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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4508-4509 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.6797
Intra-CSF Rituximab for Lymhomatous MeningitisDepartment of Neurology, Neuro-Oncology, University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA
Oncology, Huntsman Cancer Center, Salt Lake City, UT To the Editor: Dr Rubenstein and his colleagues are to be congratulated for their article detailing the pharmacokinetics of a novel intra-CSF agent, rituximab, administered intraventricularly in 10 patients, nine with primary CNS lymphoma (PCNSL) and one with systemic CNS lymphoma. Nine of these 10 patients had cytologically documented lymphomatous meningitis (LM), and three had intraocular lymphoma.1 A maximum-tolerated dose was defined as 25 mg in a study utilizing intra-CSF rituximab administered twice per week for a total of nine treatments. Several issues regarding this article are relevant and warrant additional discussion. A common occurrence after administration of intra-CSF xenobiotics is the occurrence of chemical meningitis, which not reported as an adverse event in this study.2,3 The lack of a transient inflammatory CSF response is peculiar although it may have been mitigated by concurrent oral steroid therapy, commonly used in patients with PCNSL and half of patients in the study. (Note that one patient did experience transient sacral paresthesias after intralumbar rituximab administration.) Secondly, and not emphasized in the article, rituximab delivered by the intralumbar route resulted in a 20- to 30-fold smaller maximum CSF concentration in the ventricles when compared with intra-Ommaya administration. Similar findings are seen with other drugs administered intralumbar and may severely limit the efficacy of intralumbar drug treatment of LM. From a practical perspective, this study supports the use of intraventricular, but not intralumbar rituximab. Response to intra-CSF rituximab was assessed in three compartments: brain parenchyma, CSF, and vitreous. However, not easily explained was the response in brain (reported in one patient) because intra-CSF administrated drug has limited intraparenchymal penetration (ie, fewer than 5 mm).4 Furthermore, a response in the vitreous compartment (in the same patient) would not be anticipated as no CSF vitreous anatomic communication exist, and therefore, rituximab access to the vitreous would be restricted. Furthermore, a variety of studies have suggested intra-CSF administered therapy is insufficient to treat intravitreous lymphoma. Four patients had isolated LM, a reflection of the study population (nine of 10 with PCNSL), among whom three complete responses were seen (lasting 7 weeks, 4 months, and 9 months, respectively). Evaluating patients with secondary LM (ie, metastasis from systemic non-Hodgkin's lymphoma) likely would provide a clearer estimate of intra-CSF rituximab efficacy. Another aspect of the study that was not emphasized or reported in detail was the status of CSF flow as assessed by radioisotope ventriculography. If intra-CSF chemotherapy is to be administered, assessing CSF flow by radioisotope will demonstrate whether there is free communication between CSF compartments, and if it is predictive of drug toxicity and survival. Particularly in novel intra-CSF drug studies, performance of CSF flow studies before any intra-CSF therapy and detailed reporting of the results of those studies is essential. In this trial, flow studies were delayed for 3 weeks in two patients, and were performed "within 1 week of the initiation of intrathecal rituximab" in the remaining eight patients. The last issue is that of the utility of intra-CSF rituximab in patients with LM as the majority of patients with CD20-positive non-Hodgkin's lymphoma are presently treated with systemic rituximab. Consequently and similar to systemic recurrence after rituximab, LM occurring as a late metastatic CNS complication would likely represent recurrent rituximab refractory lymphoma. These comments are not meant to diminish the results of this elegant study. Rather these comments reflect the difficulty encountered in treating patients with LM and the lack of standardization regarding treatment. LM is a complicated and devastating disease with limited therapeutic options such that a new intra-CSF therapeutic agent would indeed be welcome. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Rubenstein JI, Fridlyand J, Abrey L, et al: Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 25:1350-1356, 2007 2. Glantz M, Jaeckle K, Chamberlain MC, et al: A randomized trial comparing intrathecal sustained-release ara-C (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 11:3394-3402, 1999 3. Glantz M, Jaeckle KA, Chamberlain MC, et al: A randomized trial of a slow-release formulation of cytarabine for the treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116, 1999 4. Chamberlain MC, Kormanik P: Prognostic significance of co-existent bulky metastatic central nervous system disease in patients with leptomeningeal metastases. Arch Neurol 54:1364-1368, 1997
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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