MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma: the Nordic Lymphoma Group MCL7 VALERIA trial.

Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multi-centre phase Ib-II trial, we evaluated safety and efficacy of minimal residual disease (MRD)-driven venetoclax, lenalidomide and rituximab in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary endpoint was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase II dose was lenalidomide 20 mg daily, days 1-21, venetoclax 600 mg daily after ramp-up, and rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in blood was reached, treatment was continued for another 3 months. If then confirmed, treatment was stopped. 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission (CR), 8 partial remission (PR)) and 40% (4 CR, 2 PR) for patients previously failing a BTK inhibitor. Median progression-free survival (PFS) was 21 months, and median overall survival 31 months. TP53 mutation was associated with inferior PFS (p<0.01). 28 pts (48 %) discontinued treatment in molecular remission, and 25 remain MRD-negative after a median of 17.4 months. Hematological toxicity was frequent, with 52/59 (88%) pts with G3-4 neutropenia and 21/59 (36%) pts with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax, lenalidomide and rituximab is feasible, tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure.