Zeidan, Amer M.

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 <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 : CD47 is a transmembrane protein ubiquitously expressed in human cells. CD47 is overexpressed in various malignancies and is correlated with negative prognosis in AML and MDS (Chao et al. Curr Opin Immunol.2012; Majeti et al. Cell.2009). Interaction of CD47 with signal-regulatory protein alpha (SIRPα) expressed on macrophages inhibits phagocytosis (Kim et al. Leukemia.2012). CC-90002, a humanized anti-CD47 monoclonal antibody, blocks CD47/SIRPα interactions, thereby enabling macrophage-mediated killing of tumor cells. In preclinical studies, CC-90002 demonstrated antibody-mediated phagocytosis of several hematologic cancer cell lines, including AML cells. CC-90002 also demonstrated a rapid and substantial reduction in tumor burden in AML xenograft models. Herein, we report results from CC-90002-AML-001 evaluating CC-90002 in patients (pts) with R/R AML and high-risk MDS. Methods : In this phase I multicenter study (NCT02641002), CC-90002 was administered intravenously once/week for 4 weeks of each 42-day cycle during cycles 1−4 then once every 4 weeks during a maintenance phase of 28-day cycles. Pts were enrolled in cohorts of escalating dose levels using a modified 3+3 design. The primary objectives were to determine preliminary safety and tolerability, non-tolerated dose (NTD), maximum tolerated dose (MTD), and/or recommended phase 2 dose. Secondary objectives were to measure preliminary efficacy, pharmacokinetics, and the presence and frequency of anti-drug antibodies (ADAs). Results: As of July 18, 2018, 24 pts with R/R AML and 4 pts with high-risk R/R MDS were enrolled. Pts received CC-90002 at 0.1 mg/kg (n=6), 0.3 mg/kg (n=6), 1 mg/kg (n=6), 2 mg/kg (n=4), and 4 mg/kg (n=6). Median age was 70 years (range, 28-85) and 16 (57%) were male. The most common AML subtypes were AML with myelodysplasia-related changes (n=9) and AML not otherwise specified (n=9). All 4 pts with MDS were classified as having refractory anemia with excess blasts-2 and high- or very high-risk disease per the Revised International Prognostic Index Scoring System. The median number of prior systemic anticancer regimens was 3 (range, 1-10), and 29% of pts had prior stem cell transplants. The median treatment duration was 6.9 weeks (range, 2-44). Four pts experienced a dose-limiting toxicity, consisting of grade 4 disseminated intravascular coagulation and grade 4 cerebral hemorrhage in 1 pt (0.1 mg/kg), grade 3 purpura in 1 pt (0.3 mg/kg), grade 4 congestive cardiac failure and grade 4 acute respiratory failure in 1 pt (1 mg/kg), and grade 4 sepsis in 1 pt (4 mg/kg). The most common (≥30%) any-grade treatment-emergent adverse events (TEAEs) were diarrhea (46%); thrombocytopenia (39%); febrile neutropenia and aspartate aminotransferase increased (36% each); and anemia, alanine aminotransferase increased, and cough (32% each). A total of 23 pts (82%) had serious TEAEs with febrile neutropenia (n=10), bacteremia (n=4), pneumonia (n=4), and general physical health deterioration (n=3) occurring in>2 pts. No TEAEs led to dose reductions; however, 7 pts (25%) discontinued due to TEAEs. Overall, 82% of pts were dependent on red blood cell (RBC) transfusions and CC-90002 treatment did not interfere with continued RBC transfusion in pts on study. No pts experienced hemolysis, tumor lysis syndrome, or macrophage activation/cytokine release syndrome. Sixteen pts died during the study. The best overall response observed was stable disease in 2 pts with MDS. CC-90002 serum exposures appeared to increase with doses above 0.3−4.0 mg/kg and the terminal half-life ranged from 4.6−17.0 hours. Development of ADAs targeting CC-90002 occurred at all dose levels tested and the proportion of pts testing positive for ADAs in cycle 1 increased over time (4/27 pts at day 8, 6/25 pts at day 15, and 8/22 pts at day 22). ADAs continued to be present across different doses with increases in median serum ADA titers after cycle 1. No apparent dose-ADA relationship was observed. Conclusion: CC-90002 showed a lack of objective responses in pts with R/R AML and high-risk MDS. The MTD and NTD were not established. The CC-90002-AML-001 study was discontinued in dose escalation for lack of preliminary monotherapy activity and evidence of ADAs in most pts. CC-90002 in combination with rituximab is being explored in CD20+ NHL to enhance efficacy of CD47 blockade while reducing ADAs (CC-90002-ST-001; NCT02367196). Disclosures Zeidan: BeyondSpring: Honoraria; Seattle