Obinutuzumab (GA101) is highly effective against chronic lymphocytic leukemia cells in ex vivo B-cell depletion irrespective of high-risk prognostic markers

L Ysebaert,A Quillet-Mary,C Klein,E Laprévotte

doi:10.1038/bcj.2015.93

Abstract

The anti-CD20 monoclonal antibody rituximab has revolutionized the management of B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). Addition of rituximab to the frontline standard chemotherapy (fludarabine–cyclophosphamide, FC) within the rituximab fludarabine cyclophosphamide regimen has recently shown to statistically increase both progression-free survival (PFS) and overall survival (OS) in the randomized CLL8 phase III trial of the German CLL Group.1 This was the first example of improved OS in first-line CLL, although restricted to those patients fit enough to receive FC chemotherapy. However, the translation of these results into the clinical setting is hampered by the fact that ca. one half of CLL patients are 72 years at the time of first therapy, 40% being aged more than 75 years2 with increased burden of comorbidities (for example, kidney function impairment) and thus not eligible for FC chemotherapy.

Highlights

The anti-CD20 monoclonal antibody rituximab has revolutionized the management of B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL)
Obinutuzumab is a novel glycoengineered type II CD20 antibody that has enhanced FcgRIII affinity resulting in superior antibody-dependent cell cytotoxicity (ADCC) and antibody dependent cell phagocytosis induction as compared with rituximab; and mediates strong direct cell-death induction with a concomitant reduction in complement dependent cytotoxicity.[5]
In a series of ex vivotreated CLL whole-blood samples, Patz et al.[7] elucidated obinutuzumab mechanism of action against CLL cells, and demonstrated that the superior B-cell depletion of obinutuzumab observed is to a large extent due to enhanced ADCC through recruitment of (CD16)-bearing immune effector cells, as compared with rituximab at a saturating dose of 10 μg/ml

Summary

LETTER TO THE EDITOR

Obinutuzumab (GA101) is highly effective against chronic lymphocytic leukemia cells in ex vivo B-cell depletion irrespective of high-risk prognostic markers. We aimed to investigate whether rituximab and obinutuzumab B-cell depletion in ex vivo CLL samples is modulated by CLL-related prognostic markers, such as interphase fluorescent in situ hybridization (FISH) and conventional cytogenetics, immunoglobulin heavy-chain variable region mutational status (IGHV), β2microglobulin level, recurrent somatic mutations (for example, TP53, NOTCH1 and SF3B1) All these parameters have been linked to reduce efficacy of chlorambucil monotherapy in the UK LRF CLL4 trial.[12,13] To date, no study has evaluated the frequency of these molecular markers across patient's age groups, but it is likely that they can decrease the efficacy of chlorambucil and other chemotherapies, making it desirable to assess the efficacy of rituximab and obinutuzumab as a single agent in a large series of ex vivo-treated CLL samples. Occurence of SF3B1 mutation was rare in our cohort, despite a trend toward a slightly decreased efficacy for

Median leukocytosis per μl

Findings

CONFLICT OF INTEREST