Mutation in BCL2 Protein Confers Resistance to Venetoclax

A newly discovered recurrent mutation in the B-cell leukemia/lymphoma 2 protein mediates clinical resistance to venetoclax in patients with chronic lymphocytic leukemia.

Piers Blombery, MD

A newly discovered recurrent mutation in the B-cell leukemia/lymphoma 2 protein (BCL2) mediates clinical resistance to venetoclax in patients with chronic lymphocytic leukemia (CLL).

Researchers led by Piers Blombery, MD, detected a single heterozygous nucleotide variant in BCL2 (Gly101Val) that impairs binding of venetoclax (Venclexta) to BCL2, conferring resistance to venetoclax in both patient leukemia cells and engineered CLL cell lines. The mutation also provides a potential biomarker of impending clinical relapse.

The findings were reported by Blombery, from the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia during a press briefing at the 2018 American Society of Hematology Annual Meeting.

“Despite its efficacy, the majority of patients will relapse on venetoclax and up until now, we really didn’t have a good idea about why people were relapsing,” he said. “The mutation we have found helps to explain why venetoclax stops working in some patients. Furthermore, we have shown that in some cases the mutation can be detected in patients’ bone marrow years before clinical signs of relapse appear.”

The study cohort comprised 67 patients from 3 early-phase clinical trials with relapsed CLL treated with venetoclax, 21 of whom had CLL-type disease progression. Of these 21 patients, 15 had suitable samples for genomic analysis. Targeted amplicon next-generation sequencing of a panel of 33 genes recurrently mutated in lymphoid malignancy was performed.

BCL2 Gly101Val was detected in 4 patients with CLL-type progression on venetoclax. BCL2 Gly101Val was absent in the pre-venetoclax samples in all 4 patients.

Sequencing of 400 patients with CLL and other B-cell malignancies who had never been exposed to venetoclax did not detect the mutation in any of these patients. “This is evidence that the mutation only develops during venetoclax treatment, so it is something that patients can be screened for,” said Blombery. “In patients who develop this mutation at a low level, it would be prudent for the hematologist to begin to look for other therapies to use instead.”

Using a highly sensitive and specific droplet digital polymerase chain reaction assay, a significant level of the BCL2 Gly101Val variant “essentially begins to appear from 20 months of therapy onward [up to 25 months earlier than when standard disease progression criteria were met], so it’s quite a late mutation, but in the interim where it’s detectable, the patients inevitably progressed to overt clinical relapse and had to either come off therapy or be treated with something else,” he said.

In the laboratory, Gly101Val cells were 30- to 50-fold less sensitive to venetoclax than cells expressing wild-type BCL2. In binding assays, BCL2 Gly101Val was found to result in impaired venetoclax binding, with a reduction in the capacity of venetoclax to bind to the Gly101Val mutation by approximately 180-fold.

BCL2 Gly101Val is not the only mediator of venetoclax resistance in a patient, said Blombery. One patient harbored distinct subclones with and without the BCL2 Gly101Val mutation at disease progression. In all the patients in whom the mutation was detected, “we didn’t detect it in all the cells. The most we detected it in was in 75% of cells, which means that 25% of the cells which are resistant to venetoclax are not driven by Gly101Val,” he said.

The findings are a strong rationale for using combination therapies in the future, he indicated. “This is what happens when you give a targeted agent to a genetically complex leukemia, and second of all, it begs the rationale for giving timely immunotherapy and limiting the exposure to venetoclax and the development of this resistance,” said Blombery.

Blombery P, Anderson MA, Gong J, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract LBA7.

<<< 2018 ASH Annual Meeting