Zeitschriftenartikel zum Thema „Appelists“

El presente artículo se centra en una experiencia de propaganda fascista en el extranjero, en concreto sobre la obra de Mario Appellius, Cile e Patagonia. Empezaremos con trazar algunas de las características generales de la propaganda de Mussolini a nivel nacional e internacional, poniendo mayor énfasis sobre el concepto de cultura fascista. En segundo lugar, abordaremos el tema de la cultura fascista en el extranjero, haciendo hincapié sobre los mecanismos utilizados por el Duce para aumentar su consenso. Después, nos centraremos en la figura de Mario Appellius y analizaremos algunos capítulos de su obra dedicada a Chile, focalizándonos en la actitud del autor hacía el pequeño país andino; por último, trazaremos nuestras conclusiones subrayando los aspectos más interesantes de esta experiencia literaria de propaganda fascista en Chile.

During the Fascist ventennio, prominent Italian writers and journalists, such as Mario Appelius, Raffaele Calzini, Arnaldo Cipolla, Arnaldo Fraccaroli, Roberto Suster and Cesco Tommaselli, reported from China, Japan and Korea for Il Popolo d'Italia, Corriere della Sera and La Stampa. Their travel narratives were crucial for the creation and diffusion in Italy of the dominant representation of China and Korea as remote, decadent and exotic societies; and of Japan as a progressive society resonant with Fascist Italy. The narrativisation of these countries in Italian travelogues from the Fascist ventennio was part of a widespread discursive practice by Italian intellectuals willing to subscribe to, and actively disseminate, the guiding principles of Fascism. When emphasising China's and Korea's irreconcilable difference from, and Japan's affinity with, Fascist Italy, these intellectuals extolled the Italian race and culture, justified Italy's position in geopolitical dynamics, and propagandised the exceptionality of the Fascist ideology.

Résumé Zarca (Bernard).- Proximités socioprofessionnelles entre germains et entre alliés : une comparaison dans la moyenne durée Les phénomènes d'héritage de la position socioprofessionnelle du père par chacun des frères aîné et benjamin, ou du statut d'activé de la mère par chacune des sœurs aînée et benjamine (voire les transferts au gendre ou la bru de cette position ou de ce statut), ainsi que la tendance à ce que les frères (resp. les sœurs, les beaux-frères ou les belles-sœurs) héritent ensemble (tendance que nous appelions : complémentarité) avaient été mis en évidence pour l'année 1976 par l'étude des fratries que l'enquête Réseaux familiaux, effectuée par l'Ined cette année-là, permettait d'échantillonner. Ces phénomènes sont-ils stables dans le temps ? L'enquête Proches et parents effectuée par l'Ined en 1990 permettant de composer un échantillon de fratries équivalent au précédent, une comparaison dans la moyenne durée est possible. Les phénomènes d'héritage ou de transfert étudiés persistent dans le temps, dans la quasi-totalité de l'espace social, mais avec une force variable, telle que la tendance soit à une plus grande égalité entre les germains. Par contre, les phénomènes de complémentarité tendent à s'estomper, sauf pour les petits indépendants, c'est-à-dire dans les milieux les plus traditionnels de la société française. Cette constatation est cohérente avec ce que l'on sait des transformations de la famille au cours de la période considérée, notamment avec la plus grande individualisation de ses membres.

BACKGROUND: After many decades of stagnation, several promising novel therapies have recently been approved for the management of patients (pts) with Acute Myeloid Leukemia (AML). Many of these target pts in specific clinical and molecular subsets such as midostaurin/gilteritinib for FLT3-mutated AML, liposomal daunorubicin-cytarabine for secondary AML, and fractionated gemtuzumab ozogamicin (GO) for good risk AML. To address the dismal outlook for elderly AML patients, we now have venetoclax or glasdegib combinations. Single agent FLT3 inhibitors (resulting in ~4 m improvement in overall survival (OS)) and IDH inhibitors (response rate 40%, doubled OS in responders) have shown to be superior to traditional approaches in the relapsed setting. Although these agents are exciting, a majority of pts with AML present with intermediate and high-risk disease and only a small subset will have actionable mutations. In order to determine the impact of these newer therapies on outcome for our pts, we investigated AML outcomes for pts diagnosed and treated since 2017 and compared these with survival for similar pts treated in the prior two years (y). METHODS: We performed a retrospective chart review to identify newly diagnosed pts treated with chemotherapy over a 2y period (2015-17) prior to the first FDA approval of Midostaurin in April, 2017 (old AML era or group 1) and the 2y since approval (2017-19; new AML era or group 2). We reviewed charts of 138 AML pts meeting these criteria at our institution: 79 in group 1 and 59 in group 2. Demographics, disease-specific variables, as well as outcomes of interest (overall survival (OS), overall response rate (CR/CRi)) were collected on an IRB-approved protocol. Responses were defined according to the 2003 International Working Group (IWG) criteria. Demographics, baseline characteristics, and treatment responses were analyzed using descriptive statistics. Overall survival was estimated utilizing Kaplan-Meier (KM) survival analysis. RESULTS: Clinical characteristics were comparable in both groups. Median age was 65y with slight differences in gender distribution (Table 1). ELN risk categories (Döhner, Blood. 2017) across the groups were similarly distributed; a majority of pts had intermediate and adverse risk characteristics. As expected, more pts received newer therapies in group 2. 6 pts (7.6%) in group 1 received new drugs (as part of clinical trials), while 31 (52%) received newer therapies in group 2. Newer therapies were mostly GO (28%), midostaurin (11%) and venetoclax (11%) with lesser percentages of the more specific targeted therapies. Median follow-up was 10m for group 1 and 8m for group 2. Median OS was 13m for group 1 and 20m for group 2, but the difference was not statistically significant (p=0.29) [Figure 1]. OS was significantly better in the subgroup of older AML pts (age ≥ 60y); median OS was 7m vs. 11m in groups 1 and 2 respectively (p=0.01).Rates of CR from induction therapy were comparable in both groups (68% in group 1 versus 65% in group 2). A larger number of pts (especially older pts) in group 2 went on to allogeneic bone marrow transplant (allo-HCT). This was perhaps due to increased recognition of performance status over age in selection of pts for allo-HCT and increased utilization of reduced intensity and non-myeloablative conditioning regimens. CONCLUSIONS: Our results indicate a positive impact on survival for pts diagnosed in the era of novel therapies in a real world setting, specifically for pts presenting at older ages. A larger cohort analysis to further evaluate these findings is currently underway. The expansion of the therapeutic armamentarium as well as expanded transplant options is encouraging and offers new hope for pts diagnosed with AML Disclosures Griffiths: Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Wang:Kite: Other: Advisory role; Jazz: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role; Abbvie: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau. Thota:Incyte, Inc.: Speakers Bureau.

