Larson, Richard A.

Abstract Background: A majority of younger pts with AML receive initial therapy with a 7+3 scheme. Escalated doses of daunorubicin (dauno) in combination with standard doses of ara-C may lead to improved outcomes (Fernandez; NEJM 2009). A phase II trial of idarubicin and high-dose ara-C (IA) in combination with the histone deacetylase inhibitor vorinostat (IA+V) resulted in historically high response rates compared to IA or 7+3 (Garcia-Manero; JCO 2011). SWOG 1203 tested whether a high-dose ara-C induction with or without vorinostat could result in improved outcomes for younger AML pts compared to 7+3. Methods: The primary endpoints were comparison of event-free survival (EFS) of 7+3 vs IA vs IA+V and evaluating the frequency of allogeneic hematopoietic cell transplantation. Secondary endpoints included toxicity, remission rate, relapse-free survival (RFS), and overall survival (OS) according to treatment arm, and by cytogenetic and molecular subgroups. Because of the historical trend of cured pts in S0106, EFS was modeled with an exponential cure model, and it was assumed IA or IA+vorinostat increased the proportion of pts cured from 35% to 45% and increased median EFS among those not cured from 4.7 months to 7.1 months. Main inclusion criteria included a diagnosis of previously untreated non-APL AML by WHO criteria, age 15 to 60 years, and preserved cardiac function but no severe comorbidities. Pts with known CBF rearranged or FLT3 mutant leukemias were eligible if no other alternative clinical trials existed. Treatment was as follows: Induction: 7+3 arm: dauno 90 mg/m2 IV QD x 3 on days 1-3 with ara-C CI 100 mg/m2 QD x 7 days on days 1 to 7. IA arm: ida 12 mg/m2 QD x 3 on days 1 to 3 with 24 hours CI ara-C 1.5 gm/m2 QD for 4 days on days 1 to 4. IA+vorinostat was as IA but with vorinostat 500 mg orally TID for 3 days on days 1 to 3. Consolidation: 7+3 arm: standard high-dose ara-c at 3 gm/m2 over 3 hrs q12 hours x 6 doses for 1 to 4 cycles depending on transplant availability. IA arm: idarubicin 8 mg/m2 IV QD x 2 days on days 1 to 2 with ara-C 0.75 gm/m2 CI for 3 days on days 1 to 3 for 4 cycles. The number of consolidation cycles depended on transplant indication; a secondary aim of the study was to transplant all cytogenetically-determined high risk pts (presented in a different abstract). Results: Of 754 pts randomized, 738 were eligible (261 to 7+3, 261 to IA, and 216 to IA+V). Baseline characteristics were well balanced among all three groups. Most (75%) pts were between 40 and 60 years, 51% were male, median (range) WBC and platelets were 10.8 (0.3-800) and 49 (3-3900), respectively; marrow blast percentage was 60% (0%-100%); cytogenetics were favorable in 13% of pts, intermediate in 63%, and high-risk in 22%; FLT-3 was mutated in 21% and unknown in 31%; NPM1 was mutated in 20% and was unknown in 37%. Complete remission (CR) rates were 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). Significantly more pts received reinduction with 7+3 (24%) versus 11% with IA and 9% with IA+V (p=0.001). 48% of intermediate and unfavorable risk pts received transplant in CR1, with no significant differences among arms (p=0.44). There were no significant differences in EFS, RFS or OS among all three arms (Figure 1, all p>0.5). By cytogenetic or molecular group, there were no differences in outcome for any standard risk subset (FLT-3, NPM1, or CEBPα or cytogenetic subset), although pts with favorable cytogenetics had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (Figure 2, all p≤0.015). 30% of pts received 1 consolidation cycle, 18% 2, 16% 3, and 37% 4 cycles. Grade 5 induction toxicity rates were 4% (7+3), 8% (IA), and 9% (IA+V) by arm (p=0.07), and for toxicities related to therapy, 2%, 7%, 8%, respectively (p=0.01). Grade 4 induction toxicity rates were similar across arms (p=0.38). Conclusion: Treatment with IA is not more effective than 7+3 in younger pts with AML. Outcomes with IA or IA plus vorinostat are similar. In pts with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation. Clinical Trials Registry: NCT #0180233 Support: NIH/NCI grants CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI grant #021039 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy; BMS: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; Baxalta: Consultancy; Cyclacel: Research Funding; Celator: Research Funding; Abbvie: Research Funding; Ambit: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Lundbeck: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Merck: Consultancy; Abbvie: 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; ONO: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Ariad: Consultancy; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Agios: Research Funding; Jannsen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Agios: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Ariad: Consultancy; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB.

