@article{cfee00e6a88f4fdaa7b03b3244c78ee1,
title = "Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL",
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-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.",
author = "Piers Blombery and Lew, {Thomas E.} and Dengler, {Michael A.} and Thompson, {Ella R.} and Lin, {Victor S.} and Xiangting Chen and Tamia Nguyen and Ashish Panigrahi and Handunnetti, {Sasanka M.} and Carney, {Dennis A.} and Westerman, {David A.} and Tam, {Constantine S.} and Adams, {Jerry M.} and Wei, {Andrew H.} and Huang, {David C.S.} and Seymour, {John F.} and Roberts, {Andrew W.} and Anderson, {Mary Ann}",
note = "Funding Information: Conflict-of-interest disclosure: A.W.R., M.A.A., T.E.L., M.A.D., J.M.A., and V.S.L. are employees of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax. A.W.R., M.A.A., J.M.A., and T.E.L. are recipients of a share in royalty payments paid to the Walter and Eliza Hall Institute of Medical Research. S.M.H. has received honoraria from Gilead and nonfinancial assistance from AbbVie. C.S.T. has received honoraria and research funding from AbbVie and Janssen and honoraria from BeiGene. A.W.R. has received research funding from AbbVie, Genentech, Servier, Janssen, and BeiGene. J.F.S. receives research funding from AbbVie, Genentech, Celgene, and Janssen, and is an advisory board member for and has received honoraria from AbbVie, Acerta, Celgene, Genentech, Janssen, Roche, Sunesis, and Takeda. M.A.A. has received honoraria from AbbVie, Janssen, AstraZeneca, Novartis, and CSL Behring. T.E.L. has received honoraria from AbbVie. The remaining authors declare no competing financial interests. Funding Information: 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 MOLM-13 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. Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = feb,
day = "24",
doi = "10.1182/blood.2021012775",
language = "English",
volume = "139",
pages = "1198--1207",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",
}