Background: Patients with myelodysplastic syndromes (MDS) present across a clinical spectrum from mild disease to profound bone marrow failure and transformation to acute myeloid leukemia (AML). Those with lower risk disease are generally managed with watchful waiting and best supportive care (growth factors, blood and platelet transfusions and iron chelation; BSC), while those with higher risk disease are treated with repeated cycles of low dose "hypomethylating" chemotherapy (such as azacitidine or decitabine; HMA). A majority of patients with MDS, even those with lower risk disease, are likely to die of complications related to their diagnosis, mostly infections and bleeding but also leukemic transformation. As part of our standard approach to infection prevention, current clinical guidelines suggest annual vaccination against influenza. Patients with these disorders and their family members are advised to receive inactivated protein based vaccines rather than live vaccination approaches to limit infection risk. Most will receive high dose trivalent vaccination due to age. Despite these recommendations, limited data exist on the ability of patients with MDS across the spectrum of risk groups to respond to standard seasonal influenza vaccination. In light of the growing literature suggesting that patients with MDS have an altered immune environment, we hypothesized that they would show inferior response to standard vaccination. We sought to determine the response to influenza vaccination in patients with MDS receiving standard therapeutic management. Methods: A non-randomized study is currently ongoing at the Roswell Park Comprehensive Cancer Center for patients with MDS. Age-relevant family members are enrolled as a comparator population for vaccine response. Cohorts were stratified into 3 groups: healthy volunteers (Cohort 1), MDS patients receiving BSC (Cohort 2) and MDS patients actively receiving HMA (Cohort 3; Table 1). All participants are administered the yearly preparation of Sanofi Pasteur's Fluzone High-Dose Vaccine (containing trivalent inactivated strains: Influenza virus A (H1N1 and H3N2) and Influenza virus B). Baseline blood samples were collected prior to vaccination (day 0), and between days 25-90 and 115-185 post-vaccination. Serological responses to vaccination were determined by viral-neutralizing activity analyzed via microneutralization assay. Neutralizing antibody titers for the first year of the study were measured against seasonal influenza vaccine strains based upon the 2017-2018 vaccine product. Samples from the 2018-19 flu season are being analyzed. Results: To date 56 individuals have been recruited to the study over 2 years. Neutralizing antibody titers following vaccination are available for 20 individuals vaccinated in the 2017-18 flu season. Humoral immune responses to vaccination against different strains of Influenza virus A (H1N1 and H3N2) and Influenza virus B were observed across all cohorts (Figure 1). Response was deemed adequate if the titer for any vaccine component increased by >4 fold comparing the baseline to the day 25-90 time point. Cohort 1: 4/4 responded (100%); cohort 2: 4/4 responded (100%); cohort 3: 11/12 responded (92%). To better understand the effect of standard treatment for MDS on influenza vaccine response we are currently profiling immune cells pre and post vaccination using multi-parameter flow cytometry. Additional analyses are planned based on the number of HMA cycles received (<6, or ≥6) and cycle timing relative to vaccination. Conclusion: Patients with MDS respond to vaccination with Fluzone High Dose. Responses in patients with MDS were not statistically different from those seen in an age-relevant population of healthy family members. Additional individuals are being enrolled in order to assess whether standard HMA therapy impacts the response to influenza vaccination. These data suggest that MDS patients receiving BSC respond adequately to viral vaccination. Our preliminary data also show that patients receiving HMA therapy respond adequately to influenza vaccination. These data support the value of influenza vaccination in all patients with MDS and highlight the potential for anti-MDS immunotherapeutic vaccination strategies. Disclosures Vachhani: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Przespolewski:Jazz Pharmaceuticals: Other: PI on clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Wang:Amgen: Other: Advisory role; Agios: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Jazz: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role. Griffiths:Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; New Link Genetics: Consultancy; Genentech, Inc.: Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Persimmune: Consultancy; Partner Therapeutics: Consultancy; Persimmune: Consultancy; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; New Link Genetics: Consultancy.

Background: Immunotherapeutic approaches for myelodysplastic syndrome (MDS) show promise, but progress is limited by our incomplete understanding of the immunologic milieu. In a recent Phase I trial, we found that MDS patients with higher numbers of CD141Hi conventional dendritic cells (cDCs) were more likely to respond to NY-ESO-1 vaccination. In solid tumor models, the CD141Hi cDC is critical for initiating anti-tumor immune responses but its impact in myeloid malignancies is unknown. In studies of primary human specimens and mouse models, we tested the hypothesis that MDS patients exhibit decreased quantity and quality of CD141Hi cDCs due to impaired myeloid differentiation. Methods: Bone marrow (BM) cells were collected from MDS patients (pre-treatment) and age matched healthy donors (HD; defined as absence of hematologic malignancy). We quantified DC populations, stem, progenitor cells and interferon regulatory factor-8 (IRF-8) expression using flow cytometry and RT-qPCR. Histone modifications were assessed by chromatin immunoprecipitation. To assess DC differentiation of progenitors, human CD34+ and mouse c-kit+ cells were expanded and differentiated in vitro. Results: We found fewer CD141Hi cDCs (p<0.0001), CD1c+ cDCs (p<0.005) and plasmacytoid DCs (CD123+ pDCs; p<0.005) overall in BM samples from MDS patients (n=71) compared to HD (n=17). We stratified MDS patients based on the relative number of DCs and found that only those patients with highest number of CD141Hi cDCs had superior survival (p < 0.05). No differences in survival were seen in patients stratified by the CD1c+ cDCs (p = 0.96) and CD123+ pDCs (p = 0.32) populations. We hypothesized that decreased numbers of CD141Hi cDCs and adverse survival in MDS patients resulted from impaired differentiation of DC progenitors. We showed that MDS patients (n=19) have fewer monocyte-DC progenitors (MDP) and common DC progenitors (CDP) compared to HD (n=11; p<0.01). We then hypothesized that MDS progenitors express lower levels of IRF8, a master regulator of CD141Hi cDC differentiation. IRF8 expression was significantly lower in CDPs from MDS patients compared to HD (p<0.05). Furthermore, MDS patients with lower levels of IRF8 (n=8) in their MDPs showed a trend towards production of fewer CDPs and significantly fewer CD141Hi cDCs compared to those with higher levels of IRF8 (n=10; p<0.005). These results suggest that approaches to increase IRF8 expression could enhance CD141Hi cDC differentiation. We hypothesized that inhibition of lysine-specific histone demethylase 1A (LSD1), which increases IRF8 expression in myeloid leukemia cells, would induce CD141Hi cDC differentiation. Pharmacologic inhibition of LSD1 increased IRF8 expression (both mRNA and protein) in KG-1 cells, a model of human CD34+ cells, and in HD and MDS CD34+ progenitors (p<0.05). LSD1 inhibition in KG-1 cells resulted in increased H3K27 acetylation (3861-fold change) and H3K4 dimethylation (922.4-fold change) compared to PBS (p<0.05) at a region -70 kb to the IRF8 transcriptional start site, a putative regulatory element that demonstrated the highest level of LSD1 binding. These data indicate that LSD1 inhibition alters histone modifications at the IRF8 locus, resulting in increased expression of IRF8. Pharmacologic inhibition of LSD1 in HD CD34+ cells increased the number of mature CD141Hi cDCs in 92% of specimens (n = 12; 3.4 fold-change) compared to PBS. Similarly, LSD1 inhibition in MDS CD34+ cells increased the number of CD141Hi cDCs (n = 12) in 75% of patient specimens (16.8 fold-change) compared to PBS. IRF8 function is conserved between mice and humans. To test whether the effect of LSD1 inhibition on cDC differentiation was dependent on IRF8, we compared the effect of LSD1 inhibition on BM c-kit+ cells from Irf8 knock-out mice (Irf8-KO) and littermate controls (WT). LSD1 inhibition in WT c-kit+ cells resulted in increased numbers of CD141Hi cDCs in vitro (p<0.05). By contrast, LSD1 inhibition of Irf8-KO c-kit+ cells did not result in differentiation of CD141Hi cDCs. These data suggest that LSD1 inhibition drives CD141Hi cDCs differentiation through IRF8. Conclusion: These data reveal a previously unrecognized determinant of the immune microenvironment in MDS. The opportunity for epigenetic regulation of CD141Hi cDC differentiation in MDS offers an opportunity for intervention and a potential adjunct to immunotherapy for patients. Disclosures Sait: Celgene: Consultancy. Griffiths:Boston Scientific: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial.

