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DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of “therapy-related” NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.

Introduction Isocitrate dehydrogenase (IDH) mutations occur in ~20% of acute myeloid leukemia (AML) patients (pts) and are frequently identified in older pts. Pre-clinical data showed that cells with IDH1/2 mutation (mut) were susceptible to Venetoclax (Ven) therapy (Chan et.al., 2015). Clinical studies have demonstrated that pts with IDH1/2mut treated with Ven and azacitidine (Aza) achieved high response rates that were durable, and had longer median overall survival (mOS) (DiNardo et. al., 2020; DiNardo et. al., 2019). Herein, we further evaluated the efficacy and safety of Ven+Aza among treatment-naïve AML pts with IDH1/2 mut unfit for intensive treatment either due to comorbidities and/or age ≥ 75 yrs. Methods Data were pooled from pts enrolled in an ongoing phase 3 study (NCT02993523, data cut-off: 04Jan2020) comparing pts treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for IDH1 and 2 [RealTime IDH1 or IDH2 assay (Abbott) for phase 3 study, MyAML panel (Invivoscribe) for phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were excluded from the analyses. Results IDH1/2 mut was detected in 79 pts treated with Ven+Aza and 28 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), median age was 76 (range: 64-90)/78 (62-90) yrs. Cytogenetic risks were intermediate: 79%/68%, and poor:21%/32%. ECOG scores were: 0-1: 56%/68% and 2-3: 44%/32%. 73%/86% had de novo AML, and 27%/14% had secondary AML. IDH1 was detected in 32/11, IDH2 in 49/18, IDH2R140 in 36/15, and IDH2R172 were detected in 13/3 pts, respectively. The median number of treatment cycles received (Ven+Aza/Pbo+Aza) by IDH1/2 pts was 8 (range: 1-37)/2.5 (1-18). Complete response (CR)+CR with partial hematologic recovery (CRh) in Ven+Aza/Pbo+Aza were 72% (95% CI: 61%-82%)/7% (1%-24%) (Table). Median time to first CR/CRh response was 1.0/2.6 months (mos), and 51%/0% achieved CR+CRh by initiation of cycle (C) 2. Median duration of response (mDoR) was 29.5 [95% CI: 16.7-not reached(NR)]/15.5 (NR-NR) mos and mOS was 24.5 [15.2- NR/6.2 (2.3-12.7) mos. The separation of 95% CIs for mOS indicate superior treatment effect of Ven+Aza (Figure). In pts with IDH1, CR+CRh (Ven+Aza/Pbo+Aza) was 59%/9%. Median time to first CR/CRh response was 2.3/3.1 mos, and 25%/0% achieved CR+CRh by initiation of C2. Median DoR and OS were 21.9 (7.8-29.5)/NR and 17.5 (6.3-32.7)/2.2(1.1-5.6) mos. In pts with IDH2, CR+CRh rates were 80%/6%. Median time to first CR/CRh response was 1.0/2.1 mos and 67%/0% achieved CR+CRh by initiation of C2. Median DoR was NR (16.7-NR)/15.5 (NR-NR), and mOS was NR (17.6-NR)/13.0 (95% CI: 3.8-15.8) mos. In pts with IDH2R140, CR+CRh were 75%/7%. Median time to first CR/CRh response was 1.0/2.1 mos, and 58%/0% achieved CR+CRh by initiation of C2. Median DoR and mOS were NR (17.8-NR)/15.5 (NR-NR) and NR (15.0-NR)/12.7 (1.7-15.8) mos, respectively. Response rates in pts with IDH2R172 were 92%/0%. Median time to first CR/CRh response was 1.0/NR mos, and 92%/0% achieved response by initiation of C2. Median DoR and mOS were 16.7 (7.5-NR)/3.5 (NR-NR) and NR (12.2-NR)/13.7 (10.6-NR) mos. IDH1/2 mut pts achieved higher CR+CRh rates with Ven+Aza treatment as compared to pts with IDH not detected (72%/60%). Median DoR and mOS were 29.5 (16.7-NR)/17.5 (10.6-23.5) and 24.5 (15.2-NR)/12.3 (9.7-14.8) mos, respectively. In pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) among pts with IDH1/2 detected/IDH not detected were similar (81%/74%) and included grade 3/4 thrombocytopenia (46%/34%), febrile neutropenia (43%/41%), neutropenia (35%/33%) and anemia (29%/24%). Conclusion Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy. The safety profile was acceptable. No unexpected toxicities were noted with Ven+Aza combination. Disclosures Pollyea: Pfizer: Consultancy; Glycomimetics: Other; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Janssen: Consultancy; 47: Consultancy, Research Funding; Agios: Consultancy; Celgene/BMS: Consultancy. Dinardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios: Consultancy, Research Funding; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Arellano:Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding; Cephalon Oncology: Research Funding. Fiedler:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Gilead: Honoraria; BMS: Honoraria; BerGenBio ASA: Research Funding; Servier: Honoraria, Other; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Konopleva:Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Calithera: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:Jazz: 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; Celgene: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shinagawa:AbbVie: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: 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: 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. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Ridgeway:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kantarjian:Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Delta Fly: Honoraria; BMS: Research Funding; Aptitute Health: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding.

Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1). Olutasidenib has previously shown clinical activity in high-risk AML patients (pts) in a Phase 1 clinical trial (Watts, Blood 2019). The planned interim analysis of an ongoing Phase 2 clinical trial (NCT02719574) in R/R mIDH1 AML pts receiving single-agent olutasidenib 150 mg twice-daily showed an overall response rate (ORR) of 46%, including 33% of pts with CR/CRh (de Botton et al., ASCO/EHA 2021). Here we present data analysis on the mutational characteristics of these pts and the relationship between mutations and clinical response. Methods: The Efficacy Evaluable (EE) set comprised mIDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts 0.5×10 9/L, and platelet count >50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). IDH1 mutation subtypes were determined by central analysis, co-mutations were reported by investigators. Baseline characteristics and mutation subtypes were tabulated for the safety population and analysis of response rate by mutation type was performed on the EE set. Results: There were 153 R/R AML pts treated with olutasidenib 150 mg BID (safety set). Of those, 123 were in the efficacy evaluable (EE) set (centrally confirmed IDH1R132 mutation and received first dose at least 180 days prior to the data cut off). For the safety population, cytogenetic risk classification was favorable in 6 (4%) pts, intermediate in 109 (71%) pts, and poor in 25 (16%) pts (unknown, 13 [8%] pts). Eighty-five (56%) pts had IDH1R132C mutation subtype, followed by IDH1R132H (n=35 [23%]), IDH1R132G (n=12 [8%]), IDH1R132S (n=11 [7%]), and IDH1R132L (n=4 [3%]). Ninety-four (61%) pts had 1-3 co-mutations reported by the investigator at baseline, with 4-7 co-mutations in 20 (13%) pts, none in 6 (4%) pts, and not done/unknown in 33 (22%) pts. The most common co-mutations at baseline were: NPM1 (n=40 [26%]), DNMT3A (n=36 [24%]), and ASXL1 (n=21 [14%]. Receptor tyrosine kinase (RTK) mutations were reported in 32 (21%) pts (FLT3, n=18 [12%]; NRAS, n=10 [7%]; KRAS, n=3 [2%]; PTPN11, n=3 [2%]; KIT, n=2 [1%]; NF1, n=2 [1%]), with multiple mutations reported in some pts. For the EE population, responses were achieved in all IDH1R132 mutation subtypes, with ORR and CR/CRh response rates ranging from 27%-54% and 17%-50%, respectively (Table 1). The CR/CRh response rate was lower for pts with IDH1R132H mutations; notably, these pts tended to have a higher percentage of co-mutations, particularly mutations in NPM1 and RTK genes, including FLT3. For EE pts with available co-mutation data (n=96), the mean (SD) number of co-mutations was lower (p Conclusions: Responses were observed across IDH1R132 mutation subtypes, with a relatively lower CR/CRh response rate for pts with a R132H mutation as compared to other subtypes. Pts with a best response of CR/CRh had fewer co-mutations than pts who did not achieve CR/CRh. While the ORR was not significantly reduced for pts with RTK mutations, these pts had a lower CR/CRh response rate compared to pts without any RTK mutations. Additional genetic analyses using ddPCR for IDH1 mutations and NGS on a targeted panel of genes at baseline, best response, and end of study will be presented to further explore primary and secondary resistance mechanisms. Figure 1 Figure 1. Disclosures De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Yee: Forma Therapeutics: Research Funding; Onconova: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Jazz: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei: Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Stemline/Menarini: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Esteve: Novartis: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; Novartis: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy. Grove: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Khwaja: Pfizer, Abbvie: Honoraria; Novartis, Jazz: Speakers Bureau. Blum: Forma Therapeutics, Xencor; Celyad: Research Funding; Amerisource Bergen; Abbvie, Syndax: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Xin: Forma Therapeutics, Inc.: Current Employment. Sedkov: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Guichard: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sweeney: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Cortes: Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Fenaux: Syros Pharmaceuticals: Honoraria; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

Background: The WHO 2016 classification identifies myeloid malignancies with germline predisposition as a distinct subgroup (Arber DA et al., Blood 2016). We and other reported mutations of the DEAD-box RNA helicase 41 gene (g DDX41m) as the most common predisposition to MDS/AML (Sébert et al., Blood 2019). Relatively good outcomes have been suggested in small cohorts receiving heterogeneous treatment, but the prognostic significance of g DDX41m in AML patients (pts) treated with intensive chemotherapy (IC) has never been reported. Here, we analyzed the prognostic impact of g DDX41m in a large cohort of newly diagnosed AML pts treated with IC in 5 prospective ALFA (Acute Leukemia French Association) and FILO (French Innovative Leukemia Organization) trials. Methods: We retrospectively screened 1690 AML pts (aged 18-85y) treated in ALFA0701 (EudraCT 2007-002933-36), ALFA0702 (NCT00932412), ALFA1200 (NCT01966497), ALFA1401 (NCT02473146) and LAM-SA (NCT00590837) clinical trials for DDX41 mutations using High Throuput Sequencing. DDX41 variants with a variant allele frequency (VAF) >40% were interpreted as causal if they were pathogenic or likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) guidelines. The concurrence of a somatic DDX41 mutation was also considered as a strong evidence for the causality. Correlation between g DDX41m and covariates was realized using point biserial correlation and Fisher test for continuous and dichotomic variables, respectively. Allogeneic hematopoietic stem cell transplantation (HSCT) was considered as a time-depending variable, and all outcome analyses were stratified on the clinical trial. Results: We identified 86 unrelated pts with DDX41-related AML representing 5% of the whole cohort; 66 (77%) of them had additional somatic DDX41 mutations. Most common germline variants were p.D140fs (21%), p.M1? (8%), p.L283fs (7%) and p.K331del (5%); p.R525H and p.G530D/C/S accounted for 80% and 10% of all somatic mutations respectively. Compared to wild-type pts, DDX41-related AML were significantly older (65.5 vs 64y, p=0.036), with male predominance (74 vs 54%, p=0.002), had higher rates of normal karyotypes (77 vs 57%, p=0.006), lower WBC (2.0 vs 7.9 G/L, p After one induction course, CR/CRp was achieved in 81 (94%) DDX41-related AML compared to 1164 (73%) in DDX41-wt pts. In a multivariate analysis including WBC, ELN-2017 classification and clinical trial, presence of a g DDX41m was associated with significant higher CR/CRp achievement (OR, 5.39 [95% CI, 2.33-15.67]; p=0.0004) (Figure 1B). After a median follow-up of 47.8 months, DDX41-related AML had a median OS of 39.7 (IQR, 19.4-66.4) months compared to 29.1 (IQR,10-not reached [NR]) months in DDX41wt (p=0.045). However, the prognostic impact on OS of g DDX41m was not independent of WBC and ELN-2017 classification (p=0.5). Relapse rates in DDX41-related pts were lower at 1-year (11 vs 30%), but then increased to join the relapse rates of DDX41-wt pts at 3 years (50 vs 50%, Figure 1C). Finally, 35 DDX41-related and 288 non-favorable DDX41-wt pts received an HSCT in first CR. HSCT was associated with a prolonged OS in the non-favorable DDX41-wt cohort (HR, 0.61 [95% CI, 0.49-0.76]; p Conclusion: This is the first study evaluating the prognostic impact of g DDX41m in a large cohort of AML pts prospectively treated with IC. DDX41-related AMLs represented a rare specific entity and were associated with a higher response rate, prolonged time to relapse without independent OS advantage compared to DDX41-wt AML. These results suggest that consolidation/maintenance strategy might be adapted in these pts. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. de Botton: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Other; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Recher: Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Sebert: Abbvie: Consultancy; BMS: Consultancy.

