Clofarabine is approved by FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Also, activity has been observed in clinical trials involving adults with AML and MDS (

BLOOD.2003;102:2379–2386
;
BLOOD.2005;105:940–947
;
BLOOD.2006;108:45–51
). However, clinical development of clofarabine in the treatment of lymphomas and solid tumors has been challenging due to observed dose-limiting hematotoxicity, at relatively low doses. Preclinical animal models have shown orally administered clofarabine to have good bioavailability (∼60% in rats) and increased anticancer activity in human hematological and solid tumor mouse xenograft models when compared with IV administration. Additionally, prolonged oral administration at lower daily doses has shown superior activity when compared to IV or PO administration on a daily ×5 dosing schedule. The objective of the present study was to determine the effect of oral administration on a daily ×5 or daily ×21 dosing schedule when compared to IV daily ×5 administration in a male Fischer 344 rat model. For the comparative study, the same daily doses (i.e., 25 and 40 mg/kg/day) were used for both the daily ×5 PO and IV dose schedules. Rats on the PO daily ×21 schedule were administered the same approximate total dose/course of treatment as the daily ×5 treated rats (i.e., 6 and 10 mg/kg/day for 21 days). Circulating blood cells (e.g., RBCs, WBCs, neutrophils, lymphocytes, platelets) were evaluated at various times (days 8, 15, 22, 29, 36, and 43 of study) during and/or following treatment. Approximately 50% of the rats dosed IV at the high dose level (40 mg/kg/day) died during the five day treatment period. No deaths were observed for rats dosed the low dose (25 mg/kg/day) IV group or for any rats dosed PO on a daily ×5 or daily ×21 dose schedule. Circulating RBCs were largely unaffected by IV or PO clofarabine administration. Maximum changes occurred on Day 8 for WBC, neutrophil, lymphocyte, and platelets in all IV and PO dose groups. Most cell types recovered by Day 15 or 22 of study. Statistically significant decreases in circulating neutrophils were seen both for the low (56% decrease) and high (72% decrease) dose IV groups. Statistically significant decreases in circulating lymphocytes were observed on Day 8 for the low (41% decrease) and high (84% decrease) dose IV groups, low (37% decrease) and high (37% decrease) dose daily ×5 PO groups, and the high (26% decrease) dose daily ×21 PO group (p≤0.01). Neutrophil counts recovered rapidly, whereas full recovery of lymphocyte counts was delayed until Day 43 of study. The platelet counts were increased for most groups on Day 8, except for the high dose IV group which was decreased by approximately 50%. In conclusion, the rapid time course for the decrease and recovery of circulating white cell counts in rats indicates that cell types other than stem cells are affected by clofarabine administration. The less severe adverse effects on WBCs seen after prolonged (daily ×21) oral administration suggests that myelosuppression in clinical studies may be reduced with the use of a prolonged oral administration strategy.

Topics:
animal model, clofarabine, toxic effect, administration, oral, solid tumors, acute lymphocytic leukemia, adverse effects, drug administration schedule, hematotoxicity, lymphoma

Author notes

Disclosure:Employment: Dr. Arthaud is employed by Genzyme Corporation. Research Funding: Genzyme has provided research funding to BioAnalytical Services, Inc. to conduct these preclinical studies.

2007, The American Society of Hematology
2007
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