Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia

Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton's tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Due to the synergistic anti-tumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N=46) and Richter's transformation (RT, N =5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and AST and/or ALT elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome (TLS) related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with 100% of evaluable patients responding with 38% complete responses. The end of treatment rate of uMRD at 10-4 in bone marrow was 77% (30 out of 39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for relapsed/refractory CLL patient including those who have been previously treated with covalent BTK inhibitors. This trial was registered on ClinicalTrials.gov under identifier: NCT03379051.