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 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and 
nonresponders (50 micromol/L; range, 22 to 178 micromol/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.