Genetics: 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; 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; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria. DeAngelo:Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals Inc: Consultancy; Shire: Consultancy; Incyte: Consultancy; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy. Seet:University of California, Los Angeles: Employment. Tallman:Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: 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; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Daiichi-Sankyo: 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; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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, Research Funding; Jazz Pharmaceuticals: 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, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: 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, Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: 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, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Hock:Celgene Corp.: Employment, Equity Ownership. Burgess:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof; University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Background. Gene mutation profiling is increasingly employed for diagnosis, risk stratification, and clinical management in patients with MDS. However, current World Health Organization MDS classification is still based on histologic findings (with the exception of SF3B1 for MDS-RS), and guidelines generally suggest that clinical decisions be guided by clinico-pathologic risk stratification tools such as Revised International Prognostic Scoring System (IPSS-R). We sought to study beliefs and patterns of practice with respect to gene mutation profiling among health care providers who manage patients with MDS. Methods. A link to a 23-question web-based survey was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 5/1/2018 with 6 subsequent weekly reminders. The Qualtrics survey platform was used to record anonymous responses. We used descriptive statistics to analyze the data. No incentive was provided for responses. Results. Of 371 received responses, 262 were received from providers who did not manage MDS patients or lacked analyzable data and therefore were excluded. Of 109 eligible responses, 108 responders were from institutions representing 31 US states (one respondent was from South America). Median age of respondents was 48 years (range, 33-75); 43 (39%) were women. A third of responders (32%) worked at a university hospital, while 25%, 17%, and 5% worked at a community hospital, private practice, or other settings, respectively. While 37% of participants worked at institutions with guidelines for clinical care of MDS patients, 28% reported that their institutional guidelines recommended MDS-specific gene mutation profiling. Such testing was performed at institutions of 13% participants; institutions of 26% of responders tested a general AML panel that included MDS-specific genes. The total number of respondents whose institutions sent out either an MDS-specific gene panel or a general AML gene panel with MDS-specific genes was similar, 25% and 12%, respectively (Fig. 1). Of those who routinely perform molecular testing, 94% do so at diagnosis, 56% at relapse, 33% during preparation for stem cell transplant, 31% after the failure of hypomethylating agents (HMA), 24% during screening for a clinical trial, and 15% at initial treatment (Fig. 2). MDS gene mutation profiling was felt to be most helpful in diagnosis (rarely 11%; sometimes 49%; often 30%; always 9%), risk stratification (sometimes 31%; often 51%; always 15%), and prognosis (sometimes 31%; often 51%; always 14%); its role was more limited in response assessment (never 12%; rarely 25%; sometimes 44%; often 14%) and to predict responses to HMAs (never 5%; rarely 28%; sometimes 52%, often 14%) (Fig. 3). Various types of evidence were used to stratify MDS risk and prognosis: genetic mutations were used by nearly everyone (95%); 70% relied on morphologic findings, while gene expression/transcriptome profiling was used by 40%. Eighty-four percent of responders reported relying on conventional prognostic models like IPSS-R to identify high-risk patients for whom they would consider intensive treatment options. For this purpose, 62% would also rely on mutation profiling, and 32% would also consider higher frequency of gene mutations. While mutations in the p53 pathway were felt to