The anti-CD20 monoclonal antibody obinutuzumab (Gazyva) combined with bendamustine (Treanda; BG) in the frontline setting for patients with chronic lymphocytic leukemia was found to induce high rates of complete response and minimal residual disease negativity with no unexpected safety signals, according to results from a phase II open-label, multicenter study.
Jeff P. Sharman, MD
The anti-CD20 monoclonal antibody obinutuzumab (Gazyva) combined with bendamustine (Treanda; BG) in the frontline setting for patients with chronic lymphocytic leukemia was found to induce high rates of complete response (CR) and minimal residual disease (MRD) negativity with no unexpected safety signals, according to results from a phase II open-label, multicenter study.
Additionally, findings showed that the rate of CR or CR with incomplete blood count recovery (CRi) was 49.0%. In those patients with an investigator-assessed CR or CRi, MRD negativity was achieved by 86%, reported Jeff P. Sharman, MD, at the 2017 ASCO Annual Meeting.1
The 102 patients enrolled in the study received a median of 5.3 treatment cycles, or 88% of the 6 planned cycles, and were followed for a median of 11.0 months. Forty-eight of the 102 patients achieved a CR and 2 additional patients had a CRi at the end of therapy response visit, which occurred 2 to 3 months after the end of therapy, said Sharman, medical director of hematology research, US Oncology Network, and director of research, Willamette Valley Cancer Institute.
“There remains a population of patients for whom chemoimmunotherapy might be a desirable first-line therapy. In my mind, the stratification between a tyrosine kinase inhibitor versus chemotherapy falls along the IGHV mutation status. If you are mutated, you are going to have a more favorable response to chemotherapy. If you are going to give chemotherapy, this may be a suitable option for such a patient,” he said.
Although treatment of patients with CLL with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) has resulted in a median progression-free survival (PFS) of 55.2 months compared with 41.7 months for the combination of bendamustine and rituximab, FCR is associated with high rates of neutropenia, leukopenia, infections, and secondary neoplasms,2 he noted, especially among older patients.
In patients with CLL and comorbidities, obinutuzumab plus chlorambucil achieved a significantly longer PFS compared with rituximab plus chlorambucil (26.7 vs 15.2 months; HR, 0.39; P <.001).3 In previous studies, BG has shown promising efficacy and safety in the first-line setting in patients with CLL.
The purpose of the study presented at ASCO was to evaluate the safety and efficacy of BG induction therapy in patients with previously untreated CD20-positive CLL. Obinutuzumab was administered as an intravenous infusion of 100 mg on day 1 of cycle 1, 900 mg on day 2, 1000 mg on days 8 and 15; and 1000 mg on day 1 of the subsequent cycles. Bendamustine was administered as an intravenous infusion of 90 mg/m2 on days 2 and 3 of cycle 1, and on days 1 and 2 of cycles 2 through 6. Each cycle was 28 days.
At enrollment, the median patient age was 61 years and 44.1% had Rai stage 3/4 disease. Of the 70 patients with IGVH status evaluated, 23 had mutated IGVH and 47 had unmutated IGVH; status was unknown in 32 patients. Deletions of 17p, 11q, and 13q occurred at a rate of 3.9%, 9.8%, and 10.8%, respectively. The rate of intermediate-risk cytogenetics (trisomy 12) was 14.7%. Some 23.5% had normal cytogenetics and in 37.3%, the cytogenetic status was unknown.
“In this front-line study, we’re getting MRD-negative rates close to 90% in the peripheral blood. It puts this combination very favorably in context of prior frontline studies, using a regimen that is more tolerable than FCR,” said Sharman.
At the end of induction response visit, 32 of 75 evaluable patients (42.7%) achieved MRD negativity in the peripheral blood, including 32 of 36 (88.9%) evaluable patients who met International Workshop on CLL (iwCLL) test criteria, and 31 of 51 (60.8%) achieved MRD negativity in bone marrow. At any time after induction, 71 of 94 (75.5%) patients achieved MRD negativity in peripheral blood, including 71 of 82 (86.6%) of patients who met the iwCLL criteria.
Adverse events (AEs) were consistent with the known safety profile of obinutuzumab in patients with CLL. Seventy-five (73.5%) patients had an adverse event leading to dose modification or interruption of study drug, and 13.7% had an AE leading to withdrawal of any study drug.
The most frequent AEs of any grade were infusion-related reactions (72.5%), nausea (52.0%), and pyrexia (36.3%). The most commonly reported serious AE was pneumonia (5.9%) followed by pyrexia (4.9%) and febrile neutropenia (3.9%). The most common grade 3/4 AEs were neutropenia (26.5%) and a decrease in neutrophil count (10.8%). The authors attribute the low rate of grade 3/4 neutropenia to effective patient monitoring, prompt treatment of infections, and use of granulocyte-colony stimulating factor pretreatment in 47.1% of patients.
“The GREEN study had slightly higher rates of neutropenia; we used more G-CSF, and that seem to ameliorate that,” said Sharman. “In our study, G-CSF was optional but recommended.”