Abstract Background: Event free survival (EFS) is often used as an endpoint in AML clinical trials. EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). Here, we examined the impact of the timing of achievement of CR and censoring for HCT in the estimation of the EFS, and assessed its robustness as an endpoint in AML. Methods: All prospective trials since 2003 using anthracycline and cytarabine chemotherapy for newly diagnosed patients (pts) with AML conducted through the Alliance for Clinical Trials in Oncology, and whose primary endpoint data has been reported, were included (5 trials total). Trial 1 - randomized phase III study in older AML pts (n=504, median age 69, 61% male); trial 2 - single-arm phase II study in older FLT3-mutated AML pts (n=54, median age 67, 56% male); trial 3 - randomized phase III study in younger AML pts (n=546, median age 48, 55% male); trial 4 - randomized phase III study in younger FLT3-mutated AML pts (n=717, median age 48, 45% male); and trial 5 - single arm phase II study in core-binding factor AML pts with no restriction on age (n=61, median age 51, 51% male). Induction failure was defined as one of: no CR by 60 days (Definition 1), no CR by the end of all protocol induction courses (Definition 2), or no CR by the end of all protocol treatment (Definition 3). CR was defined as <5% blasts in a cellular marrow with recovery of >1000 neutrophils/ul (>1500 neutrophils/ul for trial 1), >100,000 platelets/ul, and no red cell transfusion requirement. EFS was defined as the time from randomization / registration to the first evidence of induction failure using each of the 3 methods above, relapse, or death from any cause. Patients last known to be alive without relapse were censored at the date of last contact. Including the 3 induction failure definitions and consideration of censoring or no censoring for HCT, the Kaplan Meier estimates of EFS were computed for the six different definitions of EFS. Results: The number of deaths was respectively 464, 38, 307, 357, and 13 across the 5 trials, with a median follow-up of 99.7, 28.2, 60.1, 58.2, and 33.5 months on the alive patients, respectively. Not considering HCT, in trial 1, the median EFS ranged from 2.0 to 4.3 months (115% difference); in trial 2, the median EFS ranged from 6.9 to 8.3 months (20% difference); in trial 3, the median EFS ranged from 9.8 to11.2 months (14% difference); and in trial 4, the median EFS ranged from 5.5 to 9.7 months (76% difference). The median EFS was not achieved in trial 5; however the 1-year EFS estimates ranged from 78 to 83% (6% difference). Consistently across all trials, as expected, the EFS estimate using the 60-day induction failure yielded the shortest estimates, whereas the end-of-treatment induction failure yielded the longest estimates. Results were similar both with and without censoring at the time of HCT as the event of interest occurred prior to transplantation in most cases. Conclusions: Although relapse and death are firm endpoints, the determination of failure to achieve CR is not consistent across studies. While there is minimal impact of censoring at HCT on EFS estimates, the median EFS estimates differed considerably based on the timing of CR used to define induction failure, with the magnitude of difference being large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. The timing of CR should be carefully examined in the historical control data used to guide the design of the next trial. Table. Table. Disclosures Uy: Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy. Stone:Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy.

