Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients

Shai Shimony; Jacqueline S Garcia; Julia Keating; Evan C Chen; Marlise R Luskin; Maximilian Stahl; Donna S Neuberg; Daniel J DeAngelo; Richard M Stone; R Coleman Lindsley

doi:10.1038/s41375-024-02230-w

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients

Leukemia. 2024 Mar 27. doi: 10.1038/s41375-024-02230-w. Online ahead of print.

Authors

Affiliations

¹ Division of Hematologic Neoplasia, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Rabin Medical Center and Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
³ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Division of Hematologic Neoplasia, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. coleman_lindsley@dfci.harvard.edu.

PMID: 38538860
DOI: 10.1038/s41375-024-02230-w

Abstract

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.