Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2023 Jan;64(1):188-196.
doi: 10.1080/10428194.2022.2136952. Epub 2022 Oct 26.

Venetoclax-based salvage therapy in patients with relapsed/refractory acute myeloid leukemia previously treated with FLT3 or IDH1/2 inhibitors

Jan Philipp Bewersdorf  1 , Rory M Shallis  2 , Andriy Derkach  3 , Aaron D Goldberg  1 , Anthony Stein  4 , Eytan M Stein  1 , Guido Marcucci  4 , Amer M Zeidan  2 , Shai Shimony  5 , Daniel J DeAngelo  5 , Richard M Stone  5 , Ibrahim Aldoss  4 , Brian J Ball  4 , Maximilian Stahl  5
Affiliations
Multicenter Study

Venetoclax-based salvage therapy in patients with relapsed/refractory acute myeloid leukemia previously treated with FLT3 or IDH1/2 inhibitors

Jan Philipp Bewersdorf et al. Leuk Lymphoma. 2023 Jan.

Abstract

FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors.

Keywords: AML; Acute myeloid leukemia; outcomes; targeted agents; venetoclax.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest disclosure: R.M.S. participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc; divested equity interest in Curis Oncology. A.D.G. received research funding from Celularity, ADC Therapeutics, Aprea, AROG, Pfizer, Prelude, and Trillium; received research funding from and served as a consultant for Aptose and Daiichi Sankyo; served as a consultant and member of advisory committees for Astellas, Celgene, and Genentech; received research funding from, served as a consultant for, and was a member of advisory committees for AbbVie; and received honoraria from Dava Oncology. A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, and Tyme. A.M.Z. served on clinical trial committees for Novartis, Abbvie, Geron and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. E.M.S. received research funding from Bayer; was a consultant for Amgen, AbbVie, Seattle Genetics, and Biotheryx; served as a consultant and received research funding from Syndax; was a member of the Board of Directors or advisory committee for PTC Therapeutics and Syros; served as a consultant and was member of the Board of Directors or advisory committee for Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech; served as a consultant, received research funding, and was a member of the Board of Directors or advisory committee for Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis; and is a current equity holder in privately held Auron Therapeutics. G.M. received research funding from Merck, served on the scientific board for BMS, and Abbvie, and participated as a speaker for Abbvie. A.S. served on the speakers bureau for Amgen. D.J.D. had a consultancy with Abbvie Amgen, Autolus, Blueprint, Forty-Seven, Glycomimetrics, Inctye, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. D.J.D. received grant/research funding Abbvie, Novartis, Blueprint, Glycomimetrics. R.M.S. received personal fees from Abbvie, Actinium, Agios, Astellas, Biolinerx, Celgene, Daiichi-Sankyo, Elevate, Gemoab, Janssen, Jazz, Macrogenics, Novartis, OncoNova, Syndax, Syntrix, Syros, Takeda, Trovagene, BerGenBio, Foghorn Therapeutics, GlaxoSmith Kline, Aprea, Innate, Amgen, BMS, Boston Pharmaceuticals, Kura Oncology, and Epizyme. R.M.S. received grant funding from Abbvie, Agios, Arog, and Novartis. IA serves on advisory boards for Amgen, Kite pharmaceuticals, AbbVie, JAZZ and Agios Pharmaceuticals, and is a consultant for Pfizer, Autolus Therapeutics and Amgen, and received research support by MacroGenics and Abbvie. B.J.B. served on the advisory board for Oncovalent. MS is a member of the advisory board for Novartis and is consulting for Curis Oncology, Haymarket Media and Boston Consulting.

Figures

Figure 1:
Figure 1:. Response assessment and OS outcomes
Figure 1 shows the response rates (%) among patients who received venetoclax-based therapy after disease progression on FLT3 inhibitors (A) and IDH1/2 inhibitors (B), respectively. OS for patients previously treated with FLT3 inhibitors (panel C) or IDH1/2 inhibitors (panel D). CR – complete remission; CRi – complete remission with incomplete hematologic recovery; MLFS – morphologic leukemia-free state; OS – overall survival; PD – persistent disease.
Figure 2:
Figure 2:. Oncoprint of molecular predictors of response
Figure 2 shows molecular patterns of response to venetoclax-based combinations on an individual patient basis. Molecular testing was performed at the time of venetoclax initiation. Molecular testing was performed either as panel testing at the participating sites or targeted testing for genes of interest.
See this image and copyright information in PMC

References

    1. DeWolf S, Tallman MS. How I treat relapsed or refractory AML. Blood. 2020;136(9):1023–32. - PMC - PubMed
    1. Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):41. - PMC - PubMed
    1. Kantarjian H, Short NJ, DiNardo C, Stein EM, Daver N, Perl AE, et al. Harnessing the benefits of available targeted therapies in acute myeloid leukaemia. Lancet Haematol. 2021;8(12):e922–e33. - PMC - PubMed
    1. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31. - PMC - PubMed
    1. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386–98. - PubMed

Publication types

MeSH terms