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CXCR4 mutações tipo WHIM ocorrem em ~30-40% do MYD88-L265P Waldenström macroglobulinemi...

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IDBMA-CXCR4-WHIM-WM
TipoRelevância terapêutica
Estadoreviewed 2026-04-27 | pending_clinical_signoff | actionability review required
DoençasDIS-WM
FontesSRC-ESMO-WM-2024 SRC-NCCN-BCELL-2025

Fatos de ação

BiomarcadorBIO-CXCR4-WHIM
VarianteCXCR4 WHIM-like nonsense / frameshift mutations (C-terminal truncation, e.g., S338X, R334X); ~30-40% of MYD88-L265P Waldenström macroglobulinemia
DoençaDIS-WM
Nível ESCATIB
Combinações recomendadasbendamustine + rituximab (1L CXCR4-mutated WM per SRC-NCCN-BCELL-2025, SRC-ESMO-WM-2024), bortezomib + dexamethasone + rituximab (BDR, 1L CXCR4-mutated alternative per SRC-NCCN-BCELL-2025), zanubrutinib monotherapy (1L CXCR4-mutated alternative — preserved efficacy vs ibrutinib in CXCR4-mut subgroup of ASPEN trial per SRC-NCCN-BCELL-2025)
Contraindicated monotherapyibrutinib monotherapy as preferred 1L in CXCR4-mutated WM (slower / less complete response per SRC-ESMO-WM-2024 — alternative; not strict contraindication)
Resumo das provasCXCR4 WHIM-like mutations co-occur in ~30-40% of MYD88-L265P Waldenström macroglobulinemia and confer relative resistance to ibrutinib (BTKi) — lower ORR and major-response rate, slower kinetics of IgM decline (Treon NEJM 2015 — initial cohort; Castillo Blood 2020 — confirmation) per SRC-NCCN-BCELL-2025, SRC-ESMO-WM-2024. CXCR4 status drives 1L therapy selection in WM: in CXCR4-mutated patients, guidelines list bendamustine + rituximab (BR) or proteasome-inhibitor- based regimens (BDR — bortezomib/dex/rituximab) as preferred over BTKi monotherapy; in CXCR4-WT patients, BTKi monotherapy (ibrutinib or zanubrutinib) is preferred. Mavorixafor (CXCR4 antagonist) has FDA orphan designation for WHIM but is investigational in WM.

Notas

ESCAT IB / OncoKB Level 3A (predictive of resistance / response modifier rather than a direct drug target). Detection: NGS targeted panel (CXCR4 C-terminal exon 2). Patients with both MYD88-L265P and CXCR4-WHIM mutation have higher disease burden (IgM, BM infiltration) per SRC-NCCN-BCELL-2025. Source-gap: SRC-ASPEN, SRC-INNOVATE-WM not yet ingested.

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