New therapeutical approaches for meningeal leukemia: The role of high dose cytosine-arabinoside (HDARAC)

Pharmacokinetic studies have indicated a high degree of penetration of HDARAC across the blood-brain barrier into cerebrospinal fluid (CSF), resulting in cytotoxic drug concentrations of cytosine-arabinoside (ara-C). Based on these considerations, we treated with systemic HDARAC overt meningeal leukemia, either isolated or with concurrent extraneurologic disease, in 16 adults with acute lymphoblastic leukemia (ALL), in one with lymphoid blast crisis of chronic granulocytic leukemia (LBC-CGL), and in 5 non-Hodgkin's lymphomas (NHL) of high grade malignancy. Treatment consisted of are-C, 3 g/m² q 12 h, by 3 h infusion for 8 doses followed by a second course of 4 doses at day 21. Patients achieving complete remission (CR) received consolidation with monthly courses of HDARAC for 4 doses. Fourteen of 22 patients (64%) obtained CR:8/8 patients with isolated meningeal leukemia and 6/14 with concurrent central nervous system (CNS) and bone marrow disease. Of the remaining 8 patients, 6 had a complete CSF clearing with persistent marrow disease. In all cases there was prompt resolution of neurologic symptoms and signs. The median duration of CR was 5 mo (range 1-12+). The most important toxicity was meylosuppression, which was predictable and manageable. Non-hematologic toxicity was limited to tolerable nausea and vomiting, drug fever, mild hepatotoxicity. No cases of neurologic toxicity occurred. These results indicate that HDARAC is a tolerable and effective treatment modality for the induction of remission in all and NHL with CNS leukemia, suggesting the potential utility of this regimen for sanctuary chemoprophylaxis in patients at high risk for CNS disease.