Background: Achieving a first complete remission (CR1) is the primary goal in the treatment of AML and is an important prognostic factor for transplantation outcome in general and even more so for autologous transplantation (AutoSCT). However, there are no data for AutoSCT indicating whether the number of chemotherapy courses (1 vs 2) needed to achieve CR1 is of prognostic significance for transplantation outcome. Methods: Using the EBMT/ALWP registry, we compared transplantation outcomes of adult patients (pts) aged ≥18 years with de novo AML that underwent a peripheral blood AutoSCT in 2000-2019 in CR1 achieved following one vs two chemotherapy courses. The primary outcome was the Leukemia Free Survival (LFS). Multivariate analysis (MVA) adjusting for differences between the groups and knowns factors were performed using Cox's proportional- hazards regression model for outcomes. Results: 1825 pts were included: 1532 (84%) with one and 293 (16%) with two induction chemotherapies courses. Time from diagnosis to AutoSCT was 4.7 (3.9-5.8) vs 5.7 (4.7-7.1) months, respectively (p 90 was higher in pts receiving 1 vs 2 inductions, 71% and 58% of pts, respectively (p Day 30 neutrophil engraftment incidence was 96% and 96.5%. Five -year non-relapse mortality (NRM) was 6.2% vs 6.0% for pts achieving CR1 with 2 vs 1 chemotherapy courses, respectively, and did not differ significantly (HR=1.31 (95% CI: 0.81-2.10), p=0.27). Five -year relapse incidence (RI) was higher :67.2% vs 52.3%, (HR=1.46 (95% CI: 1.25-1.72), p Conclusions: The five -year RI was higher and transplantation outcomes significantly inferior in pts with AML undergoing AutoSCT but who received two lines of chemotherapy to achieve CR1. Such pts may benefit from additional novel therapies in the conditioning or post-AutoSCT or be considered for allogeneic transplantation in an attempt to reduce their high RI and improve outcomes. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Introduction Allogeneic Hematopoietic Cell Transplantation (allo-HCT) has proved its efficiency in reducing Acute Myeloid Leukemia (AML) recurrence, although it was associated with high rates of complications especially in older patients. The worldwide number of allo-HCT has increased within 35 years, from 10.000 transplantations before 1985 to over a million in 2012. The decision to perform transplantation depends on the estimated risk-benefit ratio. High-risk prognostic factors include cytogenetics, age at diagnosis, presence of comorbidities and the response to treatment. By using combination of risk factors, international recommendations have been published to harmonize AML care and maximize the benefit of using allo-HCT. The principal aim of this study is to describe real life AML care management in all consecutive patients diagnosed and registered on 3 regional cancer registries in France, to analyze their outcome after different therapeutic strategies, following or not the international recommendations. Method This retrospective study included all AML patients diagnosed between January 2012 and December 2016 reported to the French population data-based of regional cancer registries specialized in hematological malignancies. Allo-HCT data were extracted from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry. Two groups of patients were defined according to the treatment received: i) group 1, patients who have received the best recommended care including allo-HCT considering HLA compatibility and best donor choice or best conventional treatment according to therapeutic guidelines based on individuals and clinical characteristics from The American Society for Blood and Marrow Transplantation guidance; ii) group 2, patients who received a treatment outside the recommendations. To study the impact of therapeutic decision on overall survival, a case-control study was performed using a one for one matching between group 1 and group 2. An exact matching on individual and disease characteristics (cytogenetic risk, Charlson score class, age group at diagnosis, subtype AML and response to treatment) allowed to pair-match patients following or not the international recommendations for therapeutic strategy. Net survival was estimated until five-year using non-parametric Pohar-Perme estimator (survival distribution compared using Grafféo test). Results A total of 1039 AML patients diagnosed from 2012 to 2016 were identified, 449 (43 %) received a curative treatment and 540 patients a non-curative treatment (hypomethylating agents, low dose of cytarabine or other palliative treatment, best supportive care combined to no effective treatment). Based on available clinical data, 430 patients were included in the study. Group 1 included 296 patients (68%), 167 males and 129 females with 54 receiving allo-HCT (32 geno-identical and 22 unrelated). Group 2 included 134 patients (31%), 72 males and 62 females with 94 receiving allo-HCT (14 geno-identical, 50 unrelated and 30 mismatched). In patients for whom allo-HCT represented the best option according to the recommendations (Figure B, n = 44), a very significant lower survival was observed in patients who did not receive allo-HCT when they were compared to patients who received allo-HCT, with a 5 year-overall survival probability of 7 % and 50 % respectively (p= 0.019). In patients for whom allo-HCT was not recommended (Figure A, n = 42), we did not observe any significant difference of survival between patients transplanted or not. Conclusion This analysis shows the importance of allo-HCT decision in AML patients, especially when following international guidelines. Although individual risks factors have been previously studied, our analysis sums up theses factors and allow to understand the importance of integrating allo-HCT in the therapeutic strategy of AML and to re-evaluate current practices and its impact on patient outcome. Figure 1 Figure 1. Disclosures Pigneux: Roche: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Amgen: Consultancy; Novartis: Consultancy, Research Funding. Forcade: Novartis: Other: travel grant. Mohty: Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

The outcome of AML patients (pts) ≥ 70 years is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy (IC) and hypomethylating agents (HMAs). We set up a multicentric European database collecting data of AML pts ≥ 70 y. The primary objective was to compare overall survival in pts selected for IC or HMAs. Individual pt data were collected from 3 European AML registries (DATAML, SAL and PETHEMA). All pts ≥70 y newly diagnosed between 01/01/2007 and 06/30/2018 were included. Variables were age, sex, diagnosis date, AML status, WBC, BM blasts %, cytogenetic risk, NPM1, FLT3-ITD mutations, first-line therapy, response, allo-SCT in first complete remission (CR), date of relapse and/or death. First-line treatments included IC, a semi-intensive regimen (fludarabine, cytarabine, filgrastim), HMAs, low-dose cytarabine (LDAC) or supportive care (SC). 3 700 AML pts ≥ 70y were identified. Pts treated with semi-intensive chemotherapy (n=464), LDAC (n=127) or SC (n=837) were not included in this analysis. Thus, the study population included 1 199 IC pts and 1 073 HMA pts. The median follow-up was 49.5 months. In the HMA group, pts were older, had lower WBC count and BM blast %, and they more frequently had ECOG > 1, secondary AML (sAML) and adverse-risk cytogenetics (CG) compared to the IC group. NPM1 and FLT3-ITD mutations were more frequent in the IC group. IC regimens were daunorubicin-AraC (n=432, 36.0%), idarubicin-AraC (n=381, 31.8%) or ida-AraC-CCNU (n=214, 17.8%). AlloSCT was performed in 70 IC pts (5.8%) and only in 7 HMA pts (0.7%) (P CR/CRi was achieved in 673 (56.1%) and 211 (19.7%) pts in the IC and HMA groups (P 1, adverse-risk CG and WBC >30 giga/L were significantly associated with a lower response rate whereas NPM1 mutation was significantly associated with a higher response rate. HMA treatment was associated with a lower response rate than IC (OR, 0.25; 95%CI : 0.20-0.31 ; P Day-60 death occurred in 247 (20.6%) and 194 (18.1%) pts in the IC and HMA groups (P=0.129). MV analysis showed that age ≥ 75 years, ECOG > 1, adverse-risk CG and WBC > 30 giga/L were significantly associated with a higher d60 death rate. HMA treatment was associated with a lower d60 death rate than IC (OR, 0.69; 95%CI : 0.54-0.88 ; P=0.003). The median OS was 10.9 (95%CI: 9.7-11.6) and 9.2 months (95%CI: 8.3-10.2) in the IC and HMA groups. OS at 1, 3 and 5 y was 46.0 (95%CI: 43.0-48.9) vs. 40.6% (95%CI: 37.6-43.7), 20.8 (95%CI: 18.3-23.4) vs. 8.3% (95%CI: 6.5-10.4) and 12.4 (95%CI: 10.2-14.9) vs 2.8% (95%CI: 1.7-4.4) in the IC and HMA groups. In MV analysis, ECOG > 1, adverse-risk CG, WBC > 30 giga/liter and sAML were significantly associated with a poorer OS. The treatment effect on OS was time-dependent (Fig 1A). To account for the non-proportionality of risks, we used a Royston and Parmar model, which took into account the interactions between time and treatment effect and allowed graphical representation of the adjusted risk of death at all times during follow-up. This model showed that HMA pts had a significantly lower risk of death before 1.5 months of follow-up ; there was no significant difference between both groups between 1.5 and 4.0 months, and OS was significantly better with IC from 4.0 months of follow-up (Fig 1B). There was no significant interaction between treatment (HMAs vs. IC) and all confounding factors (in particular age, performance status or CG risk). We also used the propensity score method. A MV logistic regression model was generated to estimate for each pt a propensity score to receive HMAs or IC. The performance of the model was estimated with the c 2-Hosmer-Lemeshow statistic (P-value= 0.169) and the C-statistic (0.82, 95%CI: 0.81-0.84). The mean propensity score was 0.320 (±0.232) in IC (N=1199) and 0.642 (±0.234) in HMA (N=1073). Based on propensity score, 532 subjects with IC were matched with 532 subjects with HMAs. The mean propensity score was the same in IC and HMA (0.491 ± 0.219) in the matched sample. The results of HMAs vs. IC comparisons on response, early mortality and overall survival (Fig 1C-D) in this subgroup of propensity score-matched pts were similar to those of the MV analysis. With a fairly long median follow-up and a large number of pts, this study shows that IC remains the treatment strategy that offers better chances for prolonged survival compared with HMAs even in AML pts ≥ 70y. Figure 1 Figure 1. Disclosures Recher: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding. Bertoli: Astellas: Consultancy; BMS Celgene: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Dumas: Daiichi-Sankyo: Consultancy; Astellas: Consultancy; BMS Celgene: Consultancy. Tavitian: Novartis: Consultancy. Platzbecker: AbbVie: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. de la Fuente: Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding; BMS: Consultancy, Speakers Bureau. Delabesse: Novartis: Consultancy; Astellas: Consultancy. Pigneux: Roche: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Amgen: Consultancy; Novartis: Consultancy, Research Funding. Montesinos: Stemline/Menarini: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Forma Therapeutics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age Regarding safety of GO-based regimen, early deaths occurred within Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

Introduction In the acute myeloid leukemia (AML) setting, artificial intelligence has mainly been used to facilitate diagnosis or to identify biological subcategories. In this work, we trained and compared machine learning and deep learning predictive models of outcome on the data of 3687 consecutive adult AML patients included in the DATAML registry between 2000 and 2019. We also trained a model to predict the best treatment for newly diagnosed AML over 70 years. Methods Feature engineering and selection were done to keep the most relevant variables among clinical and biological characteristics at diagnosis. We worked with 54 features per patient, as well as information about the treatment received (intensive chemotherapy (IC) or azacitidine (AZA)), response and survival. We compared the performance of a gradient boosting algorithm (XGBoost) and three neural networks architectures: a multilayer perceptron (MLP), a neural oblivious decision ensemble model (NODE) and a recurrent relational network (RRN). We calibrated XGBoost with a grid search algorithm, and used 5-fold cross-validation on the dataset to evaluate all the models. The Shapley Additive Explanations method (SHAP) was used to showcase the importance and influence of variables on the predictions. The Boruta algorithm was then used to extract the most important features for prediction. Results In our cohort, 3030 patients (82.2%) received IC and 657 (17.8%) AZA as first line treatment. Median overall survival (OS) was 18 and 9 months, respectively. We first designed models for OS prediction. In the IC cohort, we achieved an accuracy of 68.5% on predicting OS at the 18-month mark, an improvement of 17.5% over a naïve predictor. The Boruta algorithm selected 13 variables as the most important, with decreasing order of importance: age, cytogenetic risk, WBC, LDH, platelets count, albumin, MPO, mean corpuscular volume, CD117, NPM1 mutation, AML status, multilineage dysmyelopoiesis, ASXL1 mutation (Figure 1). When training with only these 13 variables, we achieved an accuracy of 67.8%. In the AZA cohort, we achieved an accuracy of 62.1% on predicting OS at the 9-month mark, an improvement of 11.1% over a naïve predictor. Here the Boruta algorithm selected only 7 variables: blood blasts, serum ferritin, CD56, LDH, hemoglobin, CD13 and the presence of a disseminated intravascular coagulation. When training with only these 7 variables, we achieved a 61.9% accuracy. We then designed models to predict the best treatment between IC and AZA for the 1032 patients older than 70 years. We achieved a 88.5% accuracy, which is 37.5% more than a naïve predictor given the distribution of the cohort: 51% having received IC and 49% having received AZA. For this model, 12 features out of 54 were selected by the Boruta algorithm as the most important: age, TP53 mutation, bone marrow blasts, AML status, disseminated intravascular coagulation, blood blasts, cytogenetic risk, IDH2 mutation, IDH1 mutation, presence of an infection at diagnosis, ASXL1 mutation and presence of leukostasis. Conclusion We show that predictive models can be trained on our database to predict with characteristics at diagnosis the treatment that would be chosen by an expert hematologist between IC and AZA in newly diagnosed AML, give an indication of OS with each treatment, and outperform classical statistical analysis or naïve predictors. For the task of predicting OS, the improvement over naïve predictors is maximal at the median time of OS. We show with the Boruta algorithm that a small number of variables can recapitulate the accuracy of neural networks, which renders this type of model of high interest for routine practice, especially with the advent of targeted therapies. Figure 1 Figure 1. Disclosures Vergez: Pierre Fabre Laboratory: Research Funding; Roche: Research Funding. Dumas: BMS Celgene: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Tavitian: Novartis: Consultancy. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Recher: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bertoli: Astellas: Consultancy; BMS Celgene: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy.

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Background: Despite widespread interest in pain management and opioid use across the United States, information on pain and opioid utilization in patients with relapsed or refractory acute myeloid leukemia (R/R AML) is lacking. Better understanding of patient-reported outcomes (PROs) specific to pain could be used to identify strategies to improve the quality of life in patients with R/R AML. Aim/Objective: To describe pain and opioid use in patients with FLT3 mutation-positive (FLT3mut+)R/R AML receiving either gilteritinib or salvage chemotherapy (SC) using PRO data collected from the ADMIRAL study (NCT02421939). Methods: ADMIRAL was a phase 3, open-label, multicenter, active-controlled randomized study comparing the efficacy and safety of gilteritinib to SC in patients with FLT3mut+ R/R AML. Pain was assessed using selected items from the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu; GP4 item: "I have pain") and the EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L; Pain/Discomfort domain). Data for these instruments were collected at baseline (BL), Day 1 of every treatment cycle, and end of treatment (EOT). A modified EOT (mEOT) was defined as the last PRO assessment before patient discontinuation, study data cut-off date, or patient death. Patients on high-intensity chemotherapy (HIC) were treated for up to two cycles depending on treatment response; as such, only changes from BL to Cycle 2 were evaluated. Opioid utilization, including percentage of patients using any opioid medication, specific medications, duration of use, and use by transfusion dependence, was also described. Analyses of the intention-to-treat population using analysis of covariance, including BL score, response to first-line AML therapy, and investigator-preselected SC as covariates, were conducted to estimate least squares mean (LSM) and compare the differences in pain question responses between treatment arms. Descriptive statistics were used to describe opioid utilization. Results: Of 371 eligible patients, 247 were randomized to gilteritinib and 124 to SC. The median age for both groups was 62 years and slightly more patients were female (gilteritinib, 53.0%; SC, 56.5%). Improvements at the mEOT from BL in the Fact-Leu GP4 item were observed in both gilteritinib (LSM -0.3) and SC (LSM -0.1). Scores also changed on the EQ-5D-5L at the mEOT from BL for both groups (gilteritinib, LSM 0.2; SC, LSM 0.3). No treatment differences were observed between gilteritinib vs SC on the change from BL to Cycle 2 or mEOT on the Fact-Leu GP4 item (LSM [95% CI] of -0.1 [-0.65, 0.38]; P=0.6016 and -0.2 [-0.53, 0.21]; P=0.3902, respectively) or on the EQ-5D-5L Pain/Discomfort domain (LSM [95% CI] of 0.2 [-0.21, 0.62]; P=0.3255 and -0.1 [-0.38, 0.23]; P=0.6288, respectively). During Cycles 1 and 2, no differences were identified between gilteritinib or SC on the percentage of patients using opioids (Cycle 1: 49.8% vs 55.6%; Cycle 2: 58.9% vs 62.7%, respectively) or the time-averaged duration of use (Cycle 1: 12.4 days vs 14.1 days; Cycle 2: 15.0 days vs 17.2 days, respectively). Patients on gilteritinib were less likely to use opioids during the first two cycles compared with patients on HIC, when stratified by chemotherapy intensity (Cycle 1: 49.0% vs 72.0%, P Conclusions: Patients with FLT3mut+ R/R AML receiving gilteritinib or SC demonstrated modest changes in responses to pain-related assessments at EOT compared with BL values. Opioids were used more frequently by patients receiving HIC regimens and transfusion-dependent patients receiving gilteritinib. These data suggest that treatments for FLT3mut+ R/R AML may impact opioid use; further study should be done to determine the relationships between these factors and their potential impact on overall quality of life. Disclosures Cella: DSI: Consultancy, Research Funding; Evidera: Consultancy; Ipsen: Consultancy, Research Funding; Mei Pharma: Consultancy; Oncoquest: Consultancy; ASAHI KASEI PHARMA CORP.: Consultancy; BMS: Consultancy, Research Funding; IDDI: Consultancy; Kiniksa: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Apellis: Consultancy; Alexion: Research Funding; Clovis: Research Funding; Janssen: Research Funding; Pled Pharma: Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other; BlueNote: Consultancy; Astellas: Consultancy, Honoraria; FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Abbvie: Consultancy, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding; Incyte: Speakers Bureau. Kanda:Pfizer: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Janssen: Honoraria; Shionogi: Research Funding; Chugai Pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria. Ivanescu:Astellas: Other: IQVIA employee which is a contracted by Astellas. Pandya:Astellas Pharma, Inc.: Current Employment. Shah:Astellas: Current Employment.

