Clinical, genetic, and epigenetic alterations associated with venetoclax resistance in patients, classified by class and tier of supportive evidence
| . | Class . | Gene or gene product . | CLL . | Mantle cell lymphoma . | AML . |
|---|---|---|---|---|---|
| Clinical | High bulk41 | Tier 3 | |||
| BTKi clinical resistance41 | Tier 3 | ||||
| Prior azacitidine75 | Tier 3 | ||||
| Monocytic lineage86 | Tier 2 | ||||
| Cytogenetic | Complex karyotype48,74 | Tier 1* | Tier 2 | ||
| del9p138 | Tier 1† | ||||
| Mutations/CNV | Apoptosis | TP53 mut/loss (incl del17p)41,47,81,82 | Tier 2 | Tier 2 | |
| BCL2 mut51,52,54,56 | Tier 1 | ||||
| MCL1 amp53 | Tier 1 | ||||
| BAX mut84,85 | Tier 1 | Tier 2 | |||
| Signaling | Notch1 mut (activating)41 | Tier 2 | |||
| Activated growth factor49,81 | Braf; Tier 2 | FLT3; Tier 1 Ras; Tier 2 | |||
| Cell cycle | CDKN2A/B mut/loss49 | Tier 1* | |||
| BTG1 mut49 | Tier 2 | ||||
| Epigenetic regulator | SWI/SNF family mut/loss138 | Tier1† | |||
| Expression | Apoptosis | ↓BCL2138 | Tier 1 | ||
| ↑BCLxL51,78,82,86,138 | Tier 1 | Tier 1 | Tier 1 | ||
| ↑MCL153,86 | Tier 1 | Tier 1 | |||
| ↑BCL2A1139,140 | Tier 1 | Tier 1 | |||
| ↓PUMA78 | Tier 2 | ||||
| ↓NOXA82,88 | Tier 2 | ||||
| Mitochondrial metabolism | AMPK53 | Tier 1 | Tier 1 |
| . | Class . | Gene or gene product . | CLL . | Mantle cell lymphoma . | AML . |
|---|---|---|---|---|---|
| Clinical | High bulk41 | Tier 3 | |||
| BTKi clinical resistance41 | Tier 3 | ||||
| Prior azacitidine75 | Tier 3 | ||||
| Monocytic lineage86 | Tier 2 | ||||
| Cytogenetic | Complex karyotype48,74 | Tier 1* | Tier 2 | ||
| del9p138 | Tier 1† | ||||
| Mutations/CNV | Apoptosis | TP53 mut/loss (incl del17p)41,47,81,82 | Tier 2 | Tier 2 | |
| BCL2 mut51,52,54,56 | Tier 1 | ||||
| MCL1 amp53 | Tier 1 | ||||
| BAX mut84,85 | Tier 1 | Tier 2 | |||
| Signaling | Notch1 mut (activating)41 | Tier 2 | |||
| Activated growth factor49,81 | Braf; Tier 2 | FLT3; Tier 1 Ras; Tier 2 | |||
| Cell cycle | CDKN2A/B mut/loss49 | Tier 1* | |||
| BTG1 mut49 | Tier 2 | ||||
| Epigenetic regulator | SWI/SNF family mut/loss138 | Tier1† | |||
| Expression | Apoptosis | ↓BCL2138 | Tier 1 | ||
| ↑BCLxL51,78,82,86,138 | Tier 1 | Tier 1 | Tier 1 | ||
| ↑MCL153,86 | Tier 1 | Tier 1 | |||
| ↑BCL2A1139,140 | Tier 1 | Tier 1 | |||
| ↓PUMA78 | Tier 2 | ||||
| ↓NOXA82,88 | Tier 2 | ||||
| Mitochondrial metabolism | AMPK53 | Tier 1 | Tier 1 |
The strength of evidence for a clinically important role of an associated marker in venetoclax resistance is categorized into tiers: tier 1, proven mechanism and associated with resistance in multiple patients; tier 2, plausible mechanism and observed in some patients; tier 3, associated with resistance in multiple patients, but no mechanism established. Where a molecular marker is associated with primary resistance to venetoclax, the tier is in bold. Markers associated with secondary resistance are recorded in normal font. Consistent with expectations arising from our knowledge of the regulation of apoptosis, genetic or epigenetic alterations in BCL2 family expression are common causes of secondary resistance to venetoclax.
BTKi, Bruton tyrosine kinase inhibitor; CK, complex karyotype; CNV, copy number variation.
Associated with Richter transformation.
del(9p) and SWI/SNF family mutations are causative of resistance when they co-occur.