BACKGROUND: Patient reported outcomes (PROs) are increasingly being used as key outcome measures in management of patients with chronic hematologic malignancies. Use of PROs in routine clinical care in hematology has been associated with improved patient-physician communication, enhanced shared decision making, better symptom management, and greater satisfaction with care as well as improved quality of life (QoL) (Breccia M, et al. 2015; Hirji I, et al. 2013). With a therapeutic landscape shifting towards long-term use of oral therapies in chronic myeloid malignancies (myelofibrosis (MF) and chronic myeloid leukemia (CML)), the potential for serious medication adverse events rises. Due to these concerns, pharmacists are increasingly functioning, as integral members of the healthcare team, responsible for the management of oral anticancer agents. The effectiveness and value of pharmacists in the management of oral medications for hematologic malignancies from a patient perspective is limited. Here we designed a prospective patient survey study to assess PROs of a pharmacist-led medication therapy management (MTM) program to monitor adverse events and improve adherence in adults with hematologic malignancies. METHODS: Adult patients (pts) (≥ 18 years old) prescribed an oral targeted therapy for a hematologic malignancy and who were seen by a clinical pharmacist for a MTM session were eligible. A modified validated questionnaire consisting of 22 multiple choice questions and 3 comment questions and incorporating both CTSQ & FACT-Leu (Abetz L, et al. 2005; Cella D, et al. 2012) was completed by each participant. Individual questions and responses were pooled into the following categories: education, monitoring and support. Demographics, disease-specific variables and questionnaire responses were also collected. RESULTS: 66 pts seen in the adult leukemia clinic at Roswell Park Comprehensive Cancer Center in 2019 participated in the study. Baseline characteristics for this cohort are outlined in Table 1. Median age of the cohort was 64 years old (range 31-89 yrs) and 52% were male. Hematologic malignancies included CML (64%), MF (11%), acute myeloid leukemia (AML) (8%), Ph+ acute lymphoblastic leukemia (Ph+ALL) (6%), myeloproliferative neoplasm (MPN) (6%), polycythemia vera (PV) (3%), mastocytosis (1%) and hypereosiniophilic syndrome (1%). The most common oral agents were imatinib (21%), ruxolitinib (18%), and dasatinib (17%). This cohort also included patients off BCR-ABL inhibitors as part of treatment free remission monitoring (8%) and those on novel therapies such as enasidenib (3%). Majority of pts had been on their oral agent for at least 1-5 years (55%). For each pooled category i.e., education, monitoring and support, involvement of a pharmacist was associated with positive or very positive benefits: education (98%), monitoring (96%), and support (91%) (Figure 1). There was no difference in questionnaire response by number of years on oral chemotherapy (&lt; 1 year vs. &gt; 1 year into therapy). In addition, there was no difference in questionnaire response based on diagnosis (CML vs. non-CML) or gender. For question "I feel that I have missed fewer doses of my medication due to interacting with my pharmacist", non-CML patients tend to be more positive (p = 0.0695) (Figure 2). For question "The pharmacist has provided me with tools to help me remember to take my oncology medication", patients with &gt; 1 year TKI therapy are more positive (p = 0.052) (Figure 3). CONCLUSIONS: Our study demonstrates that the involvement of subspecialty pharmacists as part of a formal MTM program, for adult pts on oral therapy for hematologic malignancies was overwhelmingly associated with positive pt reported outcomes in the areas of education, monitoring and support. The greatest positive role of the pharmacist was on education of pts at start of therapy. Pts also perceived benefits in increased long term drug compliance and improved toxicity management. These data support further investigation of pharmacist-led MTM programs as part of the care continuum for pts with hematological malignancies at high risk of non-compliance and medication-related adverse events. For instance, adolescent/young adult (AYA), ALL or APL pts on maintenance, or geriatric individuals with multiple comorbidities may particularly benefit from improved medication compliance and overall care. Disclosures Przespolewski: Jazz Pharmaceuticals: Other: PI on clinical trial. Griffiths:Celgene, Inc: Consultancy, Research Funding; Novartis Inc.: Consultancy; Genentech, Inc.: Research Funding; Persimmune: Consultancy; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Persimmune: Consultancy; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Wang:Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Kite: Other: Advisory role; Abbvie: Other: Advisory role; Agios: Other: Advisory role; Amgen: Other: Advisory role.

Several therapeutic approvals in recent years have resulted in a change in the paradigm for standard treatment of patients with newly diagnosed and relapsed/refractory (r/r) AML. Gemtuzumab ozogamicin (GO) was resurrected in 2017 for CD33+ newly diagnosed or relapsed/refractory AML using a safer fractionated dosing regimen. Since its re-approval it has been incorporated in combination with standard 7+3 (cytarabine 100mg/m2 + daunorubicin 60mg/m2; Castaigne S et al, Lancet 2012) as upfront therapy for good and intermediate risk AML patients (pts) treated at institutions with access to rapid risk stratification (molecular/cytogenetic results) including ours (Roswell Park; RP). In the five randomized studies of GO combinations for newly diagnosed AML, varied doses of cytarabine and anthracyclines were used (Lancet Oncol, 2014). In these, cytarabine doses ranged from (100-200 mg/m2), daunorubicin doses ranged from 45-60 mg/m2. These studies did not intensify daunorubicin beyond 60mg/m2 and did not incorporate FLT3 inhibitors. Previous work has demonstrated that anthracycline dose intensification (90mg/m2) provides a recognized survival advantage for younger AML pts (Luskin MR et al, 2016.), particularly those with mutations in FLT3. Optimal combination approach(s) including GO for the management of patient with AML are unclear. Adaptation of GO in combination with 7+3 for upfront AML management has led to the evolution of institutional standards to optimize early identification of good/intermediate risk AML pts. Unfortunately, there is limited data on the safety and efficacy of higher doses of daunorubicin in combination with GO and/or FLT3 inhibitors. Here we present outcomes and adverse events (AEs) using varied upfront treatment regimens in combination with GO at RP. We additionally present a cohort of r/rAML pts treated with GO alone or in combinations under an expanded access protocol (NCT02312037) at RP prior to re-approval in 2017. R/R AML pts treated on expanded access had AEs collected prospectively, all other cases were identified by retrospective chart review in accordance to IRB approval. 218 patients with a diagnosis of AML and a median age of 66.5 years were seen at RP since GO approval. Of these all good risk and 45% of intermediate risk AML underwent induction chemotherapy. During 2015-2017 r/rAML patients were treated with GO based therapy (N=32) on NCT02312037 trial. Since FDA approval another 48 pts have been treated with GO at our institution. Of the 80 patients in this cohort, N=25 underwent GO based induction therapy (Table 1). The most frequently used other combinations were: (i) daunorubicin 60mg/m2 and cytarabine 200mg/m2 (N=17), (ii) daunorubicin 90mg/m2 + cytarabine 100mg/m2, N=4), (iii) FLAG-GO (used in patients with cardiac comorbidities; N=2) and hypomethylating agents combined with GO (N=10), monotherapy was used in 45 pts. The ORR (CR+Cri) for patients treated with GO based induction was 88%. The overall (OS) and event free survival (EFS) were 48 and 17 months for induction-treated pts respectively. The most common AEs were febrile neutropenia (60%), infusion reactions (30%), transaminitis (20%), cytopenias beyond 30 days from induction (10%). The most common reason for change of therapy was disease progression. Toxicity was not higher in those patients receiving higher doses (>60mg/m2) of daunorubicin or cytarabine (200mg/m2). Two patients received GO+7+3+FLT3 inhibitors; this was well- tolerated in a very small sample. In the R/R cohort, pts received a median of 2 cycles of therapy, the ORR was 18%. GO had no activity in those treated with >2 prior regimens for relapsed disease. In conclusion, anthracycline intensification as part of a 7+3 combination with GO was not associated with increased toxicity. Although the number was small, FLT3 inhibitors following 7+3+GO were also well tolerated. These data require confirmation in a larger cohort. Our results confirm the EFS reported in the literature (18 months in ALFA 0701 study), and suggest a higher mean OS of 40 months compared with conventional 7+3 induction. The response rate for GO monotherapy in r/rAML is low and was exceedingly poor for heavily pretreated pts. Disclosures Thota: Incyte, Inc.: Speakers Bureau. Griffiths:Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding. Wang:Agios: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Amgen: Other: Advisory role; Daiichi: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau.

