Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL

P Blombery; TE Lew; MA Dengler; ER Thompson; VS Lin; X Chen; T Nguyen; A Panigrahi; SM Handunnetti; DA Carney; DA Westerman; CS Tam; JM Adams; AH Wei; DCS Huang; JF Seymour; AW Roberts; MA Anderson

Journal article

Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL

P Blombery, TE Lew, MA Dengler, ER Thompson, VS Lin, X Chen, T Nguyen, A Panigrahi, SM Handunnetti, DA Carney, DA Westerman, CS Tam, JM Adams, AH Wei, DCS Huang, JF Seymour, AW Roberts, MA Anderson

Blood | ELSEVIER | Published : 2022

DOI: 10.1182/blood.2021012775

Abstract

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-..

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University of Melbourne Researchers

Piers Blombery Author

Ella Thompson Author

Dennis Carney Author

David Westerman Author

Grants

Awarded by Leukemia and Lymphoma Society

Funding Acknowledgements

The authors are grateful to the patients who enrolled in the venetoclax clinical trials, Naomi Sprigg for collection and curation of samples, Angela Georgiou for flow cytometric sorting of hematopoietic cells, and Chris Riffkin and Leonie Gibson for engineering the MOLM13 cells. This research was supported by grants from the Snowdome Foundation (P.B. and M.A.A.), Vision Super and the Wilson Centre for Lymphoma Genomics (P.B. and D.A.W.), Jock Brockhoff Foundation (M.A.A.), the Leukemia and Lymphoma Society (USA) (Special Center of Research [7015-18] to J.M.A., A.H.W., D.C.S.H., and A.W.R.), the National Health and Medical Research Council (NHMRC) of Australia (D.C.S.H. [1156024, 1113133], A.W.R. [1113577, 1174902], M.A.A. [APP1177718]). Statistical support was provided by Michael Fahey and Mathias Bressel from the Centre for Biostatistics and Clinical Trials (BaCT), Melbourne, Australia. Illustrations created with BioRender.com. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.