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Progression on covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib). Triggers...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

IDRF-PRIOR-BTKI-PROGRESSION
TypeRed flag
Statusreviewed 2026-04-27 | pending_clinical_signoff
DiseasesNone declared
SourcesSRC-ESMO-CLL-2024 SRC-NCCN-BCELL-2025

Red Flag Origin

DefinitionProgression on covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib). Triggers selection of non-covalent BTKi (pirtobrutinib), BCL2i (venetoclax-based regimens), CAR-T (lisocabtagene maraleucel, brexucabtagene autoleucel), or PI3Ki — depending on disease (CLL, MCL, WM). Resistance often driven by BTK C481S or PLCG2 mutation.
Clinical directionde-escalate
Categoryprior-therapy-class

Trigger Logic

{
  "any_of": [
    {
      "finding": "prior_btki_progression",
      "value": true
    },
    {
      "all_of": [
        {
          "finding": "prior_btki_received",
          "value": true
        },
        {
          "finding": "best_response_to_btki",
          "value": "PD"
        }
      ]
    }
  ],
  "type": "composite_score"
}

Notes

CLL: BRUIN study (Mato 2023) — pirtobrutinib ORR 82% in BTKi-pretreated; venetoclax + obinutuzumab also active (CLL14 was 1L but venetoclax monotherapy MURANO post-BTKi shows efficacy); CAR-T (liso-cel) per TRANSCEND-CLL-004. MCL: BRUIN MCL-321 — pirtobrutinib ORR 58% post- cBTKi; brexu-cel (ZUMA-2) ORR 91% in r/r MCL. WM: pirtobrutinib in TBLINNA, venetoclax + rituximab (BGB-3111-302). BTK C481S testing recommended at progression to confirm acquired resistance vs intolerance/non-adherence (different management).

Used By

Algorithms

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