Abstract Background: Gilteritinib (ASP2215) is a novel, highly selective, potent oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD activating and FLT3-D835 resistance mutations. The objectives of this phase 1/2 study were to assess gilteritinib safety/tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- and multiple-day dosing, and antileukemic effects in patients with R/R AML. Methods: This open-label study (NCT02014558) enrolled patients (≥18 yr) into 1 of 7 dose-escalation cohorts (20-450 mg once daily [QD]) or concomitant dose-expansion cohorts. While confirmed FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 patients with FLT3 mutations (FLT3mut+); 120 and 200 mg dose levels were further expanded with ≥40 FLT3mut+ patients. The choice to expand these dose cohorts was based upon FLT3 inhibition in correlative assays and clinical activity seen during dose escalation. Safety and tolerability were primary endpoints; blood samples were drawn from patients in the dose-escalation cohorts to evaluate gilteritinib PK parameters and PD effects. Antileukemic response rates (eg, complete remission [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematological recovery [CRi], overall response rate [ORR]) were secondary endpoints. Results: Patients (N=252; 129M:123F, median age 62 yr [range: 21-90]) enrolled between October 2013 and August 2015 received ≥1 dose of gilteritinib. The study population was heavily pretreated: 70% (n=177) had ≥2 prior AML therapies, 29% (n=73) had a prior stem cell transplant, and 25% (n=63) had prior TKI treatment with sorafenib most commonly used. Across the study, 194 patients had a locally confirmed FLT3 mutation (ITD, n=159; D835, n=13; ITD-D835, n=16; other, n=6). For all enrolled patients, progressive disease (n=75), lack of efficacy (n=44), adverse events (n=34), and death (n=29) were the most common reasons for treatment discontinuation. Seven deaths were considered possibly/probably related to treatment: pulmonary embolism, respiratory failure, hemoptysis, intracranial bleed, ventricular fibrillation, septic shock, and neutropenia (all n=1). Maximum tolerated dose was determined to be 300 mg when 2 of 3 patients in the 450 mg cohort experienced diarrhea and/or hepatic transaminase elevation as dose-limiting toxicities. Diarrhea (16%) and fatigue (15%) were the most commonly reported treatment-related adverse events of any grade. Less than 5% of patients (11/252) had a maximum post-baseline QTcF interval >500 msec. Gilteritinib concentrations were generally dose proportional and showed both a long-elimination half-life (45-159 h) and substantial accumulation (3.2-10 fold) by day 15. An exposure-related increase in the inhibition of FLT3 phosphorylation with increasing doses of gilteritinib was also observed. Gilteritinib showed strong antileukemic activity in FLT3mut+ patients (ORR=49%); response was observed less frequently in patients with wild-type FLT3 (ORR=12%). While CR, CRi, and CRp occurred at all doses, responses were enriched among FLT3mut+ patients with gilteritinib steady-state trough concentrations ≥100 ng/mL, which correlated with potent FLT3 inhibition in PD assays and corresponded to doses ≥80 mg. The ORR in 169 FLT3mut+ patients receiving ≥80 mg was 52% (Table); median overall survival in this patient population was ~31 wk (range: 1.7-61; Figure) and median duration of response was 20 wk (range: 1.1-55). Clinical responses occurred in FLT3mut+ patients with -ITD, -D835, and both mutations (ORR: 55%, 17%, and 62%, respectively) as well as in FLT3mut+ patients with or without prior TKI treatment (ORR: 42% vs 56%, respectively). Conclusions: This PD-driven, first-in-human study shows that gilteritinib was well tolerated and generated frequent, prolonged, clinically important responses in FLT3mut+ patients with R/R AML. Antileukemic responses were enriched in FLT3mut+ patients treated at doses that consistently and potently inhibited FLT3 phosphorylation. The survival of these patients appears better than expected for this patient population when treated with standard therapy. Our data suggest that FLT3 inhibition may improve survival in patients with FLT3mut+R/R AML; as such, phase 3 testing of oral gilteritinib 120 mg QD in patients with FLT3mut+R/R AML after first-line therapy is underway (NCT02421939). Disclosures Perl: Astellas US Pharma Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Asana Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Altman:Janssen: Other: advisory board; BMS: Membership on an entity's Board of Directors or advisory committees; Spectrum: Other: advisory board; Ariad: Other: advisory board; Seattle Genetics: Other: advisory board; Syros: Other: advisory board. