Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody‐dependent cytotoxicity and improves overall survival against CD20+ rituximab‐sensitive/‐resistant Burkitt lymphoma (BL) and precursor B‐acute lymphoblastic leukaemia (pre‐B‐ALL): potential targeted therapy in patients with poor risk CD20+ BL and pre‐B‐ALL. (16th October 2015)

• Record Type: Journal Article
• Authors: Awasthi, Aradhana; Ayello, Janet; Van de Ven, Carmella; Elmacken, Mona; Sabulski, Anthony; Barth, Matthew J.; Czuczman, Myron S.; Islam, Humayun; Klein, Christian; Cairo, Mitchell S.
• Is Part Of: British journal of haematology. Volume 171:Number 5(2015:Dec.)
• Page Start: 763
• Page End: 775
• Publication Date: 2015-10-16
• Subjects: rituximab‐sensitive BL -- rituximab‐resistant BL -- pre‐B‐ALL -- obinutuzumab -- rituximab; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13764
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: Obinutuzumab is a novel glycoengineered Type‐II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B‐cell acute lymphoblastic leukaemia (pre‐B‐ALL). We evaluated the anti‐tumour activity of obinutuzumab versus rituximab against rituximab‐resistant (Raji 4RH) and ‐sensitive (Raji) BL and pre‐B‐ALL (U698‐M) cells in vitro and in human BL or Pre‐B‐ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, ( P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% ( P = 0·001) and U‐698‐M 47·3 ± 4·9% vs. 23·2 ± 0·5% ( P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody‐dependent cellular cytotoxicity (ADCC) with K562‐IL15‐41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% ( P = 0·001), Raji‐4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% ( P = 0·001) and U‐698‐M 70·0 ± 1·6% vs. 45·5 ± 0·1% ( P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji ( P = 0·05), Raji4RH ( P = 0·02) and U698‐M ( P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab‐sensitive/‐resistant BL and pre‐B‐ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20 + BL and/or pre‐B‐ALL.