing the expert recommendations. Conclusions Analysis of case data from this online treatment decision tool suggests ongoing differences in practice between experts and HCPs for multiple case scenarios of newly diagnosed FL, including examples of potential overtreatment in patients with low tumor burden and undertreatment of patients with suspected transformation. Consensus expert recommendations in this online tool changed the intended treatment plan of many HCPs using it and, therefore, has the potential to optimize the care of patients newly diagnosed with FL. A detailed comparison of expert and HCP practice for different case scenarios will be presented. Table Disclosures Burke: Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. Flowers:Celgene: Consultancy, Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; Denovo Biopharma: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy. 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; 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; Novartis Pharmaceuticals Corporation: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sharman:AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding.
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Vachhani, Pankit, Jonathan A. Abbas, Evelyn M. Flahavan, Esprit Ma, Tao Xu, Huan Jin, Melissa Montez, et al. "Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States." Blood 138, Supplement 1 (November 5, 2021): 2290. http://dx.doi.org/10.1182/blood-2021-147851.
Full textAbstract:
Abstract Background: Ven+HMA is now a standard treatment (Tx) for newly diagnosed (ND) AML in patients (pts) aged ≥75 years (y), or with comorbidities precluding intensive chemotherapy. The Phase 3 VIALE-A trial demonstrated clinical benefit and longer overall survival (OS) for Ven+azacitidine (Aza) vs Aza alone; however, frequent Ven dose modifications (mods) occurred due to cytopenias (DiNardo et al. NEJM 2020). We describe real world (RW) Tx practices and outcomes in ND AML pts treated with Ven+HMA in the US. Methods: This retrospective cohort study used the Flatiron Health electronic health record (EHR)-derived, nationwide, de-identified database. Pts aged ≥18 y with ND AML, initiating Ven+HMA Tx ≤30 days (d) from diagnosis, from Jun 1, 2018 to Jan 31, 2020, were included (i.e., prior to VIALE-A data availability, reflecting early experience). Ven Tx data and Tx mods (Ven dose and Tx schedule changes [in-cycle interruptions, cycle delays, schedule per cycle changes]) were abstracted from the EHR, including frequency of and reasons (where documented) for Tx mods and discontinuations (d/c). Timing of bone marrow (BM) biopsy and response to Tx were measured. BM response was defined as ≤5% blasts by BM biopsy. RW complete response/complete response with partial hematologic recovery (rwCR/CRh) was defined as ≤5% BM blasts, with platelet count >50 × 10 9/L and absolute neutrophil count >0.5 × 10 9/L, within 14 d of BM biopsy. Tx mods post-rwCR/CRh are described. Median Ven+HMA Tx duration, and OS from start of Ven Tx to d/c, death, or censoring at the last EHR activity before data cutoff (Aug 31, 2020) were examined by Kaplan-Meier analyses. Time-varying survival analyses assessed the effect of Ven Tx mods on Tx duration and OS. Results: A total of 169 eligible pts treated with Ven+HMA were included. Median age at diagnosis was 77 y, 27% of pts had an ECOG performance status ≥2, 44% had secondary AML, and the overall majority (85%) were treated in community practice. European LeukemiaNet (ELN) classification was 13% favorable, 22% intermediate, 39% adverse, and 26% unknown. By Day 7 of Tx (after ramp-up), Ven dose was 400 mg in 49% of pts, 300 mg in 3%, 200 mg in 20%, and ≤100 mg in 20%. Dose was not recorded in 8% of pts. Of 72 pts with doses <400 mg, 19 (26%) had concomitant Tx with CYP3A4 inhibitors documented in the EHR. In total, 56/169 (33%) pts had Ven dose changes in the subsequent Tx cycles, with toxicity (38%) or drug-drug interaction (25%) the most common reasons. Tx schedule changes were common and noted in 101 (60%) pts; primarily due to toxicity (78% of pts). Median time to first Tx schedule change was 33 d (95% confidence interval [CI] 28-52), at approx. 