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

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

Author(s): Blombery, P; Lew, TE; Dengler, MA; Thompson, ER; Lin, VS; Chen, X; Nguyen, T; Panigrahi, A; Handunnetti, SM; Carney, DA; Westerman, DA; Tam, CS; Adams, JM; Wei, AH; Huang, DCS; Seymour, JF; Roberts, AW; Anderson, MA;
Details: Publication Year 2022-02-24,Volume 139,Issue #8,Page 1198-1207
Journal Title: Blood
Publication Type: Research article
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.
Keywords: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse; effects; *Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/adverse effects; Female; *Hematologic Neoplasms/genetics/metabolism; Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics/metabolism; Male; Middle Aged; *Mutation; Myelopoiesis/*drug effects; *Myeloproliferative Disorders/genetics/metabolism; *Neoplasms, Second Primary/genetics/metabolism; *Sulfonamides/administration & dosage/adverse effects; Vidarabine/administration & dosage/adverse effects/analogs & derivatives; *bcl-2-Associated X Protein/antagonists & inhibitors/genetics/metabolism
Department(s): Clinical Haematology; Pathology
PubMed ID: 34469514
Publisher's Version: https://doi.org/10.1182/blood.2021012775
Open Access at Publisher's Site: https://doi.org/10.1182/blood.2021012775
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-04 07:33:15

Last Modified: 2024-10-04 07:34:42