CXCR4 WHIM-like nonsense or frameshift mutation in the C-terminal regulatory domain (e.g....

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

ID	`RF-WM-CXCR4-WHIM-MUTANT`
Type	Red flag
Status	reviewed 2026-05-08 \| pending_clinical_signoff
Diseases	`DIS-WM`
Sources	`SRC-ESMO-WM-2024` `SRC-NCCN-BCELL-2025`

Red Flag Origin

Definition	CXCR4 WHIM-like nonsense or frameshift mutation in the C-terminal regulatory domain (e.g., S338X, R334X) in Waldenström macroglobulinemia (WM). CXCR4 WHIM-like mutations co-occur with MYD88 L265P in ~30-40% of MYD88-mutant WM and cause constitutive CXCR4 signaling via loss of the C-terminal regulatory domain. These mutations confer relative resistance to BTK inhibitor (BTKi) monotherapy — lower overall response rate and major-response rate, slower IgM decline kinetics compared to CXCR4-WT MYD88-mutant WM (Treon NEJM 2015; Castillo Blood 2020). Fires to route ALGO-WM-2L step 1 to carfilzomib-based therapy (IND-WM-2L-CARFILZOMIB-CXCR4MUT) rather than zanubrutinib BTKi monotherapy (IND-WM-2L-ZANUBRUTINIB), as BTKi efficacy is substantially attenuated in CXCR4-mutated WM. Detection: CXCR4 C-terminal sequencing by targeted PCR + Sanger or NGS panel with CXCR4 C-terminus coverage. Note: stand...
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-WM-2L

Trigger Logic

{
  "any_of": [
    {
      "finding": "BIO-CXCR4-WHIM",
      "value": "positive"
    },
    {
      "finding": "BIO-CXCR4-WHIM",
      "value": "detected"
    },
    {
      "finding": "BIO-CXCR4-WHIM",
      "value": "mutant"
    },
    {
      "finding": "cxcr4_whim_mutation",
      "value": "positive"
    },
    {
      "finding": "cxcr4_mutation_status",
      "value": "positive"
    },
    {
      "finding": "cxcr4_mutation_status",
      "value": "WHIM"
    },
    {
      "finding": "cxcr4_mutation_status",
      "value": "mutant"
    }
  ],
  "type": "biomarker_status"
}

Notes

W5c RF authoring. Converts free-text `{condition: "CXCR4-WHIM mutation positive"}` in ALGO-WM-2L step 1 into a formal RF entity. Step 1 is a partial gate: the RF covers the CXCR4-mutation branch; the second branch ("bortezomib-intolerant due to baseline neuropathy AND PI-class still indicated") remains a free-text condition in the algo for MDT evaluation. Clinical rationale: CXCR4 WHIM mutations attenuate BTKi response in WM. In the iNNOVATORY-WM ibrutinib cohort, CXCR4-mutated patients had major response rate 36% vs 77% in CXCR4-WT (Treon NEJM 2015). In ASPEN zanubrutinib cohort, CXCR4 mutation status maintained as a predictive marker for attenuated response (Castillo Blood 2020 analysis). Carfilzomib-based regimens (carfilzomib + rituximab ± dexamethasone) are not BTKi-class and do not share this resistance mechanism. Note: ALGO-WM-2L step 1 also includes `condition: "Bortezomib-intolerant due to baseline neuropathy AND PI-class still indicated"` which is a clinical contraindication gate, NOT covered by this RF. That condition refers to bortezomib (step 1 routes to CaRd/carfilzomib-based, which is distinct from bortezomib). Keep as free-text MDT-evaluated condition. BMA-CXCR4-WH...

Used By

Algorithms

ALGO-WM-2L - ALGO-WM-2L