1-2 Tx cycles. At 7.2 months (mo; range 0.6-24.8) median follow-up, median Tx duration was 5.2 mo (95% CI 4.0-7.7) and median OS (mOS) was 8.4 mo (95% CI 7.2-11.1). Of the 95 pts with BM data during follow-up, 51 (54%) had their first biopsy by Day 28 (±14) of Tx (proxy for BM around Tx Cycle 1), with the majority of pts (41/51; 80%) achieving a BM response at that time. Of the 82% (78/95) of pts who had a BM response at any time, 47% (45/95) had a rwCR/CRh. Three of 95 (3%) pts with documented BM biopsy had early mortality (≤60 d of starting first-line Tx) vs 14/74 (19%) pts without documented BM biopsy. Tx mods post-rwCR/CRh occurred in 25/45 (56%) pts; dose holds occurred in 7/25 pts, cycle delays in 8/25, Tx schedule changes in 6/25, dose changes and d/c in ≤4/25. Within the entire cohort, time-varying adjusted analyses showed that, compared with pts with no Tx schedule changes, those with Tx schedule changes had a longer median Tx duration (4.2 vs 6.0 mo, respectively; non-significant) and longer mOS (7.2 vs 10.0 mo, respectively; p=0.02; Figure). Conclusions: This study reflects early RW experience with Ven+HMA Tx in a predominantly community setting, ahead of Phase 3 VIALE-A data availability. Around half of pts started on full-dose Ven, suggesting that azole prophylaxis was either deferred or not received in many pts, although not all pts on lower doses had documented CYP3A4 inhibitor Tx. Only half of pts had a documented BM biopsy at approx. Cycle 1, but a high response rate was observed in evaluated pts. While the RW cohort reported here had a shorter follow-up time and mOS than reported in clinical trials, pts with Tx schedule mods had longer OS vs those without. These observations highlight, among other points, the importance of appropriate Ven management, including early BM assessment, to optimize pts' outcomes. Figure 1 Figure 1. Disclosures Vachhani: CTI BioPharma Corp: Consultancy; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham: Current Employment; Abbvie: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Astellas Pharma: Speakers Bureau; Seattle Genetics: Research Funding; Blueprint Medicines: Consultancy. Abbas: Tennessee Oncology: Current Employment; Jazz: Consultancy, Speakers Bureau; TG: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Flahavan: Roche Products Ltd. UK: Current Employment; Roche: Current equity holder in publicly-traded company. Ma: Genentech, Inc.: Current Employment, Other: May hold equity. Xu: F. Hoffmann-La Roche AG: Current Employment. Jin: Roche: Current equity holder in publicly-traded company; Genentech Inc: Current Employment. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Huang: Genentech: Current Employment; University of Washington: Ended employment in the past 24 months. Gershon: Genentech: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of stock options in a privately-held company. Ku: Genentech: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Flores: Genentech: Current Employment; Roche: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Onishi: Genentech: Current Employment; Roche: Current Employment, Current equity holder in publicly-traded company. Bui: Abbvie: Current Employment, Other: May hold equity.
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Barrington, Sally F., Judith Trotman, Deniz Sahin, David Belada, Andrew Davies, Robert MacEwan, Carolyn Owen, et al. "Baseline PET-Derived Metabolic Tumor Volume Metrics Did Not Predict Outcomes in Follicular Lymphoma Patients Treated with First-Line Immunochemotherapy and Antibody Maintenance in the Phase III GALLIUM Study." Blood 132, Supplement 1 (November 29, 2018): 2882. http://dx.doi.org/10.1182/blood-2018-99-117235.
