EZH2 gain-of-function mutation (most commonly Y641 hotspot — Y641F/N/S/H/C + occasional A...

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

ID	`RF-FL-EZH2-Y641-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-FL`
Sources	`SRC-ESMO-FL-2024` `SRC-NCCN-BCELL-2025`

Red Flag Origin

Definition	EZH2 gain-of-function mutation (most commonly Y641 hotspot — Y641F/N/S/H/C + occasional A682G/A692V) is present in ~25% of follicular lymphoma. Drives EZH2-dependent epigenetic silencing of tumor-suppressor genes. Tazemetostat (EPZ-6438) is FDA-accelerated-approved (2020) for R/R FL with EZH2-mutated disease after ≥2 prior systemic lines (Morschhauser et al., Lancet Oncology 2020; NCT01897571). Routes 3L+ FL with confirmed EZH2 hotspot to tazemetostat 800 mg PO BID over chemoimmunotherapy or PI3Ki.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-FL-2L

Trigger Logic

{
  "any_of": [
    {
      "finding": "ezh2_mutation",
      "value": true
    },
    {
      "finding": "ezh2_y641",
      "value": "positive"
    },
    {
      "finding": "ezh2_status",
      "value": "mutated"
    },
    {
      "finding": "ezh2_hotspot",
      "value": "positive"
    }
  ],
  "type": "biomarker"
}

Notes

Tazemetostat is also active in EZH2-wildtype FL (ORR 35%) but the approved indication is EZH2-mut after ≥2 lines (ORR 69%, mPFS 13.8 mo in mutant cohort). Order EZH2 hotspot panel (NGS or targeted PCR) at first relapse so the result is in hand by 3L decision point. Tolerability profile favorable vs PI3Ki (no AIH/colitis class effect, no requirement for PJP prophylaxis); main toxicity is asthenia and cytopenia. Off-target T-cell lymphoma signal in early development resolved at approved dose. Access UA: not NSZU-reimbursed — consider compassionate-use access or EU early-access programs.

Used By

Algorithms

ALGO-FL-2L - ALGO-FL-2L