Phase I trial of nelarabine in indolent leukemias.

March 10, 2008

V Gandhi, C Tam, S O'Brien, RC Jewell, CO Jr, S Lerner, W Plunkett,

and MJ Keating

J. Oncol. Pract, March 1, 2008; 26(7): 1098-105.

Department of Experimental Therapeutics, Box 71, The University of Texas M.D.

Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

vgandhi@...

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.

PMID: 18309944

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