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ACUTE MYELOID LEUKEMIA

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML

Leukemia volume 38, pages 762–768 (2024)Cite this article

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Abstract

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42–0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50–1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

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Fig. 1: Oncoprint and response rates per treatment.
Fig. 2: Kaplan–Meier overall survival per treatment.
Fig. 3: Multivariable Cox regression overall survival analysis.
Fig. 4: Treatment pairwise subgroup analysis for OS.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Author notes

  1. These authors contributed equally: Shai Shimony, Jan Philipp Bewersdorf, Rory M. Shallis.

  2. These authors jointly supervised this work: Brian Ball, Maximilian Stahl.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Shai Shimony, Eva J. Schaefer, R. Coleman Lindsley, Evan C. Chen, Daniel J. DeAngelo, Donna S. Neuberg, Richard M. Stone & Maximilian Stahl

  2. Rabin Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Shai Shimony

  3. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jan Philipp Bewersdorf, Aaron D. Goldberg & Eytan M. Stein

  4. Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA

    Rory M. Shallis & Amer M. Zeidan

  5. Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA

    Yiwen Liu

  6. Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Eva J. Schaefer

  7. Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA

    Guido Marcucci, Jorge Ramos Perez, Anthony Stein & Brian Ball

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Contributions

SS and MS conceived and designed the study. SS, JPB, RMS, ECC, BB, and MS extracted and drafted the first manuscript. SS, YL, and DSN analyzed the data. ES reviewed and harmonized all molecular data. AMZ, AG, ES, GM, RCL, JR, AS, DJD, DSN, and RMS revised the manuscript. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Shai Shimony or Maximilian Stahl.

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Competing interests

SS, JPB, YL, EJS, GM, JRP, and BB have no disclosure. RMS (Yale) reports consultancy for BMS, Curio Science, Gilead, Servier, Rigel. AMZ reports consultancy and Honoraria for Abbvie, Pfizer, Celgene/BMS, Jazz, Incite, Agios, Servier, Boehringer-Ingelheim, Novartis, Astellas, Daiichi Sankyo, Geron, Taiho, Seattle Genetics, Otsuka, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Zentalis, Schrodinger, Regeneron, Tyme. ADG reports Consultancy for Abbvie, Astellas, Daiichi Sankyo, Genentech; Research funding from Abbvie, Aprea, Aptose, Arog, Celularity, Pfizer, Prelude; Honoraria from Dava Oncology. EMS reports consultancy for Abbvie, Agios, Aptose, Astellas, Blueprint, BMS, Calithera, CTI, DSI, Foghorn Therapeutics, Genentech, Genesis, Gilead, Janssen, Jazz, Menarini, Neoleukin, Novartis, Oncusp, Ono Pharma, PinotBio, Servier, Syndax, Syros, Cellectis, Epizyme, Kura; Research funding from Eisai, BMS; Current equity holder publicly traded company – Auron therapeutics. ECC reports research funding from Abbvie; Consultancy and Honoraria for Rigel Pharmaceuticals. RCL reports consultancy for Takeda Pharmaceuticals, Bluebird bio, Qiagen, Sarepa Therapeutics, Verve Therapeutics, Jazz Pharmaceuticals, Vertex Pharmaceuticals; Membership on board of directors in Bluebird bio. AS reports Current Employment and Current holder of stock options at Sanofi. DJD reports consultancy for Amgen, Autolus, Blueprint, Gilead, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda; received research funding from Abbvie, Novartis, Blueprint and Glycomimetrics. DSN reports equity holder in Madrigal Pharmaceuticals. RMS reports consultancy for Abbvie, CTI Biopharma, GSK, Hermavant, Ligand Pharma, Lava Therapeutics, Amgen, AvenCell, BerGenBio, Cellularity, Jazz, Kura One, Rigel Pharmaecuticals. Serves on safety committee members in Aptevo, Epizyme, Takeda, and Syntrix. MS reports consultancy and serves as a member of the board of directors in Kymera, GSK, and Rigel Pharmaceuticals.

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Shimony, S., Bewersdorf, J.P., Shallis, R.M. et al. Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML. Leukemia 38, 762–768 (2024). https://doi.org/10.1038/s41375-024-02175-0

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