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Researchers Identify First Mutation to Explain Resistance to Venetoclax

Phoebe Starr, Medical Writer
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The BCL2 Gly101Val mutation is the first genomic alteration to be identified as responsible for resistance to venetoclax, a potent and effective medication indicated for the treatment of chronic lymphocytic leukemia (CLL). The BCL2 Gly101Val mutation is unique to CLL and so far has not been described in other cancers.

“Despite the effectiveness of venetoclax, a majority of patients will relapse. Up until now, we had no idea why. The discovery of a genetic mutation that confers resistance to venetoclax offers an explanation of why venetoclax stops working in some patients,” said lead investigator Piers Blombery, MBBS, Consultant Haematologist, Peter MacCallum Cancer Centre, Melbourne, Australia.

“We have shown that in some cases the mutation can be detected in patients’ bone marrow years before clinical signs of relapse appear,” Dr Blombery told listeners at ASH 2018. “The molecular basis of venetoclax resistance is largely unknown for patients with CLL who progress and for those who go on to Richter’s transformation,” Dr Blombery continued.

Acquired Resistance Mutation

The study was based on 67 patients with relapsed CLL who received treatment with venetoclax in 3 early clinical trials: 21 with CLL-like progression, 18 with Richter’s transformation, and 28 with no disease progression. Of the 21 patients with CLL progression, 15 had samples suitable for genetic analysis with next-generation sequencing (NGS) on a panel of 33 genes; NGS was done before patients started treatment with venetoclax and when resistance developed.

BCL2 Gly101Val was identified in 4 patients with CLL progression while receiving venetoclax, but it was absent in samples from these 4 patients before starting venetoclax therapy, demonstrating that it is an acquired mutation associated with venetoclax. “BCL2 Gly101Val was not found in samples from over 400 patients with other hematologic malignancies. We also didn’t find it in any CLL patient not exposed to venetoclax. It is associated with a 180-fold decrease in the affinity to bind to the BCL2 protein,” Dr Blombery explained. “Of note, BCL2 Gly101Val is subclonal; that is, it is detectable in patients before overt clinical relapse,” he added. “The mutation appears after at least 20 months of venetoclax therapy, so it is a late mutation. Wherever it was detectable, the patient progressed to clinical relapse.”

Additional Mutations Identified

BCL2 Gly101Val is not the only mutation that contributes to resistance. BCL2 Gly101Val was present in 75% of cells, but 25% were not driven by this mutation, and other mutations were identified in those cells.

“The fact that BCL2 Gly101Val is subclonal implicates multiple mechanisms of venetoclax resistance in the same patient,” Dr Blombery said. “This provides a strong rationale for time-limited venetoclax, which several researchers are exploring. When you give patients a highly selective targeted agent like venetoclax, it doesn’t take long for resistance to develop. The mutation popped up before 2 years of therapy, so we think that is a reasonable time to stop the venet­oclax.”

“Patients can be screened for BCL2 Gly101Val while on venetoclax. If the mutation is detected, it would be prudent for the hemato­logist to begin to think about other therapies to use,” Dr Blombery said. “Perhaps a more aggressive combination therapy should be used. This disease has multiple genomic tricks up its sleeve.”

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