Acquired Mutation in BCL2 Confers Resistance to Tx in Progressive CLL

Researchers discovered and analyzed a new recurrent BCL2 mutation (Gly101Val) appearing in a cohort of patients with chronic lymphocytic leukemia (CLL)-type progressions treated with venetoclax. Results of the study (late-breaking abstract 7) were presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 1–4 in San Diego.

Venetoclax triggers high response rates (about 80%), including complete remissions, in patients with heavily pre-treated CLL via inhibition of BCL2. Nevertheless, disease in most patients will eventually progress even on treatment. Underlying molecular mechanisms that yield clinical resistance to venetoclax in the body remain to be elucidated.

Among a cohort of 67 relapsed CLL patients administered venetoclax during three early phase clinical trials, the researchers employed focused genomic evaluation in those patients with CLL-type progressions. They performed targeted ultra-deep sequencing involving a panel of 33 genes recurrently mutated in lymphoid malignancy in cases in which pre- and post-progression samples were accessible. In total, 21 patients experienced CLL progression following a median of 36 months, and 15 patients had paired samples available for detailed analyses.

In progression samples, the researchers detected a single heterozygous nucleotide BCL2 variant in 7 of 15 patients. According to the authors, on further analysis, the Gly101Val mutation “was first detected at low variant allele fraction after 19–42 months on venetoclax, up to 25 months earlier than when standard disease progression criteria were met. The Gly101Val was not detected prior to venetoclax treatment in this cohort and was not detected in a series of samples from patients treated at our institution who had not received venetoclax (CLL [n=74], NHL [n=198], myeloma [n=103]) nor has it been described in cancer (COSMIC) or population (gnomAD) databases.”

By expressing Gly101Val in two B lineage cell lines, the team determined that this mutation mediates venetoclax resistance. More specifically, Gly101Val cells were about 30 times less sensitive to venetoclax than in wild-type BCL2 cells. Furthermore in stroma, primary cells with Gly101Val showed substantially heightened venetoclax resistance, with levels of the drug higher than can be attained clinically. Without venetoclax, the Gly101Val mutant exhibited preserved normal function by protecting cell lines vs apoptosis triggered by cytotoxics with similar effectiveness to wild-type BCL2.

Of interest, not all CLL cells at progression harbored the Gly101Val mutation, which suggests that while the mutation alone can confer resistance, alternative mechanisms may be at play. The team also found that BCL2 Gly101Val impairs binding of venetoclax to BCL2 and offers a selective growth advantage vs wild-type cell when maintained with venetoclax in vitro.

The authors suggested that this novel mutation can help uncover the pathobiology of venetoclax resistance, as well as serving as a possible new biomarker for impending clinical relapse.

In an interview with Cancer Network, Mark Crowther, MD, MSc, chair and professor of medicine at McMaster University, explained the importance of the study. “This is a very elegant study. Venetoclax is a drug that’s used to treat CLL and patients become resistant to it. This study was a really nice exploration of the mechanism of this resistance,” he said. “The reason the disease comes back is that the cancer adapts and learns to overcome chemotherapy. The researchers demonstrated that here. The target of venetoclax is a chemical called BCL2, and the BCL2 molecule is changed. Presumably there’s a mutation in one cell and this one cell survives venetoclax, and the number of cells build up until resistance is manifested. The researchers showed the biology of resistance in many different ways. And they also showed that you can detect this resistance months or years before the patient actually fails the drug …. Potentially you could start to monitor patients intermittently, and when they start to show resistance on a molecular level, you might [consider] changing therapy even though they have years before they relapse clinically.”