Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

Abstract

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identifi ed at progression in 7 patients, but not at study entry. It was fi rst detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affi nity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the fi rst description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is suffi cient to confer resistance.

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

“…Indeed, in CLL, two teams have reported the acquisition of point mutations in BCL-2 by analyzing paired pre-venetoclax and progression samples from patients enrolled on venetoclax clinical trials. Glycine substitution by Valin in position 101 (G101V) was firstly identified at progression in 7/15 patients (but not at study entry) [36]. In vitro experiments on CLL cell lines demonstrated that the cells harboring G101V were approximately 30-fold less sensitive to venetoclax, due to a 180-fold reduction of venetoclax binding.…”

Molecular pathogenesis of chronic lymphocytic leukaemia

“…A recent study has also described the occurrence of the G101V mutation in BCL2 in approximately 50% of patients who progressed while on trial with venetoclax (Blombery et al ). The mutation was first apparent in patients 19 months after initiation of therapy and is believed to confer resistance to venetoclax by reducing the affinity of the BH3‐mimetic for BCL2 (Blombery et al , ).…”

Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty

“…10,39,40 However, the percentage of patients obtaining a complete response (a necessary condition to achieve undetectable MRD) on receipt of treatment with ibrutinib alone is small. 50,51 These mutations appear early and have the potential to be used as biomarkers for future disease recurrence, suggesting an opportunity for intervention. 11,41 Predicting outcomes other than PFS and overall survival, such as the likelihood of treatment failure and disease progression after treatment with BTK and BCL2 inhibitors, also could be clinically useful.…”

“…For example, BTK and PLCG2 mutations are correlated with resistance to ibrutinib and BCL2 mutations are correlated with resistance to venetoclax. 50,51 These mutations appear early and have the potential to be used as biomarkers for future disease recurrence, suggesting an opportunity for intervention.…”