Introduction: Clinical cytogenetics is the most important prognostic test for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); however, current tools do not provide a complete genome-wide picture of somatic chromosomal aberrations in those patients. We used a high-resolution genome-wide single-nucleotide polymorphism (SNP) array to identify large clonal chromosomal aberrations in pre-hematopoietic cell transplant (HCT) peripheral blood samples of patients with de novo or therapy-related AML and MDS. Methods: We used the HumanOmniExpress-24 BeadChip SNP array genotyping data generated in the DISCOVeRY-BMT study (includes patients with acute leukemia or MDS who received unrelated donor HCT between 2000-2011). Clinical data and biospecimens were obtained from the Center for International Blood and Marrow Transplant Research. Blood samples were collected at median of 7 days before HCT. We limited our analysis to patients with AML (N=1,982) and MDS (N=608). We calculated the log2 R ratio and B allele frequency (BAF) and used the Circular Binary Segmentation (SBC) algorithm to identify chromosomal aberrations spanning ≥2Mb. Results: Median age at sample collection was 48.2 (range=0.6-78.0) and 53.0 (range=0.0-74.0) years for AML and MDS, respectively. About 53% of AML and 59% of MDS patients were males, and 7.4% of AML and 15.8% of MDS patients had therapy-related disease. Among AML patients, 47.9% were in 1st complete remission and 22.8% in 2nd complete remission. For MDS, 56.1% of patients were in early stage (refractory anemia with or without ringed sideroblasts) at the time of HCT. Chromosomal aberrations were detected in 14.6% of the AML patients (n=289) and 34.7% of the MDS patients (n=211). In AML, 6.6% of those with hematological or molecular remission vs. 35.9% of those with advanced disease (not in remission) had SNP-array detected aberrations, with 0.7% of the patients vs. 8.9%, respectively carrying aberrations in ≥3 chromosomes. For MDS, chromosomal aberrations were detected in 31.4 vs. 39.0% of patients with early and advanced MDS, respectively. No differences by patient sex or race were detected in both AML and MDS (p&gt;0.05). Figure 1 shows disease-specific type and frequency of detected chromosomal aberrations. Copy-losses in chr7 (chr7-), chr5 (chr5-), and copy-neutral loss of heterozygosity (CNLOH) in chromosome 17 (chr17-CNLOH) were the most common aberrations in both diseases, with higher frequencies in MDS (chr7-, 13.8 vs. 2.4%, respectively; chr5-, 7.2 vs. 1.8%; chr17-CNLOH, 4.4 vs. 1.5%, respectively, all p&lt;0.0001). In comparison, CNLOH in chr13 was more frequent in AML than MDS (1.5 vs. 0.2%, respectively, p&lt;0.01). Figure 2A shows detected chromosomal aberrations in de novo and therapy-related AML (tAML). The following were more frequently detected in tAML than de novo disease: copy-losses of chr5 (4.8 vs. 1.6%, p=0.02) and chr13 (2.7 vs. 0.6%, p=0.02). Aberrations in chromosomes 3, 10, 14, 15, 16 and 22 were found in de novo but not in tAML. The frequencies of chr7- (4.1 vs. 2.0%, in tAML and de novo, respectively, p=0.12) and copy-gain in chr8 (0.7 vs. 1.3%, p&gt;0.99) were similar in the two disease subtypes. Figure 2B shows detected chromosomal aberrations in de novo and treatment-related MDS (tMDS). The following were more common in tMDS than de Novo MDS: copy losses in chr5 (16.7 vs. 5.5%, p&lt;0.001), chr7 (26.0 vs. 11.5%, p&lt;0.001), and chr18 (7.3 vs. 1.6%, p&lt;0.01); also copy-gain in chr11 (4.2 vs. 0.4%, p&lt;0.01), and chr17-CNLOH (9.4 vs. 3.5%, p=0.03). Unique aberrations in de novo MDS included CNLOHs in chr7 (2.5%), chr14 (1.2%), chr1 (1.0%), chr4 (1.0%) and copy-gain in chr17 (1.0%). Conclusion: High-resolution SNP array analysis provided a genome-wide landscape of large chromosomal aberrations in patients with AML and MDS. Detected aberrations were more frequent in MDS than AML patients; this is possibly affected by differences in pre-HCT initial therapy. This study showed the expected genomic landscape similarities between AML and MDS, but differences were also present (most noted was chr13-CNLOH predominance in AML). The observed differences between de novo and t-AML or t-MDS likely reflect distinct pathogenic processes. Differences between t-AML and t-MDS could be related to antecedent malignancy and/or therapeutic regimen. The impact of these detected aberrations on HCT outcomes is under investigation. Disclosures Griffiths: Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Partner Therapeutics: Consultancy. Thota:Incyte, Inc.: Speakers Bureau. Pasquini:Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Other: Advisory Board. Lee:Takeda: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Syndax: Research Funding; Incyte: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