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Smith:Astellas: Research Funding. Erba:Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Agios: Research Funding; Juno: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research Funding; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy. Gill:Astellas: Employment. Goldberg:Bristol Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA Inc: Employment; Pfizer: Honoraria; Neostem: Equity Ownership. Jurcic:Astellas: Research Funding. Larson:Astellas: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Liu:Astellas: Employment. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schiller:Incyte Corporation: Research Funding. Strickland:Celator: Research Funding; Cyclacel: Research Funding; Karyopharm Therapeutica: Research Funding; GlaxoSmithKline: Research Funding; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Ambit: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Sanofi: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Stuart:Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding. Martinelli:Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers Bureau; MSD: Consultancy; Genentech: Consultancy; Novartis: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Bahceci:Astellas: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Introduction: ASP2215 is a highly selective inhibitor of AXL and FMS-like tyrosine kinase-3 (FLT3) receptors. ASP2215 is active against both FLT3 internal tandem duplication [ITD] and D835 mutations. Prior analyses of an open-label, dose-escalation/dose-expansion study in subjects with relapsed or refractory acute myeloid leukemia (R/R AML) show ASP2215 was well tolerated from 20-300 mg and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) patients at ≥80 mg with minimal activity observed in wild-type FLT3 subjects. Here we describe the tolerability and potent activity of ASP2215 in a large cohort of FLT3+ patients. Methods: Patients (≥18 years) with R/R AML were assigned to treatment in dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. Although FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 FLT3+ subjects; 120 mg and 200 mg dose levels were further expanded with ≥40 FLT3+ subjects. Tolerability was assessed by adverse event (AE) monitoring. Response assessment was based on modified Cheson criteria and duration of response and overall survival were calculated using Kaplan-Meier estimates. Results: As of June 19, 2015,215 patients with a median age of 61 yr (range: 21-90) had received ≥1 dose of ASP2215 (safety population). Across the safety population, 65% of subjects received ≥2 prior lines of AML therapy, 29% had a hematopoietic stem cell transplant prior to ASP2215 treatment, and 23% had prior tyrosine kinase inhibitor (TKI) treatment. Approximately 73% of patients were FLT3+, of which 137 had FLT3-ITD mutation, 7 were FLT3-D835+, and 9 had both FLT3-ITD and D835. Treatment-related AEs of all Grades, reported in ≥10% of the safety population were diarrhea (16%), fatigue (13%), and increased AST (11%); <2% of subjects reported a Grade ≥3 QTc prolongation. Activity was assessed in the 133 FLT3+ patients treated with ASP2215 ≥80 mg. Overall response rate (ORR; composite complete [CRc] plus partial remission [PR]) for all FLT3+ subjects was 55% (Table). Median overall survival for FLT3+ patients receiving ASP2215 ≥80 mg was ~29 weeks (95% CI: 22-32) and was similar for patients who achieved CRc or PR (Figure). Treatment with ≥80 mg ASP2215 was associated with an ORR of 60% in FLT3-ITD subjects; ORR for the other FLT3 populations was 29% (Table). No difference was observed in median ORR of ASP2215 (≥80 mg) in TKI-naïve patients (55%) and patients with prior TKI treatment (55%). Conclusions: ASP2215, a novel AXL/FLT3 TKI, was well tolerated in subjects with R/R AML and demonstrated a strong antileukemic activity in FLT3+ subjects. Importantly, the ASP2215 response rate in these FLT3+ patients was independent of prior TKI treatment. Even in this heavily pretreated population, the survival of R/R FLT3+ AML patients who received ≥80 mg ASP2215 was longer than prior reports of cytotoxic chemotherapy or other FLT3 inhibitors. Table. ASP2215 Response Assessment 80 mg 120 mg 200 mg 300 mg 450 mg Total All FLT3+ Subjects Population, n 12 52 57 10 2 133 CRc, n (%) 5 (42) 25 (48) 28 (49) 3 (30) 0 61 (46) PR, n (%) 3 (25) 3 (6) 3 (5) 3 (30) 0 12 (9) ORR, n (%) 8 (67) 28 (54) 31 (54) 6 (60) 0 73 (55) Subjects with FLT3-ITD Only Population, n 10 46 50 8 0 114 CRc, n (%) 4 (40) 23 (50) 26 (52) 3 (38) 0 56 (49) PR, n (%) 3 (30) 3 (7) 3 (6) 3 (38) 0 12 (11) ORR, n (%) 7 (70) 26 (57) 29 (58) 6 (75) 0 68 (60) Subjects with FLT3-D835 and Subjects with FLT3-ITD and FLT3-D835 Population, n 2 5 5 1 1 14 CRc, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) PR, n (%) 0 0 0 0 0 0 ORR, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) CRc, composite complete remission (complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery); ORR, overall response rate; PR, partial response. NR, no response. Subjects with non-evaluable data (N=8) were not included in this curve. Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Disclosures Altman: BMS: Other: Advisory board; Novartis: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Seattle Genetics: Other: Advisory board; Astellas: Other: Participation in an advisory board December 2013. Off Label Use: ASP2215 is currently under investigation for the treatment of AML and is not yet approved.. Perl:Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy; Ambit/Daichi Sankyo: Consultancy; Astellas US Pharma Inc.: Consultancy. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Levis:Arog: Research Funding; Ambit: Research Funding; Takeda: Research Funding; Astellas: Consultancy. Smith:Plexxikon: Research Funding; Astellas: Research Funding. Claxton:NCI: Research Funding; Medimmune, Inc: Research Funding; Ambit Biosciences Corp: Research Funding; Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Astellas Pharma: Research Funding. Erba:Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Amgen: Consultancy, Research Funding; Celator: Research Funding; Millennium/Takeda: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Celator: Research Funding; Pfizer: Consultancy; Astellas: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Daiichi Sankyo: Consultancy. Gill:Astellas Pharma US, Inc: Employment. Goldberg:Cyclacel: Research Funding; Celetor: Research Funding; Pfizer: Research Funding; Ambit: Research Funding; Astellas: Research Funding. Jurcic:Astellas Pharma: Research Funding. Larson:Astellas: Consultancy, Research Funding. Lui:Astellas Pharma US, Inc: Employment. Ritchie:Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau; Onyx: Speakers Bureau. Sargent:Astellas Pharma US, Inc: Employment. Schiller:Sunesis: Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Wang:Immunogen: Research Funding. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Baldus:Novartis: Research Funding. Martinelli:MSD: Consultancy; ARIAD: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy; Novartis: Speakers Bureau; Roche: Consultancy. Bahceci:Astellas Pharma Global Development: Employment.

Abstract Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML. The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts. A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo. This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001). Disclosures Uy: Novartis: Research Funding. Off Label Use: Sorafenib for AML. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta Pharma BV: Research Funding. Stone:Celator: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; AROG: Consultancy; Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Juno: Consultancy; Agios: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Abstract Purpose: Clinical trials in APL have generally reported similar outcomes for children and adults. However, sub-group analysis of pediatric patients treated on 2 consecutive trials of the European APL group demonstrated that children <5 years (yr) had an increased risk of relapse (Bally et al., JCO, 2012). Here we report the effect of age < 5 yr on outcome for the North American Intergroup Study C9710. Methods: Outcomes were compared among young children (age <5 yr, n=16) to those of older age (5-12 yr, n=25 and 13-18 yr, n=45) enrolled on C9710. Treatment on C9710 included induction with daunorubicin, cytarabine and ATRA followed by two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Patients of age ≥15 yr were randomized to receive or not receive two 5-week cycles of arsenic trioxide (ATO) before the chemotherapy consolidation. However, analysis in this study of young children compared to those of older age was restricted to patients who did not receive ATO. Results: Clinical remission (CR) rates were similar between the 3 age groups (age <5 yr= 88%, age 5-12 yr= 80%, age 13-18 yr= 82%; P=0.93). Overall survival (OS) Kaplan-Meier estimates were not