CXCR4 WHIM-like mutations co-occur in ~30-40% of MYD88-L265P Waldenström macroglobulinemi...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-CXCR4-WHIM-WM |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-04-27 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-WM |
| Sources | SRC-ESMO-WM-2024 SRC-NCCN-BCELL-2025 |
Actionability Facts
| Biomarker | BIO-CXCR4-WHIM |
|---|---|
| Variant | CXCR4 WHIM-like nonsense / frameshift mutations (C-terminal truncation, e.g., S338X, R334X); ~30-40% of MYD88-L265P Waldenström macroglobulinemia |
| Disease | DIS-WM |
| ESCAT tier | IB |
| Recommended combinations | bendamustine + 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 monotherapy | ibrutinib monotherapy as preferred 1L in CXCR4-mutated WM (slower / less complete response per SRC-ESMO-WM-2024 — alternative; not strict contraindication) |
| Evidence summary | CXCR4 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. |
Notes
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.
Used By
Red flag
RF-WM-CXCR4-WHIM-MUTANT- CXCR4 WHIM-like nonsense or frameshift mutation in the C-terminal regulatory domain (e.g....