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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Wednesday, June 8, 2022
Piers Blombery, MBBS, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Australia, and colleagues conducted a study to investigate and characterize the clinical and molecular abnormalities arising outside of the target tumor compartment in patients with chronic lymphocytic leukemia (CLL) who were undergoing long-term continuous BCL2 inhibition with venetoclax. The results of this study, which were published in the journal Blood, provide further evidence supporting the central nature of the BCL2 family of proteins throughout hematopoiesis.
The investigators focused on 89 patients with CLL, 87 of whom had relapsed or refractory disease. Persistent CLL-unrelated cytopenias lasting for at least 4 months were reported in 28% of patients at a median follow-up of 75 months. Of this population, 80% exhibited clonal hematopoiesis; this group included 10 patients with therapy-related myeloid neoplasms. Therapy-related myeloid neoplasms were exclusively reported in patients with a history of combination therapy with fludarabine plus an alkylating agent; the cumulative 5-year incidence rate was 10.4% after the initiation of venetoclax, and it seemed to be consistent with the rates reported in those who did not receive this inhibitor.
A total of 32% of patients with no or minimal bone marrow CLL burden harbored mutations in the proapoptotic BCL2-family gene BAX. Based on the results of cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and provoked resistance to venetoclax killing. BAX-mutated clonal hematopoiesis seemed to occur independently of prior exposure to combination therapy with fludarabine plus an alkylating agent; it also did not appear to be associated with the incidence of therapy-related myeloid neoplasms. Single-cell sequencing detected clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. Simultaneous BCL2 and BAX mutations in the CLL cells and myeloid compartment, respectively, were reported; this finding underscored the potential of a lineage-specific adaptation to treatment with venetoclax.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.
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