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Clinical Trial
. 2002 Feb 1;99(3):1038-43.
doi: 10.1182/blood.v99.3.1038.

The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction

John C Byrd  1 , Shinichi Kitada, Ian W Flinn, Jennifer L Aron, Michael Pearson, David Lucas, John C Reed
Affiliations
Free article
Clinical Trial

The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction

John C Byrd et al. Blood. .
Free article

Abstract

Rituximab is a chimeric monoclonal antibody directed at CD20 with significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a proportion of patients with CLL receiving rituximab treatment have in vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a pathway similar to fludarabine and other chemotherapeutic agents is intricately involved in the blood elimination of tumor cells after rituximab treatment. Patients having caspase-3 activation and PARP cleavage in vivo had a significantly lower blood leukemia cell count after treatment as compared to those without caspase activation. Significant down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also noted, possibly explaining in part how rituximab sensitizes CLL cells to the cytotoxic effect of chemotherapy in vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on induction of apoptosis and provides another area of focus for studying mechanisms of antibody-resistance in neoplastic cells.

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