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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4509-4511 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1284
In ReplyUniversity of California, San Francisco, San Francisco, CA
Memorial Sloan-Kettering Cancer Center, New York, NY
Stanford University School of Medicine, Stanford, CA
University of California, San Francisco, San Francisco, CA We appreciate the comments of Drs Chamberlain and Glantz regarding our recent phase I study of intraventricular rituximab in patients with recurrent CNS lymphoma.1 As described in the article, there was one episode of drug-associated meningitis, lasting approximately 15 minutes after intrathecal rituximab administered by lumbar puncture. Drug-induced meningitis was not detected in the other nine patients treated at the University of California, San Francisco (San Francisco, CA) and Memorial Sloan-Kettering Cancer Centers (New York, NY) after careful clinical assessment and detailed evaluation of CSF, before and at time points after intrathecal rituximab administration. We agree that, at this stage, our own preliminary safety and pharmacokinetic data support the intraventricular rather than intralumbar administration of this agent, at least in patients with recurrent CNS lymphoma. We also agree with the requirement for pretreatment nuclear medicine CSF flow studies in this patient population; it should however be pointed out that the results of CSF flow studies are detailed to the same extent in our report as in the cited studies of intrathecal sustained release cytarabine in neoplastic meningitis.2,3 During the course of the phase I protocol, we detected six leptomeningeal responses, two intraocular responses as well as the resolution of a small focus of parenchymal lymphoma in one patient. Since completion of the study we have obtained additional results which extend our evidence that the combination of intraventricular rituximab plus methotrexate has significant activity both within the vitreous as well as brain parenchyma in patients with refractory B-cell CNS/intraocular lymphoma. For example, one of the patients treated on the phase I intraventricular rituximab study (subject 004), who previously had exhibited refractory disease to intensive chemotherapy, intravenous rituximab, and whole-brain irradiation, went on to exhibit a complete response to rituximab administered by Ommaya reservoir. The duration of remission during intraventricular rituximab treatments (3.5 months) exceeded the patient's only previous complete response which occurred after whole-brain irradiation. Ultimately, the lymphoma relapsed during a period in which the frequency of intraventricular rituximab treatments was tapered to once every other week. The patient presented with new diplopia and ataxia: six new parenchymal lesions were identified by magnetic resonance imaging including lesions in the optic nerve, basal ganglia, thalamus, and midbrain (Fig 1). Dramatic clinical improvement within 3 days occurred after one dose of combination rituximab (25 mg) plus methotrexate (12 mg) through the Ommaya reservoir, manifest by resolution of diplopia and improvement in gait stability. A major radiographic response was detected after an additional four doses, given twice per week. A complete radiographic and clinical response was detected after 6 weeks of therapy (Fig 1). This patient did not receive glucocorticoids or systemic therapy during the course of this intervention.
An additional complete intraocular response was recently achieved in a second patient treated on an intraventricular rituximab/methotrexate protocol; this patient had recurrent bilateral intraocular lymphoma manifested by bilateral characteristic vitreal and deep retinal infiltrates which were refractory to intravenous rituximab plus combination methotrexate, procarbazine, and vincristine (Fig 2). Within 6 weeks of intraventricular treatment, a partial response was achieved in both eyes. At 10 weeks, after completion of twice weekly intraventricular combination therapy, there was improvement in vision and complete resolution of her intraocular lymphoma. The patient did not receive glucocorticoids or systemic therapy during pretreatment staging or during the course of intrathecal therapy.
These preliminary results may challenge the dogma that "intra-CSF administered therapy is insufficient to treat intravitreous lymphoma," as well as intraparenchymal disease in the brain. It is possible that increased permeability associated with the pathologic lymphoma vasculature facilitates the intratumoral penetration of rituximab within the brain and eye. A second potential explanation is that intraventricular administration of rituximab stimulates an immune response within deep sanctuary sites in the CNS. A third explanation is provided by Terson's syndrome, where communication between the CSF and vitreous is demonstrated by the association of subarachnoid hemorrhage with vitreous hemorrhage. As described in our recent report, not all brain lesions were sensitive to intraventricular rituximab: it is possible that tumors less than 1.0 cm in diameter may be more responsive at the doses used in our trial. A second, potentially important variable is the biologic phenotype of the lymphoma, as manifest by transcriptional profile, which suggests molecular correlates of rituximab sensitivity and resistance.1 A successor study is currently underway to confirm these observations and to test our hypothesis that intrathecal rituximab stimulates an immune response within the CNS. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: James L. Rubenstein, Genentech (C); Ranjana Advani, Genentech (C) Stock Ownership: None Honoraria: None Research Funding: James L. Rubenstein, Clinical Research; Lauren Abrey, Genentech Expert Testimony: None Other Remuneration: None
REFERENCES
1. Rubenstein J, 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 KA, Chamberlain MC, et al: A randomized trial of slow-relase formulation of cytarabine for the treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116 3. Glantz M, Jaeckle KA, 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 Related Correspondence
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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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