In Search of the Right Sequence for Venetoclax in CLL
Researchers reveal the results of the phase 2 CLL2-BAG trial, which evaluated sequential bendamustine followed by obinutuzumab and venetoclax in patients with CLL.
Although venetoclax has shown to be effective as a monotherapy in chronic lymphocytic leukemia (CLL), its efficacy when combined with other medications is unclear.
In a new study, researchers hypothesized that venetoclax in combination with obinutuzumab might “increase the depth of response” that was seen in a prior CLL trial with venetoclax alone.1
The trial enrolled 66 patients and 63 were evaluable by the study's conclusion, drawn from 20 sites in Germany.
Patients with an absolute lymphocyte count of at least 25,000 cells/μL or lymph nodes at least 5 cm in diameter received debulking treatments, with 2 cycles of bendamustine at 70 mg/m2 on days 1 and 2 of two 28-day cycles. Then, they received obinutuzumab at 1000 mg on days 1, 2, 8, and 15 of the first induction cycle and every 4 weeks in induction cycles 2 to 6. Oral venetoclax was started in cycle 2 at 20 mg daily and then escalated to the target dose of 400 mg daily.
At 12 weeks following the start of the last induction cycle, 60 of 63 (95%) evaluable patients were labeled responders, including all 34 (100%) treatment-naive patients and 26 (90%) patients with relapsed/refractory disease. The primary end point was the share of patients who achieved an overall response at the end of induction. Five patients (8%) experienced complete remission and 55 had a partial response.
A response to initial debulking with bendamustine alone, before even receiving obinutuzumab or venetoclax, was seen in 24 of 45 (53%) patients — and 34 of 47 (72%) patients experienced adverse events during debulking.
There were 89 treatment-related adverse events identified during the study (69 due to treatment), including neutropenia (44%), infection (14%), thrombocytopenia (12%), infusion-related reactions (8%), and secondary primary malignancy (6%). Five relapsed or refractory patients died; 3 deaths due to sepsis were attributed to treatment. Though no patients discontinued treatment as a result of adverse events, more than half of the hematological toxicities led to dose modifications, and the most frequently modified dose was venetoclax.
“The efficacy of the study treatment regime achieved in this mixed population is encouraging, especially since the [minimal residual disease] negativity rate of 91% in the peripheral blood in the treatment-naive cohort is among the highest reported so far in chronic lymphocytic leukemia,” the investigators wrote.1
While the authors of an accompanying editorial agreed that the results from CLL2-BAG (ClinicalTrials.org Identifier: NCT02401503) appeared promising, they added, “given the incidence of infectious complications in the debulking phase, the role of bendamustine in this regimen might have to be reconsidered.” Despite this issue, the authors predicted that “venetoclax will likely become an integral part of chronic lymphocytic leukemia therapy.”2
- Cramer P, von Tresckow J, Bahlo J, et al. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial [published online August 13, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30414-5
- Kallam A, Armitage JO. Venetoclax in chronic lymphocytic leukaemia: a possible cure? [published online August 13, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30442-X