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dc.contributor.authorBlombery, P
dc.contributor.authorLew, TE
dc.contributor.authorDengler, MA
dc.contributor.authorThompson, ER
dc.contributor.authorLin, VS
dc.contributor.authorChen, X
dc.contributor.authorNguyen, T
dc.contributor.authorPanigrahi, A
dc.contributor.authorHandunnetti, SM
dc.contributor.authorCarney, D
dc.contributor.authorWesterman, DA
dc.contributor.authorTam, CS
dc.contributor.authorAdams, JM
dc.contributor.authorWei, AH
dc.contributor.authorHuang, DCS
dc.contributor.authorSeymour, JF
dc.contributor.authorRoberts, A
dc.contributor.authorAnderson, MA
dc.identifierpii: S0006-4971(21)01541-X
dc.identifier.citationBlombery, P., Lew, T. E., Dengler, M. A., Thompson, E. R., Lin, V. S., Chen, X., Nguyen, T., Panigrahi, A., Handunnetti, S. M., Carney, D., Westerman, D. A., Tam, C. S., Adams, J. M., Wei, A. H., Huang, D. C. S., Seymour, J. F., Roberts, A. & Anderson, M. A. (2021). Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.. Blood,
dc.description.abstractThe BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. 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 for CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (³ 1 of neutropenia, thrombocytopenia, anemia) lasting ³4 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 (tMNs). tMNs 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 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 tMNs. 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.
dc.publisherAmerican Society of Hematology
dc.titleClonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.
dc.typeJournal Article
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentMedical Education
melbourne.affiliation.departmentCentre for Cancer Research
melbourne.affiliation.departmentMedicine (St Vincent's)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
dc.rights.licenseCC BY
melbourne.openaccess.statusPublished version
melbourne.contributor.authorTam, Constantine
melbourne.contributor.authorHandunnetti, Sasanka
melbourne.contributor.authorWesterman, David
melbourne.contributor.authorSeymour, John
melbourne.contributor.authorThompson, Ella
melbourne.contributor.authorBlombery, Piers
melbourne.contributor.authorCarney, Dennis
melbourne.contributor.authorRoberts, Andrew
melbourne.contributor.authorAnderson, Mary Ann
melbourne.accessrightsAccess this item via the Open Access location

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