be helpful in terms of risk stratification and treatment decisions by 70% of responders, 43%, 39%, 31%, 26% 23%, 20%, and 3% considered mutations in spliceosome, DNA methylation, transcription factors, histone modification, signaling, RAS pathway, and cohesin genes, respectively, to be useful as well. Approximately 31% of responders were not certain as to which mutations would affect risk stratification and management choices and said they needed to review literature. The respondents also cited multiple limitations to wider clinical use of MDS gene mutation profiling (Fig. 4). Conclusions. Our survey demonstrates widespread use of gene mutation profiling in the management of patients with MDS, but also reveals substantial variability in beliefs, practices, testing logistics, and interpretation of molecular profiling. Our findings emphasize the need for high-quality data to develop consensus evidence-based guidelines for gene profiling of MDS patients. Disclosures Sekeres: Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bejar:AbbVie/Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Foundation Medicine: Consultancy; Astex/Otsuka: Consultancy, Honoraria; Modus Outcomes: Consultancy; Takeda: Research Funding; Genoptix: Consultancy. Gore:Celgene: Consultancy, Research Funding. Zeidan:Ariad: Consultancy, Speakers Bureau; Gilead: Consultancy; Incyte: Employment; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy.

Abstract Background. Transfusion of blood products is an integral component of the management of patients with acute leukemias. However, high-quality evidence and clinical trial data to support specific practices of blood product transfusion in this population are limited. We hypothesized that there is wide variation in blood product transfusion practices among providers in North America who manage patients with acute leukemia. Methods. A 30-question web-based survey about transfusion practices was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 7/6/2015 with 4 subsequent weekly reminders. The distribution list included 9,859 recipients, of whom at least 741 were providers who treated patients with acute leukemia. Responses were anonymous, and the survey distribution was approved by the respective cooperative group chairs. Descriptive statistics were used to analyze the data. Results. Of 254 responses received, 113 were excluded as they were returned by recipients not directly treating patients with acute leukemia. Another 30 responses were excluded due to incomplete data, leaving 111 responses (43.7%) eligible for the primary analysis. Of those, 109 responders were from North America representing 83 institutions in 33 states and the province of Ontario. Eighty-four of the included responders (75.7%) were physicians, and 44 (39.6%) were females. Median age of responders was 44 years (range, 26-76). A hemoglobin (Hb) level of ≤7 g/dL was the most commonly used threshold (44%) for red blood cell (RBCs) transfusions to asymptomatic stable hospitalized patients, followed closely by 8 g/dL (38%) (Figure 1). In the outpatient setting, the most commonly reported threshold was 8 gm/dL (49%) (Figure 1). Most providers reported that they "always" use leukocyte-reduced (93%) and irradiated (79%) RBCs. A platelet level of 10,000/µL was the threshold for platelet transfusions in the stable non-bleeding hospitalized patients cited by the majority of responders (76%) (Figure 2). This platelet level remained the most common threshold for platelet transfusions for non-bleeding patients in the outpatient setting (49%), although 31% of responders reported a higher threshold of 20,000/µL. A preference for single-donor apheresis platelets was reported by 81% respondents, and 57% use these products exclusively. Most providers (70%) reported always using irradiated platelets. With respect to cryoprecipitate and plasma infusions, nearly half of the respondents reported a threshold fibrinogen level of 100 mg/dL as a trigger for administering a product to a stable non-bleeding patient (Figure 3). The most commonly reported platelet threshold for performing a bone marrow biopsy (BMB) was 10,000/μL (69% of responders), followed by 20,000 (21%), 50,000 (6%), and 30,000 (4%). Therapeutic anticoagulation was held by most responders (80%) before performing a BMB. Most responders (73%) reported a platelet level of 50,000/µL as the lowest level for performing a lumbar puncture (LP) without prophylactic platelet transfusion. Conclusions. This survey demonstrates wide variability in blood product transfusion patterns among providers who treat patients with acute leukemias. A platelet level of 10,000/µL is the most common trigger for platelet transfusions for stable non-bleeding patients in both inpatient and outpatient settings. This, along with a platelet threshold of 50,000/µL for performing an LP, appear to be most widely accepted practices. Our findings emphasize the need to obtain high-quality data to develop consensus evidence-based guidelines for transfusion practices in acute leukemia with the goal of limiting unnecessary transfusions without compromising patient outcomes. