Bendamustine Followed by Obinutuzumab Plus Venetoclax in Treatment-Naive and Relapsed/Refractory CLL
In a German phase II trial reported in The Lancet Oncology, Cramer et al found promising response rates with bendamustine followed by obinutuzumab (Gazyva) plus venetoclax (Venclexta) in both treatment-naive and relapsed/refractory chronic lymphocytic leukemia (CLL).
In the trial, patients with an absolute lymphocyte count ≥ 25,000 cells/μL or lymph nodes ≥ 5 cm in diameter received sequential treatment, starting with debulking with two cycles of bendamustine at 70 mg/m2 on days 1 and 2 of each of two 28-day cycles. Debulking was followed by induction and maintenance with obinutuzumab at 1,000 mg on days 1, 2, 8, and 15 of the first induction cycle; every 4 weeks in induction cycles 2 to 6; and every 12 weeks as maintenance. In addition, oral venetoclax was started in induction cycle 2 at 20 mg/d and then escalated weekly over 5 weeks to the target dose of 400 mg/d.
The primary endpoint was the proportion of patients achieving overall response at the end of induction. Patients who received at least two induction cycles were included in the efficacy analysis.
Response Rates
Of a total of 66 patients enrolled between May 2015 and January 2016, 3 were excluded from efficacy analysis on the basis of receiving less than 2 induction cycles. Of the remaining 63 patients, 34 (54%) were treatment-naive and 29 (46%) had relapsed or refractory disease. At the end of the induction, response was achieved in 60 patients (95%), including all 34 treatment-naive patients (100%) and 26 patients with relapsed/refractory disease (90%).
Among responders, complete remission, clinical complete remission/complete remission with incomplete recovery of bone marrow, and partial response occurred in 9%, 41%, and 50% of treatment-naive patients and 7%, 21%, and 62% of relapsed/refractory patients, respectively. Also among responders, 91% and 83% were minimal residual disease–negative in the peripheral blood.
Adverse Events
The most common grade 3 or 4 adverse events were neutropenia (11%), anemia (11%), thrombocytopenia (6%), and infection (6%) during debulking and neutropenia (44%); and infection (14%), thrombocytopenia (12%), infusion-related reactions (8%), and secondary primary malignancy (6%) during induction. A total of 89 serious adverse events were reported, consisting primarily of infections (4 in 4 patients during debulking and 18 in 11 patients during induction) and cytopenia. Death occurred in 5 relapsed/refractory patients, with 3 deaths due to sepsis considered related to the study treatment.
The investigators concluded, “The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favorably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation.”
Paula Cramer, MD, of the German CLL Study Group, University of Cologne, is the corresponding author for The Lancet Oncology article.
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