From the Journals

Novel mutations contribute to progression of venetoclax-treated CLL



Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

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