This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Avramis, V. I. Articles by Holcenberg, J. S. Search for Related Content PubMed PubMed Citation Articles by Avramis, V. I. Articles by Holcenberg, J. S.

Pharmacology of Fludarabine Phosphate after a Phase I/II Trial by a Loading Bolus and Continuous Infusion in Pediatric Patients¹

Childrens Hospital Los Angeles, Division of Hematology/Oncology, University of Southern California, Los Angeles, California 90027 [V. I. A., J. S., J. S. H.]; Saint-Jean-Sur-Richelieu, Quebec, Canada [J. C.]; Childrens Cancer Study Group, Los Angeles, California 91101 [M. K., G. D. H.]; University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 [L. J. E.]; Pediatric Branch, National Cancer Institute, Bethesda, Maryland [D. G. P.]; Harbor/UCLA Miller's Childrens Hospital, Long Beach, California 90509 [J. F.]; Childrens National Medical Center, Washington, DC [G. R.]

Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m² followed by 23.5 mg/m²/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m² and an infusion of 30.5 mg/m²/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-ß-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-ß-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-ß-D-arabinofuranosylcytosine to 1-ß-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-ß-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-ß-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.

¹ This work supported by the American Cancer Society (H-306 to VIA), by USPHS (U10-CA02649), and by the Neil Bogart Laboratories, a division of the T. J. Martell Foundation for Leukemia, Cancer and AIDS Research.

² To whom requests for reprints should be addressed, at Division of Hematology-Oncology, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027.

Received 6/11/90. Accepted 8/17/90.

This article has been cited by other articles:

				D. P. Lee, J. M. Skolnik, and P. C. Adamson Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency J. Clin. Oncol., November 20, 2005; 23(33): 8431 - 8441. [Abstract] [Full Text] [PDF]

				E. J. Estlin, S. Cotterill, C. B. Pratt, A. D. J. Pearson, and M. Bernstein Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children's Cancer Study Group and the Pediatric Oncology Group J. Clin. Oncol., May 9, 2000; 18(9): 1900 - 1905. [Abstract] [Full Text] [PDF]

				J. M. Kolesar, A. K. Morris, and J. G. Kuhn Review : Purine nucleoside analogues: Fludarabine, pentostatin, and cladribine: Part 1: Fludarabine Journal of Oncology Pharmacy Practice, January 1, 1996; 2(3): 160 - 181. [Abstract] [PDF]