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MCL with acquired BTK C481S (rarely C481R/F/Y) mutation after progression on covalent BTK...

Vue déterministe de l'entité source de la LJAM. L'autorité clinique demeure avec les ID de la source cités et l'état d'approbation de l ́examinateur.

IDRF-MCL-POST-BTKI-C481-ACTIONABLE
TypeSignal d’alerte
Étatreviewed 2026-04-30 | pending_clinical_signoff
MaladiesDIS-MCL
SourcesSRC-ESMO-MCL-2024 SRC-NCCN-BCELL-2025

Origine du drapeau rouge

DéfinitionMCL 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 MCL-321, Wang Lancet Oncol 2024; pirtobrutinib in cBTKi-pretreated MCL ORR 51%, mPFS 7.4 mo). Routes 3L+ post-cBTKi MCL with confirmed C481-axis resistance to pirtobrutinib over chemoimmunotherapy or alternative cBTKi (which would not regain activity given the on-target resistance mechanism).
Direction cliniqueintensifier
Catégorieprior-therapy-class
Algorithme de décalageALGO-MCL-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 in MCL (similar prevalence to CLL ~80% on cBTKi PD). 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. Brexucabtagene autoleucel (CAR-T, ZUMA-2) is the alternative for CAR-T-eligible post-cBTKi MCL; pirtobrutinib preferred for CAR-T-ineligible (age, comorbidity, organ dysfunction). Access UA: pirtobrutinib not yet NSZU-listed; international early-access pathways.

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Indication