Highlights

Single-cell RNA sequencing of bone marrow from TP53-mutated AML patients showed a decrease in cells expressing anti-apoptotic genes like BCL2 and MCL1 after venetoclax and azacitidine treatment.

Immune cells increased both in number and in gene expression levels associated with cytotoxicity post venetoclax combination therapy, verifying immune recovery.

Residual AML cells expressed CD47 and CLL1, suggesting a role for ancillary treatment targeting antigens expressed on residual TP53-mutated AML cells.

HighlightsThe BCL-2 inhibitor venetoclax combined with the hypomethylating agent azacitidine or with low-dose cytarabine significantly improves response rates and overall survival (OS) for newly diagnosed unfit and relapsed / refractory (R/R) acute myeloid leukemia (AML) patients. We retrospectively analyzed our experience with venetoclax combination therapy in 41 unfit AML patients (23 untreated, 18 R/R). Overall response rates were 78.3% for untreated patients and 61.1% for R/R patients. TP53 alterations were observed in 13 patients (31.7%) and were identified as an independent predictor of poor outcome (p=0.0008). We further conducted single-cell RNA sequencing in bone marrow, sampled before and after venetoclax and azacitidine treatment, of three TP53-mutated AML patients who achieved complete remission (CR) or CR with incomplete hematologic recovery. After treatment, numbers of cells expressing anti-apoptotic genes such as BCL2 and MCL1 decreased. CD4 T cells, cytotoxic CD8 T cells, and NK cells significantly increased both in number and in levels of gene expression associated with cytotoxicity post-treatment, confirming immune recovery in the tumor microenvironment. Residual AML cells expressed CD47 and CLEC12A (CLL1). These results indicate that venetoclax combination therapy of AML is promising in real-world clinical practice and suggest a role for ancillary treatment targeting antigens expressed on residual AML cells as a therapeutic strategy in TP53-mutated AML.

J.A. received research grant and honoraria from AbbVie. Y.E. received research funding from AbbVie. T.T. received research funding from Bristol Myers Squibb and Sysmex. M.A. received research funding from Century Therapeutics and Daiichi-Sankyo and received research grants from Sumitomo Pharma, Chugai Pharmaceutical, Kyowa Kirin, AbbVie, Shionogi, Eisai, and Daiichi Sankyo.

J.A. received research grant and honoraria from AbbVie. Y.E. received research funding from AbbVie. T.T. received research funding from Bristol Myers Squibb and Sysmex. M.A. received research funding from Century Therapeutics and Daiichi-Sankyo and received research grants from Sumitomo Pharma, Chugai Pharmaceutical, Kyowa Kirin, AbbVie, Shionogi, Eisai, and Daiichi Sankyo.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Research Ethics Committee, Faculty of Medicine, Juntendo University School of Medicine approved Genetic Mutation Analysis of Hematological Diseases for this study on 1 October 2012 (approval number: M12-0866) and Retrospective Study on Venetoclax Combination Therapy for Acute Myeloid Leukemia, for this project on 21 April 2022 (approval number: E22-0051). This study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.

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Yes

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All data produced in the present study are available upon reasonable request to the authors.