Bendamustine followed by obinutuzumab and venetoclax appeared safe and effective for treatment of patients with chronic lymphocytic leukemia, according to results from the open-label, phase 2 CLL2-BAG trial.
Ninety-five percent of patients who completed at least two cycles of induction had responses, and researchers observed no unexpected or cumulative toxicities.
“Several targeted agents for CLL with impressive activity have become available in recent years, leading to profound changes in the treatment of this disease,” Paula Cramer, MD, a member of the German CLL Study Group and physician in the department of internal medicine at University Hospital in Cologne, Germany, and colleagues wrote. “Venetoclax [Venclexta; AbbVie, Genentech] induces programmed cell death through selective inhibition of the antiapoptotic B-cell lymphoma-2 protein, which is upregulated in CLL cells. ... We hypothesized that combining venetoclax with the more potent type II anti-CD20 antibody obinutuzumab [Gazyva, Genentech] would further increase the depth of response.”
The analysis included 66 adults (median age, 59 years; 76% men) with CLL, 35 of whom were treatment naive and 31 of whom had relapsed/refractory disease.
Patients with high tumor burden received debulking with two cycles of 70 mg/m2 IV bendamustine on the first and second days of each 28-day cycle.
The induction phase included six cycles of 1,000 mg IV obinutuzumab on days 1, 2, 8 and 15 for the first induction cycle and every 4 weeks in cycles 2 through 6; oral venetoclax started during cycle 2 at 20 mg daily with weekly dose escalation over 5 weeks to a target dose of 400 mg daily.
During the maintenance phase, patients received 1,000 mg obinutuzumab every 12 weeks and venetoclax for up to 24 months.
Overall response rate according to investigator assessment served as the primary endpoint.
Investigators excluded three patients from the efficacy analysis because they received fewer than two induction cycles.
Median follow-up was 16 months.
At the end of induction, 95% of patients (95% CI, 87-99) had responded, including 100% (n = 34) of treatment-naive patients and 90% (n = 26) of relapsed/refractory patients.
Eighty-seven percent (n = 55) of patients achieved minimal residual disease negativity in peripheral blood.
Researchers included all patients who received at lease one dose of the study drug in the safety analysis.
The most common grade 3 or grade 4 adverse events observed during debulking included neutropenia (11%), anemia (11%), thrombocytopenia (6%) and infection (6%).
The most common grade 3 or grade 4 adverse events observed during induction included neutropenia (44%), infection (14%), thrombocytopenia (12%), infusion-related reaction (8%) and secondary primary malignancy (6%).
Overall, researchers observed 89 serious adverse events — including 69 they deemed related to treatment — the most common of which were infections and cytopenia.
Five deaths occurred among relapsed/refractory patients, including three cases of sepsis deemed treatment-related and two of Richter’s transformation that were not related to treatment.
“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote. “Furthermore, the fact that an all-comer population, including patients with few or no other therapeutic options, was included into this trial needs to be taken into account. Except for the three fatal sepsis cases, adverse events were generally manageable.”
Although these results are promising, especially based on occurrence of minimal residual disease negativity, the role of bendamustine in this regimen might have to be reconsidered given the incidence of infections during debulking, Avyakta Kallam, MD, and James O. Armitage, MD, of University of Nebraska Medical Center, wrote in an accompanying editorial.
“In particular, in patients with previous exposure to bendamustine or other chemotherapy regimens containing fludarabine, re-exposure to bendamustine might put them at an increased risk of infections without much benefit,” Kallam and Armitage wrote.
With more drug combinations under evaluation for CLL, studies will be required to determine the best drug sequence and appropriate usage, they added.
“Although long-term follow-up is necessary to establish the duration of responses after venetoclax is stopped, venetoclax will probably become an integral part of CLL therapy,” Kallam and Armitage wrote. “There is reason to hope that combinations such as ibrutinib [Imbruvica; Pharmacyclics, Janssen], obinutuzumab or rituximab [Rituxan; Genentech, Biogen], and venetoclax will induce true complete remissions in most treatment-naive patients and that some of these complete responders will ultimately be cured.” – by Cassie Homer
Disclosures: AbbVie and F. Hoffmann-La Roche funded the study. Cramer reports research funding from F. Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis; honoraria from F. Hoffmann-La Roche and Janssen-Cilag; advisory board roles with AbbVie, AstraZeneca, Janssen-Cilag and Novartis; and travel grants from F. Hoffmann-La Roche, Gilead, Janssen-Cilag and Mundipharma. Please see the study for all other authors’ relevant financial disclosures. Armitage reports personal fees from Ascentage and Samus Therapeutics, a board of directors role with Tesaro, and an independent data monitoring committee member role with Conatus. Kallam reports no relevant financial disclosures.