Central nervous system pharmacology of antileukemic drugs

The blood-brain barrier provides a pharmacologic sanctuary for leukemic cells within the central nervous system (CNS), protecting them from the cytotoxic effects of systemic antileukemic therapy. Attempts to overcome this problem have included specific CNS-directed treatment in the form of direct intrathecal drug injection, cranial irradiation, and alteration in the dose and schedule of systemic agents to enhance their CNS penetration. Use of these treatments and strategies has led to the effective prevention and control of meningeal leukemia. Intrathecal therapy, primarily with methotrexate or cytosine arabinoside, is a form of regional chemotherapy that can achieve very high drug concentrations at the target site [i.e., in the meninges and cerebrospinal fluid (CSF)] with a low total dose. Therefore, there is minimal systemic toxicity. The dose and schedules, clinical pharmacology, and toxicities of the commonly used intrathecal agents are discussed in detail in this article. Another approach to overcoming the limited penetration of antileukemic drugs into the CNS has been the use of high-dose systemic therapy. Methotrexate and cytosine arabinoside in high doses have produced favorable clinical responses in patients with overt meningeal disease, and pharmacokinetic studies have documented cytotoxic concentrations of these drugs within the cerebrospinal fluid. A clear understanding of the CNS pharmacology of the antileukemic drugs is required in order to use these agents in the safest and most efficacious manner for the treatment of meningeal leukemia.