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Multicenter Study
. 2024 Sep 24;8(18):4845-4855.
doi: 10.1182/bloodadvances.2024012858.

Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML

Jan Philipp Bewersdorf  1 , Shai Shimony  2 , Rory M Shallis  3 , Yiwen Liu  4 , Guillaume Berton  5 , Eva J Schaefer  2   6 , Amer M Zeidan  3 , Aaron D Goldberg  1 , Eytan M Stein  1 , Guido Marcucci  7 , Rebecca P Bystrom  2 , R Coleman Lindsley  2 , Evan C Chen  2 , Jorge Ramos Perez  7 , Anthony Stein  7 , Vinod Pullarkat  7 , Ibrahim Aldoss  7 , Daniel J DeAngelo  2 , Donna S Neuberg  4 , Richard M Stone  2 , Sylvain Garciaz  5 , Brian Ball  7 , Maximilian Stahl  2
Affiliations
Multicenter Study

Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML

Jan Philipp Bewersdorf et al. Blood Adv. .

Abstract

Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).

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Conflict of interest statement

Conflict-of-interest disclosure: R.M. Shallis provided consultancy for Bristol Myers Squibb (BMS), Curio Science, Gilead Sciences, Servier, and Rigel. A.M.Z. received research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, MedImmune/AstraZeneca, Boehringer Ingelheim, Cardiff Oncology, Incyte, Takeda Pharmaceuticals, Novartis, Aprea Therapeutics, and ADC Therapeutics; participated in advisory boards, provided consultancy for, and received honoraria from AbbVie, Otsuka Pharmaceutical, Pfizer, Celgene/BMS, Jazz Pharmaceuticals, Incyte, Agios Pharmaceuticals, Boehringer Ingelheim, Novartis, Acceleron Pharma, Astellas Pharma, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda Pharmaceuticals, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable Labs, Orum, and Tyme; and served on clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, AbbVie, ALX Oncology, Geron, and Celgene/BMS. A.D.G. participated in advisory boards and provided consultancy for AbbVie, Astellas Pharma, Daiichi Sankyo, Genentech, BMS, and Molecular Partners; received honoraria from DAVA Oncology; received research funding from AbbVie, Aprea, Aptose Biosciences, AROG Pharmaceuticals, Celularity, Kura, Pfizer, and Prelude; and served on safety monitoring committees for AbbVie and Kura. E.M.S. received research funding from Bayer, Syndax, Daiichi Sankyo, Celgene Pharmaceuticals, and Novartis; served as a consultant for Amgen, AbbVie, Seattle Genetics, Biotheryx, Syndax, Astellas Pharmaceutical, Agios Pharmaceuticals, Genentech, Daiichi Sankyo, Celgene Pharmaceuticals, and Novartis; was a member of the board of directors or advisory committee for PTC Therapeutics, Syros, Astellas Pharmaceutical, Agios Pharmaceuticals, Genentech, Daiichi Sankyo, Celgene Pharmaceuticals, and Novartis; and is a current equity holder in privately held Auron Therapeutics. R.C.L. provided consultancy for Takeda Pharmaceuticals, bluebird bio, Qiagen, Sarepta Therapeutics, Verve Therapeutics, Jazz Pharmaceuticals, and Vertex Pharmaceuticals. E.C.C. received research funding from AbbVie and provided consultancy for Rigel Pharmaceuticals. A.S. declares stock ownership in Sanofi. D.J.D. received honoraria from Amgen, Autolus, Blueprint, Gilead, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda Pharmaceuticals, and research funding from AbbVie, Novartis, Bluprint, and Glycomimetics. D.S.N. declares equity ownership in Madrigal Pharmaceuticals. R.M. Stone provided consultancy for AbbVie, CTI Biopharma, GlaxoSmithKline, Hermavant, Ligand Pharma, Lava Therapeutics, Amgen, AvenCell, BerGenBio, Celularity, Jazz Pharmaceuticals, Kura One, and Rigel, and participated in drug and safety monitoring boards for Aptevo, Epizyme, Takeda Pharmaceuticals, and Syntrix. S.G. declares a consulting or advisory role with AbbVie, Astellas, BMS/Celgene, Jazz Pharmaceuticals, and Servier, and received travel grants from Gilead. B.B. served on advisory boards for BMS, Rigel, and Oncovalent Therapeutics. M.S. served on advisory boards for Novartis, Kymera, Sierra Oncology, GlaxoSmithKline, Rigel, BMS, and Taiho; consulted for Boston Consulting and Dedham Group; and participated in CME activities for Novartis, Curis Oncology, Haymarket Media, and Clinical Care Options. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Molecular and cytogenetic profile and response for patients with NPM1-mutant AML treated with intensive chemotherapy and HMA/VEN. An oncoprint shows the molecular and cytogenetic profile and response for patients with NPM1-mutant AML treated with intensive induction chemotherapy and HMA/VEN. Only mutations present in at least 2% of the patient cohort and evaluated in at least 66% of patients were included.
Figure 2.
Figure 2.
OS by treatment type, patient age, and transplant status. (A) OS from the time of treatment initiation for the entire cohort of patients with newly diagnosed NPM1-mutant AML aged ≥60 years by treatment type (intensive induction chemotherapy [IC; red] vs HMA/VEN [blue]). Because there were statistically significant differences in treatment assignment by age, we performed a (B) subgroup analysis restricted to patients aged 60 to 75 years . (C) OS for patients who underwent an allo-SCT by type of initial AML treatment.
Figure 3.
Figure 3.
Comparison of OS by treatment assignment in patients with abnormal cytogenetics and with and without concurrent FLT3-ITD mutations. (A) OS from the time of treatment initiation in patients with AML aged ≥60 years with normal and abnormal cytogenetics by treatment type (IC vs HMA/VEN). (B) OS from the time of treatment initiation in patients with AML aged ≥60 years with and without concurrent FLT3-ITD mutations. Cyto, cytogenetics; MUT, mutant; WT, wild-type.
Figure 4.
Figure 4.
Multivariable regression model of OS. Forest plot shows HRs for death with associated 95% CIs of variables included in the final multivariable regression model. The type of frontline treatment (IC vs HMA/VEN) was not statistically significantly associated with OS in this model.
Figure 5.
Figure 5.
Subgroup analysis of OS for HMA/VEN vs intensive chemotherapy. Forest plot shows a comparison of OS for patients treated with HMA/VEN vs intensive induction chemotherapy (IC) by molecular subgroups. Cox proportional hazards models were adjusted for treatment (IC vs HMA/VEN) and age category (60-75 years and >75 years), except for the subgroups defined by age category, which are based on unadjusted Cox proportional hazards models.
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