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


METHODS
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.


CONCLUSIONS
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.
Gandhi
Varsha
V
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. vgandhi@mdanderson.org
Plunkett
William
W
Bonate
Peter L
PL
Du
Min
M
Nowak
Billie
B
Lerner
Susan
S
Keating
Michael J
MJ
D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000368:Aged; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077866:Clofarabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015394:Molecular Structure; D009367:Neoplasm Staging; D012008:Recurrence; D014018:Tissue Distribution; D016896:Treatment Outcome
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine