Background
Phase 2, open-label, single-arm study. N=31 patients with R/R HCL or HCL variant (HCLv), heavily pretreated (median 3 prior therapies). Venetoclax + obinutuzumab was based on venetoclax's BCL-2 inhibition (HCL is BCL-2-dependent) plus obinutuzumab's anti-CD20 activity — the first prospective study of a BCL-2 inhibitor combination in HCL. Published NEJM Evidence 2023.
Interventions and follow up
Regimen: Venetoclax ramp-up to 400 mg PO daily + obinutuzumab IV (C1: 100 mg D1, 900 mg D2, 1000 mg D8/D15; C2–6: 1000 mg D1) — R/R HCL and HCL variant
Primary endpoint: CR rate (bone marrow biopsy-confirmed)
mFollow up: 25 months
Primary endpoint: CR rate (bone marrow biopsy-confirmed)
mFollow up: 25 months
Results
CR rate: 68%
ORR: 97%
uMRD (BM flow cytometry): 58% of all patients (85% of CRs)
2-yr PFS: 89%
2-yr OS: 100%
HCLv subgroup: ORR 100%, CR 50%
ORR: 97%
uMRD (BM flow cytometry): 58% of all patients (85% of CRs)
2-yr PFS: 89%
2-yr OS: 100%
HCLv subgroup: ORR 100%, CR 50%
Adverse events
Hematologic: Neutropenia grade ≥3 55% (most common); thrombocytopenia grade ≥3 23%
Infusion/TLS: Obinutuzumab infusion-related reactions any grade 48%, grade ≥3 3%; clinical TLS 0%, laboratory TLS 3%
Infections/Other: Grade ≥3 infections 13%; grade ≥3 AEs 58%; no treatment-related deaths
Infusion/TLS: Obinutuzumab infusion-related reactions any grade 48%, grade ≥3 3%; clinical TLS 0%, laboratory TLS 3%
Infections/Other: Grade ≥3 infections 13%; grade ≥3 AEs 58%; no treatment-related deaths
Conclusions
Venetoclax + obinutuzumab achieved a 68% CR rate and 97% ORR in R/R HCL/HCLv with 89% 2-year PFS — notably including HCL variant (BRAF WT), which does not respond to BRAF inhibitors or cladribine. This offers an important option for variant HCL and for patients who cannot receive vemurafenib or moxetumomab.
Key Limitations
Small single-arm study: N=31, no comparator; HCLv subgroup very small
Off-label combination: Neither agent is FDA-approved for HCL
Limited follow-up: 25 months; durability and optimal treatment duration undefined
Off-label combination: Neither agent is FDA-approved for HCL
Limited follow-up: 25 months; durability and optimal treatment duration undefined
Clinical Context
Venetoclax + obinutuzumab is used off-label for R/R HCL and is particularly valuable for HCL variant and BRAF-wild-type disease, where BRAF-targeted agents are ineffective and purine analogs are less active. It complements the R/R HCL armamentarium alongside vemurafenib±rituximab, dabrafenib+trametinib, and moxetumomab pasudotox; sequencing is individualized by mutation status and prior therapy.