In the past year, there has been a paradigm shift in the treatment of elderly and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) with the approval of venetoclax (Ven) plus hypomethylating agents (HMA) or low dose Ara-C (LDAC). Ven/ HMA has shown an impressive complete response + complete response with incomplete count recovery (CR+ CRi) rate of 67% and a median overall survival (OS) of 17.5 months in older patients (pts) (median age 74 years) with intermediate and poor risk cytogenetics (Dinardo C et. Blood 2019). Similarly, Ven/LDAC resulted in a CR+ CRi rate of 54% with a median overall survival of 10.1 mos (Wei A et al JClinOnc 2019). However, to date, it is not known how the outcomes of Ven/HMA and Ven/LDAC compare with HMA or intensive chemotherapy in newly diagnosed AML pts. Methods To address this issue, we conducted a retrospective analysis of newly diagnosed AML adult pts treated with Ven-based regimens at our institution. All data was collected under an IRB approved protocol. Demographics, disease characteristics (including cytogenetics and molecular profiles), treatment details (drugs, duration, mortality and causes of death), and clinical outcomes including response and OS were analyzed. Results were compared to a historical cohort of elderly pts treated with HMA alone or intensive (7+3 based) induction chemotherapy as previously reported1. Results 31 newly diagnosed AML patients treated at our single academic institution between 2017-2019 were identified. The median age of the group was 75 years (51-90; 29 patients ≥ 60 years) with 20/31 (64.5%) males and 11/31(35.5%) females. 13/31(41.9%) patients had de-novo AML whereas 18/31 (58.1%) had high risk AML (AML with prior hematological abnormality, t-AML). By ELN 2017 risk stratification 2(6.4%),12(38.7%),17(54.8%) were favorable, intermediate, adverse risk respectively. Molecular profiling results was available for 23/31(74.2%) patients, TET2 and TP53 were the most common mutations present in 9 (29.0%) and 8 (25.8%) patients, respectively. 3/31(9.6%) patients subsequently received an allogeneic-HSCT as of August 1, 2019. The median follow-up was 112 days (9-600 days). Median number of cycles received were 2 (1-21). 15/31 (48%) pts were considered responders (CR, CRi, MLFS), 9 of 31(29%) were non-evaluable (N/E). Of these 7/9 patients died before repeat biopsy, 2/9 patient did not have a repeat biopsy. 2/31(6.4%) experienced partial response, 2/31(6.4%) had stable disease and 3/31(9.6%) had refractory disease. 30-day and 60-day mortality was 2/31(6.4%) and 6/31(19.3%) respectively. Two thirds of treated patients (20/31, 64.5%) are alive. Of the 11 patients who died 5 (45.5%) died due to pneumonia/sepsis, 3 (27.3%) died due to progressive disease, 2 (18.2%) withdrew therapy due to poor performance status and 1(9.1%) CNS bleed. There was no statistical difference in de-novo vs high risk AML, ELN 2017 risk stratification (favorable + intermediate vs adverse) when compared for response (responders vs others) or status (alive vs dead). We then compared our Ven/chemotherapy outcomes with prior data from our institution of newly diagnosed elderly pts treated with HMA or intensive chemotherapy (IC)1. There was a statistically significant difference for response favoring Ven based regimen vs HMA (48.3% vs 25.6% p=0.02); however, no significant difference was seen when comparing Ven/chemo with IC (48.3% vs 50%, p=0.87) (table 1). Similarly, no significant difference was observed in 60-day mortality when IC and HMA based therapy was compared with Ven based regimen (p=0.85 and 0.87 respectively) (table 2). Longer follow up in the Ven/chemotherapy arm is required to make any meaningful conclusion for differences in OS if any (figure A). Conclusion In our single institution retrospective review, we found higher rates of 60-day mortality than reported in a prior phase 1 multi-institute clinical trial (DiNardo et al. Blood 2019). However, response rates with Ven/chemo were significantly better than HMA alone and were equivalent to those of IC in similar elderly AML pts at our institute. We conclude that induction chemotherapy with Ven/based regimens could result in similar responses as IC in older AML pts. References 1-Gupta, Neha, et al. "Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients≥ 60 years old." American journal of hematology90.7 (2015): 639-646. Disclosures Griffiths: Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Genentech, Inc.: Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Celgene, Inc: Consultancy, Research Funding; Novartis Inc.: Consultancy; Abbvie, Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Wang:Jazz: Other: Advisory role; Kite: Other: Advisory role; Abbvie: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role.

Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) or relapsed/refractory (r/r) AML represent a high-risk populations with poor long-term outcomes following standard induction chemotherapy with 7+3. Until 2017, there was no standard regimen for these patients. CLAG ± M has been described in the literature to result in significant responses in r/r AML (Wierzbowska et al, Eur J Haematol 2008), and as front-line therapy for s-AML following azanucleoside failure (Jagal et al, Leuk Res 2014). Here we describe our institutional experience (RP) with CLAG±M as a standard induction/re-induction strategy for r/r and s-AML patients. We further compare our institutional data for s-AML patients treated on label with CPX-351 compared to CLAG±M. Methods: Medical records were retrospectively reviewed to identify pts treated with CLAG±M for r/r or untreated s-AML. S-AML pts treated with CPX-351 as induction therapy following FDA approval for these indications were also identified as a comparator cohort. Treatment, demographics, disease-specific variables, and overall survival outcomes were collected under an institutional review board approved protocol. Results: 60 pts with r/r (n=44; 73.3%) or s-AML (n=16; 26.7%) were treated with CLAG±M between 2003-18. 12 pts (19%) did not receive mitoxantrone. The median age of treated pts was 65 years (y;range 21 - 77) and 40 were male (63.5%). Cytogenetics were high-risk in 26 pts (41.3%) and intermediate risk in 37 pts(58.7%), 10 (15.9%) had 17p abnormalities. 41 (65.1%) pts had previously received hypomethylating (HMA) therapy. The overall response rate (ORR=CR+CRi+PR) was 81.7%; 41 pts achieved CR/CRi (68.3%), and 8 achieved PR (12.7%), 25 (39.7%) went on to allogenic stem cell transplant (AlloT). The most common adverse event (AE) was infection (58.7%, n=37). Thirty-day (d) mortality was 5%, and 60-d mortality was 14%. Median overall survival (OS) was 313 d (range 172 - 503), median progression-free survival (PFS) was 225 d (range 135 - 423). Similar response rates, OS and PFS were seen comparing pts with intermediate and high-risk cytogenetics, r/r and s-AML, and those with 17p abnormalities. The addition of mitoxantrone did not impact outcome (Table 1). Younger pts (&lt;60yo) had improved OS (613 vs. 141 d; p=0.007) and PFS (313 vs. 186 d; p=0.022) as compared to older (≥ 60yo) (Figure 1). We then examined outcomes for the subset of s-AML (n=16) pts treated with CLAG±M and compared them with a cohort of s-AML pts treated at our institution with CPX-351 following it's FDA approval for this indication. Median age of CLAG-M cohort was 65.5y (range 24 - 77), most 75% (12), were male, 7 pts (43.8%) had high-risk and 9 (56.3%) intermediate-risk cytogenetics. 14 pts (87.5%) had prior HMA exposure. The ORR with CLAG+M was 81.3%; 8 pts (50%) achieved CR/CRi and 7 (43.8%) went on to AlloT. The most common AE was infection (43.8%, n=7). Thirty- and 60-d mortality were 0% and 12% respectively. The OS was 423 days (range 71 - not reached). When compared to s-AML pts treated with CPX-351 (n=22), the ORR following CLAG±M was significantly higher at 81.3% vs. 40.9% (p=0.02). However, no difference was noted in CR/CRi rate, OS (Figure 2), or transplant percentage. Of particular note 14 pts (87.5%) in the CLAG±M cohort compared to 3 (13.6%) in the CPX-351 cohort had received prior HMA (p=&lt;0.001), a notoriously challenging to treat population (Table 2). Conclusions: Our institutional analysis suggests that CLAG+M results in a remarkably high ORR (81.7%) and excellent OS of 10.4 m in adult pts with r/r and s-AML. Responses were observed despite a cohort with higher risk features including prior HMA, high-risk cytogenetics, and 17p abnormalities. ORR were similar independent of age, but younger pts (&lt; 60yo) had better OS and PFS compared to older counterparts. Equivalent responses were seen irrespective of anthracycline inclusion. S-AML pts treated with CLAG±M had significantly higher ORR, but a similar OS compared with a sequential cohort of RP treated pts who received CPX-351. CLAG±M is active and tolerable with high response rates and excellent OS in r/r and s-AML pts with poor risk clinical features (prior HMA, p53 mutations, older age, high risk cytogenetics, inability to tolerate anthracycline therapy). Prospective clinical trials of this regimen compared with alternative regimens (CPX-351, venetoclax/HMA) are warranted. Disclosures Przespolewski: Jazz Pharmaceuticals: Other: PI on clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Griffiths:Persimmune: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Novartis Inc.: Consultancy; Boston Scientific: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Boston Scientific: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Persimmune: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial. Wang:Amgen: Other: Advisory role; Agios: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role.

