SPECIAL DEPARTMENTS
Authors: İbrahim Barışta, Stephen B. Howell
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.9.2003 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10784644 İbrahim Barıştaxİbrahim BarıştaSearch for articles by this author Stephen B. HowellxStephen B. HowellSearch for articles by this author Show More Hacettepe University AnkaraTurkeyUniversity of California at San Diego La JollaCA https://doi.org/10.1200/JCO.2000.18.9.2003 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse09052000In Reply:Dr Barişta raises the question of whether intrathecal administration of 50 mg of DepoCyt™ (cytarabine; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) increases the risk of the development of neutropenia in patients with lymphomatous meningitis receiving concurrent systemic chemotherapy. This slow-release formulation of cytarabine can maintain cytotoxic concentrations in the CSF for more than 14 days in most patients. Barişta concludes from this that leakage of cytarabine into the systemic circulation likely accounts for the three episodes of grade 4 neutropenia that were observed in three of the 14 patients receiving DepoCyt reported in our recent article.1In the controlled trial of DepoCyt versus free cytarabine for the treatment of lymphomatous meningitis, grade 4 neutropenia was observed on three of 74 cycles in three of the 14 patients receiving this drug. Each patient had only a single episode of neutropenia. The episodes of neutropenia were not unexpected; they were all temporally linked to the administration of systemic chemotherapy at doses commonly associated with severe neutropenia in patients who each had received extensive prior chemotherapy. In one patient with an AIDS-related lymphoma, grade 4 neutropenia was noted on the day of DepoCyt administration 10 days after intravenous (IV) administration of 420 mg of cyclophosphamide, 126 mg of etoposide, and 26 mg of doxorubicin. In a second patient, the neutropenia was discovered 29 days after IV administration of 55 mg of cisplatin, 3.2 g of ifosfamide, and 4.4 g of cytarabine, which was 12 days after the last DepoCyt injection. In the third patient, neutropenia developed on the day of DepoCyt administration, which was 9 days after IV injection of 85 mg of doxorubicin, 1.3 g of cyclophosphamide, and 2.4 mg of vincristine. Neutropenia was not observed in any patient not receiving systemic chemotherapy. It is also noteworthy that, when considering all patients thus far treated with DepoCyt or free cytarabine in the five clinical trials completed to date, neutropenia occurred on 7% of cycles in patients treated with DepoCyt, whereas it occurred on 10% of cycles in patients receiving standard intrathecal therapy with cytarabine 50 mg twice a week. Thus, despite the slow release of cytarabine from DepoCyt, the risk of significant systemic toxicity is no greater.As Barişta notes, systemic leakage of methotrexate after intrathecal administration has been reported to contribute to the development of neutropenia. However, the pharmacokinetics of intrathecally administered cytarabine and methotrexate are quite different. After exiting the CSF and entering the systemic circulation, cytarabine has a plasma half-life of only 17 minutes,2 whereas methotrexate has a terminal half-life of 6 to 20 hours.3 Thus, after intraventricular administration of methotrexate at a dose of 6.25 mg/m2, systemic levels of up to 0.1 μmol/L were readily measured.4 However, after intrathecal administration of even 75 mg of DepoCyt, no measurable amounts of either cytarabine or its principal metabolite uracil arabinoside were detectable in the plasma.5 Given the experience with continuous IV infusions of cytarabine for up to 7 days,6 it is unlikely that a total dose of 50 mg of cytarabine would have a measurable effect on neutrophil count, even if administered directly into the systemic circulation over 7 days. Thus it is quite unlikely that intrathecal administration of DepoCyt poses a significant risk of medically serious neutropenia, even in patients receiving concurrent systemic chemotherapy.2. 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Arch Neurol 50::261,1993-264, Crossref, Medline, Google Scholar2. Frei E III, Bickers JN, Hewlett JS, et al: Dose schedule and antitumor studies of arabinosyl cytosine (NSC 63878). Cancer Res 29::1325,1969-1332, Medline, Google Scholar