Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate-grade non-Hodgkin's lymphoma

Central nervous system (CNS) relapse of non-Hodgkin's lymphoma (NUL) is usually fatal despite therapy and effective prophylaxis is desirable. Patients at high-risk usually receive intrathecal (IT) prophylaxis, although its efficacy is unproven. We therefore analyzed the outcome of all patients with newly diagnosed intermediate-grade NHL receiving IT prophylaxis from 1991 to 1999. Twenty-six patients were identified and analyzed. All were free of CNS involvement at diagnosis with negative cerebrospinal fluid (CSF) cytology. Disease stage was IE in 7, and IV in 19, with a median of two extranodal sites involved. Serum lactate dehydrogenase was elevated in 65%, and the median International Prognostic Factors Index score was 3 (range 0-5). Anthracycline-based chemotherapy was used in all cases and included high-dose methotrexate +/- ara-C in six patients. The median number of IT treatments was 5 (range 1-12) and comprised methotrexate +/- steroid in 15, together with ara-C in 11. The actuarial 3-year CNS-relapse rate was 26 +/- 10%. Six CNS-relapses were observed and involved the spinal cord or brain parenchyma in two cases each, and the leptomeninges in four patients. Treatment-related variables associated with higher CNS-relapse rates (34-50%) were: delay of greater than or equal to 14 days from diagnosis to first IT injection, < 5 IT treatments, delay of IT prophylaxis until after attaining CR and systemic treatment lacking high-dose methotrexate +/- ara-C (each P less than or equal to 0.17). IT CNS prophylaxis, as used here, was inadequate. Alternative approaches should be pursued.