significantly different (log rank P=0.84), and 5 yr OS rates were 77% (age <5 yr), 80% (age 5-12 yr), and 84% (age 13-18 yr). Similarly, event-free survival (EFS) Kaplan-Meier estimates were not significantly different (log rank P=0.48), and 5 yr EFS rates were 56% (age <5 yr), 47% (age 5-12 yr), and 59% (age 13-18 yr). Young children did not have a higher relapse rate (5-yr cumulative incidence of relapse by age: <5 yr=29%, 5-12 yr=49%, 13-18 yr=29%). Conclusions: Results of this intergroup trial demonstrate that ATRA administration during induction, consolidation and maintenance leads to CR rates >80% and 5 yr OS rates >75%. These results are superior to recently published results of pediatric non-APL acute myeloid leukemia and confirm results from the prior APL intergroup trial (INT0129) that demonstrated that ATRA in induction and/or maintenance significantly improved outcomes for pediatric APL (Gregory et al., Ped Blood and Cancer, 2009). Our sub-group analysis showed no association of age with outcomes in children treated with this regimen. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Abstract Abstract 3315 The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(Tipifarnib), as maintenance therapy for acute myeloid leukemia (AML). Patients (pts) with AML in remission after requiring salvage therapy (primary induction failure or second or subsequent remission) or over the age of 60 in first remission were eligible. A confirmatory bone marrow exam was required within 2 weeks prior to randomization. Pts were eligible if they were in a complete remission (CR) or morphologic remission (MR). Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Adequate blood counts (absolute neutrophil count >= 1000/mm3 and platelet count >=50,000/mm3), and normal renal, and hepatic function were required within 2 weeks of randomization. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of this study was to compare disease free survival in the two groups. Although the study has completed accrual, an insufficient number of events have been recorded at this point to allow for evaluation of the survival data. However, toxicity data are now available. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). Seventy-three pts (51%) were male and 135 pts (94%) were white. Seventy-three pts were enrolled onto the treatment arm (Arm A) and 71 pts were enrolled onto the observation arm (Arm B). When the study was initially opened, pts on Arm A were treated with tipifarnib at a dose of 400 mg BID with dose reductions and interruptions defined per protocol for toxicity. After the first planned interim analysis, based on toxicity data, the ECOG Data Monitoring Committee recommended that the starting dose be decreased to 300 mg BID. The majority of pts enrolled on the study were in first CR (CR1) (Table 2). Among the 30 pts treated with the initial 400 mg BID dose, 23 pts (77%) had their dose held or reduced to a lower dose in the subsequent treatment cycles. For the 41 pts whose initial dose was 300 mg BID, 61% required either dose modification (n=19) or discontinued (n=6) due to toxicity. Table 1: Baseline characteristics Arm A 400 mg BID n=31 Arm A 300 mg BID n=42 Arm B Observation n=71 CR1 16 (52%) 34 (81%) 47 (66%) >CR1 10 (32%) 8 (19%) 16 (23%) Unknown 5 (16%) 16 (11%) Table 2: Toxicity Toxicity Type Arm A 400 mg n=31 Arm A 300 mg n=41 Arm B Observation n=69 Grade (n) Grade (n) Grade (n) 3 4 3 4 3 4 Hemoglobin 1 1 6 1 1 2 Leukocytes 2 4 16 4 3 Neutrophils 5 8 3 7 1 Platelets 4 10 11 11 1 5 Cardiac-ischemia 1 Fatigue 1 Diarrhea 1 Nausea 1 Febrile neutropenia 1 1 Infection w/gr 3-4 neutrophils (ANC) 1 Infection Gr0-2 ANC 1 1 3 GGT 1 Hypokalemia 1 Confusion 1 Agitation 1 Neuropathy-sensory 1 Back pain 1 Worst degree Non Hematologic 4 2 9 1 1 While non-hematologic toxicity was acceptable, significant hematologic toxicity was seen in pts treated at an initial dose of either 400 mg or 300 mg BID (Table 2). Of note, hematologic toxicity was also seen on the observation arm although less frequently than with both treatment doses. Non-hematologic toxicity was much less frequent overall and there were no significant non-hematologic toxicities in the observation arm. Reduction of the initial dose did not ameliorate either the hematologic or non-hematologic toxicity seen on the treatment arms. There was however no fatal toxicity at either dose level. Results of the randomization with respect to efficacy remain essential to determining the utility of this agent as maintenance therapy in AML. Disclosures: No relevant conflicts of interest to declare.

