In an attempt to maximize the therapeutic index and to overcome the large variations in 1-β-D-arabinofuranosylcytosine (ara-C) plasma levels and host toxicities that have been documented with standard HDara-C regimens (3 g/m2 over 3 h every 12 h ×8 or ×12 doses), pediatric patients with acute lymphocytic leukemia or lymphoma in relapse were treated with a regimen of loading bolus followed immediately by continuous infusion of ara-C. In addition, patients received a single dose of etoposide (VP-16, 1 g/m2) prior to the ara-C administration. In four patients, total body irradiation was administered as part of a bone marrow transplantation preparative regimen after the ara-C administration. The regimen was designed to attain and maintain plasma steady-state concentrations (Css) of ara-C three to four times the Km2 value of ara-C, which was determined with purified deoxycytidine kinase from the patients' tumor cells prior to treatment. Eight patients age 0.75 to 16 years with relapsed acute lymphocytic leukemia (three patients) or lymphoma (five patients, one with bone marrow involvement), received a test dose of 3 g/m2 ara-C injected over 1 h, and the plasma kinetics were determined. The peak plasma ara-C concentration of ara-C ranged from 57 to 199 εM with an average concentration of 103 ± 49 εM; the half-lives of distribution (t1/2,α) and elimination (t1/2,α) averaged 17 ± 7 min and 4.04 ± 3.1 h, respectively. The mean area under the plasma concentration time curve from 0 to 12 h (AUC0→12h) of ara-C averaged 386.8 ± 328.0 εMh (mean, ± SD, n = 8). The peak concentration of uracil arabinoside averaged 501 ± 123 εM, and it was eliminated with a t1/2,el of 2.3 ± 0.6 h. The patients then received an individualized loading bolus (mean = 0.5 g/m2) followed by a continuous infusion regimen of ara-C (mean = 130 mg/m2/h), to achieve a Css in the range of 20 to 35 εM. The obtained plasma Css were similar to the desired ones, averaging in variation 10.7% ± 8.2%. The percentage of variation of correlation of the AUC following the loading bolus plus the continuous infusion from 12 to 72 h was only 12.4% (mean = 2158 εMh, n = 8), whereas the percentage of variation of correlation of the AUC after the test dose of ara-C in the same patients was 84.8%. The total dose of ara-C administered with this regimen averaged 41.4 ± 16.0% (mean ± SD, n = 8) of the dose that the patients would have received if they had been given the standard HDara-C regimen (3 g/m2) for the same duration of treatment. Both of the evaluable patients with lymphoma undergoing bone marrow transplantation achieved a complete remission after ara-C, etoposide and total body irradiation. In a non-bone marrow transplantation trial one complete remission and one partial remission were observed among three patients with relapsed acute lymphocytic leukemia and one patient with lymphoma that had relapsed in the bone marrow. This regimen uses a loading bolus followed immediately by continuous infusion, which administers an intermediate dose level of ara-C, achieves a uniform drug exposure (AUC) in each patient, with fewer variations in plasma concentrations. This new ara-C regimen shows promising antitumor activity with tolerable toxicity and can be administered as part of a combination therapy.

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Supported in part by Grant CA 38905 from NIH, National Cancer Institute, and by grants from The Upjohn Company and from the T. J. Martell Foundation.

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