Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma.

Abstract

Rituximab (IDEC-C2B8, Mabthera, Rituxan), a chimeric monoclonal antibody against the B-cell specific CD20-antigen, has been demonstrated to be effective in the treatment of non-Hodgkin's B-cell lymphoma (B-NHL). Previous in vitro studies have shown that direct complement-dependent cytotoxicity (CDC), ADCC and apoptosis are important in the rituximab-induced killing of lymphoma cells. It is, however, unknown whether rituximab penetrates the blood-brain barrier. Therefore, we studied rituximab levels and complement (C) activation in blood and cerebrospinal fluid (CSF) following intravenous rituximab therapy in a patient with relapsing non-Hodgkin's lymphoma with central nervous system (CNS) involvement. Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period. The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 microg/ml during the first 2 hours). After the first infusion the proportions of lymphocytes positive for the CD19- and CD20-antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both). In CSF the rituximab concentration increased after successive infusions, but remained below 0.55 microg/ml (compared to a Cmax of 400 microg/ml in peripheral blood). Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS. Thus, it appears that an intact blood-brain barrier restricts the entry of rituximab into the CNS. Possible options to circumvent this would be dose escalation or intrathecal rituximab treatment.

• Authors: A Harjunpää, T Wiklund, J Collan, R Janes, J Rosenberg, D Lee, A Grillo-López, S Meri
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 42 Issue 4 Pg. 731-8 (Aug 2001) ISSN: 1042-8194 [Print] United States
• PMID: 11697503 (Publication Type: Case Reports, Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• complement C3a, des-Arg-(77)-
• Rituximab
• Complement C3a

Topics

• Antibodies, Monoclonal (administration & dosage, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Murine-Derived
• Blood Circulation (immunology)
• Blood-Brain Barrier
• Central Nervous System (immunology)
• Cerebrospinal Fluid (chemistry, cytology, drug effects)
• Complement Activation (drug effects)
• Complement C3a (analogs & derivatives, cerebrospinal fluid, drug effects, metabolism)
• Humans
• Lymphoma, B-Cell (cerebrospinal fluid, drug therapy, pathology)
• Male
• Middle Aged
• Rituximab