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Chronic Lymphocytic Leukemia
Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study
Ferrata Storti Foundation
Véronique Leblond,1 Melih Aktan,2 Christelle M. Ferra Coll,3
Caroline Dartigeas,4 Jens Kisro,5 Marco Montillo,6 João Raposo,7 Jean-Louis Merot,8 Susan Robson,9 Ekaterina Gresko,9 Francesc Bosch,10 Stephan Stilgenbauer11 and Robin Foà12
1UPMC GRC11-GRECHY, AP-HP Hôpital Pitié-Salpêtrière, Paris, France; 2Istanbul Üniversitesi, Turkey; 3Institut Català d'Oncologia (ICO), Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Barcelona, Spain; 4Hôpital Bretonneau CHU de Tours, France; 5Onkologische Schwerpunktpraxis Lübeck, Germany; 6Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 7Hospital de Santa Maria, Lisbon, Portugal; 8IQVIA, St Ouen, France; 9F. Hoffmann-La Roche Ltd., Basel, Switzerland; 10University Hospital Vall d’Hebron, Barcelona, Spain; 11Internal Medicine III, Ulm University, Germany and 12Hematology, ‘Sapienza’ University,
Haematologica 2018 Volume 103(11):1889-1898
Rome, Italy
ABSTRACT
The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb 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 days 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 two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treat- ed (126 with obinutuzumab monotherapy, 193 with obinutuzumab-flu- darabine-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%), throm- bocytopenia (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 dur- ing the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-ben- damustine (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 three months post treatment exceeded 80% for all obinutuzumab-chemotherapy com- binations. 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: 01905943).
Introduction
Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 antibody, which has demonstrated significant activity and adequate tolerability in chronic lympho- cytic leukemia (CLL), including studies where the drug was administered as monotherapy or combined with chemotherapy.1-7 Based on the results of the piv- otal phase III CLL11 trial,2,3 in which the combination of obinutuzumab and chlo- rambucil (G-Clb) was shown to be clinically superior (in terms of progression-free survival and treatment response) to rituximab plus chlorambucil in adult patients with previously untreated CLL and comorbidities, obinutuzumab was approved
Correspondence:
veronique.leblond@aphp.fr
Received: December 21, 2017. Accepted: July 4, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2017.186387
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1889
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