Bendamustine/Rituximab Induction Followed by Venetoclax/Rituximab Consolidation in Frontline Treatment of Chronic...

We hypothesized that a time-limited frontline treatment strategy with abbreviated chemoimmunotherapy followed by targeted consolidation could achieve durable disease control with manageable toxicity in CLL. We evaluated the safety and efficacy of short-course bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation. In a multicenter, single-arm Phase 2 trial (NCT03609593), previously untreated CLL/SLL needing therapy received BR for three 28-day cycles followed by venetoclax ramp-up to 400 mg daily plus rituximab every 28 days for six cycles; venetoclax continued to 12 cycles (total treatment, 15 months). The primary endpoint was overall response rate (ORR); key secondary endpoints included uMRD, PFS/OS, and safety per CTCAE v4. Forty-two patients were enrolled (median age 61.5 years; 64% unmutated IGHV; 29% complex karyotype; 10% TP53 aberrancy); 93% completed all planned therapy. At end of treatment, ITT ORR was 86% (CR/CRi 64%, PR 21%); among efficacy-evaluable patients, ORR was 100% (CR/CRi 75%). End-of-therapy uMRD was achieved by 83% in bone marrow and 84% in blood among efficacy-evaluable patients. Three-year PFS and OS were 87.5% and 92.7%. TLS risk was downstaged after BR, and no TLS events occurred. Febrile neutropenia occurred in 12% of patients. Two on-study deaths due to COVID-19 occurred; no Richter transformation occurred. Time-limited BR-VR achieved high uMRD rates and durable remissions with a manageable safety profile. While the treatment landscape in CLL has largely shifted toward chemotherapy-free regimens, these data demonstrate the biological proof-of-concept that limited induction chemotherapy can effectively mitigate TLS risk and facilitate safe outpatient ramp-up of venetoclax.