Background
Phase 2, open-label, single-arm study. N=30 patients with R/R Hairy Cell Leukemia (HCL) relapsed after or refractory to purine analog therapy, all BRAF V600E-mutated. Vemurafenib (BRAF V600E inhibitor) + rituximab was based on the rationale that BRAF inhibition induces response while rituximab consolidates and deepens remission. Published NEJM 2021.
Interventions and follow up
Regimen: Vemurafenib 960 mg orally twice daily × 8 weeks + rituximab 375 mg/m² IV every 2 weeks × 8 doses — relapsed/refractory hairy-cell leukemia
Primary endpoint: CR rate (BM biopsy-confirmed, standard HCL criteria)
mFollow up: 37 months
Primary endpoint: CR rate (BM biopsy-confirmed, standard HCL criteria)
mFollow up: 37 months
Results
CR rate: 100% (30/30)
uMRD (BM flow cytometry): 87% (26/30)
uMRD (allele-specific PCR for BRAF V600E): 67%
3-yr RFS: 78%
3-yr OS: 97%
uMRD (BM flow cytometry): 87% (26/30)
uMRD (allele-specific PCR for BRAF V600E): 67%
3-yr RFS: 78%
3-yr OS: 97%
Adverse events
Cutaneous/Constitutional: Rash/photosensitivity any grade 57%, grade ≥3 7%; keratoacanthoma/cutaneous SCC 13% (BRAFi class effect); arthralgia 43%; fatigue 43%
Infusion/Hematologic: Rituximab infusion reactions any grade 23%, grade ≥3 3%; no grade ≥3 hepatotoxicity
Other: Grade ≥3 AEs 27%; no treatment-related deaths
Infusion/Hematologic: Rituximab infusion reactions any grade 23%, grade ≥3 3%; no grade ≥3 hepatotoxicity
Other: Grade ≥3 AEs 27%; no treatment-related deaths
Conclusions
Vemurafenib + rituximab achieved a 100% CR rate with 87% uMRD negativity in purine-analog R/R HCL, with 78% 3-year RFS — the deepest remission data reported in R/R HCL, and a chemotherapy-free option that spares cumulative myelosuppression.
Key Limitations
Small single-arm trial: N=30, no comparator
Restricted to BRAF V600E: Not applicable to BRAF-wild-type HCL variant
Limited follow-up: 37 months; long-term relapse rates and re-treatment outcomes unknown
Restricted to BRAF V600E: Not applicable to BRAF-wild-type HCL variant
Limited follow-up: 37 months; long-term relapse rates and re-treatment outcomes unknown
Clinical Context
Vemurafenib + rituximab is a preferred chemotherapy-free regimen for relapsed/refractory BRAF V600E-mutated classic HCL, supported by high uMRD-negative CR rates. Single-agent vemurafenib produces shallower, less durable responses, supporting the rituximab combination. Alternatives include dabrafenib+trametinib, moxetumomab pasudotox, and venetoclax-based therapy; HCL variant (BRAF WT) does not respond to BRAF inhibitors.