IDH mutations are strongly enriched in cytogenetically normal AML harboring NPM1 mutation (CN-NPM1mut-AML). The impact of these mutations on response to treatment is still a matter of debate. In the ELN 2017 classification, NPM1mut/FLT3-ITD allelic ratio >0.5 (FLT3-high) are considered intermediate-risk AML, whereas NPM1mut/ FLT3-ITD neg or 4 Log reduction) in 86% vs 53% of pts (p-value=.04). Nine (19%) and 24 (18%) pts received an allogeneic transplantation in CR1. The median time between CR1 and relapse was 11 months and 8 months, in IDHmut and IDHwt pts, respectively (p-value=.008). Day-100 non-relapse mortality was 8% and 12% respectively (p-value=ns). Median follow-up is 45 months (range, 2.4-115). Median EFS and OS are 21 months vs 12 months (p-value=.01) and 112 vs 23 months (p-value=.02), in the IDHmut vs IDHwt groups respectively (Figure). No survival differences were observed between IDH1mut and IDH2mut AML patients. Multivariate analyses with age>65, FLT3-high and IDHmut as covariates showed that IDHmut was independently associated with a higher EFS (HR=1.7, ranges 1.1-2.6) and OS (HR=1.7, ranges 1.1-2.7). Our results suggest that IDHmut is associated with a better response and a good disease control with high-dose chemotherapy. Nevertheless, some relapses still occur justifying the use of an IDH inhibitor combined with first-line chemotherapy or in a post-remission maintenance setting. Figure Disclosures No relevant conflicts of interest to declare.

Introduction: RARA-positive (RARA+) AML patients represent a subset of non-APL AML characterized by high RARA expression levels, which can be identified by a novel blood-based biomarker test that predicts sensitivity to SY-1425, an oral selective RARα agonist (McKeown, Cancer Discovery 2017; Vigil, ESH 2017). Approximately 30% of relapsed/refractory (R/R) AML patients are RARA+, similar to the prevalence in newly diagnosed (ND) unfit AML (Vigil, ESH 2017). Evidence of synergistic activity of SY-1425 with azacitidine (aza) in preclinical models supported clinical development of the combination (McKeown, Haematologica 2018), which is currently being evaluated in RARA+ R/R AML and ND unfit AML (NCT02807558). Early data of SY-1425 in combination with aza demonstrated a high CR rate and a rapid onset of response in RARA+ ND unfit AML (Cook, ASH 2018; de Botton, ESH 2019), supporting evaluation of the combination in a RARA+ R/R cohort. Initial data for the RARA+ R/R AML cohort are presented here. Methods: RARA+ R/R AML patients enrolled on the trial received aza at 75 mg/m2 IV/SC daily on days 1-7 followed by SY-1425 at 6 mg/m2/day PO in divided doses twice daily on days 8-28 of each 28-day cycle. Objectives included characterization of activity by overall response rate (ORR) per IWG criteria, characterization of composite complete response rate, time to response, overall survival (OS), and evaluation of safety. Results: A total of 28 patients were treated, with data available through 27 May 2020 reported here. Baseline characteristics included 13 (46%) male, median age 74 (30-87), and 12 (43%) with marrow blasts > 30%. Patients were heavily pretreated with 12 (43%) having received 3 or more prior regimens, including 19 (68%) with prior HMA and/or venetoclax treatment; 17 (61%) with prior HMA; and 9 (32%) with prior venetoclax in combination with HMA or LDAC. Nine (32%) patients were reported as both HMA and venetoclax naïve. Two (7%) had received prior allogenic stem cell transplant. Time on treatment was up to 6.5 months. 17 (61%) patients had discontinued treatment, most commonly due to progressive/resistant disease (29%). Among the 20 response-evaluable patients, the ORR was 20% with 4 pts having an IWG response; 3 (15%) attaining a CRi, all at the first response assessment at Cycle 2 Day 1, and 1 (5%) achieving MLFS at Cycle 3 Day 1. Two patients discontinued treatment approximately 1 month after initial response and the other 2 responders (1 CRi and 1 MLFS) continued treatment. Of those who did not achieve an IWG response, 7 (35%) achieved reductions in bone marrow blasts ≥25% not meeting criteria for IWG response, 8 (40%) had stable disease, and 1 (5%) had disease progression. Median OS for all treated patients (n=28) was 5.9 months (95% CI: 3.8, NE). The AE profile of the combination is consistent with that previously reported for single-agent SY-1425 or aza in AML. Most common AEs (all grades/causality) included nausea (39%), constipation (29%), pyrexia (29%), and fatigue, hypertriglyceridemia, diarrhea and vomiting (25% each). Hematologic AEs ≥ grade 3 included thrombocytopenia (18%), anemia (18%), febrile neutropenia (14%) and neutropenia (7%). The majority of non-hematologic AEs were low grade. The most frequent SAEs included febrile neutropenia, pyrexia and sepsis (11% each). Conclusions: SY-1425 in combination with aza was generally well-tolerated with clinical responses observed in this heavily pretreated relapsed/refractory AML population. The early OS estimate is encouraging, especially given the prevalence of HMA +/- venetoclax prior treatment in the study population. SY-1425 in combination with aza shows potential as a novel regimen for the treatment of RARA+ R/R AML. Disclosures Stein: Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Syndax: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cluzeau:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: data safety monitoring board; Abbvie: Honoraria. Rousselot:Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding. Rizzieri:Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees. Braun:Daiichi Sankyo: Honoraria; Servier: Research Funding. Bixby:GlycoMimetics: Research Funding. Roboz:Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Kelly:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Volkert:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zhou:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Incyte: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Kang-Fortner:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Roth:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs < 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p < 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.

Minimal/measurable residual disease (MRD) assessment in the course of acute myeloblastic leukemia (AML) monitoring is a topic that currently reaches undisputable interest. Multiparameter flow cytometry (MFC) appears as a valuable, rapid tool to assess response to therapy. Within the European LeukemiaNet (ELN) a task force has promoted the use of a backbone panel of monoclonal antibodies likely to cover both the most common leukemia associated immunophenotyping patterns (LAIP) and different from normal (DfN) immunophenotypes (Schuurhuis et al., Blood 2018). Classical gating strategies of MRD assessment however rely on supervised/operator-dependent approaches. The development of mass-cytometry has led to the emergence of new unsupervised analysis software. Among them, the FlowSOM (Flow Self Organizing Maps) R-based solution has been recognized as the most efficient, applicable to both mass and classical flow cytometry. Combination of the R-based FlowSOM definition of self-organized minimal spanning trees (MST) and the Kaluza® classical flow cytometry analysis software allows for a combined exploration of a normal bone marrow (NBM) matrix (derived from 19 normal BM samples)together with individual diagnosis and follow-up (FU) samples. This strategy was applied to 40 AML patients treated with a conventional 3+7 regimen for whom at least post induction FU was available, together with targets allowing for molecular MRD assessment (NPM1, RUNX1, CBFB-MYHorBCR-ABL). According to previously published panels (GEIL, Cytometry part B, 2018), two tubes were tested in MFC and results were compared to molecular MRD results for 96 FU time points. All patients could be evaluated in MFC at all time points. Comparison of molecular and MFC data showed an overall good concordance (80.2%), especially for FU1 time points (87.5%) with a sensitivity of 0.89 and a specificity of 0.75. Yet, outcome after induction appeared to be more correlated with MFC-negative MRD. This work also allowed to demonstrate the particular ability of the FlowSOM algorithm to disclose subtle chemoresistant subclones during FU. Moreover, by systematic comparison of normal bone marrow and FU points, MRD could be asserted without ambiguity and regenerating BM identified as such. Of note, this work could be performed on retrospective data, based on the fact that instruments were harmonized as reported (Lacombe et al. Leukemia, 2016) and identical panels were used all along. This makes this strategy easily transferrable to a network of laboratories using consensus settings and panels, as proposed by the European LeukemiaNet (Schuurhuis et al., Blood 2018). All in all, this study shows that unsupervised MFC MRD assessment appears as an accurate tool to appreciate response to chemotherapy in AML, and the FlowSOM + Kaluza method, combined with a systematic diagnostic FU / NBM multicomparison approach, increases the resolving power in the monitoring of MRD compared to the classic LAIP/different from normal approaches as implemented to date. Disclosures Dumas: Abbvie:Honoraria;Jazz-pharmaceutical:Consultancy;Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding, Speakers Bureau.

Background. Acute myeloid leukemia (AML) with unfavorable cytogenetics remains a therapeutic challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch and cell death (Picou et al., Pharmacol Res 2018;136:45-55). Objectives. The FILO group launched a pilot clinical study to evaluate the feasibility, safety and efficacy of the adjunction of a commercial FO emulsion (OMEGAVEN) to 3+7 in untreated AML with unfavorable cytogenetics. Patients and methods. The FAMYLY trial was a multicenter single-arm phase II study. Eligible patients had a diagnosis of untreated AML with unfavorable cytogenetics, 18 years old or above. For patients with WBC < 30 G/L, FO was administered at 2 mL/kg/d IV 2 days before 3+7 induction chemotherapy (daunorubicin 60 mg/m² days 1-3 and cytarabine 200 mg/m²/d as a continuous infusion days 1-7), until day 7 of induction. For patients with WBC >= 30 G/L, FO and 3+7 were started concomitantly, and FO was administered until day 9. The primary objective was complete response (CR) on the BM aspirate at the end of induction. Data from 75 patients with adverse cytogenetics and treated with daunorubicin and cytarabine in LAM2001 study (Lioure et al., Blood 2012) was used as a historical control. Serial blood samples were collected before treatment, and on days 1 and 3 after start of treatment, to evaluate the expression of NRF-2 target genes and antioxidant enzymes by RT-qPCR. Results. Thirty patients were included. The median age was 54 years (range: 30-64 years), and only 3 patients were hyperleukocytic. FO administration raised the plasma levels of EPA and DHA (p Conclusions. Altogether, FO emulsion adjunction to 3+7 is feasible and safe. Although CR rate improvement was not shown in this cohort of high-risk patients, further research aiming at finding the sufficient dose to trigger an NRF-2 response in vivo should be considered. ClinicalTrials.gov identifier: NCT01999413. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: OMEGAVEN (fish oil emulsion) in Acute Myeloid Leukemia

Introduction: Elderly pts with R/R AML not eligible for cytotoxic therapy have limited therapeutic options, and dismal outcomes with available therapies. In preclinical studies, inhibition of BCL-2 and MDM2 with Ven and Idasa, respectively, has demonstrated potent synergistic apoptotic activity. In this ongoing, open-label, Phase Ib study, the safety, tolerability, and preliminary efficacy of Ven+cobimetinib (Arm A) and Ven+Idasa (Arm B) is being assessed in R/R AML (NCT02670044). Initial analysis indicated a tolerable safety profile for Ven+Idasa. Here, we present updated safety and efficacy results from Arm B. Methods: Pts (≥60 years) with R/R AML or secondary AML, previously treated for an antecedent hematologic disease but treatment naïve for AML, and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. The maximum tolerated dose of Ven+Idasa was determined by two-dimensional dose escalation. Pts received Ven orally (PO) daily (400 or 600mg) + Idasa PO daily on Days (D) 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Responses were assessed according to revised International Working Group Response Criteria 2003. Pharmacokinetic (PK) analyses were performed on plasma samples on Cycles (C) 1 and 2, D1 and 5, and C4, D1. Exploratory assessments included minimal residual disease (MRD), assayed centrally at Covance Laboratories using 8-color flow cytometry. Data cut-off was June 21, 2019. Results: At data cut-off, 49 pts were treated with Ven+Idasa. Median age was 72 years (range 62-93); Eastern Cooperative Oncology Group performance status 0-1: 84%; refractory AML: 57%; relapsed AML: 33%; and secondary previously untreated AML: 10%; Intermediate-I or Intermediate-II European Leukemia Net (ELN) risk classification: 66%; adverse ELN classification: 30%; de novo (49%) versus secondary (51%) AML; and median prior lines of treatment: 1 (range 1-4). Most common adverse events (AEs; any grade) irrespective of attribution were diarrhea (90%) and nausea (78%); the most common grade ≥3 AEs were febrile neutropenia (45%), neutropenia (27%), and thrombocytopenia (25%; Table 1). Laboratory tumor lysis syndrome occurred in 3 pts; none resulted in treatment discontinuation. Ven and Idasa treatment discontinuation due to AEs were noted in 18% and 20%, respectively, most commonly due to infections. 30- and 60-day mortality rates were 6% and 17%, respectively. No apparent PK drug-drug interaction was found between Ven and Idasa; overlap in Ven and Idasa exposure was substantial over the doses tested. Anti-leukemic response rate (complete response [CR] + CR with incomplete platelet count recovery [CRp] + CR with incomplete blood count recovery [CRi] + partial response [PR] + morphologic leukemia-free state [MLFS]) across all dose levels was 41% (Table 2). Across the two Ven 600mg cohorts being considered for the recommended Phase II dose (RP2D), the anti-leukemic response rate was 50% (CR+CRp+CRi rate 29%). Median time to CR+CRp+CRi+PR was 1.4 months (range 1-3), with a median response (CR+CRp+CRi) duration of 4.9 months (range 0.6-9.7). Median overall survival in all pts and in the Ven 600mg cohorts was 4.4 months and 5.7 months, respectively, with a median follow-up of 3.4 months (range 0.03-18). Individual pt responses are shown in Figure 1. MRD negativity ( Conclusions: The non-chemotherapy combination of Ven+Idasa demonstrated encouraging safety and efficacy in elderly pts with R/R AML who were ineligible for cytotoxic chemotherapy. The anti-leukemic response rate at the dose levels being considered for the RP2D was 50%, with a CR+CRp+CRi rate of 29%. Updated predictive biomarker data will be presented. Evaluation of Ven+Idasa RP2D is ongoing, and will be followed by dose expansion. Disclosures Daver: Otsuka: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Takeda: Research Funding; Genentech, Verastem: Consultancy. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Brandwein:Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Roche: Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Olin:Ignyta: Research Funding; Clovis: Research Funding; Spectrum: Research Funding; Revolution Medicine: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Mirati Therapeutics: Research Funding; MedImmune: Research Funding; AstraZeneca: Research Funding. Martinelli:Amgen: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria. Pigneux:Novartis: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Astellas: Honoraria; Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria. Pollyea:Celyad: 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; Diachii Sankyo: 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; Celgene: 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; Forty-Seven: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Roboz:Orsenix: 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; 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; Trovagene: 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; 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; 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; 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; 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; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tafuri:Celgene: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. 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. Dail:Genentech: Employment, Equity Ownership. Green:Genentech Inc.: Employment. Kirschbrown:Genentech, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Ott:Roche: Employment, Equity Ownership. Onishi:Genentech, Inc.: Employment. Wang:Genentech, Inc.: Employment; Roche: Equity Ownership. Konopleva:Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership. OffLabel Disclosure: Venetoclax (VEN; ABT-199/GDC-0199) is a highly selective, potent, oral B-cell lymphoma-2 (BCL-2) inhibitor. Idasanutlin (idasa; RG7388) is an orally available, small molecule antagonist of MDM2 (mouse double minute; Mdm2 p53 binding protein homolog).