Full textAbstract:
Abstract Introduction: Evidence suggests that baseline 18fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography-derived parameters, such as metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax), may predict progression-free survival (PFS) in patients (pts) with follicular lymphoma (FL) treated with first-line R-CHOP immunochemotherapy. However, data from pts routinely treated with bendamustine or antibody maintenance are lacking, and several methods have been used to evaluate PET metrics for tumor burden in pts with lymphoma. This prospective exploratory analysis assessed the prognostic value of baseline MTV, total glycolytic activity (TLG), and SUVmax for PFS and overall survival (OS) in pts with FL treated with first-line obinutuzumab (GA101; G) or rituximab (R) plus chemotherapy (chemo) in the Phase III GALLIUM study (NCT01332968; Marcus et al. N Engl J Med 2017), using two published methods for measuring tumor burden. Methods: Pts ≥18 years with previously untreated FL (grade 1-3a) and advanced disease (Stage III/IV or Stage II with tumor diameter ≥7cm) requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg intravenous [IV] on days [D] 1, 8, and 15 of cycle [C] 1 and D1, C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemo (CHOP, bendamustine, or CVP). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. After an early protocol amendment, PET imaging at baseline and end of induction (EOI) was mandatory in the first 170 pts and optional thereafter. Independent reviewers segmented FDG-avid tumors applying thresholds of I) standardized uptake value (SUV)max ≥2.5, and II) SUVmax ≥41% of lesional maximum SUV and a minimum volume of 1mL, using MIM software. Results were analyzed for the PET intent-to-treat population. MTV, TLG, and SUVmax were split into quartiles: Q1, <25%; Q2, 25-49%; Q3, 50-74%; and Q4, 75-100%, based on their distribution in the available population. Investigator-assessed PFS and OS were estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Hazard ratios refer to stratified log-rank tests comparing Q2, Q3, and Q4 with Q1, adjusted for the randomization stratification factors FLIPI score and chemo regimen. Multivariable Cox analyses were also undertaken to investigate whether baseline MTV quartiles and other covariates were prognostic for PFS. Statistical significance at 0.05 was determined using the Wald test. Results: Of 1202 enrolled FL pts, 609 had a baseline PET scan and 521 had baseline PET scans available for all quantitative assessments by central review; 303 pts (58%) received bendamustine, 179 (34%) CHOP, and 39 (8%) CVP. After a median follow-up of 57 months, none of the 3 baseline PET parameters (MTV or TLG measured by either method or SUVmax) significantly predicted PFS (Table). Multivariable analysis, which included baseline pt and disease characteristics, confirmed that MTV did not predict PFS. Consistent with the primary analysis, receipt of G-chemo was an independent predictor of improved PFS. Conclusions: Contrary to previous reports, these prospective data from the Phase III GALLIUM study show that baseline quantitative PET metrics do not predict PFS or OS in FL pts receiving first-line immunochemotherapy (of whom the majority received bendamustine) followed by antibody maintenance treatment, irrespective of the measurement method applied. Conversely, a previously reported analysis from GALLIUM suggests that PET-complete metabolic response at EOI assessed using Lugano 2014 criteria is a strong predictor of long-term outcome in these pts. Table. Table. Disclosures Barrington: EPSRC: Research Funding; Department of Health (England): Research Funding; F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; National Institute of Health Research: Research Funding; MRC: Research Funding; CRUK: Research Funding. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding. Sahin:Roche: Employment, Equity Ownership. Belada:Janssen-Cilag: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Davies:Janssen: Consultancy, Honoraria; GSK: Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Acerta Pharma: Consultancy, 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, Speakers Bureau; Kite: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Pfizer: Research Funding. MacEwan:Consultant Radiologist/ Nuc Med Physician: Consultancy. Owen:Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Honoraria; Janssen: Honoraria, Research Funding; Teva: Honoraria; AbbVie: Research Funding. Ptáčník:F. Hoffman-La Roche: Honoraria. Hiddemann:F. Hoffman-La Roche: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Mattiello:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Meignan:F. Hoffman-La Roche Ltd: Honoraria.
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Kostakoglu, Lale, Paola Berchialla, Federico Dalmasso, Larry A. Pierce, Umberto Vitolo, Maurizio Martelli, Laurie H. Sehn, et al. "A Prognostic Model Integrating PET-Derived Quantitative Parameters and Image Texture Analyses Using Radiomics in a Large Prospective Phase III Trial, GOYA." Blood 134, Supplement_1 (November 13, 2019): 883. http://dx.doi.org/10.1182/blood-2019-123450.
