KIT D816V activating point mutation (exon 17, activation loop) in advanced systemic masto...

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

ID	`RF-ADVSM-KIT-D816V`
Type	Red flag
Status	reviewed 2026-05-08 \| pending_clinical_signoff
Diseases	`DIS-MASTOCYTOSIS`
Sources	`SRC-EXPLORER` `SRC-NCCN-SM-2025` `SRC-PATHFINDER`

Red Flag Origin

Definition	KIT D816V activating point mutation (exon 17, activation loop) in advanced systemic mastocytosis (ASM, SM-AHN, mast cell leukemia per WHO 2022). KIT D816V is present in >90% of systemic mastocytosis cases and is the defining molecular driver. D816V confers resistance to imatinib (steric clash at the drug-binding site; imatinib is INACTIVE against D816V). However, avapritinib — a type I KIT inhibitor designed to bind the active (DFG-in) conformation — potently inhibits D816V kinase activity. Fires to route ALGO-ADVSM-1L step 1 toward avapritinib (IND-ADVSM-1L- AVAPRITINIB) as the preferred 1L option, contingent on adequate platelet count (≥50 ×10⁹/L; enforced as a separate condition in the step all_of gate). If platelets <50 ×10⁹/L or avapritinib is inaccessible despite D816V positivity, midostaurin (IND-ADVSM-1L-MIDOSTAURIN) remains appropriate. Clinical evidence: - PATHFINDER (avapriti...
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-ADVSM-1L

Trigger Logic

{
  "any_of": [
    {
      "finding": "BIO-KIT",
      "value": "D816V"
    },
    {
      "finding": "kit_mutation",
      "value": "D816V"
    },
    {
      "finding": "kit_d816v_status",
      "value": "positive"
    },
    {
      "finding": "kit_d816v_status",
      "value": "detected"
    },
    {
      "finding": "kit_d816v_status",
      "value": "mutant"
    },
    {
      "finding": "kit_exon17_mutation",
      "value": "D816V"
    }
  ],
  "type": "biomarker_status"
}

Notes

W5c RF authoring. Converts free-text `{condition: "KIT D816V positive"}` in ALGO-ADVSM-1L step 1 (all_of composite) into a formal RF entity. The step uses all_of: [biomarker gate, platelet-count gate] — this RF formalizes the biomarker half; the platelet-count condition (≥50 ×10⁹/L) remains a free-text MDT-evaluated condition in the algo (no platelet- threshold RF entity in current KB design). Clinical rationale: Avapritinib has superior molecular response depth vs midostaurin (KIT D816V VAF reduction in BM; Gotlib JCO 2023 PATHFINDER cohort). Platelet threshold of ≥50 ×10⁹/L is from avapritinib prescribing information due to risk of intracranial hemorrhage in severe thrombocytopenia. Midostaurin does NOT have this platelet restriction — rationale for algo step 2 fallback. Important KIT D816V disambiguation: This RF is for SYSTEMIC MASTOCYTOSIS (DIS-MASTOCYTOSIS). KIT mutations in GIST are exon 11/9/13/17, not the same D816V codon; imatinib is active against GIST KIT exon 11/9 but NOT D816V. This RF must NOT be triggered in GIST patients. The `relevant_diseases: [DIS-MASTOCYTOSIS]` constraint ensures disease-scoped routing. BMA-KIT-D816V-MASTOCYTOSIS (ESCAT IA): confirms evidence...

Used By

Algorithms

ALGO-ADVSM-1L - ALGO-ADVSM-1L