Background: AZA monotherapy has demonstrated improvement in OS in HR MDS, clinically meaningful and durable responses continue to be limited to a subset of patients (Silverman 2006). One obvious strategy is to develop doublet therapy with drugs that are effective monotherapy in HR MDS and can be administered effectively and safely in combination with AZA. Several agents have been combined with AZA in first line therapy for pts with HR-MDS achieving ORR and CR/PR rates that are comparable to AZA monotherapy (ORR 38% and CR/PR of 24%) (Ades ASH 2018; Sekeres JCO 2017). RAS and other signaling molecules in the Ras pathway are frequently mutated in HR MDS and are proposed to drive leukemic transformation (Takahashi 2013). Given that rigosertib interferes with the RAS-binding domain of RAF kinases and inhibits the RAS-RAF-MEK & the PI3Ks pathways (Athuluri-Divakar, Cell 2016), it is an attractive candidate for combination with AZA. Furthermore, in vitro combo of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skiddan AACR 2006). We report updated results from a Phase II study in a subset of patients receiving oral rigosertib in combination with standard dose AZA as first line therapy for HR MDS. Methods: In the Phase II study 09-08, a total of 39 treatment-naïve HR MDS/RAEB-t patients received oral rigosertib in combination with standard dose AZA. Rigosertib was given at 840mg/day (560 mg in the morning & 280mg in the afternoon); or 1120mg/day (560 mg in the morning & 560mg in the afternoon or 840 mg in the morning and 280 mg in the afternoon) (Maniar ASH 2018). Responses were determined by 2006 IWG criteria including transfusion independence (56 days without PBC or PLT transfusions). Oral rigosertib was administered on D1-D21 of a 28D cycle. Parenteral AZA 75mg/m2/day was administered for 7days from D8. Patients were evaluable for response if they received 3 cycles of therapy. Results: Median age of the pts was 64 years (42-90). IPSS-R score at study entry was 9 were Intermediate, 8 were High and 17 were Very High Risk (VHR). In total 20 pts were transfusion-dependent at study entry. CR/PR responses were observed across all IPSS-R cytogenetic prognostic subgroups: Very Poor 60%, Poor 25%, Intermediate 37.5% & Good 25%. CR/PR responses were also observed across all higher IPSS-R prognostic risk categories: Very High 42%, High 17% and Intermediate 25%. A summary of clinical benefit/risk is provided in Table 1 below. Median duration of response was 12.2 mos (0.1-24.2+) and median duration of treatment was 8 mos (1.3-27.3). Time to first and best responses was 1/4 mos. Four pts continue to respond to therapy. 10 AEs led to D/C: urinary tract pain (2), and 1 each for urinary retention, hematuria, hydronephrosis, osteolysis, cerebral haemorrhage, WBC count decreased, neutrophil count decreased, & abd pain. The most frequent AE in table 1, are similar to AEs reported for both rigosertib and AZA as monotherapies, & the GU toxicities were mitigated using specific management guidelines. The majority of MDS pts who experienced AEs ≥Grade 2 were successfully managed and continued to receive the doublet on study. Conclusion: The efficacy (90% ORR & 34% CR) and safety of oral rigosertib and AZA in combination is favorable as first line therapy in pts with HMA naïve HR MDS and are comparable to historical results for standard dose AZA monotherapy (ORR 38% and &lt;20% CR). The transfusion independence (TI) of 30% in HR MDS pts is clinically meaningful and needs to be confirmed in a large randomized phase III study. Oral rigosertib in combination with AZA was well tolerated and has now been administered in repetitive cycles for more than two years. Rigosertib is attractive combination partner for AZA because of the oral formulation, non-overlapping toxicity, mechanism of action and synergy. Based on the efficacy results and favorable safety profile, a pivotal Phase III trial in higher-risk HMA naive MDS population is planned. Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Atallah:Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy. Shammo:Otsuka: Consultancy, Honoraria; CTI Pharma: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Speakers Bureau; Astex Pharma: Research Funding. Griffiths:Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy; Partner Therapeutics: Consultancy; Celgene, Inc: Consultancy, Research Funding. Khaled:Alexion: Consultancy, Speakers Bureau; Omeros: Consultancy; Daiichi Sankyo: Other: Travel support. Adesanya:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Woodman:Onconova Therapeutics, Inc.: Employment. Fenaux:Jazz: Honoraria, Research Funding; Aprea: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Silverman:Medimmune: Research Funding; Celgene: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.

Background: Older AML patients often present with comorbidities and may have a compromised ability to tolerate intensive chemotherapy. These patients are more likely to have AML secondary to MDS/MPN and are considered to have a biologically distinct disease compared to their younger counterparts, with more frequent occurrence of adverse-risk cytogenetic abnormalities and mutations in genes regulating epigenetic modifications. In addition, the heterogeneity of driver mutations within a single patient contributes to limited responses to standard induction chemotherapy. While FLT3 mutations occur in this population, they are often subclonal, adding to the challenge of eradicating AML in older adult patients. Studies combining sorafenib or midostaurin with standard induction chemotherapy have shown relatively modest improvements in response rates and survival, and relapses, both early and late, remain a major concern. There is a major unmet need for optimizing chemotherapy and TKI treatment in this medically fragile population. We here report the safety and efficacy results in newly diagnosed older patients with FLT3 mutant AML treated with crenolanib, a type I FLT3 inhibitor, in combination with intensive induction and consolidation chemotherapy (NCT02283177). Methods: Fifteen consecutively treated patients, aged 61-75 (median age: 68), at four academic cancer centers were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered continuously starting 24 hours after chemotherapy until 72 hours prior to the next chemotherapy cycle. Consolidation consisted of up to 4 cycles of high-dose cytarabine (HiDAC: 1 g/m2) q12h on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance with crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Results: Fourteen patients completed induction chemotherapy (one patient withdrew consent at day 19). Crenolanib could be safely combined with either daunorubicin or idarubicin based induction chemotherapy. The most common adverse events (grade ≥3) were diarrhea, nausea, and febrile neutropenia. Ten of 14 patients were able to receive full doses of crenolanib during induction. The major reason for dose reduction was edema in 3 patients and GI bleeding in 1 patient. There was one treatment-related death, with 93% survival at 30 and 60 days and 87% survival at 100 days. Complete remissions with full count recovery (CR) were achieved in 10 of 15 patients after just one cycle of induction chemotherapy. Two patients achieved a complete remission after reinduction for an overall CR rate of 86%. Of the 12 patients who achieved CR, 10 patients received HiDAC consolidation, with two patients unable to receive consolidation therapy on study. Three patients received crenolanib maintenance after multiple cycles of HiDAC consolidation. Six patients underwent HSCT and 3 received crenolanib maintenance. As of July 2019, median OS for the intent to treat population is 20.2 months. One-year survival was 67% and 5 patients remain alive and in remission. All 5 long term survivors were ≤70 years old. All surviving patients received either multiple cycles of HiDAC or HiDAC plus transplant, and 4/5 underwent crenolanib maintenance. The patient who did not receive transplant completed 3 cycles of HiDAC consolidation and a full year of crenolanib maintenance. Summary/Conclusion: This safety study shows that crenolanib can be combined at full doses (100mg TID) for the duration of 7+3 induction, consolidation, and maintenance in older patients with FLT3 mutant AML. Therapy was relatively well tolerated, with less than one third of patients requiring dose reductions. Long-term survival rates are encouraging in this high-risk population, but additional studies are needed to confirm the efficacy of this combination older adults. Figure 1 Disclosures Wang: Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Griffiths:Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Genentech, Inc.: Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Walter:Jazz Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; BiVictriX: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Tallman:Hematology Oncology of Indiana: Honoraria; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; University of Oklahoma Medical Center: Honoraria; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Mayo Clinic: Honoraria; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; Amgen: Consultancy; 14th Annual Miami Cancer Meeting: Honoraria; Danbury Hospital Tumor Board: Honoraria; International Conference in Leukemia: Honoraria. Goldberg:ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; DAVA Oncology: Honoraria. Messahel:Arog Pharmaceuticals: Employment. Stone:Pfizer: Consultancy; Stemline: Consultancy; Astra-Zeneca: Consultancy; Argenix: Other: DSMB; Otsuka: Consultancy; Astellas: Consultancy; Argenix: Other: DSMB; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Biolinerx: Consultancy; Biosight: Consultancy; Trovagene: Consultancy; Arog: Consultancy, Research Funding; Takeda: Other: DSMB; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Abbvie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Takeda: Other: DSMB; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Jazz: Consultancy; Trovagene: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; Macrogenics: Consultancy; Agios: Consultancy, Research Funding; Biosight: Consultancy; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Pfizer: Consultancy; Trovagene: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Macrogenics: Consultancy; Otsuka: Consultancy; Argenix: Other: DSMB; Astellas: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biolinerx: Consultancy.