Full textAbstract:
Introduction: Our objective was to develop a prognostic model that predicts progression-free survival (PFS) and overall survival (OS) to enable risk-adapted strategies in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We retrospectively investigated the value of quantitative image texture features (i.e. 'radiomics' evaluating tumor heterogeneity) using FDG PET/CT data sets in a large, prospective Phase III trial, GOYA (NCT01287741). Methods: In the GOYA trial, which compared obinutuzumab versus rituximab both in combination with CHOP chemotherapy, there was no significant treatment effect between the two arms, thus the two arms were combined for this study. Baseline PET/CT images with regions of interests (ROIs) defined by qualified physicians were analyzed for radiomics features. Image texture features (ITF) were computed using the open-source and validated PET Oncology Radiomics Test Suite (PORTS). The clinical risk factors (International Prognostic Index [IPI], Ann Arbor stage, extranodal disease, bulky disease), cell of origin (COO), standard PET-derived metrics (standard uptake value [SUV]-mean, SUV-max, total metabolic tumor volume [TMTV], total lesion glycolysis [TLG]), SUV histogram metrics (variance, skewness, and kurtosis), and ITF were evaluated for prediction of PFS and OS. TMTV was estimated using adaptive thresholding. Prognostic models were generated by means of multivariate Cox regression analysis, modeling PFS, and OS. In the absence of an independent patient cohort for external model validation, an internal validation, based on c-index and Brier score, was carried out using bootstrap resampling methods. Stratification of patients into risk groups was achieved through maximally selected rank statistics. Multivariate analysis was also carried out on a subgroup of patients with available COO information. Results: The median follow-ups for PFS and OS were 46 and 50 months, respectively. Baseline PET scans were available for 1334 patients with detectable lesions, and 1077 baseline scans were evaluable for calculating ITFs. In the univariate analysis, high TMTV, histogram mean, histogram variance, and the ITFs gray-tone spatial dependence matrices (GTSDM) difference entropy and low gray-level zone length matrix (GLSZM) small zone high gray emphasis were risk factors for PFS, while high TMTV, histogram mean, and the ITF GTSDM inverse difference moment were risk factors for OS (Table 1, showing 95% CI, HR, and p-values for both univariate and multivariate analyses). In multivariate analysis, the risk factors included IPI, Ann Arbor stage, high TMTV, histogram mean, and GTSDM inverse difference moment; results were generally consistent in the multivariate subgroup analysis on patients with COO data available (Table 1). Based on the multivariate model, the probabilities for PFS and OS at 2 and 4 years for individual patients were established (Table 2). By combining TMTV (four categorical groups) with ITF, COO, and predictive clinical factors, three prognostic subgroups of treatment failure risk were identified: low (55% of patients), intermediate (34%), and high (11%). Hazard ratios for high and intermediate risk compared with low risk were 2.16 (p<0.001) and 1.17 (p=0.004) for PFS, and 3.82 (p<0.001) and 1.85 (p<0.001) for OS. The corresponding probability of survival at 2-years for high, intermediate and low risk groups were 87%, 82%, and 75% for PFS, and 94%, 90%, and 82% for OS. The 4-year survival probabilities were 83%, 77%, and 68% for PFS, and 91%, 86%, and 75% for OS (Table 2). For PFS, the accuracy of the Cox model was 0.63 with clinical variables only, 0.65 with the addition of TMTV, and 0.69 with the addition of ITFs; for OS, the corresponding values were 0.63, 0.65, and 0.70. Conclusion: A model including PET-derived quantitative ITF, in addition to significant clinical features, was able to predict survival probability for untreated DLBCL patients with good precision. The proposed PET-based prognostic model may help identify patients who could benefit from risk-adapted treatment modifications or novel approaches. Acknowledgments: GOYA was sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial assistance, under the direction of Lale Kostakoglu, was provided by Katie Smith of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Dalmasso:I-See s.r.l.: Employment. Pierce:Precision Sensing LLC: Equity Ownership. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Sehn:Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria. Trněný:Takeda: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bolen:Genentech, Inc.: Employment; F. Hoffmann-La Roche: Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lee:Genentech: Employment; F. Hoffman-La Roche: Equity Ownership. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Kinahan:Co-founded PET/X LLC: Equity Ownership; Philips Medical: Research Funding; GE Healthcare: Research Funding; F. Hoffmann-La Roche: Consultancy. Chauvie:International Agency on Atomic Energy (IAEA): Consultancy; Co-owner of Dixit srl (spin-off University of Torino): Equity Ownership; F. Hoffmann-La Roche: Research Funding; Fondazione Cassa di Risparmio di Cuneo (CRC): Research Funding; Italian Foundation on Lymphoma (FIL): Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; SIRTEX: Speakers Bureau.
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Clemow, D. B., C. Sapin, T. Hibi, M. C. Dubinsky, S. Vermeire, S. Schreiber, T. H. Gibble, et al. "A186 ASSOCIATION OF ULCERATIVE COLITIS BOWEL URGENCY IMPROVEMENT WITH CLINICAL RESPONSE AND REMISSION." Journal of the Canadian Association of Gastroenterology 6, Supplement_1 (March 1, 2023): 31–32. http://dx.doi.org/10.1093/jcag/gwac036.186.