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Onconova: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Prebet:CELGENE: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Stone:Merck: Consultancy; AROG: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Novartis: Research Funding; Juno: Consultancy; Amgen: Consultancy; Roche/Genetech: Consultancy; Celator: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Barbarotta:Celgene, BMS, Novartis: Speakers Bureau. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract On behalf of the ECOG-ACRIN Cancer Research Group Background: Venous thromboembolism (VTE) occurs in 2-12% of patients with acute leukemia (AL) despite disease and therapy-associated thrombocytopenia, and can be associated with significant morbidity and mortality. Due to limited high-quality studies, there are no evidence-based guidelines for VTE prophylaxis in this patient population. Based on our experience and the lack of consensus guidelines, we hypothesized that there would be a wide range in provider practice regarding methods of VTE prevention in patients with AL. To determine the current individual practices in North America, we devised a web-based survey of VTE prophylaxis practice among clinicians caring for patients with AL. Methods: An anonymous 19 question web-based survey, approved by the Johns Hopkins Institutional Review Board, was distributed by email to members of the ECOG-ACRIN Cancer Research Group on 10/22/14. Four reminders were sent at two-week intervals with the survey closing on 12/8/14. Results: Of the total 215 respondents, 64 were excluded for the following reasons: 52 did not directly manage medical care of AL patients, 3 referred AL patients to other centers, 5 left blank responses to all questions regarding VTE prophylaxis, 1 was a duplicate entry, and 3 described their position as support or office staff. One hundred fifty-one responses were eligible for analysis, with a response rate of 20.9% among physicians who treated leukemias. One hundred forty-seven were from the United States and 4 from Canada, representing 88 different institutions and 37 states or provinces. Overall, 47% and 45% of providers reported using pharmacologic VTE prophylaxis during induction and consolidation phases, respectively. Among the providers using pharmacologic prophylaxis, 60% designated 50,000/μL as the platelet count threshold below which they would hold prophylaxis and 26% used a platelet count of 30,000/μL. Fewer providers chose a platelet count of 20,000/μL (4%), 75,000/μL (4%), and 100,000/μL (2%). Lastly, 2% held prophylactic anticoagulation only in the setting of an active bleed and 2% reported variable thresholds. Approximately 15% of providers did not utilize any VTE prophylaxis while 36% used mechanical methods and ambulation. Among providers who did not recommend pharmacologic prophylaxis, the most commonly cited reasons were the perceived high risk of bleeding (51%), absence of data supporting use (38%), and perceived low risk of VTE (11%). Conclusions: These results demonstrate wide variation in clinician practice regarding VTE prevention in hospitalized AL patients during induction and consolidation therapy. Our findings emphasize the need to develop standardized, evidence-based guidelines in this at-risk population. VTE: venous thromboembolism, AL: acute leukemia, SC: subcutaneous, TED: thromboembolic deterrant stockings, SCD: sequential compression device Figure 1. Practice patterns of VTE prophylaxis for AL patients during induction and consolidation therapies Figure 1. Practice patterns of VTE prophylaxis for AL patients during induction and consolidation therapies Disclosures Barbarotta: Celgene, BMS, Novartis: Speakers Bureau. Prebet:CELGENE: Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Key Points In the largest study of HMAs in RR-AML to date, 16% of patients achieved CR/CRi and experienced a median OS of 21 months. Low proliferative disease (peripheral blood blasts <5%) was associated with improved response and OS.