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Clinical Trial
. 2025 Apr;39(4):854-863.
doi: 10.1038/s41375-025-02531-8. Epub 2025 Feb 25.

Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia

Courtney D DiNardo  1 , Wei-Ying Jen  2 , Koichi Takahashi  2 , Tapan M Kadia  2 , Sanam Loghavi  3 , Naval G Daver  2 , Lianchun Xiao  4 , Patrick K Reville  2 , Ghayas C Issa  2 , Nicholas J Short  2 , Koji Sasaki  2 , Sa A Wang  3 , Jillian K Mullin  2 , Sherry Pierce  2 , Corey Bradley  2 , Gautam Borthakur  2 , Abhishek Maiti  2 , Yesid Alvarado  2 , Naveen Pemmaraju  2 , Alessandra Ferrajoli  2 , Mahesh Swaminathan  2 , Maro Ohanian  2 , Hussein A Abbas  2 , Danielle Hammond  2 , Jan Burger  2 , Fadi Haddad  2 , Guillermo Montalban-Bravo  2 , Kelly Chien  2 , Lucia Masarova  2 , Musa Yilmaz  2 , Nitin Jain  2 , Michael Andreeff  2 , Guillermo Garcia-Manero  2 , Steven Kornblau  2 , Farhad Ravandi  2 , Elias Jabbour  2 , Marina Y Konopleva  5 , Hagop M Kantarjian  2
Affiliations
Clinical Trial

Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia

Courtney D DiNardo et al. Leukemia. 2025 Apr.

Abstract

Intensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML.ClinicalTrials.gov Identifier: NCT03214562.

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Conflict of interest statement

Competing interests: CDD reports research Support from: Abbvie, Astex, BeiGene, BMS, Cleave, Foghorn, Jazz, Loxo, Servier and Personal fees from: Abbvie, Astellas, BMS, GSK, GenMab, Genentech, Gilead, Jazz, Loxo, Notable Labs, Servier, Schrodinger. NGD has received grants or contracts from Hanmi, Trovagene, Fate Therapeutics, Novimmune, and GlycoMimetics; consulting fees from Arog, Novartis, Jazz, Celgene, Syndax, Shattuck Labs, and Agios; and grants or contracts and consulting fees from Daiichi-Sankyo, Bristol-Meyers Squibb, Pfizer, Gilead Sciences, Inc., Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, and Trillium. GCI received consultancy or advisory role fees from Novartis, Kura Oncology, Syndax Pharmaceuticals, Abbvie and NuProbe and received research funding from Celgene, Novartis, Kura Oncology, Syndax Pharmaceuticals, Merck, Cullinan Oncology, Astex and NuProbe. NJS has received consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi; research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure; and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene. HA has received consulting fees from Molecular Partners; research funding from Genentech, GlaxoSmithKline, and EBD-300; and honoraria from Illumina. FR has served as a consultant for AbbVie, reports receiving research grants from Astellas Pharma Inc. and Celgene/BMS, and has received honoraria from Astellas Pharma Inc. and Celgene/BMS. EJ has received consulting fees and research funding from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, ASTX Pharmaceuticals, AstraZeneca, Autolus, BMS, Genenenctech, Hikma, Kite, Novartis, Pfizer, Takeda Oncology, and Jazz. MYK has received consulting fees from AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F Hoffman-La Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, and Vincerx; research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, and Stemline; honoraria from AbbVie, Baxk Therapeutics, Genentech, and Stemline Therapeutics; stock options in Reata Pharmaceuticals; and holds patents with Novartis, Eli Lilly, and Reata Pharmaceutical. HMK has received honoraria, consulting or advisory role fees from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda and research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis. TMK has received research funding from AbbVie, Amgen, Astex, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage Pharma, GenFleet Therapeutics, Astellas Pharma, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion Therapeutics, GlycoMimetics, Sellas, and Regeneron Pharmaceuticals; and has received personal fees from AbbVie, Agios, BMS, Genentech, Hikma, Jazz Pharmaceuticals, Novartis, Servier, Sellas, and PinotBio. Ethics approval: The University of Texas MD Anderson Cancer Center Institutional Review Board (2016–0979).

Figures

Figure 1:
Figure 1:. Treatment Schema
Treatment schedule for FLAG-IDA+VEN. Note that the idarubicin dose in induction differs for the ND (8mg/m2) and RR (6mg/m2) cohorts. Pegfilgrastim may be given in lieu of continued daily filgrastim after chemotherapy is completed. *Venetoclax is given for 7 days each cycle and requires dose adjustment if concomitant cytochrome P450 3A inhibitors are administered. #The protocol allows for two further cycles of idarubicin in consolidation and it is often given during cycles 3 and 5. However, it may be omitted in patients in deep remission with persistent cytopenias. Mcg: micrograms; mg: milligrams, m2: meter squared; kg: kilograms
Figure 2:
Figure 2:. Consort Diagram
Patient flow through the study is shown. ND: newly diagnosed; RR: relapsed / refractory; SCT: allogeneic stem cell transplant; NR: no response; LTFU: lost to follow-up; too early: patients planned for further cycles who had not yet started at data cut; maintenance: patients taken off protocol and transitioned to maintenance therapy.
Figure 3:
Figure 3:. OS and EFS in the ND Cohort
(A) OS and EFS in the entire ND AML cohort; (B) OS stratified by ELN 2022 risk groups; (C) OS stratified by TP53 mutation status; (D) OS stratified by presence of MECOM rearrangements; (E) OS stratified by presence of KMT2A rearrangements; (F) Landmark analysis of OS in ELN 2022 intermediate and adverse risk patients. OS: overall survival; EFS: event-free survival; ND: newly diagnosed; ELN: European LeukemiaNet.
Figure 4:
Figure 4:. Patterns of Relapse in ND Patients
Mutations detected via NGS and karyotypic abnormalities at first relapse in the ND cohort. Relapses are most often characterized by TP53 or RAS pathway mutations or acquired adverse cytogenetic abnormalities. NGS: next-generation sequencing; ND: newly diagnosed; ELN: European LeukemiaNet.
Figure 5:
Figure 5:. OS and EFS in the RR Cohort
(A) OS and EFS of the entire RR cohort; (B) OS stratified by salvage number and TP53 mutation status; (C) OS stratified by TP53 mutation status; (D) OS stratified by presence of MECOM rearrangements; (E) OS stratified by presence of KMT2A rearrangements; (F) Landmark analysis of OS in the RR cohort. OS: overall survival; EFS: event-free survival; RR: relapsed or refractory; S1 & TP53WT: patients in first salvage with wild-type TP53; S2+ or TP53mut: patients in second salvage or later, or who had mutated TP53.
See this image and copyright information in PMC

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