ABSTRACT
Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.
Subject(s)
Antineoplastic Agents/therapeutic use , Arginine/analogs & derivatives , Butyrates/therapeutic use , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/virology , Ganciclovir/therapeutic use , Lymphoma/drug therapy , Lymphoma/virology , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Arginine/adverse effects , Arginine/pharmacokinetics , Arginine/therapeutic use , Butyrates/adverse effects , Butyrates/pharmacokinetics , Child , Child, Preschool , Drug Therapy, Combination , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/pathology , Female , Ganciclovir/adverse effects , Ganciclovir/pharmacokinetics , Humans , Lymphoma/etiology , Lymphoma/pathology , Male , Middle AgedABSTRACT
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 non-Hodgkin 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.
