Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment.

Abstract

PURPOSE:

Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocytic leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias. The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-agent clofarabine in CLL.

EXPERIMENTAL DESIGN:

Previously treated patients with relapsed/refractory CLL were eligible for this study. Clofarabine was infused over 1 hour daily for 5 days. Most patients received 3 or 4 mg/m2/d x 5 days, whereas the other two were treated with 15 mg/m2/d x 5 days. Clinical outcome and associated pharmacologic end points were assessed.

RESULTS:

Myelosuppression limited the maximum tolerated dose of clofarabine to 3 mg/m2/d on this schedule. Cellular pharmacokinetic studies showed a median clofarabine triphosphate concentration in CLL lymphocytes of 1.5 micromol/L (range, 0.2-2.3 micromol/L; n = 9). In the majority of cases, >50% of the analogue triphosphate was present 24 hours after infusion, indicating prolonged retention of the triphosphate in CLL cells. Although cytoreduction was observed, no patients achieved a response. In vitro clofarabine incubation of leukemic lymphocytes from 29 CLL patients showed that clofarabine monophosphate accumulated to a higher concentration compared with the triphosphate. Nonetheless, the triphosphate increased in a dose-dependent fashion and upon successive clofarabine infusions, suggesting benefit from greater doses given at less frequent intervals.

CONCLUSION:

Levels of clofarabine triphosphate at higher doses and prolonged maintenance of clofarabine triphosphate in leukemic lymphocytes provide a rationale to treat CLL in a weekly clofarabine schedule.

• Authors: Varsha Gandhi, William Plunkett, Peter L Bonate, Min Du, Billie Nowak, Susan Lerner, Michael J Keating
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 13 Pg. 4011-7 (Jul 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16818700 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenine Nucleotides
• Arabinonucleosides
• Clofarabine

Topics

• Adenine Nucleotides (administration & dosage, adverse effects, pharmacokinetics)
• Aged
• Arabinonucleosides (administration & dosage, adverse effects, pharmacokinetics)
• Clofarabine
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Infusions, Intravenous
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Lymphocytes (drug effects)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Molecular Structure
• Neoplasm Staging
• Recurrence
• Tissue Distribution
• Treatment Outcome