CLL progression on venetoclax — either acquired BCL2 G101V (or rarer D103Y, A113G, R107_R...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | RF-CLL-VEN-RESISTANT-ACTIONABLE |
|---|---|
| Type | Red flag |
| Status | reviewed 2026-04-27 | pending_clinical_signoff |
| Diseases | DIS-CLL |
| Sources | SRC-ESMO-CLL-2024 SRC-NCCN-BCELL-2025 |
Red Flag Origin
| Definition | CLL progression on venetoclax — either acquired BCL2 G101V (or rarer D103Y, A113G, R107_R110dup) mutation, or clinical PD on venetoclax-based regimen with or without identified mutation. BCL2 G101V abolishes venetoclax binding; mechanism affects ~50% of post-venetoclax progressors (Blombery 2019). Routes back to BTKi-class therapy (cBTKi if BTKi-naive, pirtobrutinib if cBTKi-exposed) over re-challenge with venetoclax; CAR-T (liso-cel, TRANSCEND-CLL-004) is an option in heavily pretreated fit patients. |
|---|---|
| Clinical direction | intensify |
| Category | prior-therapy-class |
| Shifts algorithm | ALGO-CLL-2L |
Trigger Logic
{
"any_of": [
{
"finding": "bcl2_g101v_mutation",
"value": true
},
{
"finding": "bcl2_resistance_mutation",
"value": "positive"
},
{
"finding": "venetoclax_resistance",
"value": true
},
{
"all_of": [
{
"finding": "prior_venetoclax_received",
"value": true
},
{
"finding": "best_response_to_venetoclax",
"value": "PD"
}
]
},
{
"all_of": [
{
"finding": "prior_venetoclax_received",
"value": true
},
{
"finding": "venetoclax_progression",
"value": true
}
]
}
],
"type": "biomarker"
}
Notes
Venetoclax retreatment is feasible (~70% ORR) when initial response was deep (uMRD) and treatment-free interval ≥18-24 mo, particularly when given as a fixed-duration course (CLL14-style) — flag does NOT fire for "completed planned 12-cycle ven+obinutuzumab and progressed >24 mo later". Flag fires for: (1) PD on continuous venetoclax, (2) PD on fixed-duration with TFI <18 mo, (3) acquired BCL2 G101V. Combinations under study (venetoclax + pirtobrutinib — BRUIN-CLL-322; ven + obinutuzumab + acalabrutinib — CLL17). BCL2 mutation testing at PD by ddPCR (preferred — high sensitivity for low-VAF subclones) or NGS; can predate clinical PD by 12-24 mo. Access UA: venetoclax is NSZU-listed for CLL R/R; pirtobrutinib not yet listed.
Used By
Algorithms
ALGO-CLL-2L- ALGO-CLL-2L
Indications
IND-CLL-3L-LISOCEL- IND-CLL-3L-LISOCEL