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.