Full textAbstract:
Abstract Background Ulcerative colitis (UC) can result in a high prevalence of bowel movement urgency (BU), significantly reducing patient quality of life. Purpose Early BU improvement association with later clinical endpoint improvements was examined in moderately-to-severely active UC patients (pts) treated with mirikizumab (miri). Method BU was evaluated in Phase 3 randomized placebo (PBO)-controlled 12-week induction (LUCENT-1, NCT03518086) and 40-week maintenance (LUCENT-2, NCT03524092) trials with miri. Pts received IV miri 300mg or PBO during induction. Week (W)12 miri responders were rerandomized at LUCENT-2 baseline (BL) to subcutaneous miri 200mg or PBO. BU was measured with 11-point Urgency Numeric Rating Scale (UNRS) from 0 (no urgency) to 10 (worst possible). Pts’ UNRS scores were an average from 7 consecutive days prior to visit. Association of pts with BU Clinically Meaningful Improvement (CMI) or BU remission between BL and W4 with the proportion of pts achieving clinical response, and clinical, endoscopic, or symptomatic remission at end of W12 was assessed. For pts who achieved clinical response at W12, the analyses were repeated for the end of maintenance based on W12 BU status. Logistic regression models with treatment, urgency (BU CMI or BU Remission), treatment-by-urgency group interaction, and stratification factors were fitted to examine the association between early urgency improvement and later clinical endpoints. Result(s) Treatment-by-urgency group interactions were not statistically significant across clinical outcomes for induction and maintenance. For induction, treatment and urgency status were statistically significant. Pts experiencing BU CMI or BU remission at W4 were consistently more likely to achieve clinical response, and clinical, endoscopic, or symptomatic remission at W12 for both treatment groups. For remission, only treatment main effect was statistically significant. Among miri induction clinical responders (an enriched population), BU CMI or BU Remission at end of induction (W12) was not associated with later maintenance efficacy outcomes (W52). Miri-treated pts achieved higher rates of clinical response, and clinical, endoscopic, or symptomatic remission at W52 than with PBO regardless of BU CMI or BU Remission at W12 (Table). Image Conclusion(s) Early BU Improvement, CMI or Remission, was associated with better clinical outcomes during induction for miri and PBO pts, showing BU is a sensitive predictor of early clinical outcomes. Among miri induction responders, miri consistently provided better maintenance of response and remission rates than PBO. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest D. Clemow Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, T. Hibi Grant / Research support from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, S. Vermeire Consultant of: AbbVie, Arena Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, ProDigest, Progenity, Prometheus Therapeutics and Diagnostics, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance Biopharma, and Tillots Pharma AG, Speakers bureau of: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Janssen, Pfizer, Robarts Clinical Trials, and Takeda, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, L. Peyrin-Biroulet Grant / Research support from: AbbVie, Fresenius Kabi, Merck Sharp & Dohme, and Takeda, Consultant of: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillots Pharma AG, Viatris, and Vifor Pharma, M. Watanabe Grant / Research support from: AbbVie, Alfresa Pharma, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical, Consultant of: AbbVie, Boehringer Ingelheim, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Nippon, and Takeda, Speakers bureau of: EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Janssen, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Japan, Takeda, and Zeria Pharmaceutical, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared
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Clay, E. Leila Jerome, Miranda Bailey, Dan Drozd, Jincy Paulose, Nicholas Ramscar, Kieran Mace, and David Wormser. "A Patient-Centric Approach to Improve the Understanding of Sickle Cell Disease Using Real-World Data." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-139148.