INTRODUCTION: Standard chemotherapy regimens for AML are not effective in many patients (pts), necessitating the use of targeted therapies. FMS-like tyrosine kinase 3 (FLT3), a cytokine receptor tyrosine kinase expressed in early hematopoietic precursor cells, regulates the proliferation and differentiation of these cells. FLT3 mutations resulting in constitutive signaling are common in AML (~30% of pts), including internal tandem duplication (ITD) in the juxtamembrane (~25%) and point mutations in the tyrosine kinase domain (TKD; ~5%). Hematopoietic stem cell transplantation (HSCT) remains the best chance for a cure, especially in pts with R/R AML; however, data suggest that HSCT can affect the quality of life of pts, both negatively and positively (Wood, 2016; Wong, 2016). While data regarding the relationship between pt-reported outcomes (PRO) and transplant status exist, data from controlled clinical trials, especially trials focused on pts with AML, are scarce. Gilteritinib is an orally administered, potent, selective FLT3 inhibitor with single-agent activity in R/R FLT3-mutation-positive (FLT3mut+) AML. Results from ADMIRAL, a global, randomized, phase 3 study (NCT02421939), demonstrated that gilteritinib improves response and survival compared with salvage chemotherapy (SC) in pts with FLT3mut+ R/R AML. The objective of this analysis was to examine the relationship between PROs and transplant status in pts with FLT3mut+ R/R AML using data collected from ADMIRAL. METHODS: ADMIRAL was a phase 3, open-label, multicenter, randomized study that compared the efficacy and safety of gilteritinib therapy to SC in pts with FLT3mut+ R/R AML. In this study, pts who had a stem cell donor identified and achieved a response allowing them to undergo HSCT could do so without leaving the study. PRO instruments used in this study included the EuroQol Five Dimension Five Level Scale Questionnaire (EQ-5D-5L), Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), Brief Fatigue Inventory (BFI), Functional Assessment of Chronic Illness Therapy - Dyspnea (FACIT-Dys), and two leukemia-specific items (dizziness and mouth sores). BFI was completed at baseline (BL), Day 1, 8, and 15 of Cycle 1, Day 1 and 15 of Cycle 2, Day 1 of every treatment cycle thereafter, and end of treatment (EOT). All other instruments were completed at BL, Day 1 of every treatment cycle, and EOT. In this analysis, time-to-definitive-deterioration (TDD) values were compared between gilteritinib pts who did or did not undergo HSCT during the study period. In this study, pts in the SC arm who received HSCT were required to leave the study, though they were followed for OS outcomes; as such, PRO data for SC pts were not considered here. TDD was defined as the duration of time from the date of randomization to death or deterioration of ≥1 change threshold unit compared with BL. Change threshold units connote a clinically meaningful change to a pt and were obtained from literature, if published, or from a distribution-based method when no threshold was available from the literature. Kaplan-Meier curves with two-sided 95% confidence intervals were used to estimate the distribution of TDD. RESULTS: A total of 371 pts (n=247, gilteritinib; n=124, SC) were randomized and included in the intent-to-treat population. Of 247 gilteritinib-treated pts, 63 (25.5%) underwent HSCT; 55.6% (n=35/63) of these pts achieved complete remission (CR) or CR with partial hematologic recovery (CRh). Gilteritinib-treated pts who underwent HSCT were found to have significantly improved TDD scores across all EQ-5D-5L (n=43), FACT-Leu (n=40), and BFI (n=41) measures compared with gilteritinib-treated pts who did not undergo HSCT (P CONCLUSIONS: Results demonstrate that undergoing HSCT is associated with significantly longer TDD. Specifically, median TDD values associated with all measures of fatigue, disease symptomology, and quality of life assessed in this study were significantly longer in pts who underwent HSCT compared with pts who did not. This shows HSCT significantly improved QOL in pts with FLT3mut+ R/R AML in the ADMIRAL trial. Disclosures Cella: FACIT.org: Equity Ownership. Ritchie: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; Genentech: Other: Advisory board; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Pigneux:Novartis: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Roche: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Daichi: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Kanda:Pfizer: Research Funding; MSD: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Takara-bio: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Mochida: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Alexion: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Otsuka: Research Funding; Novartis: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Sanofi: Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding. Ivanescu:Astellas: Consultancy. Pandya:Astellas Pharmaceuticals: Employment. Shah:Astellas: Employment.

INTRODUCTION: The incidence of AML in the United States has steadily increased over the last decade and, in 2019, it is estimated AML will affect 21,450 new patients (pts) and lead to 10,920 deaths. This increase is largely due to the aging population. In older pts, the ability to cure AML with chemotherapy is low and the risk of R/R AML is increased. The majority of pts with AML will require inpatient hospitalization and this results in a burden on healthcare systems. Nevertheless, there is little information regarding the relationship between PROs and hospitalization in pts with AML. In AML, the ability to target specific AML-associated mutations with oral medications is an important innovation which could lead to decreased hospitalization of older pts and decreased burden on healthcare systems. Gilteritinib is a once-daily, potent, selective FLT3 inhibitor with single-agent activity in FLT3mut+ R/R AML that is orally administered in the outpatient setting. The objective of this analysis was to examine the relationship between PROs and hospitalization in gilteritinib-treated pts with FLT3mut+ R/R AML using data collected from the ADMIRAL study (NCT02421939). METHODS: ADMIRAL was a phase 3, open-label, multicenter, active controlled, randomized study that compared the efficacy and safety of gilteritinib therapy to salvage chemotherapy (SC) in pts with FLT3mut+ R/R AML. PRO instruments used in this study were the Brief Fatigue Inventory (BFI), EuroQol Five Dimension Five Level Scale (EQ-5D-5L), Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), Functional Assessment of Chronic Illness Therapy-Dyspnea (FACIT-Dys), and two leukemia-specific items (mouth sores and dizziness). BFI data were collected at baseline (BL), Day 1, 8, and 15 of Cycle 1, Day 1 and 15 of Cycle 2, Day 1 of every treatment cycle thereafter, and end of treatment (EOT). Data for all other instruments were collected at BL, Day 1 of every treatment cycle, and EOT. To determine the impact of hospitalization on PRO scores, longitudinal trajectories of PRO scores prior to hospitalization were modelled using a linear mixed effects model; trajectory-adjusted mean change (TAMC) was calculated by determining the differences in pre-hospitalization PRO trajectories and post-hospitalization PRO scores. Standardized effect size was calculated by dividing TAMC by standard deviation at BL; effect sizes of 0.2, 0.5, and 0.8 were characterized as small, medium, and large, respectively. In this analysis, PROs were not considered for SC pts; SC pts who received high-intensity SC were expected to receive only ≤2 cycles of treatment. Therefore, only gilteritinib-treated pts in the intent-to-treat population with any type of hospitalization are included in the analysis. RESULTS: Of 371 eligible pts, 247 were randomized to gilteritinib and 124 to SC. Median age for gilteritinib-treated pts was 62 years (range: 20-84) and slightly more pts were female (131/247; 53.0%). Any hospitalization was significantly associated with worsening PRO scores across most subscales; only two did not have significant TAMCs: FACT-Leu Functional Well-Being and FACT-Leu Social Well-Being. Hospitalization in an intensive care unit (ICU) was also significantly associated with worsening PRO scores across most subscales. Subscales that did not have significant TAMCs following hospitalization in an ICU were the BFI Severity, FACIT-Dys Dyspnea Subscale, FACIT-Dys Functional Limitation Subscale, FACT-Leu Emotional Well-Being, FACT-Leu Functional Well-Being, and EQ-5D-5L Visual Analog Scale (Table). Across all subscales, effect sizes were small to medium, where medium effect sizes were associated with TAMCs following ICU hospitalization. CONCLUSIONS: In this study, hospitalization was associated with significantly worse PRO scores in pts who have FLT3mut+ R/R AML. Treatments that can be administered in the outpatient setting, thereby reducing the rate/duration of hospital stays, represent a major therapeutic advancement in this disease. Disclosures Ritchie: Tolero: Other: Advisory board; Genentech: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Cella:FACIT.org: Equity Ownership. Pigneux:Daichi: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Pfizer: Honoraria. Kanda:Shionogi: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Taisho-Toyama: Research Funding; Otsuka: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Takara-bio: Consultancy, Honoraria; Asahi-Kasei: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Mochida: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Tanabe Mitsubishi: Research Funding; Taisho-Toyama: Research Funding; Novartis: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Otsuka: Research Funding; Alexion: Consultancy, Honoraria; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Ivanescu:Astellas: Consultancy. Pandya:Astellas Pharmaceuticals: Employment. Shah:Astellas: Employment.

Background High-resolution sequencing has improved prognostication of AML. A multistage model (MM), based on a knowledge bank (KB) of 1540 patients (pts) treated between 2004 and 2010, has been set up to improve outcome prediction and tailor therapeutic decision, including SCT (Gerstung, Nat Genet 2017). Validation of overall survival (OS) predictions by this KB has been reported (Huet, Blood 2018). Given progresses of SCT over the last decades, whether such a KB approach can be harnessed to personalize SCT decision in first remission (CR1) remains unclear. We addressed this question in younger AML pts treated intensively. Methods From 03/2009 to 09/2013, the multicentric ALFA-0702 study (NCT00932412) enrolled 713 pts with de novo AML aged 18-60 years old, excluding APL and CBF AML. Pts with protocol-defined non-favorable risk AML were eligible for SCT from a matched donor (Thomas, J Clin Oncol 2017). High throughput sequencing of 41 genes and ligation-dependent RT-PCR was done in 656 pts (92%). Risk stratification was assessed according to ELN 2017 (Döhner, Blood 2017). Of the 100 variables used by the MM, 3 clinical (splenomegaly, LDH and Hb levels) and 24 genetic variables (genes mutated in at most 5.3% in the KB) were unavailable. After imputation of missing data based on the KB, individualized 5y-OS predictions were done for each patient in 3 scenarios: no SCT, SCT in CR1 or SCT after first relapse, as previously described (Gerstung, Nat Genet 2017). Results Median age at diagnosis was 46 years. Median follow-up was 4.2 years. Overall, 302, 282 and 72 pts were never transplanted, transplanted in CR1 or after relapse, respectively (resp). ELN 2017 risk was favorable (Fav), intermediate (Int) and adverse (Adv) in 31%, 31% and 38% of the 647 evaluable pts, resp. 5y-OS was 77.7%, 58.3% and 42.2% in Fav, Int and Adv pts, resp (Fav versus [vs] Int P Considering SCT in CR1 as a time-dependent variable, there was a significant interaction between ELN 2017 risk and SCT in CR1 (P We investigated the ability of the KB approach to determine the subset of patients that may benefit from SCT in CR1 rather than at relapse (per Gerstung, Nat Genet 2017). An estimated 128 patients (ELN 2017 Fav/Int/Adv in 34.6%, 45.7% and 19.7%) would have a 10% improvement in 5y-OS if allografted in CR1. However, in these 128 pts, the effect of SCT in CR1 on OS did not differ from that in the other 528 pts (interaction test P=0.31). We therefore sought alternative ways to inform SCT decision based on KB predictions. The KB approach predicted a 5y-OS We next combined ELN 2017 risk and KB-predicted OS into a single rule to guide SCT decision. Only pts with both ELN 2017 Int/Adv risk and a KB-predicted 5y-OS Conclusion The Knowledge bank approach predicts OS of younger adults with AML more accurately than ELN 2017. ELN 2017 and KB risk predictions may be combined to optimize indications of SCT in CR1. Figure Disclosures Berthon: JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; PFIZER: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Pigneux:Jazz: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Pfizer: Honoraria. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Thomas:ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria. Dombret:Institut de Recherches Internationales Servier (IRIS): Research Funding; CELGENE: Consultancy, Honoraria; AGIOS: Honoraria.

