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CLL avec mutation BTK C481S acquise (rarement C481R/F/Y) après progression sur BTK covalent...

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IDRF-CLL-POST-BTKI-C481-ACTIONABLE
TypeSignal d’alerte
Étatreviewed 2026-04-27 | pending_clinical_signoff
MaladiesDIS-CLL
SourcesSRC-ESMO-CLL-2024 SRC-NCCN-BCELL-2025

Origine du drapeau rouge

DéfinitionCLL 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.
Direction cliniqueintensifier
Catégorieprior-therapy-class
Algorithme de décalageALGO-CLL-2L

Logique de déclenchement

{
  "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.

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Algorithmes

Indication