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Phase I Trial of Nelarabine in Indolent Leukemias

Varsha Gandhi, Constantine Tam, Susan O'Brien, Roxanne C. Jewell, Carlos O. Rodriguez, Jr, Susan Lerner, William Plunkett, Michael J. Keating

From the Departments of Experimental Therapeutics and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoSmithKline, Research Triangle Park, NC

Corresponding author: Varsha Gandhi, PhD, Department of Experimental Therapeutics, Box 71, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: vgandhi{at}mdanderson.org

Purpose: To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses.

Patients and Methods: Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle.

Results: Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 µmol/L; range, 35 to 1,438 µmol/L; n = 10) and nonresponders (50 µmol/L; range, 22 to 178 µmol/L; n = 15).

Conclusion: Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.

Supported in part by Grants No. CA57629 and CA81534 from the National Cancer Institute, US Department of Health and Human Services, Bethesda, MD.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.