Abstract Purpose: Recent studies have demonstrated differential outcomes for adolescents and young adults (AYAs) vs. children treated for acute myeloid leukemia. Here we analyze outcomes by age group for APL patients treated on the North American Intergroup Study C9710. Methods: Patient characteristics and outcomes were compared between children (<15 yr, n=55) vs. AYAs (15-31 yr, n=42). To control for differences in treatment center, only young adults registered at Children’s Oncology Group (COG) treatment sites were included. Treatment included induction with daunorubicin, cytarabine and ATRA. All patients (pts) received two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Pts ≥15 yr were randomized to an additional two cycles of arsenic trioxide (ATO). Sub-group analysis was also performed to exclude pts ≥15 yr who received ATO and thus compare only patients <15 yr vs. ≥15 yr who had not received ATO. Results: Children and AYAs had similar characteristics of gender, race/ethnicity, Sanz risk grouping and M3v histology. Among all pts enrolled at COG sites on the study, complete response (CR) rates were similar (<15yr =85% vs. ≥15yr =81%, P=0.59). AYAs had improved 5 yr disease-free survival (DFS) from time of CR compared to younger pts (<15 yr =47% vs. ≥15 yr =70%, log rank P=0.05), and there was a trend toward difference in 5 yr event-free survival (EFS) (<15 yr =46% vs. ≥15 yr =63%, log rank P=0.13). Overall survival (OS) at 5 years was not significantly different (<15 yr =82% vs. ≥15 yr =75%, log rank P=0.47). Twenty-three of 42 pts ≥15 yr received ATO consolidation cycles, which may have contributed to their improved DFS and EFS. Thus, we analyzed outcomes by removing from the analysis patients ≥15 yr who received ATO consolidation cycles, and compared pts <15 yr who did not receive ATO (n=55) to pts ≥15 yr who were randomized to no ATO (n=19). CR rates were again similar (<15 yr =85% vs. ≥15 yr no ATO =84%, P=1.0). There was no significant difference in other outcomes including 5-yr DFS from time of CR (<15 yr =47% vs. ≥15 yr no ATO =63%, log rank P=0.31), 5-yr EFS (<15 yr =46% vs. ≥15 yr no ATO=53%, log rank P=0.89), or 5-yr OS (<15 yr =82% vs. ≥15 yr no ATO=79%, log rank P=0.78). Conclusions: The C9710 study demonstrated improved EFS, DFS and OS among adult patients receiving ATO consolidation compared to those who did not receive ATO (Powell et al., Blood, 2010). The current analysis of results for AYAs versus younger pediatric pts showed improved DFS among the whole AYA cohort (of which 55% received ATO consolidation) compared to pts <15 yr (of which 0% received ATO). When the analysis was restricted to AYA pts not receiving ATO, however, the results of this intergroup APL trial showed similar CR, DFS, EFS and OS for AYAs and younger pts. Thus, unlike other subtypes of AML, APL appears to have a consistent response across the pediatric and AYA age groups. The most recent COG clinical trial in APL is now evaluating whether pediatric patients can also benefit from ATO consolidation. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Abstract Abstract 676 Although maintenance therapy has been shown to be of value in Acute Lymphoid Leukemia, its role in non M3 Acute Myeloid Leukemia (AML) has never been proven. Studies have been limited by issues related to efficacy as well as toxicity. The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(tipifarnib), as maintenance therapy for AML. Patients(pts) with AML in remission after requiring salvage therapy or over age 60 in first remission were eligible. A confirmatory bone marrow exam prior to randomization was required to demonstrate a complete remission (CR) or morphologic remission(MR). Absolute neutrophil count >1000/mm3, platelet count >=50,000/mm3, normal renal, and hepatic function were required. Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of the study was to compare disease free survival (DFS) in the two groups. The study was designed with 84% power to detect a 76% relative increase in the median DFS from 3.4 months to 6 months (mo). The final analysis was to take place when 111 events had taken place. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). The majority of pts enrolled on the study (67%) were in first CR. Seventy three pts were enrolled onto the treatment arm and 71 pts were enrolled onto the observation arm. When the study initially opened, tipifarnib was given at a dose of 400 mg BID with dose reductions and interruptions as per protocol for toxicity. Based on the first interim analysis, toxicity data, the starting dose was decreased to 300 mg BID. Significant hematologic toxicity was seen in patients at both 300 and 400 mg. The majority of patients experienced >=grade 3 neutropenia or thrombocytopenia. There was 1 episode of febrile neutropenia. Non-hematologic toxicities were minimal. At the time of 110 events (90 relapses and 100 deaths), the final analysis of the study was conducted. The relapse rate was 60.3% on tipifarnib vs 64.8% for observation. Median DFS and 10 and 12 mo DFS