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Multicenter phase I trial of intraventricular immuno-chemotherapy in recurrent CNS lymphoma

James L. Rubenstein, Jing Li, Lingjing Chen, Ranjana Advani, Jan Drappatz, Elizabeth Gerstner, Tracy Batchelor, Hendrikus Krouwer, James Hwang, Glenna Auerback, Cigall Kadoch, Clifford Lowell, Pamela Munster, Soonmee Cha, Marc A. Shuman, Lloyd E. Damon

Abstract

Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although intravenous administration of rituximab mediates superior disease control of systemic non-Hodgkin's lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely because of minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy in systemic lymphoma, we conducted the first phase I study of intraventricular immuno-chemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg (N=3) or 25 mg (N=11) intraventricular rituximab twice-weekly over four weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (12 mg) during the second treatment each week. Greater than 150 doses were administered without serious toxicity. In a population with NHL refractory to a median of five prior therapies, 75% of patients achieved complete cytologic cerebrospinal fluid (CSF) responses and 43% of patients achieved an overall complete response (CR) in CSF and/or brain parenchyma. Two patients achieved a first CR of CNS NHL with intraventricular rituximab/methotrexate, including one with CNS lymphoma refractory to high-dose systemic and intrathecal methotrexate plus intravenous rituximab. Intraventricular rituximab in combination with methotrexate is feasible and highly active in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. Registered at clinicaltrials.gov: NCT00221325.

  • Submitted July 5, 2012.
  • Accepted November 4, 2012.