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Intrathecal 6-Mercaptopurine: Preclinical Pharmacology, Phase I/II Trial, and Pharmacokinetic Study

Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892 [P. C. A., F. M. B., C. A. A., R. F. M., A. J. G., D. G. P.], Children's Hospital of Los Angeles, Los Angeles, California 90054 [J. S. H.], and Pharmacy Department, NIH, Bethesda, Maryland 20892 [P.K.N.]

For over 30 years, oral 6-mercaptopurine (6-MP) has been a mainstay of systemic maintenance therapy for acute lymphoblastic leukemia. Despite its efficacy as an antileukemic agent, 6-MP has not been previously administered by the intrathecal (IT) route. In anticipation of a clinical trial of IT 6-MP, preclinical cytotoxicity and pharmacology studies were performed to define a safe, effective dose. The optimal concentration (>1 µM) and duration of exposure (>12 h) to 6-MP required for cytotoxicity were determined in vitro using human leukemia cell lines. The dose required to achieve the desired cerebrospinal fluid concentrations in humans was derived from pharmacokinetic parameters determined in rhesus monkeys. A phase I/II study was then performed in pediatric patients with refractory meningeal leukemia. Nine patients (aged 3.5 to 16 years) with chronic meningeal leukemia (2 to 6 central nervous system relapses) were entered onto the study. All had previously failed, at a minimum, IT methotrexate, IT cytarabine, and cranial (± spinal) radiation. A 10-mg IT dose of 6-MP (calculated to produce cytotoxic cerebrospinal fluid levels for 12 h) was administered twice weekly for 4 weeks. There were four complete responses and three partial responses. The duration of complete responses ranged from 7 to 22 weeks. Observed toxicities were not dose limiting and included mild headache (three patients) and minimal nausea (two patients). Pharmacokinetic studies performed in patients confirmed that cerebrospinal fluid concentrations of 6-MP were >1 µM for 12 h. These results indicate that the IT administration of 6-MP is feasible, is not associated with significant toxicity, and has definite activity in patients with refractory meningeal leukemia.

¹ To whom requests for reprints should be addressed, at Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, 9000 Rockville Pike, Bethesda, MD 20892.

² Present address: Mayo Clinic, Rochester, MN 55905.

³ Present address: Adria Laboratories, Columbus, OH 43216.

Received 7/10/91. Accepted 9/11/91.

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