and overall survival (OS) are documented in Table 1. Kaplan Meier curves for DFS and OS are presented. As the difference in median DFS is not considered significant (9.3 vs 5.8 mo, log rank p value 0.21), in July 2011, pts and physicians were informed of the lack of evidence of benefit so they could decide if they wished to continue drug. However an unplanned analysis of the data demonstrates a statistically significant improvement in OS at 10 months in pts who received tipifarnib. (70% vs 48%, p=0.05). While the benefit is subsequently lost, given a median survival measured in months, an increase in the number of pts alive and/or without disease at 10–12 mo is of value, particularly in the absence of noteworthy toxicity. Future studies are needed to better determine the role of maintenance therapy in pts with AML. Tipifarnib Observation Median DFS (months) 9.3 (95% CI:5.7, 13.3) 5.8 (95% CI: 3.7, 8.8) p=0.21 OS rate at 10 mo 70% (95% CI: 58%, 79%) 48% (95% CI: 36%, 60%) p=0.05 OS rate at 12 mo 59% (95% CI: 47%, 70%) 44% (95% CI: 32%, 55%) p=0.07 DFS rate at 10 mo 47% (95% CI: 36%, 59%) 32% (95% CI: 21%, 43%) p=0.07 DFS rate at 12 mo 39% (95% CI: 28%, 50%) 30% (95% CI: 20%, 41%) p=0.26 Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Abstract Abstract 1038 The relationships of inherent disease-related characteristics and of treatment to the nature of APL cell clones that emerge at disease relapse are poorly understood. We studied these relationships in 45 patients who relapsed after ATRA/chemotherapy treatment on the non-arsenic trixoxide arm of intergroup phase III trial C9710 (Powell, et al. Blood, Epub). Four variably-expressed APL cell clonal markers were assessed: PML-RARA ligand binding domain mutations (LBD-M), FLT3 internal tandem duplication mutations (ITD), FLT3 receptor tyrosine kinase mutations (D835; RTK-M) and additional chromosome abnormalities (ACA), i.e., in addition to the hallmark t(15;17). The methods for mutation analysis of PML-RARA and FLT3 have been reported and were RNA transcript-initiated supplemented by selected quantitative FLT3 mutation analyses initiated from DNA. Karyotype data were derived by standard cytogenetic methods. Four patients were excluded from analysis because the sample level of PML-RARA, as determined by quantitative RT-PCR, was insufficient to exclude possible false-negative mutation results. In 41 evaluable patients, the marker incidences were: LBD-M, 44%; ITD, 37%; RTK-M, 12%; ACA (22 tested), 59%. At presentation, the corresponding incidences were: LBD-M, 0% (by high-sensitivity testing a minor subclone of the relapse mutation was found in 2/7 patients tested); ITD, 43% (37 tested); RTK-M, 22% (37 tested); ACA, 24% (34 tested). The low frequency of RTK-M impeded further analysis. The other markers, using relapse determinations, were assessed for potential associations between the markers and with the following parameters: age, sex, presenting WBC count, PML-RARA type, time to relapse, relapse on or off ATRA treatment (on = taking or within 30 days of discontinuing) and post-relapse survival. The most essential positive findings are summarized below:Association of Marker with Parameter or Other MarkerCases with ParameterCases without Parameterp-valuePretreatment parameters: LBD-M with WBC count < 5,000/uL12/18 (67%)7/23 (30%)0.030 ITD with WBC count >10,000/uL10/15 (67%)5/26 (19%)0.006 ITD with S-form PML-RARA15/15 (100%)10/26 (38%)<0.0001Relapse parameters: ITD with lack of ACA1/7 (14%)12/15 (80%)0.007 LBD with relapse On-ATRA11/18 (61%)7/23 (30%)0.064 Off-ATRA only: LBD with lack of ITD0/7 (0%)9/16 (56%)0.019 The results confirm reports, which tested pretreatment samples, of a strong association between FLT3ITD mutations present at relapse and high WBC count and S-form PML-RARA. At relapse, there was, also, divergent selection of ITD-harboring vs ACA-harboring clones. LBD-M occurred more frequently in patients with low presenting WBC counts. They, also, occurred in patients who relapsed while on ATRA, consistent with an ATRA selective role for clones harboring LBD mutations. A significant segregation of patients with LBD-M or ITD was observed after relapse off ATRA treatment (p = 0.019), while no segregation was observed in overall relapse patients (p = 0.346) or after relapse on ATRA (p = 0.316). In 2 patients who relapsed on ATRA, quantitative analysis indicated that LBD-M and ITD mutations must be present in the same APL cell clone. There were no significant survival differences related to any clonal marker (post-relapse survival = 66%). Although the small number of cases is cautionary, the overall data suggest that LBD-M may have an overriding, dominant APL clone selection role in relapse that occurs on ATRA therapy. Other inherent clinicopathologic characteristics of APL may predispose to divergent molecular pathways of disease progression and relapse in patients alternatively harboring clones with LBD-M or ITD after the termination of ATRA selection pressure. Disclosures: No relevant conflicts of interest to declare.