HAEMATOLOGICA, vol.103, no.11, pp.1889-1898, 2018 (SCI-Expanded)
The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, Phase 3b study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg, alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients or bendamustine for any patient), on day 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over 2 days. The primary endpoint was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil and 538 with obinutuzumab-bendamustine). Grade >= 3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%) and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade >= 3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% (clinical and laboratory; highest incidence with obinutuzumab-bendamustine [9.3%]) and infections in 53.7% (grade >= 3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at 3 months post-treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. Clinicaltrials.gov identifier: NCT01905943.