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

Autor:	Blombery P; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Lew TE; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Dengler MA; University of Melbourne, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Division on Oncology, Medical University of Graz, Graz, Austria; and., Thompson ER; University of Melbourne, Melbourne, VIC, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Lin VS; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Chen X; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Nguyen T; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Panigrahi A; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia., Handunnetti SM; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia., Carney DA; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia., Westerman DA; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Tam CS; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia., Adams JM; University of Melbourne, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Wei AH; The Alfred Hospital and Monash University, Melbourne, VIC, Australia., Huang DCS; University of Melbourne, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Seymour JF; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia., Roberts AW; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Anderson MA; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Feb 24; Vol. 139 (8), pp. 1198-1207.
DOI:	10.1182/blood.2021012775
Abstrakt:	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. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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