A newly discovered recurrent mutation in the B-cell leukemia/lymphoma 2 protein in patients with chronic lymphocytic leukemia has been linked to venetoclax resistance.
Piers Blombery, MD
Clinical resistance to venetoclax (Venclexta) is mediated by a newly discovered recurrent mutation in the B-cell leukemia/lymphoma 2 protein (BCL2) in patients with chronic lymphocytic leukemia (CLL), according to findings presented during the 2018 ASH Annual Meeting.
Piers Blombery, MD, from the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, reported that his research group detected a single heterozygous nucleotide variant in BCL2(Gly101Val) that impairs the binding of venetoclax to BCL2,causing a resistance to the agent in both patient leukemia cells and engineered CLL cell lines. This mutation could be a potential biomarker for clinical relapse.
“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.
BCL2Gly101Val was detected in 4 patients with CLL-type progression on venetoclax.BCL2Gly101Val 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 theBCL2Gly101Val 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-typeBCL2. In binding assays,BCL2Gly101Val 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.
BCL2Gly101Val is not the only mediator of venetoclax resistance in a patient, said Blombery. One patient harbored distinct subclones with and without theBCL2Gly101Val 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.