CLL with acquired BTK C481S (rarely C481R/F/Y) mutation after progression on covalent BTK...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | RF-CLL-POST-BTKI-C481-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 with acquired BTK C481S (rarely C481R/F/Y) mutation after progression on covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib). C481S abolishes covalent binding of cBTKi to BTK; non-covalent BTKi (pirtobrutinib) retains activity (BRUIN, Mato Lancet 2021; pirtobrutinib in cBTKi-pretreated CLL ORR 82%, mPFS 19.6 mo). Routes 2L+/3L+ post-cBTKi CLL with confirmed C481-axis resistance to pirtobrutinib over chemoimmunotherapy or alloHCT. |
|---|---|
| Clinical direction | intensify |
| Category | prior-therapy-class |
| Shifts algorithm | ALGO-CLL-2L |
Trigger Logic
{
"all_of": [
{
"any_of": [
{
"finding": "prior_btki_received",
"value": true
},
{
"finding": "prior_cbtki_received",
"value": true
}
]
},
{
"any_of": [
{
"finding": "btk_c481s_mutation",
"value": true
},
{
"finding": "btk_c481_mutation",
"value": "positive"
},
{
"finding": "btk_resistance_mutation",
"value": "C481S"
},
{
"finding": "plcg2_mutation",
"value": true
}
]
}
],
"type": "biomarker"
}
Notes
Distinguish from RF-PRIOR-BTKI-PROGRESSION (universal, broad) — that flag fires on any cBTKi PD; this flag is mutation-confirmed C481S resistance, the canonical mechanism of acquired cBTKi resistance (~80% of CLL patients with progressive disease on cBTKi). PLCG2 mutations (R665W, S707F/Y, L845F) are an alternative resistance mechanism (~15%) — also responds to pirtobrutinib. Test at PD by ddPCR or NGS on peripheral-blood mononuclear cells (sensitivity better than BM in CLL). Venetoclax + rituximab (MURANO) and CAR-T (TRANSCEND-CLL-004 with liso-cel, ORR 80%, CR 18% in heavy pretreatment) are the alternative options for pirtobrutinib- ineligible or pirtobrutinib-progressed; combinations under study (pirto + ven; pirto + ven + obinutuzumab — BRUIN-CLL-321/322). Access UA: pirtobrutinib not yet NSZU-listed; international early-access pathways.
Used By
Algorithms
ALGO-CLL-2L- ALGO-CLL-2L
Indications
IND-CLL-3L-LISOCEL- IND-CLL-3L-LISOCEL