Full textAbstract:
Background: Sickle cell disease (SCD) comprises a group of inherited blood disorders, and is a complex, multi-system, disease. SCD is associated with a variety of clinical complications that affect multiple organ systems. These complications are driven primarily by vaso-occlusion and hemolytic anemia, and can result in end-organ damage and early death. Painful vaso-occlusive crises (VOCs) are a characteristic feature of SCD and can require healthcare intervention. Despite recent advances in the screening, management and treatment of SCD, gaps remain in our understanding of the disease in the real-world setting. These include how best to transition from pediatric to adult care and how to manage specific complications. Currently, most real-world evidence (RWE) is generated from information captured in payer databases, which is not as comprehensive as the information recorded in electronic medical records (EMRs). Despite being potentially valuable sources of real-world, clinical information, EMRs for individual patients in the USA are not centralized, often being held by multiple healthcare providers using different EMRs. This fragmented system prevents generation of clear, comprehensive RWE, both in general and for SCD specifically. Furthermore, there is a lack of harmonization between EMR companies/systems in the types of information included and how it's recorded. A separate approach that collates all available data from EMRs into a single, comprehensive record prior to RWE analysis would therefore greatly improve the accessibility of the available information and the quality of subsequent data analysis. Aims: In contrast to existing RWE, this study explores the value of collating EMRs for each patient into a single, consistently structured format, with the aim of developing richer RWE to complement existing data on SCD. It is hypothesized that the resulting longitudinal overview of each patient's care will contribute to an improved understanding of SCD in the real-world setting: firstly, by better capturing how many VOCs patients with SCD experience, with an indication of the proportion of VOCs that are being home-managed; secondly, by gaining deeper insights into the prevalence and progression of end-organ damage and any association with VOCs; and finally, by highlighting the type and site of care of SCD in the real world (eg medications, treating healthcare professional [HCP] specialties and the type of clinic visited). Study design: The study population will comprise 400 patients with SCD from the USA. Patient recruitment occurs directly via social media and indirectly through a variety of partnerships including HCPs and patient advocacy groups. To enroll, patients sign an informed consent form allowing their de-identified medical information to be shared with third-party organizations to advance SCD research. Enrolled patients gain access to their medical records via a dashboard. The key inclusion criteria are: a confirmed SCD diagnosis (irrespective of phenotype); aged ≥16 years at enrollment; and ≥1 inpatient admission for a VOC in the 12 months prior to enrollment. The key exclusion criterion is the absence of medical records. Components of EMRs collected include doctors' notes, laboratory and test results, clinical imaging and treatment records. Human-curated natural language processing and machine learning is used to extract, structure and code data from the structured sections and unstructured narrative text of the EMR. All medical records, from all visits, will be collected where possible and are expected to comprise ≥7 years of retrospective data for each patient. Results: Between 1 December 2019 and 24 June 2020, a total of 46 patients with a mean age of 36 years (SD 9.7) were enrolled. For each patient, a median of 6.8 years of data from a median of 32.5 providers were obtained. Conclusions: The evidence derived from this study aims to advance the understanding of real-world practices in the management of SCD. It may also provide further learnings regarding the prevalence of complications and any association between VOCs and end-organ damage. Generating a single, structured overview of all EMRs for each patient allows for richer insight generation and a more comprehensive analysis of RWE, compared with existing approaches. The insights gained from this RWE may inform future studies and clinical trials in SCD, with the ultimate aim of improving the quality of life of patients. Disclosures Clay: Novartis: Consultancy; GBT: Consultancy. Bailey:Novartis Pharmaceuticals Corporation: Current Employment. Drozd:F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; PicnicHealth: Current Employment, Current equity holder in private company. Paulose:Novartis Pharma AG: Current Employment. Ramscar:Novartis Pharma AG: Current Employment. Mace:Roche/Genentech: Ended employment in the past 24 months; PicnicHealth: Current Employment. Wormser:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company.
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Jaeger, Ulrich, Alexander Egle, Ingrid Simonitsch-Klupp, Sonja Heibl, Peter Neumeister, Ella Willenbacher, Florian Erlsbacher, Julian Larcher-Senn, Michael A. Fridrik, and Richard Greil. "Phase II Single-Arm "Window-of-Opportunity" Study of a Combination of Obinutuzumab and Venetoclax in Early Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) - First Results of the AGMT NHL15B Study." Blood 136, Supplement 1 (November 5, 2020): 26. http://dx.doi.org/10.1182/blood-2020-136953.
