Histone deacetylase inhibitors as venetoclax-sensitising partners in acute myeloid leukaemia: Mechanisms, pharmacology and translational perspectives.

Authors

Jaebok Lee, Marc Diederich

Published in

British journal of pharmacology. Aug 16, 2026. Epub Aug 16, 2026.

Abstract

Venetoclax combined with hypomethylating agents has improved treatment for older or unfit patients with acute myeloid leukaemia (AML), but resistance and relapse remain common. This review analyses the rationale for combining venetoclax with inhibitors of histone deacetylase (HDAC). Class I histone deacetylase 1/2/3-dependent suppression of myeloid cell leukaemia 1 and de-repression of pro-apoptotic BCL-2 homology domain 3 (BH3)-only genes provide the strongest mechanistic basis, whereas HDAC6/heat shock protein 90, autophagy, immune-modulatory and super-enhancer mechanisms remain context-dependent and incompletely validated in primary AML under venetoclax exposure. Effects of HDAC inhibition must also be interpreted in the context of tumour protein 53 status. Early HDAC inhibitor-containing composite regimens, particularly chidamide-based CACAG-VEN (chidamide, venetoclax, azacitidine, low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor), report high response rates, including overall response rate of 76.5-98.0%, complete remission/complete remission with incomplete count recovery or composite complete remission of 73.5-93.3%, and measurable residual disease negativity of 44-61%. This six-component regimen does not isolate the contribution of HDAC inhibition. Future development should prioritise biomarker-selected trials that hold non-HDAC components constant, incorporate pharmacodynamic HDAC engagement and BH3 profiling, and account for cytochrome P450 3A-mediated drug interactions. HDAC inhibitor-venetoclax combinations are mechanistically rational, but standard-of-care positioning requires randomised or pharmacodynamic validation.

PMID:
42604808
Bibliographic data and abstract were imported from PubMed on 17 Aug 2026.

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