Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia
Authors: Lachowiez Curtis , DiNardo Courtney D. , Takahashi Koichi , Loghavi Sanam , Xiao Lian-Chun , Kadia Tapan M. , Daver Naval , Adeoti Maria , Short Nicholas J. , Sasaki Koji , Wang Sa A , Borthakur Gautam , Issa Ghayas C. , Maiti Abhishek , Alvarado Yesid , Pemmaraju Naveen , Montalban-Bravo Guillermo , Masarova Lucia , Yilmaz Musa , Jain Nitin , Andreeff Michael , Garcia-Manero Guillermo , Kornblau Steven M. , Ravandi Farhad , Jabbour Elias J. , Konopleva Marina , Kantarjian Hagop 
Published: November 2021

Abstract

Background: Multiagent induction chemotherapy consisting of fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA) results in complete remission in ~ 85% of newly diagnosed patients with acute myeloid leukemia (ND-AML), yet 30-40% experience relapse. Combining the BCL-2 inhibitor venetoclax (VEN) with chemotherapy results in synergistic leukemic cell death, inferring FLAG-IDA+VEN may improve outcomes in ND-AML.
Design: A phase 1b/2 study evaluating FLAG-IDA+VEN (Fig. 1A) in ND and relapsed/refractory (R/R) AML patients 18 years of age. Phase 1b results were previously reported (DiNardo, JCO 2021). The Phase 2 (P2) portion enrolled patients into two cohorts: ND and R/R-AML. ND-AML outcomes are reported herein.
Objectives: The primary P2 objective is determination of overall activity of FLAG-IDA+VEN including overall response rate (ORR: CR+CRi+CRh+MLFS+PR). Secondary objectives include determination of overall survival (OS), event-free survival (EFS), duration of response (DOR), and biomarkers predictive of VEN sensitivity.
Results: Forty-one patients with ND-AML (de novo AML: n=29, secondary AML [sAML]: n=7, therapy-related AML [tAML]: n=5) enrolled. Median age was 44 years (range 20-65). ELN risk was favorable, intermediate, and adverse in 20%, 37%, and 44% of patients. Common mutations included NRAS (29%; n=12), IDH2 (17%; n=7), RUNX1 (15%, n=6), and NPM1 (15%, n=6). TP53 mutations and KMT2A-rearrangements were identified in 10% (n=4) and 12% (n=5) of patients at diagnosis, respectively.
The median number of treatment cycles received was 2 (range 1-6). The ORR was 98% (CR: n=30 [73%], CRh: n=5 [12%], CRi: n=1 [2%], MLFS: n=4 [10%]) and CRc (CR+CRh+CRi) rate was 88% (n=36). 92% of CRc patients attained MRD-negative status by flow cytometry. Median time to best response was 29 days (range 22-94). Sixty-six percent (n=27) of patients transitioned to allogeneic transplantation (HSCT) after a median of 3.8 (range 3.2-4.9) months. Median DOR was NR (95% CI: 17-NR). Median cycle length for cycles 1 and 2 were 31 and 41 days. Median time to count recovery (ANC 500 cells/mm 3 and platelet count 50,000 cells/mm 3) was longer following cycle 2 compared to cycle 1 (47 vs. 32 days, p-value &lt; 0.001). Common adverse events included febrile neutropenia (39%; n=16), pneumonia (24%; n=10), and bacteremia (19%; n=8). No 30 or 60-day mortality occurred. Nine patients relapsed (ELN intermediate: N=3, adverse: N=6) including 100% of patients with baseline TP53 mutations (N= 4), and the one patient with inv(3). TP53 mutations were identifiable in 67% (n=6) of patients at relapse, including two patients without TP53 mutations at diagnosis. Four deaths have occurred, all in the setting of relapsed disease.
With median follow up of 16 months, median OS and EFS are both NR, with 1-year OS and EFS rates of 96% and 77%, respectively (Fig. 1B). Patients with KMT2A rearrangements (n=5) and NPM1, IDH1, and/or IDH2 mutations (n=13) have experienced an 18-month survival rate of 100%. Patients with TP53 mutations at diagnosis have significantly inferior OS (24 months vs. NR, p-value: 0.03) and EFS (median EFS 8 months vs. NR, p-value &lt;0.001) compared to patients with wild-type TP53.
A propensity score matched analysis compared to a historical cohort of patients receiving frontline FIA (fludarabine, idarubicin, cytarabine) induction (N=74) at our institution indicated FLAG-IDA+VEN was associated with improved median OS (NR vs. 47 months, p-value: 0.022), and a trend towards improved OS and EFS in patients not undergoing HSCT (FLAG-IDA+VEN vs. FAI median OS: 24 vs. 19 months, p-value: 0.09; median EFS: NR vs. 8 months, p-value: 0.064). On multivariate analysis, increased age and ELN risk group correlated with increased risk of death (age [HR 1.05, 95% CI: 1.02-1.09, p-value: 0.001]; ELN risk group [HR 1.92; 95% CI: 1.185-3.11, p-value: 0.008]), while decreased risk was observed based on treatment with FLAG-IDA+VEN vs. FIA (HR 0.28, 95% CI: 0.096-0.84, p-value: 0.02).
Conclusions: FLAG-IDA+VEN induction and consolidation results in high MRD-negative CRc rates in ND-AML with an expected safety profile. Durable responses were observed at 12-months, with favorable outcomes compared to historical cohorts of intensive therapy. Patients with TP53 mutations treated with FLAG-IDA+VEN experience inferior outcomes compared to patients with wild-type TP53. Prospective randomized trials are warranted to confirm these results.
Figure 1 Figure 1.

Disclosures
DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Kadia: Amgen: Other: Grant/research support; Liberum: Consultancy; Jazz: Consultancy; Ascentage: Other; Novartis: Consultancy; Cellonkos: Other; Sanofi-Aventis: Consultancy; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; Pulmotech: Other; Genfleet: Other; Astellas: Other. Daver: ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Wang: Stemline Therapeutics: Honoraria. Borthakur: Astex: Research Funding; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Alvarado: Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding. Pemmaraju: Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; MustangBio: Consultancy, Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Jain: Genentech: Honoraria, Research Funding; Servier: Honoraria, Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Beigene: Honoraria; Fate Therapeutics: Research Funding; Incyte: Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Andreeff: Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Senti-Bio: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; ONO Pharmaceuticals: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Glycomimetics: Consultancy; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Breast Cancer Research Foundation: Research Funding. Ravandi: Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Agios: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; KisoJi: Research Funding. Kantarjian: Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

OffLabel Disclosure:
Will describe use of venetoclax in combination with FLAG-IDA induction and consolidation therapy in AML.