Full textAbstract:
Background: Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis with a median overall survival (OS) of less than 2 years. Relapse immuno-chemotherapy followed by autologous stem cell transplantation is the standard of care, but response rates are still not satisfactory and a substantial number of patients are ineligible for transplant or aggressive therapies. Novel antibodies, small molecules and CAR-T cell therapies have been explored for this population. We initiated a study with obinutuzumab and venetoclax to evaluate the effect of a chemo-free regimen in these refractory or early relapsing DLBCL patients with the option to prepare these patients for cell therapy. Study design and Methods: Twenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression and CD20 positivity were included in this prospective, Fleming-design Phase II single-arm study. Obinutuzumab was given i.v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following 21-day cycles. Venetoclax was given at 800mg daily p.o. Treatment was repeated for up to 3 cycles. Eligible patients were planned to either proceed to stem cell transplantation or receive up to 9 cycles of maintenance if ineligible for transplant. The primary endpoint was objective response rate by Lugano 2014 criteria after 3 cycles (investigator assessed). Secondary objectives included dose-limiting toxicities, response duration, progression-free and overall survival and ability to proceed to further stem cell transplantation. A biomarker program investigated histopathologic, genomic and biological factors associated with outcome. The trial was registered under Eudract Nr. 2016-001760-10 andNCT02987400. Results: The ITT population consisted of 21 patients (median age 64 years, 9 M, 12F) with refractory or early relapsed DLBCL after 1 (N=11) to 4 previous lines of therapy. The majority of patients received 3 cycles of obinutuzumab-venetoclax (range 1-8). The regimen was well tolerated. No DLTs were observed. Adverse events were observed in 85.7% with gastrointestinal disorders and administration site conditions being most prominent. Cytopenias were reported in 23.8% and infections in 19%. Severe adverse events were observed in 19%. The objective response rate was 38.1% (8/21 patients) with a best response of 5 CR (23.8%) and 3 PR (14.2%). Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and an overall survival of 59.3% at 168 days. All deaths were due to underlying disease. Three of 6 responding patients eligible for transplant went on to ASCT, while 2 CR patients refused. Overall, 6 patients received ASCT and 3 patients anti-CD19 CAR-T cells. Three patients received further maintenance cycles. At final visit, 20% of patients were still in CR while 73.3% of patients had progressed. Overall the data indicate that this therapy creates a response period of approximately 3 months in responding patients. Progressive disease was treated with various regimens including chemo-immunotherapy, bispecific agents, antibody-drug conjugates, immunomodulators or small molecules. To date, 7 patients have died. Characteristics of responding patients include very good or good R-IPI as well as low number of previous therapies (median=1). BCL2 expression and genomic features are currently being analysed and will be presented at the meeting. Conclusion: Obinutuzumab and Venetoclax represents a chemo-free relapse regimen with low toxicity for DLBCL with the ability to induce objective responses in 38.1% of patients including complete remissions. Its potential to serve as a "window-of-opportunity", relapse- or bridging-treatment in preparation for stem cell or CAR-T cell therapies will be further increased by identification of clinical or biological predictors of response. Supported by a grant from Roche Austria. Disclosures Jaeger: F. Hoffmann-La Roche: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Heibl:BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Willenbacher:AbbVie: Honoraria; Roche: Honoraria. Erlsbacher:Assign Data Management and Biostatistics GmbH: Current Employment. Larcher-Senn:Assign Data Management and Biostatistics GmbH: Current Employment. Fridrik:Roche: Consultancy, Other; AbbVie: Consultancy, Other. Greil:BMS: 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; Janssen: 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; Daiichi Sankyo, Gilead: 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; Novartis: 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; Astra zeneca: 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.
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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.
Full textAbstract:
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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Callaghan, Michael U., Claude Négrier, Ido Paz-Priel, Tiffany Chang, Sammy Chebon, Michaela Lehle, Johnny Mahlangu, et al. "Safety and Efficacy of Emicizumab in Persons with Hemophilia a with or without FVIII Inhibitors: Pooled Data from Four Phase III Studies (HAVEN 1-4)." Blood 136, Supplement 1 (November 5, 2020): 3–5. http://dx.doi.org/10.1182/blood-2020-137438.
Full textAbstract:
Introduction: Emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in people with hemophilia A (PwHA). The primary efficacy and safety of emicizumab were reported previously, but long-term data are limited. Here, data from a wide age-range of PwHA with/without factor (F)VIII inhibitors enrolled in the Phase III HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637), and HAVEN 4 (NCT03020160) studies are pooled to establish the durable efficacy and safety of emicizumab. Methods: The studies enrolled pediatric and adult PwHA with/without FVIII inhibitors. Participants received emicizumab prophylaxis 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. All participants assigned to receive emicizumab (including those assigned to control arms who later switched) are included in this analysis. Participants and/or caregivers recorded outcomes of bleeding events via the Bleed and Medication Questionnaire (BMQ). Data from HAVEN 1-4 were pooled for an aggregate analysis