Researchers have identified a novel candidate resistance mutation that reduced venetoclax binding in a patient with relapsed/refractory follicular lymphoma treated with venetoclax.1

Although the male patient, aged 55 years, initially responded to venetoclax as part of a phase 1 clinical trial, after 29 months on therapy, his disease recurred. Biopsy samples of the lymphoma were taken prior to venetoclax treatment and after progression. In addition to mutations in CREBBP, KMT2D, and EZH2, there was an aberrant somatic hypermutation of the BCL2 gene with the presence of multiple mutations in the 5ʹ untranslated region and the first coding exon.

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The posttreatment biopsy sample had 7 BCL2 mutations that were not found in the initial biopsy sample.

“Strikingly, one of the mutations acquired during venetoclax treatment was predicted to result in a phenylalanine substitution to an isoleucine at amino acid 104 of the BCL2 protein, which is located at the venetoclax binding site of BCL2,” the researchers wrote. “The [variant allele frequency] of the Phe104Ile mutation (12.3%) was the highest of the newly acquired BCL2 mutations in the post-venetoclax sample (estimated cancer cell fraction approximately 50% based on immunohistology) consistent with its presence in a significant proportion of the tumor compartment.”

The researchers then investigated whether the Phe104Ile mutation conferred resistance to venetoclax, and found the RS4;11 cells that overexpressed the mutant were more than 40 times less sensitive to venetoclax than RS4;11 BCL2 wildtype cells.

“Whilst any of the newly observed BCL2 mutations in our patient may have contributed to clinical resistance, our experimental data strongly suggest the Phe104Ile as an important candidate resistance mutation in this patient,” the researchers wrote. “Our observations in this case provide a strong rationale for investigating the role of acquired BCL2 mutations as a result of [aberrant somatic hypermutation] as a venetoclax resistance mechanism in patients with follicular lymphoma.”

Reference

Blombery P, Birkinshaw RW, Nguyen T, et al. Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma [published online June 24, 2019]. Br J Haematol. doi: 10.1111/bjh.16069