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

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 103 r/r AML patients. We present here duration of response and long-term survival results. M ethods: We conducted a phase 2 study of guadecitabine using different regimens and doses (randomized 5-day regimen cohorts of 60 mg/m2/d vs 90 mg/m2/d SC) and a cohort of 10-day regimen in the first 1-4 cycles at 60 mg/m2/d followed by subsequent cycles of 5-day regimen). Response and duration of response were assessed using IWG 2003 criteria: Complete Response (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete count recovery (CRi). CR+CRp+CRi was defined as composite CR (CRc). Overall survival (OS) was assessed using the Kaplan-Meier (KM) method. Response status for each dose/regimen cohort and the overall treated population were assessed with analyses of duration of response and long-term survival. Results: The study completed enrolment of 103 r/r AML patients: 50 patients received 5-day regime at 60 mg/m2/d (24 patients) or 90 mg/m2/d (26 patients), and 53 patients received the 10-day (60 mg/m2/d). Median follow up was 2.4 years (29.1 months). Patients' characteristics for the 103 r/r AML patients enrolled included median age of 60y (range 22-82y), poor risk cytogenetics in 41%, prior hematopoietic cell transplant (HCT) in 18%, median number of prior regimens 2 (range 1-10), primary refractory to induction therapy in 47%, and 41% had a high disease burden of BM blasts &gt;40%. There was no significant difference in CR or OS between 60 and 90 mg/m2/d 5-day regimen but the CR and CRc rates were higher on the 10-day regimen (19% and 30% respectively) vs the 5-day regimen (8% and 16%). When all regimens analyzed together, 24/103 patients (23.3%) achieved CRc. Responses (CRc) were achieved in several poor prognosis subgroups including 19% in patients with poor risk cytogenetics, 31% of refractory patients, 26% of patients who relapsed after prior HCT, and 22% in patients with early relapse (&lt; 6 months from their prior treatment). Of the 24 CRc patients, 15 (63%) were refractory to induction, 8 (33%) had poor risk cytogenetics, and 5 (21%) had prior HCT, and 14 (58%) went on to receive HCT following response. Median overall duration of response for patients with CR, and CRc were 7 and 7.8 months respectively. After long term follow up, median OS has not been reached in patients who achieved CRc (either CR or CRp/CRi). The 2-year survival rate was 57% for CR, and 50% for CRp/CRi (Fig. 1). Median OS has not yet been reached and was similar in CRc patients who went on to receive HCT post CRc (14 patients) compared to CRc patients who did not receive HCT post treatment (10 patients) (Fig.2). The 2-year survival rate was also similar for both groups (50% for those receiving HCT vs 60% for those who did not undergo HCT). Most patients were still on guadecitabine treatment until death, progression, or HCT with no other subsequent treatment. Guadecitabine was well tolerated in all cohorts with Grade 3 or higher AEs related to the drug seen in 42% of patients predominantly myelosuppression and related infections. There was no related serious AEs leading to death. The results highlight the long survival benefit for guadecitabine responders that exceeds duration of response and seems irrespective of post treatment HCT. The results also suggest that in r/r AML patients treated with guadecitabine, CRp/CRi seem to confer a similar survival benefit to CR patients suggesting that the incomplete peripheral blood count recovery may reflect continued treatment-related myelosuppression rather than active residual disease. Summary/Conclusions: In a phase 2 study of HMA guadecitabinein heavily pretreated r/r AML patients, 47% of whom had refractory disease, CR, CRp, and CRi all conferred long survival benefit. With a median follow up of almost 2.5 years, more than half of responding patients were still alive at 2 years and their median OS has not yet been reached. In addition, treatment with guadecitabine allowed post treatment HCT in 58% of responders. Disclosures Griffiths: Celgene, Inc: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Novartis Inc.: Consultancy; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Partner Therapeutics: Consultancy. Kantarjian:Daiichi-Sankyo: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Immunogen: Research Funding; Astex: Research Funding; BMS: Research Funding; Amgen: Honoraria, Research Funding. O'Connell:BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Yee:Astex: Research Funding; Hoffman La Roche: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ritchie:Genentech: Other: Advisory board; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board; Celgene, Incyte, Novartis, Pfizer: Consultancy. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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

Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int'l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study). Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of &lt;1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting. Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Griffiths:New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Persimmune: Consultancy; Partner Therapeutics: Consultancy; Boston Scientific: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial. Yee:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Zeidan:Ariad: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Astellas: Honoraria; Seattle Genetics: Honoraria; Cardinal Health: Honoraria; Novartis: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Dao:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Canada: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Fazal:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Research Funding; Astra Zeneca: Research Funding; Gilead Sciences: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Roboz:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Keer:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Sunesis: Research Funding; Takeda: 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; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 206 AML patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response (CR, CRi, or CRp based on 2003 IWG criteria, grouped together as composite CR or CRc), and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 206 AML patients: 103 patients (50%) for each of Treatment Naïve (TN) unfit for intensive chemotherapy, and relapsed/refractory (r/r) AML. Median age was 68.5y (range 22-92y), ECOG PS ≥2 in 26%, poor risk cytogenetics in 41%, secondary AML in 26%, and median baseline BM blasts % was 40% in the total AML population. 108 patients (52.4%), and 155 patients (75%) received <4 and <6 cycles respectively. The primary reasons for treatment discontinuation before 4 and 6 cycles respectively (% from the total population of 206 patients) were early progression (20.4, and 30.6%), and early death (12.6%, and 17%). However, 9.7% and 14% discontinued treatment before 4 or 6 cycles respectively as a result other less objective reasons such as patient decision, investigator decision, or adverse events which might have been manageable without treatment discontinuation. The landmark analysis population included 161 patients for 4-cycle analysis, and 133 for the 6-cycle analysis. In those patients, there were no major differences in baseline characteristics between those who received at least 4 or 6 cycles and those who did not. In the landmark analysis comparing those who received at least 4 cycles (97 patients) and those who did not (64 patients), CRc rate was 62% vs 25% (p < 0.0001) and median OS was 13.7 m vs 6.1 respectively (HR 0.53, 95% CI 0.37-0.75, p 0.0003). In the landmark analysis comparing those who received at least 6 cycles (51 patients) and those who did not (82 patients) the CRc rate was 82.4% vs 35.4% (p < 0.0001), and median OS of 19.9 m vs 8.8 m respectively (HR 0.42, 95% CI 0.27-0.64, p <0.0001). The results were consistent when TN and r/r AML patients were analyzed separately. More interestingly the landmark OS benefit in patients who received at least 4 or 6 cycles was also evident in patients who did not have an objective CRc. Patients with no CRc who received at least 4 cycles had a median OS of 8 m vs 5.4 m in those who did not (HR 0.63, 95% CI 0.40-0.98,p 0.04). Patients with no CRc who received at least 6 cycles had a median OS of 12.9 vs 8 m in those who did not (HR 0.40, 95% CI 0.17-0.94, p 0.03). Summary/Conclusions: In a prospective phase 2 study of 206 TN and r/r AML patients treated with the HMA guadecitabine, patients who were alive at or beyond 3 and 5 months who continued treatment for at least 4 or 6 cycles respectively achieved a highly significant response and survival benefit compared to those who discontinued treatment before cycle 4 or 6. The survival benefit was evident even in patients who did not have an objective response. Reasons for treatment discontinuation should be weighed carefully before stopping HMA treatment with guadecitabine before 4 or 6 cycles in AML patients to maximize response and survival benefit. Failure to achieve an objective response after 4 cycles should not be a reason for treatment discontinuation as long as patient can still benefit. Disclosures Yee: MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Griffiths:Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; New Link Genetics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Genentech, Inc.: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Daver:Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Glycomimetics: Research Funding; NOHLA: Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding.

