Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax

Abstract

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

BCL2 Protein Progressively Declines during Robust CLL Clonal Expansion: Potential Impact on Venetoclax Clinical Efficacy and Insights on Mechanism

“…Thus, based on this study's findings, we consider it probable that during venetoclax treatment of patients, the highly divided CLL cells with the greatest capacity for generating AIDCA-driven mutations will preferentially survive. Once these actively cycling cells later revert to relatively quiescent circulating cells with upregulated BCL2 [72,73], analogously to the transition of germinal center B cells into memory cells [74], any clonal variants with functional BCL2 gene mutations that impair venetoclax binding to BCL2 [14,75] will be venetoclax resistant and could eventually become the dominant CLL subclone [30,70,71]. This hypothesis is consistent with evidence that BCL2 mutations in CLL clonal populations occur prior to treatment and are acquired during treatment [14,15,18].…”

Mechanisms of resistance to venetoclax in hematologic malignancies

“…Interestingly, BCL-2 family proteins may undergo posttranslational modifications, including phosphorylation, which alter their activity and may influence mitochondrial apoptosis. 39 Importantly, in the study performed by Guieze et al, 37 patients refractory to venetoclax had detected growing subclones of CLL cells with an amplified region on chromosome 1q23. 40 This region encodes MCL-1 protein and PRKAB2 with the regulatory subunit of AMP-activated protein kinase (AMPK) genes.…”

“…22,23,35,36 A study performed outside clinical trials revealed that Gly101Val and/or Asp103Tyr mutations were present in 16.7% of patients treated with venetoclax as monotherapy or combined with rituximab. 37 Ninety percent of them further relapsed (median time of follow-up of 26 months (7-32 months)). 37 All of the changes were detected using standard-of-care droplet digital polymerase chain reaction (ddPCR) tests.…”

“…37 Ninety percent of them further relapsed (median time of follow-up of 26 months (7-32 months)). 37 All of the changes were detected using standard-of-care droplet digital polymerase chain reaction (ddPCR) tests. Hypothetically, screening for Gly101Val and Asp103Tyr mutations may be implemented in daily practice to identify resistance before clinical progression.…”

“…Hypothetically, screening for Gly101Val and Asp103Tyr mutations may be implemented in daily practice to identify resistance before clinical progression. 37 Interestingly, Gly-101Val was present after cessation of venetoclax treatment for over 6 months 17 and in 3 out of 7 patients with CLL who failed to clear minimal residual disease (MRD) after 1 year of treatment with venetoclax. 35 Consequently, further studies are essential to evaluate Gly101Val in the context of re-treatment with venetoclax.…”