San Francisco, CA—The results of a phase 1b study of the combination of venetoclax plus rituximab (Rituxan) showed encouraging safety and excellent activity in patients with chronic lymphocytic leukemia (CLL). Venetoclax will move on to a phase 3 trial comparing venetoclax plus rituximab versus bendamustine (Treanda) plus rituximab in patients with previously treated CLL. The drug is also being studied in acute myeloid leukemia (AML).
The study included 49 patients with relapsed/refractory CLL who had a maximum of 3 previous myelosuppressive regimens and no previous transplant. The complete response (CR) rate was encouraging.
“Venetoclax plus rituximab is highly active in relapsed/refractory CLL, achieving an overall response rate of 88% and a complete response rate of 31%. The results suggest that rituximab adds to the efficacy of venetoclax,” said lead investigator Andrew W. Roberts, MBBS, PhD, Bone Marrow Transplant Physician and Clinical Hematologist, Royal Melbourne Hospital, Parkville, Victoria, Australia.
“Seventeen patients became minimal residual disease-negative on treatment, which is impressive bone marrow clearance,” Dr Roberts noted.
Venetoclax (formerly ABT-199/GDC-0199) is an oral selective BCL-2 inhibitor that rapidly induces responses in approximately 80% of patients with relapsed/refractory CLL as a single agent. Venetoclax has synergy with rituximab in preclinical models of CD20-positive lymphoid malignancies. This study was undertaken to determine if the addition of rituximab would improve the efficacy of venetoclax.
The study was designed to identify a maximal tolerated dose of venetoclax and the optimal schedule for using the drug with rituximab and the safety of the combination, but remarkable bone marrow clearance was observed with this combination, said Dr Roberts.
Discontinuations were reported in 10 patients, 1 after the occurrence of tumor lysis syndrome, which led to adjustments in the schedule by modifying the dose of venetoclax and giving 1 dose of rituximab every 4 weeks. “The new schedule overcomes tumor lysis syndrome,” Dr Roberts said.
Venetoclax was generally well-tolerated, with mild gastrointestinal toxicity and grade 3 or 4 myelosuppression (47% neutropenia, 16% thrombocytopenia, and 14% anemia).
The overall response rate was 88%; 31% of patients achieved CR or CR with incomplete platelet recovery, 45% showed partial response (PR), and 12% showed unconfirmed PR.
“Good responses to the combination were observed in patients with del17p, known to have poor prognosis,” Dr Roberts said.
Overall, 9 of the 15 patients who achieved CR showed no minimal residual disease, and 1 patient with CR showed no minimal residual disease at 14 months. Of the patients with PR, 8 had no minimal residual disease. Of the 5 patients who achieved CR and discontinued therapy, none has progressed to date (up to 26 weeks).
Based on toxicity and efficacy data, 400 mg is the recommended dose. Slightly more neutropenia, gastrointestinal toxicity, and dose reductions were observed at higher doses.
During the question and answer session, Dr Roberts was asked about biomarkers for venetoclax. He said that most patients with CLL express BCL2 and are sensitive to this drug, and, in his opinion, biomarkers for response are not needed in this setting.
Acute Myeloid Leukemia
A separate presentation showed encouraging first results from a phase 2 clinical trial evaluating venetoclax in patients with AML, justifying further investigation of this drug in AML.
Venetoclax achieved an overall response rate of 15.5%; there were 5 patients who achieved CR, 4 of whom had incomplete platelet recovery. These responses were in patients with relapsed/refractory AML or patients who received venetoclax as frontline therapy but who were unfit for intensive treatment.
“AML is an aggressive cancer with low survival rates, and there is a high need for new, effective treatment options. The results of this trial of venetoclax are encouraging and warrant additional study in patients with AML,” said Marina Y. Konopleva, MD, PhD, Associate Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston.