Michael Choi, MD
Combining the BCL-2 inhibitor venetoclax (Venclexta) with the anti-CD20 agent rituximab (Rituxan) led to objective responses in 86% of patients with relapsed/refractory chronic lymphocytic leukemia (CLL), results from the phase Ib M13-365 study showed.
A majority of the 49 patients involved in the trial achieved complete responses with or without complete hematologic recovery.
“Venetoclax plus rituximab is highly active in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL),” said Michael Choi, MD, an assistant professor of Medicine at the University of California, San Diego. “Bone marrow biopsy in all patients showed that 57% were MRD negative.”
The most frequently reported grade 3/4 adverse events were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%), Choi reported. Nonhematologic toxicities were common but generally mild, the most common being gastrointestinal toxicity.
As a single agent, venetoclax has been shown to induce rapid and deep responses in patients with relapsed/refractory CLL/SLL. About 80% of patients achieve objective responses, and 20% attain complete responses.
Studies involving preclinical models of CD20-positive lymphoid malignancies suggested therapeutic synergy with the combination of venetoclax and rituximab. Investigators in a multicenter trial evaluated the combination in an open-label clinical study involving patients with relapsed/refractory CLL/SLL.
Eligible patients met the International Working Group on CLL criteria for treatment, had an ECOG performance status of 0 or 1, and had acceptable hematologic, hepatic, and renal laboratory values.
The patients received venetoclax doses ranging from 200 to 600 mg/day plus rituximab at a starting dose of 375 mg/m2 on day 1 of the first month and then 500 mg/m2 on day 1 of months 2 through 6. The experience with venetoclax identified 400 mg/day as the recommended phase II dose.
Patients who achieved complete remission could stop venetoclax but remain on study. One patient who achieved an MRD-negative partial response also opted to stop venetoclax.
Patients who stopped treatment were monitored at 3-month intervals for disease progression. If the disease progressed, patients could restart venetoclax, following a weekly ramp-up dosing schedule.
Primary outcome measures were to evaluate objective response, complete response, MRD rate, outcomes in patients who stopped venetoclax after achieving a complete response or MRD-negative partial response, and to assess retreatment with venetoclax in patients who had progressive disease off therapy.
The 49 patients had a median age of 68 and had received a median of 2 prior therapies. Choi said that 28 patients (57%) previously had rituximab and 28 had received fludarabine-containing therapy. He also reported that 21 patients were rituximab refractory and nine were fludarabine refractory. Nine patients had a 17p deletion.
The data showed that 51% of patients achieved complete response with or without complete hematologic recovery and 35% attained partial response. Only 2 patients had progressive disease as best response.
An analysis of bone marrow response showed that the combination led to MRD-negative complete responses in 20 patients, MRD-positive complete responses in 5 patients, MRD-negative partial responses in 8 patients, and MRD-positive partial responses in 8 patients. Six patients were not evaluable.
The median time to complete response was 8.5 months. Choi reported that 13 patients who achieved deep objective responses stopped venetoclax after a median treatment duration of 10 months. In 10 of 13 cases, patients attained MRD-negative complete responses, and 1 patient had an MRD-negative partial response. Two additional patients with MRD-positive complete responses also stopped venetoclax.
The patient who stopped venetoclax after achieving a MRD-negative partial response at 3 months remained MRD-negative at 7 months.
The 2 patients who achieved MRD-positive complete responses both developed asymptomatic CLL progression after 24 months off therapy and both restarted venetoclax. One patient achieved a partial response with 10% bone marrow involvement with venetoclax monotherapy. Rituximab was subsequently added to treatment in an attempt to achieve a deeper response.
The second patient achieved a partial response with venetoclax monotherapy and remains on treatment, Choi reported.
Based on data from this trial, the FDA granted a breakthrough therapy designation to venetoclax in January 2016 for use in combination with rituximab to treat patients with relapsed/refractory CLL. The designation will expedite the development and review of the combination in this setting.
The FDA granted an accelerated approval to single-agent venetoclax in April 2016 for the treatment of patients with CLL who have a 17p deletion and have received at least 1 prior therapy.