of emicizumab efficacy and safety. Efficacy endpoints include calculated mean annualized bleed rates (ABRs; discrete, consecutive 24-week treatment intervals), model-based ABRs (calculated via negative binomial regression for full study period), percentage of participants with zero and 1-3 treated bleeds, and annualized cumulative dose of coagulation factor (ACD). Safety endpoints include incidence of adverse events (AEs) and AEs of special interest. Results: Overall, 400 PwHA in HAVEN 1, 2, 3 and 4 (n=113, 88, 151, and 48, respectively) are included in the efficacy analysis for a total of 970.3 patient years (cutoff: 15 May 2020). The safety population comprises 399 PwHA who received ≥1 dose of emicizumab (1 PwHA was randomized to receive emicizumab but did not start treatment). The median age at baseline was 28.5 (range 1-77) years. The majority of participants were White (66.8%) or Asian (18.8%); 52.3% had FVIII inhibitors. In the 24 weeks prior to study entry, 60.9% of participants had target joints. The median duration of efficacy period was 120.4 (interquartile range 89.0-164.4) weeks; 85.0% of participants had an efficacy period of ≥74 weeks; 11 participants (2.8%) discontinued study treatment. Across all 4 studies, 90.9-94.8% of the observation period was covered by completed BMQs. Across all studies, the model-based treated bleed ABR was 1.4 (95% confidence interval 1.1-1.7); treated bleed ABRs remained low throughout, and were seen to decrease with successive 24-week treatment intervals (Table 1). During Weeks 121-144 (n=170), 82.4% of participants had zero treated bleeds, and 15.3% of participants had 1-3 treated bleeds. During the same period, 91.8% and 90.0% had zero treated spontaneous/joint bleeds respectively (Figure 1). The proportion of participants with target joints reduced from 60.9% prior to study entry to 4.6% at Weeks 1-24, then <1.5% in all subsequent treatment intervals. ACD of FVIII (Table 2), activated prothrombin complex concentrate (aPCC) and activated recombinant FVII (rFVIIa, Table 3) generally decreased across each 24-week treatment interval. Emicizumab was well tolerated (Table 4), and no participants discontinued due to AEs beyond the five previously described (Oldenburg et al. N Engl J Med 2017; Young et al. Blood 2019; Mahlangu et al. N Engl J Med 2018; Pipe et al. Lancet Haem 2019). At data cut, 1 fatality, 3 thrombotic microangiopathies (TMAs), and 4 thromboembolic events (TEs) have been reported; all but 1 occurred in HAVEN 1. All TMAs and 2 of 4 TEs were associated with concomitant aPCC use. The percentage of participants with ≥1 drug-related AE in Weeks 1-24, 25-48 and 49-72 were 28.8%, 6.8%, and 3.0% respectively; over the same intervals, injection site reactions were observed in 23.3%, 4.8%, and 2.5% of participants. Conclusions: With nearly 3 years of follow-up, emicizumab maintained low bleed rates in PwHA of all ages, with/without FVIII inhibitors. ABRs continued to decrease and the proportion of participants with zero treated bleeds increased with each consecutive 24-week period; the trend was the same for the proportion of participants with zero joint bleeds and almost all target joints resolved. The ACDs of FVIII, aPCC, and rFVIIa decreased with successive treatment intervals. Emicizumab remains well tolerated over long-term follow-up, and no new safety concerns have been identified to date. Disclosures Callaghan: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylum: Current equity holder in publicly-traded company; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Sancillio: Other. Négrier:CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Chebon:F. Hoffmann-La Roche Ltd: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Lehle:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company. Mahlangu:CSL Behring, Catalyst Biosciences, Freeline Therapeutics, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Consultancy; South Africa Medical Research Council, Wits Health Consortium, Colleges of Medicine of South Africa: Membership on an entity's Board of Directors or advisory committees; CSL Behring, Catalyst Biosciences, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Speakers Bureau; BioMarin, CSL Behring, Freeline Therapeutics, Novo Nordisk, Novartis, Pfizer, Sanofi, F. Hoffmann-La Roche Ltd, uniQure: Research Funding. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Kruse-Jarres:Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy; CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau. Mancuso:Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Sobi, PedNet Foundation: Consultancy; Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Octapharma, Grifols, Sobi: Speakers Bureau; Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Catalyst, Kedrion, Sobi: Membership on an entity's Board of Directors or advisory committees; Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy: Current Employment. Niggli:F Hoffmann-La Roche Ltd: Current Employment. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Shima:Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Consultancy. Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding. Schmitt:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Asikanius:Fimea: Current Employment; F Hoffman-La Roche Ltd: Ended employment in the past 24 months; F Hoffmann-La Roche Ltd: Divested equity in a private or publicly-traded company in the past 24 months. Levy:F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months; Spark Therapeutics: Current Employment; Baxalta US: Patents & Royalties: Royalties from ADAMTS13 patent . Pipe:Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Oldenburg:Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Speakers Bureau; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche. Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Other; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Membership on an entity's Board of Directors or advisory committees; University Clinic Bonn: Current Employment; Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Takeda: Research Funding; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Honoraria.