Obinutuzumab, lenalidomide, and venetoclax for the initial treatment of patients with advanced-stage follicular lymphoma: Results of the Phase Ib/II LEVERAGE study.

Follicular lymphoma (FL) is the most common indolent lymphoma. Although chemoimmunotherapy is effective, toxicity remains problematic, and novel treatments are required. We performed a Phase Ib/II study of obinutuzumab, lenalidomide, and venetoclax in patients with treatment-naïve, high tumor burden, advanced-stage FL. During induction (6 × 28-day cycles), patients received obinutuzumab and venetoclax (in four dose levels from 400 mg day [D]1-10 to 800 mg daily) from Cycles 1 to 6 and lenalidomide (20 mg Days 1-21) from Cycles 2 to 6. Patients with complete response (CR) received 2 years maintenance obinutuzumab, while partial responders received 2 years obinutuzumab plus 6 months of venetoclax and lenalidomide. Genomic characterization and measurable residual disease (MRD) monitoring were performed using targeted next-generation sequencing (NGS) by circulating tumor DNA (ctDNA). Fifty patients were enrolled with a median age 60. No maximum tolerated dose was defined, and the Phase II dose of venetoclax was 800 mg daily. The CR rate and objective response rate were 86% and 92%, respectively. At median follow-up of 18.3 months, the 2-year progression-free survival and overall survival rates were 92% and 100%, respectively. The most common any-grade adverse events were neutropenia (72%), diarrhea (52%), and upper respiratory infection (48%). Undetectable MRD after one cycle of therapy had a 95% negative predictive value for relapse, while detectable MRD after three cycles of therapy had a 75% positive predictive value. Obinutuzumab, lenalidomide, and venetoclax are active in patients with treatment-naïve high tumor burden FL; however, myelosuppression impacted deliverability. ctDNA MRD is a promising biomarker in FL.