Introduction: Enasidenib is approved for the treatment of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 mutation (mIDH2+) in the USA. To compare the relative effectiveness of enasidenib with standard of care (SoC) in terms of overall survival (OS) among patients with mIDH2+ R/R AML who are ineligible for hematopoietic cell transplantation (HCT), a propensity score matching (PSM) analysis was performed using data from the phase 1/2 AG221-C-001 single-arm trial and a real-world chart review study of patients from France (France chart review [FCR] study) and historical data from the AML Study Group (AMLSG) database. Methods: Individual patient data (IPD) were obtained from the phase 1/2 AG221-C-001 trial for enasidenib (100 mg/day) and from the FCR study and AMLSG database for SoC. Data from the FCR study and AMLSG database were combined to create a single pooled SoC group. Based on clinician feedback and data availability, 6 clinically important covariates (history of HCT before baseline, age, number of prior lines of AML therapy at baseline, cytogenetic risk at baseline, history of myelodysplastic syndromes [MDS], Eastern Cooperative Oncology Group performance status) were used for propensity score calculation and matching. Patients from the 2 groups were matched using nearest neighbor 1:1 matching with a caliper of 0.2 standard deviations (SDs) of the logit transform of the propensity score. A comparison of means, SDs, and standardized mean differences (SMDs) between treatment groups was conducted for each covariate to assess the balance between the pre- and post-match populations. Hazard ratios (HRs) were estimated using doubly robust Cox proportional hazard models that adjusted for the aforementioned covariates. Sensitivity analyses were conducted using alternative matching algorithms, weighting methods, and covariates. Additional sensitivity analyses excluding patients with early events (landmark analyses) were conducted. Results: Before matching, considerable differences existed between the enasidenib (N = 195) and SoC (N = 258) groups (i.e. SMDs > 0.10 were observed for nearly all covariates), and OS was numerically in favor of enasidenib (HR 0.82, 95% confidence interval [CI] 0.66-1.01). After matching, the enasidenib and SoC groups (N = 144 per group) were mostly well balanced (SMDs for all covariates except for prior MDS were < 0.10), and enasidenib was associated with significantly longer OS than SoC (HR 0.61, 95% CI 0.47-0.80). The median OS was 8.8 months (95% CI 7.5-10.7) for enasidenib and 4.4 months (95% CI 3.5-6.1) for SoC (Figure). Sensitivity analyses (i.e., analyses using alternative matching algorithms, weighting methods and covariates, and landmark analyses) delivered results consistent with the primary analysis. Conclusions: The results of this study suggest that enasidenib may prolong survival compared with SoC for patients with mIDH2+ R/R AML who are ineligible for HCT. The incorporation of 2 separate data sources (i.e. the FCR study and AMLSG database) into a combined SoC group increases the generalizability and robustness of these findings. Additional studies should aim to validate these findings using data sources from other countries and assess the comparative efficacy of enasidenib with SoC for other clinically important outcomes. Disclosures De Botton: Syros: Consultancy; Servier: Consultancy; Janssen: Consultancy; Daiichi: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Celgene Corporation: Consultancy, Speakers Bureau; Forma: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pierre Fabre: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Brandwein:Roche: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Wei:Celgene: Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax; Genentech: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Honoraria; Servier: Honoraria, Research Funding; Macrogenics: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas: former employee, Honoraria; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria. Weber:Celgene Corporation: Research Funding. Pigneux:Roche: Honoraria; Pfizer: Honoraria; Daichi: Honoraria; Amgen: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria. Boissel:NOVARTIS: Consultancy. Paschka:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Amgen: Other: Travel expenses; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Takeda: Other: Travel expenses; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel expenses; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Nehme:Celgene Corporation: Employment, Equity Ownership. Frattini:Celgene Corporation: Employment, Equity Ownership. Marion-Gallois:Celgene Corporation: Employment. Wang:Celgene International: Employment, Equity Ownership. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Siddiqui:Celgene: Consultancy; Cornerstone Research Group: Employment. Qadeer:Cornerstone Research Group: Employment; Celgene Corporation: Consultancy. Döhner:Pfizer: Research Funding; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Swuibb: Research Funding; Astex: Consultancy, Honoraria; Arog: Research Funding; Astellas: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and approximately 3-4% of MDS pts. Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors on releasing differentiation block in IDHm leukemia models in vitro. Methods: The Phase 1 study (NCT02719574) assessed the safety, PK/PD, and clinical activity of olutasidenib in patients with IDH1m AML or MDS. Eligibility criteria included: IDH1m AML or MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts not eligible for or refusing standard therapy], adequate liver and renal function. There were no restrictions for concomitant non-anticancer medications. IDH1m variant allele frequency (VAF) and co-mutations were measured at baseline and during treatment. Available safety data are presented for all pts (AML/MDS); efficacy data are presented for AML pts only. Results: As of April 12, 2019, 32 pts had been treated with single agent (SA) olutasidenib and 46 pts with olutasidenib in combination (COMBO) with AZA; median time on treatment was 4.2 mo for SA (range: 10% of pts, including thrombocytopenia (28% vs 33%), febrile neutropenia (22% vs 28%), anemia (22% vs 20%), pneumonia (16% vs 11%), and leukocytosis (13% vs 15%); COMBO-treated pts had more Gr 3/4 neutropenia (6% vs 28%), fatigue (6% vs 15%), and nausea (0% vs 9%). No QTcF prolongation was reported in SA while 3 (7%) pts treated with COMBO reported prolonged QTcF (1 Gr 3). Ten (13%) pts had differentiation syndrome (4 SA; 6 COMBO), which resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care. None led to treatment discontinuation. Nineteen (24%) pts died on treatment or within 28 days of the last dose, no deaths were considered treatment-related. For AML pts, clinical responses occurred in 39% SA and 54% COMBO (CR 15% and 23%, respectively; Table 1). CRs were durable (up to >27 mo); disease control (SD >13 mo) was observed in pts without an IWG-defined response. Of the 59 AML pts (23 SA; 36 COMBO) who were transfusion-dependent at baseline, 26 (11 [48%] SA; 15 [42%] COMBO) and 21 (9 [39%] SA; 12 [33%] COMBO) became transfusion-independent (seen in all response categories) during 28 and 56 days on treatment, respectively. For R/R AML pts, median survival was 8.7 mo for SA and 12.1 mo for COMBO; for TN AML pts, median survival was 8.8 mo for SA (n=4) and not reached for COMBO. For R/R and TN AML patients with available pre- and on-treatment samples, IDH1m clearance or significant reduction (VAF Conclusions: SA and COMBO olutasidenib has shown favorable safety and clinical activity in IDH1m R/R AML with a SA ORR of 41% (95% CI: 21, 64) and a COMBO ORR of 46% (27, 67), and durable disease control. Olutasidenib induces deep responses with IDH1 mutation clearance in a subset of treated pts. Phase 2 investigations of SA and COMBO olutasidenib at the RP2D are ongoing in multiple IDH1m AML populations. Additional combinations are also being explored. Disclosures Watts: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Baer:Forma: Research Funding; Kite: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Al Therapeutics: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Prebet:pfizer: Honoraria; novartis: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Pigneux:Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Novartis: Honoraria. Montesinos:Abbvie: 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, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Wang:Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Agios: Other: Advisory role. Seiter:Novartis, Incyte, Celgene, Astellas, Sanofi: Speakers Bureau; Novartis, Astellas,: Consultancy; Novartis, Forma, Sun Pharma, Celgene, Jazz, Roche: Research Funding. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. De Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; FORMA: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Astellas: Consultancy. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ferrell:Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; Agios: Consultancy; Forma Therapeutics: Research Funding. Dao:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kelly:FORMA Therapeutics: Employment. Sweeney:FORMA Therapeutics: Employment. Forsyth:FORMA Therapeutics: Employment. Guichard:FORMA Therapeutics: Employment. Brevard:FORMA Therapeutics: Employment. Henrick:FORMA Therapeutics: Employment. Mohamed:FORMA Therapeutics: Employment. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding.

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative option for acute myeloid leukaemia (AML). A major improvement of conditioning regimen has been realized in the last two decades, offering the opportunity for older patients to undergo HSCT with an acceptable toxicity profile. Unfortunately, relapse remains the main cause of death, and only few studies analyzed the survival of patients presenting with post-HSCT AML relapse and their treatment options. The purpose of this study was to analyze the survival of patients with post-HSCT AML relapse, to describe the treatment options and to search for factors associated with poor prognosis at relapse. In this study, we collected the data of all the patients transplanted between January 2005 and December 2014 at Bordeaux university centre and showing AML relapse after HSCT. Between 2005 and 2014, out of 312 HSCT for AML, one hundred patients relapsed at our center with a median time from transplant of 123.5 days (11-2726 days). Median age was 55 years old (range 17-65), 44 patients were male. Donors were matched related for 49 patients, unrelated for 35 patients, and cord blood units were used in 16 patients. Conditioning regimen was reduced for 70 patients and myeloablative for 30 patients. According to the Disease Risk Index, 4 patients were considered at low risk, 29 patients at intermediate risk, 43 patients at high risk and 11 patients at very high risk. Thirty one per cent of patients had refractory disease. Before relapse, 31 patients developed Acute Graft Versus Host Disease (GVHD) and 9 patients developed Chronic GVHD. At relapse, 62 patients were still on cyclosporine and 22 on steroids. Eighty four patients presented an isolated bone marrow relapse, while 5 patients showed isolated extramedullary relapse, and 11 mixed relapse. With a median follow-up from relapse of 106 days (0-3619 days), the 1 and 2-year overall survival (OS) were 24% and 13%, respectively. At final follow-up 8 patients were still alive. For alive patients, median follow-up from relapse was 1524 days (980-3619 days). Median age was 39 years old (20-57 years old), DRI was considered at intermediate risk for 2 patients, at high risk for 5 patients and at very high risk for 1 patient. No patient was FLT3 mutation. In univariate analysis, factors associated with better OS at relapse were age < 45 years old, male gender, performance status at relapse > 70%, and no initial FLT3 mutation. Male gender, performance status at relapse, early relapse and no initial FLT3 mutation were associated with a better OS in multivariate analysis. Seven patients responded to immunosuppression tapering and 19 patients to first line treatment containing local radiotherapy, chemotherapy and/or Donor Lymphocyte Infusion (DLI). Developing GVHD after immunosuppression tapering or DLI was associated to disease response: Seven patients responded after immunosuppression only of whom 4 after developing GVHD (p=0.0013). Twelve patients responded after DLI of whom 7 after developing GVHD (p=0.05). Patients receiving an association of chemotherapy and DLI showed a better response and a better survival compared to chemotherapy only (p= 0.03). Patients with FLT3 mutation did not respond to any treatment. This study confirms the severity of AML relapse after HSCT with a poor long term OS. The particularly poor impact of FL3 mutation suggests the use of targeted therapy in a prophylactic setting. Immunomodulatory approaches resulted in disease response in some patients and should be evaluated prospectively to identify clinical and biological factors predictive of the response. Disclosures No relevant conflicts of interest to declare.

Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data. Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy. Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12. Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count >10/nl. Median WBC was significantly lower (P Complete remission (CR) after induction therapy was achieved in 75% (194/259) of the CTX/ATRA group, in 93% (162/174) of the ATO/ATRA±CTX group, and in 50% (13/26) of the less intensive group. Two pts of the CTX/ATRA group and one patient after ATRA only were refractory. Early death rates were 24% (n=63) after CTX/ATRA, 7% (n=12) after ATO/ATRA±CTX and 46% (n=12) in the less intensive group. A logistic regression model revealed age above 75 yrs (odds ratio [OR], 0.53; P=0.02) higher WBC (OR, 0.35; P10/nl) was associated with an inferior RFS in CTX/ATRA (P10/nl; hazard ratio [HR], 2.36; P75 yrs (HR, 2.07; P Conclusions: The ATO-based regimen for first line treatment of elderly APL pts was associated with excellent and sustained response rates. Our data demonstrate the important potential of ATO/ATRA in the primary management of older APL pts. Disclosures Fenaux: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Introduction: Effective treatment options for patients (pts) with R/R AML are limited and novel therapies are needed. Previous pre-clinical data have shown that venetoclax (VEN) plus cobimetinib (cobi) or idasanutlin (idasa) may be synergistic. MEK and MDM2 inhibition have been shown to down-regulate MCL-1, overcoming a resistance pathway to BCL-2 inhibition in AML (Han, ASH 2016; Pan, ASH 2014). We report preliminary results from a dose-escalation study evaluating VEN plus cobi or idasa in pts with R/R AML. This is the first study evaluating novel-novel oral combinations with VEN in pts with AML. Methods: This open-label, multicenter study evaluates the safety, tolerability and efficacy of VEN + cobi or idasa in pts ≥60 yrs old with R/R or secondary AML who have received therapy for a prior antecedent hematological disease and are not eligible for cytotoxic therapy (NCT02670044). Two-dimensional dose escalation is being used to establish the maximum tolerated dose (MTD) for each combination. Pts on Arm A received VEN PO daily + cobi PO on Days 1-21, and pts on Arm B received VEN PO daily + idasa PO on Days 1-5 in 28-day cycles. Dose limiting toxicities (DLTs) were assessed for the first cycle. Results: As of 25 April 2017, 42 pts were treated in the dose-escalation stage. Arm A included 4 cohorts: VEN 400 mg + cobi 40 mg (n=4), VEN 600 mg + cobi 40 mg (n=7), VEN 800 mg + cobi 40 mg (n=4) and VEN 400 mg + cobi 60 mg (n=7); Arm B included 3 cohorts: VEN 400 mg + idasa 200 mg (n=3), VEN 600 mg + idasa 200 mg (n=8) and VEN 400 mg + idasa 400 mg (n=9). Median age was 72 (range 60-93) yrs and median number of prior therapies was 2 (range 1-10). 19% (8/42) were ECOG 2, 62% (26/42) of pts were refractory to last therapy and 48% (20/42) of pts had secondary AML. According to ELN risk classification, 29% were intermediate-I, 34% intermediate-II and 34% were adverse risk. Most common AEs in both arms are summarized in Table 1. In the VEN + cobi arm, the majority of deaths on study were due to progressive disease (PD); 3 deaths were due to AEs of sepsis, pneumonia and respiratory failure. Three DLTs were reported: 1 diarrhea (Gr 3) in VEN 600 mg + cobi 40 mg and 1 diarrhea (Gr 3) and 1 decrease in ejection fraction (EF) (Gr 3) in VEN 400 mg + cobi 60 mg. The Gr 3 decrease in EF occurred in the setting of sepsis and was subsequently not considered related to study treatment. Due to the higher rates of Gr ≥3 diarrhea (57%) in VEN 400 mg + cobi 60 mg, this dose level will no longer be evaluated in this study. The VEN 800 mg + cobi 40 mg cohort is ongoing. In the VEN + idasa arm, the most common cause of death was PD; 1 death was due to an AE of sepsis. Four DLTs were reported: 1 generalized muscle weakness (Gr 3) and 1 diarrhea (Gr 3) in VEN 600 + idasa 200 mg and 1 acute coronary syndrome (Gr 3) and 1 elevated bilirubin (Gr 4) in VEN 400 mg + idasa 400 mg. Additional dose cohorts evaluating VEN + idasa are ongoing. When compared to monotherapy data at the same dose, preliminary PK analyses suggest that VEN exposure is slightly lower, while cobi and idasa exposures are similar. Preliminary efficacy for the VEN + cobi arm showed 2 CRs (9%), 1 CRp (4.5%) and 1 CRi (4.5%) for an overall response rate (ORR) of 18% (4/22); duration of response (DOR) ranged from 1 to 5 mo, with 1 response ongoing at data cut-off. For the VEN + idasa arm, 1 CR (5%), 1 CRp (5%), 1 CRi (5%) and 1 PR (5%) were achieved for an ORR of 20% (4/20); DOR ranged from 1.3 to 6.7 mo, with 1 response ongoing at data cut-off. In the VEN 600 mg + idasa 200 mg cohort, the ORR was 38% (3/8) with 1 CR, 1 CRp, and 1 CRi. Of the pts who did not achieve a response by IWG criteria, anti-leukemic activity was seen in an additional 7 pts who achieved ≥ 50% bone marrow blast reduction from baseline (3/22 [14%] pts on VEN + cobi and 4/20 [20%] pts on VEN + idasa). Baseline mutation profiling was available in 32 of 42 pts and is summarized for responders in Table 2. Of the 9 pts who had an IDH1/2 mutation at baseline, 44% (4/9) achieved a response (1 on VEN + cobi and 3 on VEN + idasa). Of the 3 pts with known p53 mutations on the VEN + idasa cohorts, none achieved a response. Conclusions: Preliminary results show that VEN plus cobi or idasa can be administered with appropriate risk mitigation measures for GI toxicity and early evidence of clinical activity in R/R AML pts. Dose finding is ongoing and the MTD for both combinations has not yet been determined. Preliminary ORR for the VEN 600 mg + idasa 200 mg cohort was encouraging at 38%. Safety, PK and efficacy data will be updated at the time of presentation. Disclosures Daver: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Yee: Oncoethix: Research Funding; Novartis Canada: Honoraria; Astex: Research Funding; Karyopharm: Research Funding; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kelly: Abbvie: Honoraria; Pharmacyclics: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Roboz: Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Kshirsagar: Genentech, Inc: Other: Services via contractor. Dail: Genentech, Inc.: Employment. Wang: Genentech: Employment. Mobasher: Roche: Equity Ownership; Genentech: Employment. Chen: 4. F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hong: Genentech: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership.

BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: 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. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Introduction: B-ALL with t(4;11)(q21;q23) (t(4;11) B-ALL) is a well characterized adult B-ALL subtype associated with an unfavorable prognosis, mainly due to a high relapse risk, which is followed by a poor outcome. In order to prevent relapse during frontline treatment, alloHCT in CR1 is recommended by many cooperative groups, although the specific outcome and prognostic factors related to this procedure have been scarcely analyzed. Patients and Methods: We searched in the ALWP-EBMT database all adult patients (pts) (i.e., ≥18 year-old) with B-ALL reported to harbor a t(4;11) translocation who underwent an alloHCT in CR1 from a matched related or unrelated (10/10 or 9/10) donor during the 2000-2016 period, and analyzed their outcome. The prognostic value of the MRD status at the time of transplant, as reported by centers, was specifically addressed. In addition, a comparative analysis with analogous pts with normal karyotype B-ALL (NK B-ALL) was performed, adjusting for main significant variables including the pre-transplant MRD status. Results: Overall, we identified 151 pts with t(4;11) B-ALL and 567 with NK B-ALL. Compared to NK B-ALL, pts with t(4;11) B-ALL were older (median age, 38.1 vs. 33.8, p=0.028), presented with a higher WBC count (114 vs. 7.9x109/L¸ p MRD at the time of alloHCT was undetectable in 62 (69%) of the 90 pts with available information, and showed a strong favorable impact on outcome, with a lower RI (21 vs. 45% at 2 years, p=0.003) and higher LFS (67 vs. 27%, p=0.00004), OS (81 vs. 26%, p=0.000005)and GRFS (47 vs. 24%, p=0.01) compared to pts with detectable MRD at transplant. The prognostic value of the pre-transplant MRD status was confirmed in a multivariate analysis (performed among patients with known MRD status), in terms of RI (HR=0.23, CI: 0.09-0.55; p=0.0011), NRM (HR=0.16, 0.05-0.52; p=0.0023), LFS (HR=0.20, 0.10-0.40; p=10-5), OS (HR=0.14, 0.07-0.30; p Comparison between t(4;11) B-ALL and NK B-ALL showed a strong impact of the MRD status. In univariate analysis, outcome after alloHCT in both t(4;11) B-ALL and NK B-ALL groups was similar in pts without detectable MRD at transplant, with comparable RI (21 vs. 26%, p=0.35), NRM (12 vs. 18.5%, p=0.37), LFS (67 vs. 56%, p=0.14), and OS (81.4 vs. 69%, p=0.069). In contrast, among pts with detectable MRD at alloHCT, LFS and OS were superior in NK B-ALL compared to t(4;11) B-ALL pts (50 vs. 27%, p=0.02; and 62 vs.26%, p=0.01, respectively). In multivariate analysis, and considering MRD-negative NK B-ALL as the reference category, t(4;11) B-ALL pts allografted without detectable MRD showed a better LFS (HR=0.624,0.335-0.978; p=0.04) and OS (HR=0.523,0.296-0.925; p=0.02). On the contrary, MRD-positive t(4;11) pts showed a worse outcome compared to the remaining MRD-stratified subgroups, with higher RI (HR=3.28,1.63-6.60; p=.0009), and shorter LFS (HR=2.42,1.65-4.93; p=0.00017) and OS (HR=3.51,2-6.18; p=1x10-5) (Figure 1). Conclusions: Outcome of adult pts with t(4;11) B-ALL who received an alloHCT in CR1 is favorable, especially in those with a negative MRD status pre-alloHCT. These results, when compared to previously reported results in non-allografted pts, strongly suggest a neat beneficial effect of alloHCT for this adult B-ALL subset. Nonetheless, further studies should evaluate the magnitude of this benefit in comparison with contemporary non-allograft post-CR strategies, as well as the optimal management for pts failing to achieve a MRD-negative status. Disclosures Socié: Alexion Pharmaceuticals, Inc.: Consultancy. Schmid: Celgene: Research Funding, Speakers Bureau; MoilMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau. Mohty: Sanofi: Honoraria, Speakers Bureau.

While the t(8;21) translocation is one of the most recurrent chromosomal abnormalities in acute myeloid leukemia, prognostic studies have been hampered by the relatively few number of patients reported. We thus performed a large retrospective study in 161 adults and children with t(8;21) acute myeloid leukemia, all prospectively enrolled in 6 different trials conducted in France between 1987 and 1998 (median follow-up 4.9 years). Prognostic studies were performed in the 154 patients who achieved a complete remission. Individual data were registered, including sex, age, blood and marrow counts, extramedullary disease, and cytogenetics. The value of allogeneic stem cell transplantation versus chemotherapy as postremission therapy was evaluated according to the intent-to-treat principle. Estimated 5-year disease-free survival (DFS) and overall survival were 52% and 59%, respectively. Outcome was not significantly better in patients from the stem cell transplantation group (estimated 5-year DFS and survival, 56% vs 52% and 67% vs 57%; P =.55 and.64, respectively). White blood cell count (WBC) was the only identified prognostic factor. To further take into account the spontaneous differentiation potential of the leukemic clone, a WBC index was derived as the product of WBC by the ratio of marrow blast. This WBC index was a more powerful factor than the original WBC, allowing us to distinguish 3 subgroups of patients with different outcomes (low index, < 2.5; intermediate index, 2.5-20; high index, 20 or more). In multivariate analysis, the WBC index was the only prognostic factor for DFS (P =.003), complete remission duration (P =.002), and overall survival (P =.04).

Background.Treatment of APL in the elderly with conventional ATRA-anthracycline based CT regimens is associated, like in younger patients, with very few relapses, but high death rates (CR rate of 87.3%, 10-year CIR of 9.3%, 21.7% deaths in CR, and a 10-year OS of 58% in patients aged> 65 years in our previous APL trials ;Blood 2010 115:1690). Recent results have shown that, in standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + CT regimens while being less myelosuppressive (Lo Coco, NEJM 2014; Burnett, Lancet Oncol, 2015) thus constituting a very appealing approach for elderly patients. However, when our APL 2006 trial started, the feasibility of treatment of APL without CT was unknown. Furthermore, access to ATO still remains limited for frontline treatment of APL in most countries. We present results of APL 2006 trial, where we combined ATO to ATRA and reduced CT in patients aged older than 70 with standard risk APL (baseline WBC Methods. Between 2006 and 2015, newly diagnosed APL patients (pts)>70 years with WBC 1 G/L and platelets> 50G/l after the first consolidation course was 16.2 and 11.9 days in the original vs 5.6 and 4.0 days in the amended protocol (p Conclusion. In this very old patient population (>70 years) with standard risk APL, addition of ATO, that allowed reduction of the amount of CT administered, was associated with high CR rates, without any increase (and a possible reduction) in the relapse rate compared to our previous experience with ATRA-CT regimens. However, reduction of mortality in CR with this regimen was only seen when consolidation CT was reduced to one single day of Ida. This is further evidence of the role of ATO in a patient population in whom myelosuppression must be avoided. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas:Pfizer: Consultancy. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC> 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC>1 G/L after consolidation 2 was 22, 25 and 19 days (p50G/l was 24, 26 and 20 days (p Conclusion: Very high CR rates and very few relapses are now obtained in high risk APL on a large multicenter basis using classical ATRA and CT (including AraC) for induction and consolidation, and maintenance treatment, but at the expense of 5 to 7% deaths in CR. Addition of ATO to this regimen did not further reduce relapses, and added some myelosuppression if CT contained AraC. However, if ATO was added and AraC omitted from consolidation cycles, relapses were not increased, while myelosuppression and deaths in CR were reduced. ATO therefore appears useful in high risk APL. We are currently comparing, in the international APOLLO trial, the "classical" ATRA-CT approach and a prolonged ATO-ATRA regimen with only 2 days of Ida during induction treatment, hoping to further reduce myelosuppression and possibly relapses. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

INTRODUCTION Recurrent somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite, D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in multiple solid tumors and hematologic malignancies. Approximately 6-10% and 9-13% of adults with acute myeloid leukemia (AML) carry mutations in IDH1 (mIDH1) or IDH2 (mIDH2), respectively. AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme under evaluation in multiple ongoing single agent and combination clinical trials [NCT02074839, NCT02073994, NCT02632708, NCT02677922]. This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study [NCT02074839]. METHODS Patients with advanced mIDH1-positive hematologic malignancies received AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously in 28-day cycles. Primary objectives were determination of safety, maximum tolerated dose (MTD), and selection of a dose schedule for expansion cohorts and future studies. Secondary objectives included clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML. Determination of mIDH1 VAF was performed using the FoundationOne® Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent time points on study. This NGS assay reports IDH1 mutations for samples with VAF ≥1%, with median coverage 500X. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having mIDH1 at baseline and at least one on-study sample with no reported mIDH1. RESULTS Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from 300-1200 mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common (≥30%) being diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Longitudinal mIDH1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low mIDH1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in mIDH1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120. CONCLUSION This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance as determined by NGS. Further analysis of the mutational profiles is planned. AG-120, a potent, selective, oral inhibitor of mIDH1 continues to demonstrate a well-tolerated safety profile in patients with advanced hematologic malignancies, and induced objective single-agent durable responses. The data continue to support the efficacy and safety of single agent AG-120 and provide evidence that the underlying biology of the disease is altered by treatment. Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120 Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120. / Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Disclosures DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. de Botton:Novartis: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy. Stein:Agios: Other: advisory board; Celgene: Other: advisory board; Novartis: Other: advisory board. 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. Pollyea:Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Celgene: Other: advisory board, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding. Altman:Syros: Honoraria; BMS: Honoraria; Janssen Pharmaceuticals: Honoraria; Novartis: Honoraria. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Pigneux:Sunesis: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Liu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Sacolick:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yen:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hurov:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Choe:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stone:Amgen: Consultancy; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy.

Background: Prognosis for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with lower response rates and shorter survival compared with younger patients. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML, is minimally metabolized, evades P glycoprotein receptor-mediated efflux, and has activity independent of p53 status. In the phase 3 VALOR trial, overall survival (OS) was significantly improved with vosaroxin plus cytarabine vs placebo plus cytarabine in a prespecified analysis in patients ≥ 60 years of age (median OS: 7.1 mo vs 5.0 mo, respectively; HR = 0.75 [95% CI: 0.62-0.92]; P = 0.0030). At the time of the primary analysis (September 2014), patients had been followed for a median of 24.4 months (as estimated by the reverse Kaplan-Meier method). Here, after a median follow-up of 39.9 months, we provide updated survival information for patients ≥ 60 years treated in the VALOR trial. Methods: In VALOR, patients with refractory or first relapsed AML were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 h, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min, d 1, 4; 70 mg/m2 in subsequent cycles) or placebo. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] lasting < 90 d) or were in first relapse (early relapse: CR1 lasting 90 d to 12 mo; late relapse: CR1 lasting 12 mo to 24 mo). Randomization was stratified by age (< 60, ≥ 60 years), disease status (refractory, early relapse, late relapse), and geographic location (US, non-US). Patients were followed for survival until death. At the time of the primary analysis (September 2014), 63/451 (14%) patients ≥ 60 years were alive and in continued follow-up. Results:As of Jan 22, 2016, 33/451 patients ≥ 60 years treated in the VALOR trial were alive and in continued follow-up: 23/226 (10.2%) in the vosaroxin/cytarabine arm and 10/225 (4.4%) in the placebo/cytarabine arm. Updated OS data in patients ≥ 60 years of age was consistent with the primary analysis, demonstrating a significant improvement with the addition of vosaroxin (Figure; HR = 0.75 [95% CI: 0.62-0.91]; P = 0.0017). The survival benefit associated with vosaroxin/cytarabine was durable, as demonstrated by the separation of the survival curves through 48 mo. At 24 and 36 mo after randomization, the estimated survival rate was twice as high with vosaroxin/cytarabine as with placebo/cytarabine in patients ≥ 60 years (17.0% vs 8.5% and 12.8% vs 6.0%, respectively). The OS benefit was consistent across various age subgroups in the population ≥ 60 years of age; in patients 60-64 years (n = 124), 65-74 years (n = 293), and 75-84 years (n = 34), vosaroxin/cytarabine treatment increased median survival by 2.9 mo (8.1 vs 5.2 mo; HR = 0.72 [95% CI: 0.49-1.06]), 2.0 mo (7.0 vs 5.0 mo; HR = 0.76 [95% CI: 0.60-0.97]), and 2.2 mo (5.5 vs 3.3 mo; HR = 0.72 [95% CI: 0.36-1.45]) over placebo/cytarabine treatment, respectively. An improvement in OS was observed among patients ≥ 60 years who received post-treatment transplantation (n = 91; 19.9 mo with vosaroxin/cytarabine vs 12.2 mo with placebo/cytarbine; HR = 0.70 [95% CI: 0.43-1.13]) and those who did not (n = 360; 5.3 mo vs 3.8 mo, respectively; HR = 0.75 [95% CI: 0.60-0.92]). When analyzed by disease status, the greatest OS benefit was observed in patients ≥ 60 years with refractory disease (n = 210; 6.7 mo with vosaroxin/cytarabine vs 3.8 mo with placebo/cytarabine; HR = 0.75 [95% CI: 0.57-1.00]) and those with early relapse (n = 154; 6.5 mo vs 3.9 mo, respectively; HR = 0.62 [95% CI: 0.44-0.87]). In patients ≥ 60 years with late relapse (n = 87), median OS was similar in both treatment arms (9.2 mo with vosaroxin/cytarabine vs 9.8 mo with placebo/cytarabine; HR = 1.06 [95% CI: 0.68-1.66]). Conclusions: After a median of 39.9 months of follow-up in the VALOR trial, the OS observed in patients ≥ 60 years of age treated with vosaroxin/cytarabine remains significantly improved versus placebo/cytarabine, with a separation of the survival curves through 48 months. The OS benefit is consistent among all older patients, even those ≥ 75 years of age, and is seen in patients with and without post-treatment transplantation. The updated survival data from VALOR continue to support the use of vosaroxin/cytarabine as a treatment option in patients ≥ 60 years of age with R/R AML. Disclosures Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ritchie:Novartis: Honoraria, Research Funding; Celgene: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria; Arian: Speakers Bureau. Vey:Sunesis: Honoraria. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Schiller:Incyte Corporation: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Erba:Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Horst:Amgen, Novartis, Pfizer, Gilead, Agios: Consultancy; Amgen, Regeneron: Research Funding; Celgene: Honoraria. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Craig:Sunesis: Employment, Equity Ownership. Ward:Sunesis Pharmaceuticals: Consultancy, Employment. Smith:Sunesis: Employment, Equity Ownership. Stuart:Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding.

Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34(+) cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 x 10(6) CD34(+) cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m(2)) and either SCF (20 micrograms/kg/d) combined with filgrastim (5 micrograms/kg/d) or filgrastim alone (5 micrograms/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 micrograms/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 x 10(6) CD34(+) cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P =.008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 x 10(6) CD34(+) cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34(+) cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 x 10(6)/kg, P =.003) and all leukaphereses (12.4 v 8.2 x 10(6)/kg, P =.007). Total colony-forming unit-granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34(+) cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34(+) cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 x 10(6) CD34(+) cells/kg.

In a single institution, we have used recombinant interferon- (IFN-) to treat 116 newly diagnosed Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients and analyzed the predictive factors for response and survival. The patients whose median age was 50.3 years (range, 9 to 70) were administered IFN- (5 million units/m2/d) subcutaneously. The IFN- dose was subsequently adjusted to maintain the white blood cell and platelet counts between 1.5 and 5 × 109/L, 50 and 100 × 109/L, respectively. At diagnosis, the Sokal score was used to classify the patients into three groups: low (n = 57), intermediate (n = 42), and high risk (n = 16). A complete hematological response (CHR) was achieved in 93 cases (80.2%). Of the 116 patients, 113 were available for cytogenetic evaluation. Fifty patients (43%) achieved a major cytogenetic response (MCR) (=65% marrow Ph− cells), 37 of them having a complete cytogenetic response (CCR). The estimated 5-year survival of the 116 patients was 68% ± 11% (95% confidence interval [CI]) with a median follow-up of 42 months (range, 3 to 114) and 85% ± 11% (95% CI) with a median follow-up of 30.9 (range, 3 to 111) when patients were censored at the time of transplantation. Event-free survival at 5 years (adding death and transplant as event) was 46% ± 11% (95% CI). Using proportional hazards regression to study time-dependent variables, we confirmed that the most significant factor associated with survival was the cytogenetic response (MCR or CCR) (P < .0001). This factor was independent compared with the Sokal score and baseline variables used to calculate the Sokal score. Moreover, using either univariate or multivariate analysis, the achievement of CHR within 3 months was strongly correlated with MCR (P < .0001). Minimum cytogenetic response (mCR, ie, at least 5% of Ph− metaphases) at 3 months was also a significant predictive factor for MCR (P < .0001). These results show that IFN- can induce a high rate of hematological and cytogenetic response when administered in doses leading to myelosuppression. Factors such as the achievement of CHR and mCR within 3 months could be useful to identify early those patients who will not respond to IFN- and who need alternative treatments such as stem cell transplantation.

Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.

Umbilical cord blood transplantation (UCBT) is an alternative in the absence of related or unrelated HLA-matched donor. Defects in the mechanisms of immuno-surveillance, due to the absence of antigen-experienced lymphoid subsets transferred in the cord blood unit (CBU), render recipients more prone to viral infections. Our center conducted a clinical trial testing the benefit of ex vivo amplification of the CD34+ fraction (using SCF, FLT3L, TPO and GCSF) enriched from one CBU on hematopoietic reconstitution, while the CD34- fraction was infused at the same time as the expanded fraction (NCT01034449). We intended to simultaneously evaluate the potential impact of such a procedure on the immune reconstitution following freeze-thaw cycle for the CD34- fraction and on the expansion potential of lymphoid progenitors from CD34+ fraction. We prospectively analyzed fresh patient samples from the clinical trial (called the EVEX), at different time points (Day 42, D100, D180, D360), and, in parallel, from patients receiving one or two un-manipulated CBU during the same period (Control group - CTRL). Immune monitoring included flow cytometry analysis of T-cells (CD3+, CD4+, CD8+) and sub-compartments, B-cells (CD19+), NK cells (CD3-CD16+CD56+) and Dendritic cells (DC). Sixteen patients were included in EVEX, of which 12 were analyzed (4 excluded: 1 not grafted, 1 graft infection, 2 primary rejections before Day 42) and 12 patients in CTRL. In the EVEX group, all patients received reduced intensity conditioning, compared to 6 out of 12 in the CTRL group. GVHD prophylaxis was similar. EVEX showed a shorter duration of neutropenia compared to the CTRL (8.5 versus 17 days, p=0.02). NK and B-cell subsets recovered earlier than T-cells, reaching median normal values at 3 and 6 months, respectively. NK cell count tended to be lower in EVEX, starting at 3 months until 1 year. B-cell counts were lower for EVEX at D360. Both groups recovered T-cells within 12 months, but, interestingly, EVEX recovered earlier, reaching Healthy Donor (HD) median values as soon as D180. The CD4+ T-cells (CD4+T) recovered within 12 months for both groups, with EVEX values tending to plateau at low normal values (Fig 1). CD8+ T-cells (CD8+T) reached HD values within 12 months with an earlier recovery for EVEX (Fig 1). We characterized CD4+T and CD8+T compartments with CD45RA and CD27 delineating: naïve (TN: CD45RA+CD27+), central memory (TCM: CD45RA-CD27+), effector memory (TEM: CD45RA-CD27-) and late effector (TEMRA: CD45RA+CD27-) T-cells. Among the CD4+T, TN and TCM gradually increased until D360 for CTRL, while EVEX reached a plateau at D180. EVEX showed a higher TEMRA CD4+T count at D360. Thus, the plateau observed in the whole CD4+T at D180 in EVEX suggested an altered capacity to induce new CD4+T (thymic output or peripheral expansion), or an exhaustion phenomenon. To this end, we evaluated thymic function via CD31 expression among TN CD4+T and TREC analysis by qPCR. Both methods showed a decreased thymic function in EVEX after D180, probably related to the age difference observed (median: 52 vs. 26 years old for EVEX and CTRL, respectively). TEM and TEMRA CD8+T subsets were higher starting at D180 for the EVEX group. There was no difference between groups for myeloid or plasmacytoid DC. Group outcomes differed in terms of chronic GVHD (cGVHD) (1 vs. 6 patients for EVEX and CTRL respectively, p=0.024). Among the subsets playing a role in cGVHD pathogeny, no difference was found in Treg/Tcon ratio (Treg = CD25hiCD127lo CD4+T, Tcon = non-Treg CD4+T), but memory B-cell subset tended to be greater in CTRL from D42 to D180 (median time of cGVHD onset = 186.5 days). CMV reactivation rate was similar in both groups, occurring around 42 days post transplant. Vdelta-2 negative γd T-cells were greater in EVEX early after infection (D42), suggesting a comparable anti-CMV innate function. However, when looking at adaptive anti-CMV immunity with ELISpot, we found reduced IFNg-secreting cells in EVEX, although group size was small. In conclusion, patients receiving ex vivo expanded CBU showed faster hematopoietic reconstitution than un-manipulated CBU and comparable recovery of the main immune subsets. Baseline clinical differences observed between groups may have impacted on some of the immune findings. A prospective and randomized trial would help to better analyze if the expansion procedure has an impact on immune reconstitution. Disclosures Milpied: Celgene: Honoraria, Research Funding.

In elderly pts, the prognosis of AML associated with poor risk cytogenetics or secondary to either MDS or previous cancer is so bad that only supportive care or investigational studies are usually recommended. Fit patients may achieve CR after conventional induction, but early relapse appears to be nearly inescapable whatever classical consolidation or maintenance therapy is used. Therefore, the GOELAMS investigated the impact of a maintenance using two agents mainly used in MDS, ie AZA and Len. Between March 2011 and February 2013, 117 pts from 27 centers (median age 69 yrs; 60-80) with previously untreated poor prognosis AML were included. Poor Risk factors were either preceding MDS (n=52), previous cancer (n=37) or centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities, n=65), monosomal karyotypes (n=54), del or - 5 (n=61) or 7 (n=44), 3q abnormality (n=9) or MLL rearrangement except for t(9;11) (n=5). Median WBC was 2.9 G/L (0.5-160), 7 pts had WBC ≥ 30 G/L. Induction chemotherapy included Lomustine 200 mg/m² po d1, Idarubicine 8 mg/m²/d (d1-5), Cytarabine 100mg/m²/d CI (d1-7). Patients in CR received 12 maintenance cycles alternating every 28 days AZA (sc 75 mg/m²/d1-7) and Len (10mg/d1-21), which started if PMN and platelets were >1 G/L and 100 G/L respectively. After d42, subsequent cycles were reduced to 50 mg/m²/d and 5 mg/d. GCSF was allowed in case of PMN < 0.5 G/L after 7 days or febrile neutropenia. At the end of induction, CR was achieved in 56% (65 pts) without any predictive factor, 9% died from infection (n=6), cerebral hemorrhage (n=1) or MOF (n=4) and 35% (41pts including 5 CRp) failed to achieve CR. The 12 planned maintenance courses could be given to 21 pts (32%) (median: 6). Few toxicities were observed. AZA courses were slightly more toxic than Len courses (table 1). Table 1.AZA courses %Len courses %Gr 3/4 neutropenia46.8/ 27.339.7 /17.6Antibiotics for fever at home6.97Hospitalization for febrile neutropenia0.52.7RBC transfusions55.4Gr 3 Thrombopenia2016Platelets transfusion8.67.9Interval between courses > 35 days26.118.4Median time interval between courses31 d28 dCourses with doses reductions9.621.6 Maintenance courses were interrupted because of relapse (n= 34, 77%), alloSCT (n=4 %), count error (n=1 %) or toxicities (n =5, 11%) occurring after Len (depression, vascular purpura and pseudomembranous diarrhea, sudden death, all during cycle 1) or after Aza (atrial fibrillation and cardiac dysfunction). Twenty Gr3/4 AE were reported among 441 cycles (0.56%/courses). Median follow-up for survivors was 38 mo (26-47). Median OS was 10 mo, with 21% 2y OS. Median CR duration was 7 mo (1-30). Impact of prognostic factors on DFS is shown table 2. Within poor risk factors, Cytogenetic abnormalities appeared as even poorer than previous MDS or cancer. Table 2.CR %CR NDFS median moP VALUE1y DFS %2y DFS %All patients56657.941.512.3Age ≥ 7058.3288.6 vs 7.746.417.9WBC ≥ 3.3 G/L48.1267.0 vs12.423.111.5Previous MDS51.92713.8 vs 6.4.0551.922.2MDS only68.41316.8 vs 6.4.00869.230.8Previous cancer54207.5 vs 7.9355Cancer only80812.4 vs 7.755012.5Poor cytogenetic53445.1 vs 15.3.0429.56.8Complex caryotype49.2324.8 vs 12.9.012259.4Monosomal caryotype50274.6 vs 12.9.00218.57.4Chromosome 5 abnormality52.5325 vs 13.8.00218.86.3Chromosome 7 abnormality54.5243.6 vs 12.00120.84.23q55.6510.4 vs 7.740017p deletion48.5165.0 vs 10.52512.5MLL8043.4 vs 8.4250poor cytogenetic + MDS42.997.7 vs 7.944.422poor cytogenetic + cancer46.774.8 vs 7.928.90poor cytogenetic + cancer + MDS71.453.4 vs 8.4200cancer + MDS00---Poor cytogenetic only rev aza57.5236.3 vs 12.9.05521.74.3Poor cytogenetic only SA255436.430.220.9 In the previous GOELAMS SA2 trial, 78 pts with poor risk cytogenetics without secondary leukemia received the same LIA induction followed in CR by maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. In the present study, the DFS of the group of pts with poor risk cytogenetics without previous cancer or MDS is very similar. This alternating azacitidine/lenalidomide maintenance improved DFS and OS of pts without poor risk cytogenetics (median 15.7 and 24 mo). In this setting, it could be randomly compared to conventional chemotherapy maintenance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: 60-70% of AML patients have an indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their treatment. Among those who undergo allo-HSCT, prognosis and quality of life depended on presence or absence of graft versus host disease (GvHD). Immune stimulation supports the principle of GvHD and graft versus leukemia (GvL) after allo-HSCT. The impact of immune activation prior to allo-HSCT on the pathogenesis of GvHD has never been evaluated. The aim of this study was to determine whether immune stimulation induced by infection or drug toxicity before transplantation increased the incidence of acute GvHD (aGvHD) in AML patients. Materials and methods: 345 AML patients were transplanted in first complete remission (CR) in 21 French centers from 2009 to 2013 after prospectively enrollment in the ALFA-0702 trial (patients aged 18-60y, de novo AML, favorable-risk AML excluded). Clinical data (skin, gut and liver infections or drug toxicities) before allo-HSCT were collected from the ALFA database and clinical data (skin, gut and liver aGvHD) after allo-HSCT were collected from the SFGM-TC database (ProMise). GvHD grading was defined according to Glucksberg criteria. Infection and drug toxicity grading was defined according to CTCAE v4.0. Mann-Withney and Kruskall-Wallis tests were used for continuous variables. Chi-square test was used for non-continuous variables. Overall survival (OS) and progression free survival (PFS) were assessed by Kaplan Meier method. Results: Median age at transplant and M/F sex ratio were 45 years (range, 19-61) and 195/150, respectively. Cytogenetics was intermediate-1, intermediate-2 and unfavorable in 24, 164, 144 patients according to ELN classification, respectively. 82.5% of the patients had reached CR after one cycle of induction. 193 (53%) patients presented infections during induction and 46 (17%) during consolidations. Moreover, 110 (30%) patients suffered from drug toxicity during induction and 36 (10%) during consolidations. Allo-HSCT was performed in all patients after one to three cycles of consolidation. 132 (36%) patients received reduced intensity conditioning. Sex matching was female in male for 74 (21%) patients. ABO matching was matched for 187 and mismatched for 158 patients. HLA matching was related for 138 and unrelated for 198 patients. Source of graft was bone marrow, peripheral stem cell and cord blood in 108, 217 and 12 patients, respectively. 181 (47%) patients underwent aGvHD, most frequently skin aGvHD (stage 1-2: 27.5%; stage 3-4: 9.5%). First, we observed a significant increase of incidence of aGvHD (all grades) if skin toxicities occurred during induction (45/57% for no toxicity and toxicities all grades, respectively p=0.07) or consolidations (46/70% for no toxicity and toxicities all grades, respectively p=0.04). Secondly, we observed a significant increase of skin aGvHD in cases of skin toxicities during induction [stage 0/1-2/3-4 skin aGvHD: 66/27/7% and 47/32/21% for no toxicity and toxicities all grades, respectively (p=0.001)] or consolidations [stage 0/1-2/3-4 skin aGvHD: 64/28/8% and 35/35/30% for no toxicity and toxicities all grades, respectively (p Conclusion: Skin immune stimulation induced either by infections during consolidations or by drug toxicity during induction and/or consolidations significantly increased the incidence of skin aGvHD. Nevertheless, we found no impact on OS and PFS in our cohort. Our results confirm the participation of inflammatory process in the physiopathology of GvHD. These data should be confirmed in a larger study to determine whether patients with prior infection and/or drug toxicity to allo-HSCT should receive different GvHD prophylaxis strategies. Disclosures Deconinck: PFIZER: Research Funding; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; LFB loboratory: Consultancy; ROCHE: Research Funding; CHUGAI: Other: Travel for international congress.