Introduction: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is physiologically expressed during embryogenesis, largely disappears by birth, but can be reexpressed pathologically in transformed tissues of many hematological and solid cancers. VLS-101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). Methods: This first-in-human, Phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and efficacy of VLS-101 in patients unselected for tumor ROR1 expression who had previously treated chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Richter transformation lymphoma (RTL). VLS-101 was infused over 30 min every 3 wk until cancer progression or intolerable toxicity. After accrual of 1 patient at the first dose level, cohorts were enrolled by 3+3 dose escalation with additional patients accrued and intrapatient dose escalation permitted to refine estimates of maximum tolerated dose and recommended dosing regimen (RDR). Results: 32 patients were enrolled, including 19 males and 13 females with median (range) ages of 70 (54-84) ys; ECOG performance status (n) of 0 (18), 1 (10), or 2 (4); and tumor types (n) of MCL (15), CLL (7), DLBCL (5), FL (3), MZL (1), and RTL (1). Patients had received a median (range) of 4 (1-24) prior systemic therapies including hematopoietic stem cell transplantation (5) and/or chimeric antigen receptor (CAR)-T or -natural killer (NK) cells (6). Among patients with MCL, 15/15 (100%) had received a Bruton tyrosine kinase inhibitor (BTKi), 13/15 (87%) discontinued the BTKi due to progressive disease, and 2/15 (13%) discontinued for atrial fibrillation after 15.6 or 68.5 months of BTKi therapy. Patients (n) by VLS-101 starting dose were 0.5 (1), 1.0 (3), 1.5 (3), 2.25 (11), and 2.5 (14) mg/kg. With intrapatient dose escalation, many patients (n) received a maximum of 2.25 mg/kg (12) or 2.5 mg/kg (17) during VLS-101 therapy (range: 1 to 13 cycles). Cycle 1 DLTs (n/N) by mg/kg dose level were 0.5 (0/1), 1.0 (0/3), 1.5 (0/3), 2.25 (1/11 [9%] Gr 4 neutropenia), and 2.5 (2/14 [14%]; one Gr 4 neutropenia; one Gr 3 diarrhea of uncertain cause). Gr 4 neutropenia occurred in 9/32 (28%) patients; 1/32 (3%) had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. Baseline Gr 1 neuropathy was present in 10/32 (31%) patients. On-study reversible Gr 3 neuropathy occurred in 3/32 (9%) patients; no Gr 4 neuropathy occurred. Except for Gr ≤2 alopecia in 3/32 (9%) patients, other adverse events were not obviously drug-related. Considering all 175 infusions administered, drug-related infusion reactions, vomiting, tumor lysis syndrome, rash, hepatic or renal abnormalities, or QT prolongation were not observed. PK showed changes in ADC and MMAE exposures proportional with VLS-101 dose and a mean ADC half-life of ~2.5 d. PD indicated exposure-dependent ROR1 occupancy on circulating CLL cells. No neutralizing anti-drug antibodies were detected. Objective tumor responses were not seen in patients with other tumor types but were observed in 7/15 (47%) of patients with MCL (4 partial; 3 complete) and in 4/5 (80%) of patients with DLBCL (2 partial; 2 complete). From start of therapy, 6/7 patients with responding MCL have responses ongoing at 35, 38, 45, 47, 50, and 58 wk and 2/4 patients with responding DLBCL have responses ongoing at 23 and 47 wk of follow-up. Conclusions: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS-101 RDR was 2.5 mg/kg every 3 wk. Efficacy results provide clinical proof of concept for targeting ROR1 with VLS-101 and demonstrate durable objective responses in patients with advanced MCL or DLBCL, including those with prior BTKi or cellular therapies. Phase 1-2 studies of VLS-101 monotherapy and combination therapy in patients with hematological cancers and solid tumors are planned. Figure Disclosures Wang: Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Oncternal: Consultancy, Research Funding; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Guidepoint Global: Consultancy; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria. Barrientos:Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Janssen: Honoraria; AstraZeneca: Consultancy. Furman:Verastem: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barr:AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Choi:Genentech: Consultancy; Pharmacyclics/Abbvie: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Rule:Janssen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy. Flanders:VelosBio: Current Employment, Current equity holder in private company. Jessen:VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Riebling:VelosBio: Current Employment, Current equity holder in private company. Graham:Ce3: Current Employment. King:Ce3: Current Employment; VelosBio: Consultancy; AI Therapeutics: Consultancy. Schmidt:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Johnson:Zentalis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current equity holder in publicly-traded company; Neoleukin: Current equity holder in publicly-traded company; Oncternal: Divested equity in a private or publicly-traded company in the past 24 months; Appelis: Divested equity in a private or publicly-traded company in the past 24 months; Acerta: Patents & Royalties; VelosBio: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Miller:Cleveland BioLabs: Consultancy, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Cancer Genetics: Current equity holder in publicly-traded company; Incuron: Consultancy; Zentalis: Consultancy, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; EpiThany: Current equity holder in private company; AstraZeneca: Current equity holder in publicly-traded company; VelosBio: Consultancy, Current Employment, Current equity holder in private company; AI Therapeutics: Consultancy, Current equity holder in private company; Catalys Pacific: Consultancy. Spurgeon:Cardinal Health: Honoraria; VelosBio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Beigene: Research Funding; Verastem: Research Funding.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received <4 cycles (p <0.0001) and median OS of 20.4 m compared to 15.2 m respectively (HR 0.78, 95% CI 0.45-1.3, p 0.36). Those who received at least 6 cycles (44 patients) had an OR rate of 82% compared to 26% in 43 patients who received < 6 cycles (p<0.0001), and median OS of 23.8 m vs 13.6 m respectively (HR 0.51, 95% CI 0.3-0.85, p 0.009). Results were consistent when r/r MDS/CMML and HMA-naïve MDS/CMML were analyzed separately. Landmark OS analysis also favored those who received guadecitabine for at least 4 or 6 cycles compared to those who received <4 and < 6 cycles even in the absence of objective response (OS HR of 0.82 and 0.42 respectively) but the sample size was small to show statistical significance (p 0.58 and 0.10 respectively) Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit. Disclosures Savona: Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: 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. Kantarjian:Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Griffiths:Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Persimmune: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Podoltsev:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Alexion: 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; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Samus Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Other: Grant funding, Research Funding; Arog Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AI Therapeutics: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.