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Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax

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Abstract

Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4 months and the median overall survival (OS) was 6.6 months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.

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Acknowledgments

We would like to acknowledge the service provided by the DNA Sequencing Core of the First Core Laboratory, National Taiwan University College of Medicine.

Funding

This study was funded by MOST 104-2314-B-002-128-MY4 and 106-2314-B-002-226-MY3 from the Ministry of Science and Technology (Taiwan) and MOHW 107-TDU-B-211-114009 from the Ministry of Health and Welfare (Taiwan).

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  1. Hsin-An Hou and Hwei-Fang Tien contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan

    Yu-Wen Wang, Yu-Wen Chen & Hsing-Yu Lin

  2. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Cheng-Hong Tsai, Chien-Chin Lin, Feng-Ming Tien, Ming Yao, Yun-Chu Lin, Chien-Ting Lin, Chieh-Lung Cheng, Wen-Chien Chou, Hsin-An Hou & Hwei-Fang Tien

  3. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Chien-Chin Lin & Wen-Chien Chou

  4. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chien-Chin Lin & Feng-Ming Tien

  5. National Taiwan University Cancer Center, National Taiwan University, Taipei, Taiwan

    Feng-Ming Tien, Yun-Chu Lin, Chieh-Lung Cheng & Jih-Luh Tang

  6. Tai-Cheng Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan

    Chien-Ting Lin & Jih-Luh Tang

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Contributions

Y.-W.W. was responsible for data management and interpretation, statistical analysis, and manuscript writing; C.-H.T. and F.-M.T. were responsible for mutation analysis and interpretation; C.-C.L., Y.-W.C., H-Y.L., M.Y., Y.-C.L., C.-T.C., T.-C.L., J.-L.T., and W.-C.C. contributed patient samples and clinical data; H.-A.H. designed, planned, and coordinated the study over the entire period, analyzed and interpreted data, and wrote the manuscript. H.-F.T. planned and coordinated the study over the entire period and wrote the manuscript.

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Correspondence to Hsin-An Hou.

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Conflict of interests

Author Yu-Wen Wang declares that she has no conflict of interest. Author Cheng-Hong Tsai declares that he has no conflict of interest. Author Chien-Chin Lin declares that he has no conflict of interest. Author Yu-Wen Chen declares that she has no conflict of interest. Author Hsing-Yu Lin declares that she has no conflict of interest. Author Ming Yao declares that he has no conflict of interest. Author Yun-Chu Lin declares that she has no conflict of interest. Author Chien-Ting Lin declares that he has no conflict of interest. Author Chieh-Lung Cheng declares that he has no conflict of interest. Author Jih-Luh Tang declares that he has no conflict of interest. Author Wen-Chien Chou declares that he has no conflict of interest. Author Hsin-An Hou has received research grants from Celgene Corporation. Author Hwei-Feng Tien has received research grants from Celgene Corporation.

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Wang, YW., Tsai, CH., Lin, CC. et al. Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax. Ann Hematol 99, 501–511 (2020). https://doi.org/10.1007/s00277-020-03911-z

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