Introduction: The rate of early mortality in patients treated for acute myeloid leukemia (AML) reflects a balance of efficacy and safety outcomes. In the randomized phase 3 VALOR trial in patients with first relapsed or refractory AML, rates of 30-day (7.9% vs 6.6%, respectively) and 60-day (19.7% vs 19.4%, respectively) mortality were comparable between vosaroxin plus cytarabine and placebo plus cytarabine arms. The treatment-related mortality (TRM) score is a prognostic scoring system to predict risk of 30-day mortality with intensive treatment protocols in patients with newly diagnosed AML (Walter, 2011, J Clin Oncol 29:4417-4424). The "simplified TRM" score includes age, performance status (PS), platelet count, serum albumin, type of AML (secondary vs primary), white blood cell count, blast percentage in the peripheral blood, and serum creatinine. Here we present a multivariate analysis to identify baseline predictors of 30-day and 60-day mortality and a post hoc analysis of the 30-day mortality by TRM score to inform the assessment of treatment risk in VALOR patients. Methods: In VALOR, patients were randomized 1:1 to receive vosaroxin (90 mg/m2 intravenously [IV] over 10 min in cycle 1 and 70 mg/m2 in subsequent cycles, d 1 and 4) plus cytarabine (1 g/m2 IV, over 2 h, d 1-5) or placebo plus cytarabine. Baseline factors associated with 30-day mortality and 60-day mortality in patients treated with vosaroxin/cytarabine were identified from a univariate logistic regression analysis. Factors with significant associations (P < 0.10 by Type 3 P values) that were considered clinically and biologically relevant were included in a multivariate logistic regression model in the overall safety population. A stepwise selection procedure with entrance and retention criteria set to 0.05 was employed to reduce the risk factors to a parsimonious set. Simplified TRM scores were calculated retrospectively according to Walter 2011. Results: A total of 705 patients were included in the safety population (355 treated with vosaroxin/cytarabine and 350 treated with placebo/cytarabine). Based on multivariate analysis, vosaroxin/cytarabine treatment was not predictive for increased 30-day or 60-day mortality. Eastern Cooperative Oncology Group PS > 1 was predictive (P < 0.05) of 30-day mortality (odds ratio [OR] = 3.2) and 60-day mortality (OR = 2.1). Additional predictive factors identified for 30-day mortality were hemoglobin < 10 g/dL (OR = 3.8) and bilirubin > 1.0 mg/dL (OR = 3.3). For 60-day mortality, other predictive factors were albumin ≤ 3.6 g/dL (OR = 2.0), intermediate or high bone marrow blasts (10% to < 30% [OR = 2.6] or ≥ 30% [OR = 6.3]), prior myelodysplastic syndrome (OR = 2.2), and achievement of complete remission with first-line therapy (OR = 0.66). Age (< 65 y vs 65-69 y vs 70-74 y vs ≥ 75 y) was not a significant predictor of early mortality in the vosaroxin arm in the univariate logistic regression and therefore was not selected for multivariate analysis, although interestingly, age was predictive of 30-day mortality in the control arm. When added to the final multivariate model, age was of borderline significance (P = 0.0606). The median simplified TRM score at baseline was 2.6 (range 0-21) in the vosaroxin/cytarabine arm and 2.6 (range 0-33) in the placebo/cytarabine arm. Most patients (473/554, 85%) for whom a simplified TRM score could be calculated had a score < 8. Patients with lower TRM scores had lower rates of 30-day mortality (Table). Conclusions: Several individual baseline factors independently predicted risk of early mortality in patients with relapsed/refractory AML treated with vosaroxin or placebo plus cytarabine. In addition, the previously validated TRM score for predicting early mortality in newly diagnosed AML also predicted mortality in this relapsed/refractory population. In future studies of vosaroxin (and other intensive regimens), patient selection based upon these predictors of early mortality should be considered. Table. Thirty-Day Mortality by TRM Simplified Score TRM Simplified Score 30-Day Mortality, n/N (%) Pla/Cyt (n = 350) Vos/Cyt (n = 355) Total (N = 705) < 8 7/228 (3.1) 10/245 (4.1) 17/473 (3.6) 8 to < 16 6/31 (19.4) 5/31 (16.1) 11/62 (17.7) ≥ 16 3/10 (30.0) 5/9 (55.6) 8/19 (42.1) Missing 7/81 (8.6) 8/70 (11.4) 15/151 (9.9) Disclosures Lancet: Seattle Genetics: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy. Ritchie:Onyx: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau. Strickland:Amgen: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation. Schiller:Sunesis: Honoraria, Research Funding. Vey:Sunesis: Other: Steering Committee Member. Erba:Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Recher:Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kell:Sunesis: Consultancy, Honoraria. Krug:Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria; Sunesis: Speakers Bureau; Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees. Page:Sunesis: Employment. DeVault:Sunesis: Consultancy. Hwang:Sunesis: Consultancy. Craig:Sunesis: Employment, Equity Ownership. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding.

Background: Clofarabine has been shown as effective as single-agent or in combination with cytarabine in various populations of AML patients. Nevertheless, two randomized studies failed to demonstrate prolonged survival when compared to low-dose cytarabine in older AML patients (Burnett, 2013) or intermediate-dose cytarabine (IDAC) in patients aged 55y or more with relapsed/refractory AML (Faderl, 2012). As this was likely due to excessive toxicity and poor compliance in these difficult-to-treat populations, we made the hypothesis that a more apparent benefit might be observed during post-remission therapy. We thus randomly assessed the role of CLARA combination (clofarabine + IDAC) versus high-dose cytarabine (HiDAC) as consolidation cycles in younger AML patients. Methods: Between 2009 and 2013, 713 patients aged 18-60y old with de novo AML (CBF-AML excluded) were enrolled in the ALFA-0702 trial by 33 French centers. They received a timed-sequential induction with daunorubicin (60 mg/m2, day 1-3; 35 mg/m2, day 8-9), cytarabine (500 mg/m2 CI, day 1-3; 1 g/m2/12h bolus, day 8-10) and G-CSF priming. A first salvage with idarubicin and HiDAC may be proposed to patients not achieving CR/CRp after this first course. Patients in CR/CRp with non-favorable AML (according to ELN classification) or those who needed the salvage (late CR/CRp) were eligible for: 1) allogeneic stem cell transplantation (SCT) if they had a sibling or fully matched unrelated donor; or 2) randomization for consolidation with three HiDAC (3 g/m2/12h cytarabine, day 1/3/5; G-CSF priming) or CLARA (30 mg/m2 clofarabine, day 2-6; 1 g/m2/12h cytarabine, day 1-5; G-CSF priming) cycles if no identified donor. Primary endpoint was relapse-free survival (RFS), patients receiving allogeneic SCT in first CR/CRp after randomization (late donor identification) being censored at SCT time. Secondary endpoints were cumulative incidence of relapse (CIR) and death in first CR/CRp (CID), overall survival (OS), and safety. Anticipating a 35% SCT rate in randomized patients, 230 patients should be randomized to demonstrate a 20% gain in 2-year RFS. A sensitivity analysis without SCT censoring was planned. Results: Among 468 CR/CRp patients of interest (465/552 non-favorable AML + 3/161 favorable AML with late CR/CRp), 221 were randomized between HiDAC (n=114) and CLARA (n=107) consolidation and 247 were not randomized for the following reasons: 181 had an identified donor for SCT; 19 had favorable ELN genotype even if no evidence of normal karyotype; and 47 were negatively selected (13 early relapses, 1 early death, 18 AEs, 15 drop-out). The ITT analysis was conducted in these 221 eligible patients (median age, 48y; 136 intermediate-risk, 85 unfavorable-risk; 18 late CR/CRp; without imbalances between randomization arms), the remaining 9 randomized patients having non-eligibility criteria (6 favorable-risk AML and 3 not in CR/CRp). Among these patients, the rate of SCT in first CR/CRp was higher than anticipated (50%; 55 patients in each arm). With a median follow-up of 37.4 months and SCT censoring, 2-year RFS was 52.1% (40-68) in the CLARA arm versus 30.5% (20-46) in the HiDAC arm (HR, 0.62 [0.39-0.99]; p= 0.042). This was due to a lower CIR in the CLARA arm (44.0 versus 67.7%; p= 0.023) with similar CID (3.9 versus 1.9%, p= 0.60). At 2 years, OS was 68.1% (56-82) in the CLARA arm versus 49.8% (38-66) in the HiDAC arm (p= 0.18). Interestingly, the gain in CIR and RFS was observed in both intermediate- and unfavorable-risk groups and persisted after adjustment on AML risk and age. As expected, these gains were lower when not censoring at SCT (2-year RFS, 57.8 versus 45.6%; p= 0.12). In the 110 randomized patients allografted in first CR/CRp, no differences in post-SCT outcome were observed according to randomization arm. In Mantel-Byar time-dependent analysis, longer RFS was observed after SCT in the HiDAC arm (HR, 0.45; p= 0.004), while not in the CLARA arm (HR, 0.71; p= 0.26). Finally, CLARA cycles were associated with higher hematologic toxicity, more infections and more liver toxicities than HiDAC cycles, especially after cycle 1. Conclusions: As compared to HiDAC, clofarabine-based consolidation improved RFS in younger patients with intermediate- and unfavorable-risk AML in first CR/CRp. CLARA combination might thus become a new standard for post-remission therapy in these patients, especially in those who may not benefit from allogeneic SCT. Disclosures Off Label Use: CLOFARABINE is not currently approved for this indication.. De Botton:Agios pharmaceuticals: Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m2 per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m2 (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Purpose: Best supportive care is generally offered to older patients presenting with refractory/relapsed acute lymphoblastic leukemia (ALL). There is clearly a need for new therapeutic approaches in these older patients for whom aggressive chemotherapies cannot be administered. Materials and Methods: The present study evaluated the addition of epratuzumab (hLL2), a humanized monoclonal therapeutic antibody against CD22, to the combination of vincristine and dexamethasone in older patients (>55 years) with relapsed/refractory CD22+ B-ALL. The salvage regimen consisted of epratuzumab 360 mg/m²/d iv days 1, 8, 15, and 22, vincristine 2 mg iv days 1, 8, 15 and 22, and dexamethasone 40 mg/d po days 1, 8, 15, and 22. Morphologic and phenotypic minimal residual disease (MRD) responses were determined between 4 and 6 weeks from day 1. Results: Between November 2010 and December 2013, 26 patients from six French centers were enrolled in the study. One case was excluded because of progression before receiving the treatment, while 2 younger patients were inappropriately included (49-year old female in fourth relapse and 32-year old female with refractory second relapse). Among the 25 patients considered for analyses, there were 13 males and the median age was 65 years. Eighteen, 4, 1, and 1 patients were in first, second, third, and fourth relapse, respectively, and one case had refractory B-ALL. Median percentage of blasts in bone marrow was 72%. Karyotypes were as follow: normal n=8; Ph+ n=6, complex n=1, MLL rearrangement n=1, hyperdiploidy n=2, hypodiploidy n=2, 17p duplication n=1, del9p n=1, t(1;19) n=1, t(13;14) n=1, 14 abnormality n=1. Median interval between diagnosis and salvage regimen was 16 months. Three patients were previously allotransplanted. Two patients died of progression during treatment. Salvage regimen was overall well tolerated, since the large majority of grade 3/4 toxicities were expected pancytopenia. One grade 3 toxicity was related to the first epratuzumab infusion, but the patient received the three other infusions without events. One grade 3 renal injury and one grade 4 hypertriglyceridemia of unclear etiology also were documented. The overall response rate was 40% (n=10), including 4 complete responses (CR) and 1 CR with incomplete platelet recovery (CRp) (20%), and 5 partial responses (PR) (20%). Two patients in CR/CRp were documented with negative MRD. All patients in CR/CRp and 1 patient in PR received a second cycle as consolidation. All patients died of disease progression, except two non-responder cases. Median OS was 4 months (range: 0.5-43). Median DFS for those achieving CR/CRp was 4 months (range: 1-8). Conclusion: Non-intensive chemoimmunotherapy combining vincristine/dexamethasone/epratuzumab provides encouraging results in this very high-risk, refractory/relapsed, older population. These results pave the way for integrating epratuzumab within first-line chemotherapies in older CD22+ B-ALL patients. This trial is registered at http://clinicaltrials.gov/ct no.NCT01219816. Disclosures Leguay: Gilead Sciences: Research Funding. Goldenberg:immunomedics: Employment. Wegener:immunomedics: Employment.

In younger patients with acute myeloid leukemia (AML), standard intensive induction chemotherapy combines anthracyclins and cytarabine (Ara-C). While dosage is usually determined according to body-surface area (BSA), various chemotherapy adjustments are empirically performed in patients with high BSA from full dose administration to capping doses. The aim of the present study is to determine the outcome of younger AML patients with high BSA at diagnosis. Between November 2001 and April 2005, the prospective GOELAMS 2001 trial enrolled patients between 18 and 60 affected with non promyelocytic AML.1,2 Briefly, patients randomly received either daunorubicin or idarubicin in association with standard dose Ara-C during induction therapy. Height, weight and induction chemotherapy doses were registered at diagnosis. BSA was evaluated using the formula of Dubois and Dubois. BSA was categorized in low (BSA ≤1.5m2), intermediate (1.5 823 patients were eligible to induction therapy. 43 (5%), 638 (77%), 91 (11%) and 51 (6%) patients displayed low, intermediate, high or very high BSA at diagnosis, respectively. Median age, performance status, karyotype group were similar in all BSA groups. On the contrary, male gender was enriched in high and very high BSA groups (86% and 88%, respectively). During induction therapy, 20 patients (39%) with very high BSA were administered reduced dose (decrease of > 10% in anthracyclin or Ara-C dosing compared to full dose) versus 8%, 4% and 7% in low, intermediate or high BSA subgroups (p Compared to patients with intermediate BSA, patients with a low or high BSA displayed a similar OS and EFS. On the contrary, patients with a very high BSA displayed a decreased 5-year OS (27% (95% CI, 18-43) vs 47% (95% CI, 44-51), p= 0.006, figure 1A) and LFS (22% (95% CI, 13-36) vs 41% (95% CI, 37-45), p=0.004). Non-relapse mortality was similar in the very high or intermediate BSA groups, suggesting that intensive therapy was similarly tolerated in intermediate or very high BSA patients. Meanwhile, relapse incidence was increased in patients with a very high BSA compared to intermediate BSA patients (61% (95% CI, 46-73) vs 44% (95% CI, 40-48), p = 0.02, figure 1B). Conclusion: patients with a very high BSA display an adverse outcome, due to an increased relapse incidence. Meanwhile, non-relapse mortality is not significantly increased in very high BSA patients. These data suggest that patients with very high BSA should receive full dose induction chemotherapy. Bibliography; 1. Recher C , Bene MC, Lioure B et al. Leukemia, Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. Leukemia 2014; 28:440-3. 2. Lioure B, Bene MC, Pigneux A et al. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood 2012; 119: 2943–2948. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.