Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment

Abstract

Most lymphomas that involve the central nervous system are B-cell neoplasms that express the cell surface molecule CD20. After intravenous administration, rituximab can be reproducibly measured in the cerebrospinal fluid (CSF) in patients with primary central nervous system lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma. Because lymphomatous meningitis is a frequent complication of nonHodgkin lymphoma, we have conducted an analysis of the safety and pharmacokinetics of direct intrathecal administration of rituximab using cynomolgus monkeys. No significant acute or delayed toxicity, neurologic or otherwise, was detected. Pharmacokinetic analysis suggests that drug clearance from the CSF is biphasic, with a terminal half-life of 4.96 hours. A phase 1 study to investigate the safety and pharmacokinetics of intrathecal rituximab in patients with recurrent lymphomatous meningitis will be implemented based on these findings. ( IntroductionCentral nervous system (CNS) involvement is associated with an adverse outcome in patients with non-Hodgkin lymphoma (NHL). 1 Most NHLs that involve the CNS are B-cell neoplasms that express CD20. 2 Dissemination within the leptomeninges represents a common pathway of progression in systemic NHL and primary CNS lymphoma and usually heralds neurologic deterioration and a fatal outcome. 3 Rituximab monoclonal antibody therapy is an effective treatment for B-cell NHL. [4][5][6][7] To date, preclinical and clinical practice involving rituximab has been limited to intravenous administration. This agent binds specifically to the antigen CD20, which is expressed on more than 90% of B-cell NHL and primary CNS lymphoma but is not expressed by normal neurons or glia in the brain.A number of preclinical models have demonstrated that therapeutic antibodies administered into the cerebrospinal fluid (CSF) are able to concentrate in and eradicate tumors within the craniospinal axis with minimal toxicity. 8,9 The primate model of drug delivery into the CSF represents a valid experimental model for the prediction of CSF drug pharmacokinetics in humans. [10][11][12][13] This is the first preclinical analysis of the safety and pharmacokinetics of rituximab administration within the craniospinal axis. Study designAll experimental procedures have been reviewed and approved by the Committee on Human Research and by the Committee on Animal Research, University of California, San Francisco.Four female cynomolgus monkeys, aged 16 to 18 years, weighing 3 to 5 kg, were obtained from Biosurg (Winters, CA). A total of 7 experiments were performed with one monkey in each experiment. Data are reported from the 4 experiments that involved suboccipital administration of rituximab. Three experiments used an Ommaya reservoir (Integra NeuroCare, Plainsboro, NJ) in the right lateral ventricle. Although intra-Ommaya administration of rituximab resulted in high CSF concentrations, the size of the res...

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

“…Under the conditions where the integrity of bloodbrain barrier (BBB) is intact, the presence of tight junctions prevents the transcellular route for diffusion of antibodies across the capillary. In general, antibody penetration into brain (cerebrospinal fluid (CSF)/serum partitioning) has been reported to be >0.1% in animal models and in human patients (88,89). These data are in line with the distribution of endogenous IgG subclasses in normal volunteers ranging from 800-to 1,000-fold less in CSF relative to that reported in serum (Fig.…”

“…Similarly, these data were reproduced following administration of weekly doses of rituximab in patients with central nervous system (CNS) lymphoma (the antibody in CSF was reproducibly detected at concentrations that were 1,000-fold less than that observed in serum). Therefore, alternative routes of administration, i.e., intrathecal route, were proposed to overcome the poor penetration of rituximab into the brain for treatment of CNS lymphoma (89).…”

Pharmacocinétique des anticorps monoclonaux

“…Plutôt que de transporter les IgG vers le SNC, le FcRn est probablement responsable d'une transcytose des IgG du SNC vers la circulation [2]. Une étude chez le singe a montré qu'après administration IV, le rituximab était mesuré dans le liquide céphalo-rachidien à des concentrations mille fois plus faibles que celles mesurées dans le sang [16]. Dans la même étude, le rituximab administré par voie intrathécale était rapidement éliminé du liquide céphalorachidien et mesurable dans le sérum [16].…”

“…Une étude chez le singe a montré qu'après administration IV, le rituximab était mesuré dans le liquide céphalo-rachidien à des concentrations mille fois plus faibles que celles mesurées dans le sang [16]. Dans la même étude, le rituximab administré par voie intrathécale était rapidement éliminé du liquide céphalorachidien et mesurable dans le sérum [16]. Le rôle du FcRn dans cet efflux des IgG reste cependant à confirmer [7].…”

A case of relapsed meningeal Burkitt's leukemia/lymphoma treated with intraventricular rituximab combined with high‐dose cytarabine

“…Based on the importance of direct complement-dependent cytotoxicity and apoptosis in rituximab-induced killing of lymphoma cells, pharmacokinetic studies have failed to demonstrate consistent rituximab CSF levels after systemic administration of conventional doses [3,4].…”