Röllig, Christoph

Background: Core binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) and is associated with a favorable outcome, particularly if treated with repetitive cycles of high-dose cytarabine as post-remission therapy. Long-time 10-year overall survival (OS) rate was reported of 58% in FLT3-ITD negative patients (pts; Allen et al. Leukemia 2013). Nevertheless, 30-40% CBF-AML pts experience relapse. FLT3-ITD mutations occur in roughly 5-10% of adult CBF-AML. However, their prognostic relevance is still controversial. Aims: To characterize CBF-AML with FLT3-ITD and compare outcomes according to their genetic background. Methods: We retrospectively studied 65 AML pts with CBF-AML and FLT3-ITD (median age at diagnosis, 54 years; range, 22-81 years) diagnosed between 1996 and 2018 within seven study groups/institutions of the US and Europe. Results: Thirty-two (49%) of the 65 pts harbored t(8;21). Median white blood cell and platelet counts at diagnosis of patients with t(8;21) and inv(16) were 18.3/nl (range, 1.8-202/nl) and 31/nl (range, 7-372/nl), respectively. AML diagnoses were de novo in 61 (94%) and therapy-related in 4 (6%) of the pts. Thirty (46%) pts were female. Cytogenetic analysis revealed additional abnormalities (abn) in 38 (58%) pts, most frequently loss of X or Y (n=13; n=12 associated with t(8;21)), complex karyotype (≥3 abn; n=12; n=7 occurring in t(8;21)), trisomy 22 (n=7, all associated with inv(16)) or trisomy 8 (overall n=6, n=5 occurring in inv(16)). Four pts were positive for both mutations, FLT3-ITD as well as FLT3-TKD. Median ITD allelic ratio were 0.44 (range, 0.003-50) and median ITD size 60 bp (range, 3-120 bp). Three older pts (median age, 75.5 years) were treated with either azacitidine + sorafenib, azacitidine + venetoclax or with etoposide + tipifarnib. All three patients receiving non-intensive therapy died within one year and were excluded from further analysis. Complete remission (CR) after anthracycline-based induction therapy was achieved in 98% (n=61/62) of patients fit for intensive treatment including two pts treated with 7+3 ± midostaurin within the RATIFY trial. One patient died during induction. Fifteen (24%) pts underwent allogeneic hematopoietic cell transplantation. Of those, 10 pts were transplanted in 1st and 5 pts in 2nd CR. Median follow-up for the entire cohort was 4.43 years (95%-CI, 3.35-8.97 years). Median and 4-year relapse-free survival (RFS) rates were 3.41 years (95%-CI, 1.26 years - not reached) and 44.9% (95%-CI, 32.9-61.4%). Median and 4-year overall survival rates (OS) were 4.48 years (95%-CI, 2.26 years - not reached) and 51.8% (95%-CI, 39.6.2-67.9%). Neither type of CBF-AML (p=0.60), nor additional chromosomal abn (p=0.80), nor presence of a complex karyotype (p=0.50) had a prognostic impact on OS. Higher age (≥60 years) was an in trend negative prognostic factor on RFS and OS (p=0.07, each). High allelic ratio (≥0.5) had no impact on RFS (p=0.3), but in trend on OS (p=0.10). Conclusions: Despite a high remission rate pts with FLT3-ITD had an inferior outcome as compared to previously published data on CBF-AML without FLT3-ITD. Thus, CBF-AML with FLT3-ITD should not be classified within the low-risk category. CBF pts with FLT3-ITD warrants further study and should be included in FLT3-inhibitor trials. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Novak:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Thiede:Daiichi Sankyo: Honoraria; AgenDix GmbH: Employment, Equity Ownership; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Levis:Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

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.