Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial
Authors: Maiti Abhishek , DiNardo Courtney D. , Ravandi Farhad , Pemmaraju Naveen , Borthakur Gautam , Bose Prithviraj , Issa Ghayas C. , Kadia Tapan M. , Short Nicholas J. , Yilmaz Musa , Montalban-Bravo Guillermo , Ferrajoli Alessandra , Jabbour Elias , Jain Nitin , Ohanian Maro , Takahashi Koichi , Thompson Philip A. , Rausch Caitlin R. , Montalbano Kathryn S , Pierce Sherry A. , Kantarjian Hagop M. , Daver Naval , Konopleva Marina 
Published: November 2020

Background: FLT3 mut confers higher risk of relapse and inferior overall survival (OS) in acute myeloid leukemia (AML). FLT3 inhibitors (FLT3i) show synergism with venetoclax (VEN), and hypomethylating agents (HMA); and clinical studies have shown promising results with HMA+FLT3i, and VEN+FLT3i in FLT3mut AML. We report the results of the first combination of VEN+FLT3i+HMA from a prospective phase 2 study.
Methods: We conducted a subgroup analysis of FLT3mut AML pts treated with 10-day decitabine and VEN (DEC10-VEN) on a phase 2 trial. Addition of FLT3i of clinician's choice was allowed. We enrolled newly diagnosed (ND) AML pts &gt;60 yrs and relapsed/refractory (R/R) pts &gt;18 yrs. Pts received DEC 20 mg/m2 for 10 days every 4-6 wks for induction followed by DEC for 5 days after CR/CRi. VEN dose was 400 mg daily or equivalent. Reduction of VEN duration was allowed in cases of myelosuppression. All pts received tumor lysis and antimicrobial prophylaxis during neutropenia. Full protocol of the study has been published previously (DiNardo et al. Lancet Haematol. 2020. In press). CRc (CR + CRp + CRi) responses were graded by the International Working Group for AML criteria (with adapted CRi criteria as presented in ADMIRAL study. NEJM 2019).
Results: Between March 2018 and March 2020 we enrolled 30 pts with FLT3mut AML. Among 14 pts with previously treated AML, 13 had R/R AML and 1 had sAML with prior HMA treatment for CMML (Table 1). Among 16 pts with treatment-naïve AML, 15 had ND AML and 1 had sAML with untreated prior MDS. All 14 pts with previously treated AML received FLT3i with DEC10-VEN including sorafenib (SORA, 6), gilteritinib (GILT, 4) and midostaurin (MIDO, 4). Among 16 pts with treatment-naïve AML 11 received a FLT3i including GILT (5), SORA (5) and MIDO (2). 5 pts did not receive a FLT3i due to low ITD ratio (1), insurance non-approval (n=1) and TKD only (3). Median dose and duration of FLT3i during cycle 1 for SORA was 400 mg BID (interquartile range [IQR] 400-400) for 15 days (IQR 14-28), for MIDO was 50 mg BID (IQR 50-50) for 15 days (IQR 14-21) and for GILT was 120 mg daily (IQR 120-120) for 14 days (IQR 14-28). For subsequent cycles, the median dose and duration of SORA was 400 mg BID for 14 days (IQR 14-28), for MIDO was 50 mg BID for 28 days (IQR 28-continuous) and for GILT was 120 mg daily for 14 days (IQR 14-14).
60-day mortality was 7% (n=1) for previously treated pts and 0% in treatment-naïve pts. There were 43 grade 3/4 adverse events, at least possibly related, including infections (with grade 3/4 neutropenia) in 40% pts, febrile neutropenia in 30% and infection (with ANC ≥1.0x109/L) in 27%. Number of treatment-naïve pts with grade 3/4 infections was comparable in those receiving DEC10-VEN vs. FLT3i+DEC10-VEN (2/5 vs 8/11, P=0.2). In treatment-naïve AML, the median time to ANC recovery was 45 days after cycle 1, and 38 days during subsequent cycles, and median time to platelet recovery was 30 days for cycle 1. In previously treated AML the CRc rate was 64% (9/14) and minimal residual disease (MRD) negativity rate by flow cytometry (FCM) was 71% and by PCR/NGS was 88%. Among R/R pts previously exposed to a FLT3i (n=8) the CRc rate was 63%, with FLT3 PCR negativity in 80% (4/5). In treatment-naïve AML the CRc rate was 88% (14/16), MRD negativity by FCM was 82%, by PCR/NGS was 100% (Table 2); and CRc rate in pts not receiving FLT3i was 80% (4/5). After a median follow-up 14.5 months (mo) the median OS and duration of response (DOR) in previously treated pts are 6.1 mo and not reached (NR), respectively; and in treatment-naïve pts are NR and 22.1 mo, respectively, with 2 yr OS of 90% (Fig. 1). 5 previously treated pts underwent stem-cell transplantation (SCT) and 1 pt received DEC + SORA maintenance afterwards with 2-yr OS of 53% in these 5 pts. 4 treatment-naïve pts underwent SCT and 2 pts received FLT3i maintenance post-SCT (SORA [1], crenolanib [1]). Causes of death (COD) in previously treated pts were pneumonia (2), intracranial hemorrhage (1) and hospice (1) in non-responding pts, and unknown reason (5) and pneumonia post-SCT (1) in responding pts. COD in treatment-naïve pts was pneumonia in CR (1) and refractory disease (1). In 10 pts who were refractory to or relapsed after 'triplet' therapy, the most frequent mutations at screening were DNMT3A (4), IDH1/2 (4), and N/KRAS (3).
Conclusion: In our experience, DEC10-VEN + FLT3i is safe and effective for previously treated FLT3mut AML, and an excellent frontline option for older pts with treatment-naïve AML.

Disclosures
Maiti: Celgene: Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Novartis: Consultancy; Syros: Honoraria; Calithera: Research Funding; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Pemmaraju:Novartis: Honoraria, Research Funding; Cellectis: Research Funding; DAVA Oncology: Honoraria; Plexxikon: Research Funding; Roche Diagnostics: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines: Honoraria; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria. Borthakur:Argenx: Consultancy; Novartis: Research Funding; GSK: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; BioLine Rx: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Incyte: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy; FTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; Treadwell Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; PTC Therapeutics: Research Funding. Bose:Pfizer, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Ascentage: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Yilmaz:Pint Pharma: Honoraria; Daicho Sankyo: Research Funding; Pfizer: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Jain:BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thompson:Genentech: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen-Cilag: Honoraria; Pharmacyclics: Research Funding; AbbVie: Research Funding. Kantarjian:BMS: Research Funding; Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Trovagene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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; KITE: 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; Amgen: 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; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: 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. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Research Funding; Calithera: Research Funding; 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; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Amgen: Consultancy.