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A change in the pocket of the survival protein BCL-2 where venetoclax has to fit. The protein still works and the drug no longer binds it. It can be detected in blood months before the disease starts growing again.
Glycine 101 sits in the BH3-binding groove of BCL-2. The valine substitution reduces the affinity of the protein for venetoclax about 180-fold on surface plasmon resonance, so the drug can no longer displace the pro-apoptotic proteins that BCL-2 is holding, while the protein continues to do its job for the cell.
Paired samples from 15 patients progressing on venetoclax in clinical trials showed G101V in seven at progression and in none at study entry. It first became detectable between 19 and 42 months of continuous treatment, and its emergence preceded clinical progression by many months (Blombery 2019). Other substitutions in the same groove have since been described, usually at low allele fraction and often several at once in one patient, which suggests convergent selection rather than a single escape route.
In plain words · A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment.
Finding this change explains why venetoclax has stopped working, and it means the next treatment should work by a different mechanism rather than being a higher dose of the same one. Because it can appear before scans or blood counts change, it is a reason for a conversation rather than for immediate treatment.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
Deep targeted sequencing of BCL2 on blood or marrow during or at progression on venetoclax, reported by residue and allele fraction. Standard-depth panels miss these variants, which are typically present in a small subclone when they first appear; serial testing is what makes the result useful, because a rising allele fraction is an early warning rather than a diagnosis of progression.
“The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry.”
Blombery et al., Cancer Discovery 2019No approval uses this readout as a threshold. It is defined by Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax.
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