Gly101Val Mutation Directly Causes Resistance to Venetoclax

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Researchers identified a single heterozygous nucleotide variant that confers resistance to venetoclax, and it’s a mutation that may be detected years before clinical relapse occurs.
Researchers identified a single heterozygous nucleotide variant that confers resistance to venetoclax, and it’s a mutation that may be detected years before clinical relapse occurs.
The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

As treatments for chronic lymphocytic leukemia (CLL) go, venetoclax, which is approved in as a monotherapy or in combination with rituximab for patients who have not seen success with prior lines of CLL therapy, is a fairly effective drug, conferring a complete remission in 20% of patients who receive it as a monotherapy and in 20% to 50% of patients who receive it in combination with rituximab. When used as a fixed-duration venetoclax-rituximab combination, 62% of patients achieved an undetectable minimal residual disease level in peripheral blood,1 said Piers Blombery, MBBS, of the University of Melbourne in Australia, during a late-breaking abstract session at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California.2

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Despite its ability to prompt complete remissions, the drug's effects are not everlasting: many of those who initially experience remission will eventually relapse over time. Dr Blombery and his team sought to harness the power of genomics to characterize the CLL-type progressions on venetoclax to help them identify the exact mechanisms of drug resistance at play in certain patients with CLL, with the goal of determining what drives that transformation of effect.

The investigators enrolled 67 patients with relapsed CLL who had been treated with venetoclax, including 21 patients with CLL-type progressions, 18 with Richter's transformation, and 28 who had not seen any progression of disease.

BCL2 Gly101Val can be detected in patient samples before clinical relapse becomes evident, noted Dr Blombery. The researchers performed sequencing on 15 of the 21 CLL-type progression patients who were determined to have suitable samples for genomic analysis both prior to being administered venetoclax and post-administration. Using a panel of 33 genes, they first found a BCL2 coding mutation (affecting the protein Gly101Val) in 4 patients with CLL-type progression who were taking venetoclax. Clinical progression occurred at approximately 30 to 60 months of therapy. They designed a highly sensitive digital-drop PCR assay (ddPCR), where they found that the mutation emerged in the bone marrow of these 4 patients up to 25 months prior to the criteria for clinical progression were met. Then, using a digital assay in the sensitivity as low as .01%, they detected the mutation in 3 additional patients with CLL — and only 1.4% to 4.3% of these cells carried the mutation. Confirmation of the mutational status in these additional patients meant that in total, 7 out of the 15 (46%) patients who experienced CLL-type progression while on venetoclax actually had the mutation.

The research team confirmed ex vivo that cells carrying the mutation were resistant to venetoclax at disease progression — a resistance characterized by a markedly decreased affinity for venetoclax, as the mutation occurred at the drug's binding site. The fact that this mutation was found in a “highly preserved” site of BCL2 prompted the researchers to analyze the issue further.

They took tumor samples from 397 patients with a range of B-cell malignancies, including 96 patients with CLL who had never received venetoclax. Through the analysis of these data, they concluded that the mutation was not present in any of these patients prior to venetoclax administration, nor had it been identified in cancer population databases. “This observation was highly specific to the context of CLL progression on venetoclax,” Dr Blombery said. Through protein binding studies, they found the mutation to Gly101Val was associated with an approximately 180-fold reduction in the ability of venetoclax to bind to BCL2.

The investigators also determined there are alternative mediators of resistance to venetoclax aside from BCL2 Gly101Val.

Additionally, in vitro, the researchers saw that BCL2 Gly101Val actually had a growth advantage compared with wild-type cells when venetoclax was present. “Therefore, not only does the Gly101Val mutation make cells increasingly less susceptible to killing by venetoclax, but we identified a selective advantage and gradual enrichment over time of cells carrying the mutation in the presence of venetoclax exposure — highly analogous to the clinical scenarios seen in our patient cohort,” Dr Blombery added.

A audience member asked Dr Blombery if it were reasonable to assume that the resistance could have occurred as a result of patients not being 100% compliant to their treatment regimens, comparing what was seen here with what can sometimes happen when patients with chronic myeloid leukemia are not adherent to their medications. Dr Blombery agreed that “there is a strong rationale there” to argue that nonadherence could have contributed to the selective pressure for outgrowth that was seen in some patients with CLL taking venetoclax.

Read more of Cancer Therapy Advisor's coverage of the ASH 2018 meeting by visiting the conference page.

References

  1. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase 3 study [published online December 3, 2018]. J Clin Oncol. doi: 10.1200/JCO.18.01580
  2. 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. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract LBA-7.

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