IGHV mutational status is a fundamental CLL risk stratifier and treatment-selection bioma...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-IGHV-UNMUTATED-CLL |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-04-27 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-CLL |
| Sources | SRC-ESMO-CLL-2024 SRC-MOZ-UA-CLL-2022 SRC-NCCN-BCELL-2025 |
Actionability Facts
| Biomarker | BIO-IGHV-MUTATIONAL-STATUS |
|---|---|
| Variant | IGHV-unmutated (≥98% homology to germline) — adverse risk; ~50-60% of CLL |
| Disease | DIS-CLL |
| ESCAT tier | IA |
| Recommended combinations | ibrutinib continuous monotherapy (1L IGHV-unmutated per SRC-NCCN-BCELL-2025, SRC-ESMO-CLL-2024), acalabrutinib ± obinutuzumab (1L IGHV-unmutated per SRC-NCCN-BCELL-2025), zanubrutinib continuous monotherapy (1L IGHV-unmutated per SRC-NCCN-BCELL-2025), venetoclax + obinutuzumab fixed-duration 12 mo (1L IGHV-unmutated per SRC-NCCN-BCELL-2025, SRC-ESMO-CLL-2024) |
| Contraindicated monotherapy | FCR (fludarabine/cyclophosphamide/rituximab) in IGHV-unmutated CLL (inferior PFS — explicitly not recommended per SRC-ESMO-CLL-2024), BR (bendamustine/rituximab) as preferred 1L in IGHV-unmutated young/fit (inferior to BTKi per SRC-NCCN-BCELL-2025) |
| Evidence summary | IGHV mutational status is a fundamental CLL risk stratifier and treatment-selection biomarker per SRC-NCCN-BCELL-2025, SRC-ESMO-CLL-2024, SRC-MOZ-UA-CLL-2022. IGHV-unmutated CLL has shorter response to chemoimmunotherapy (CIT — FCR, BR) and is now a strong indication for continuous BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib) or fixed-duration venetoclax-obinutuzumab as 1L regardless of TP53 status. CLL14 (Fischer NEJM 2019 — venetoclax + obinutuzumab fixed-duration vs chlorambucil + obinutuzumab) and ECOG E1912 (Shanafelt NEJM 2019 — ibrutinib + rituximab vs FCR) are foundational trials that demonstrated CIT inferiority specifically in IGHV- unmutated subgroups. ESMO 2024 explicitly recommends against FCR/BR 1L in IGHV-unmutated patients. |
Notes
ESCAT IA / OncoKB Level 2 (predictive biomarker — selects between drug classes, no targeted IGHV agent). IGHV-mutated favorable-risk patients without TP53 disruption have durable PFS with FCR (E1912 showed FCR was non-inferior to ibrutinib+rituximab in IGHV-mut), but FCR carries long-term MDS/AML risk so younger patients are increasingly offered targeted therapy regardless. Source-gap: SRC-CLL14-FISCHER-2019, SRC-ECOG-E1912-SHANAFELT-2019, SRC-ELEVATE-TN not yet ingested.
Used By
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