For a study, it was determined that Venetoclax, a BCL2 inhibitor, has been shown to be effective in treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In addition, because BCL2 is a key driver of survival in both myeloid progenitor and B cells, researchers explored whether clinical and molecular problems developed in the myeloid compartment after long-term venetoclax therapy of CLL in 89 patients (87 with relapsed/refractory CLL). Persistent cytopenias (one of neutropenia, thrombocytopenia, or anemia) lasting 4 months and unrelated to CLL occurred in 25 patients over a median follow-up of 75 (range 21-98) months (28%). Nearly 20 (80%) of these patients had clonal hematopoiesis, with ten having therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients who had previously been exposed to fludarabine-alkylator combination therapy, with a cumulative 5-year incidence of 10.4% after venetoclax initiation, which was consistent with rates reported for patients who had previously been exposed to fludarabine-alkylator combination therapy without venetoclax. Investigators investigated samples from patients with little or minimal bone marrow CLL burden (n=41) to see if the altered myelopoiesis was caused by mutation acquisition In 32% (13/41) of cases, mutations in the apoptotic effector BAX were found. C-terminal BAX mutations inhibited Bax localization to the outer mitochondrial membrane, resulting in resistance to venetoclax death in cellular experiments. BAX-mutated clonal hematopoiesis occurred irrespective of earlier fludarabine-alkylator combination treatment exposure and was unrelated to t-MNs. Mutations in BAX were shown to be clonally co-occurring with DNMT3A or ASXL1. They also found BCL2 alterations inside CLL cells and BAX mutations in the same patients’ myeloid compartment, showing lineage-specific adaptation to venetoclax treatment.

 

Source:ashpublications.org/blood/article-abstract/139/8/1198/476749/Clonal-hematopoiesis-myeloid-disorders-and-BAX?redirectedFrom=fulltext