Biochemical pharmacology of high dose 1-beta-D-arabinofuranosylcytosine in childhood acute leukemia

Abstract

The pharmacodynamic parameters of 1-beta-D-arabinofuranosylcytosine (ara-C) in patient plasma and its active anabolite 1-beta-D-arabinofuranosylcytosine-5-triphosphate (ara-CTP) in circulating and bone marrow blast cells were studied in 20 pediatric patients with acute leukemia. ara-C (3 g/m2) was administered as a short-term infusion over 3 h every 12 h for a total of eight doses. The peak plasma concentration of ara-C ranged from 0.02 to 5.6 microM after the first dose of ara-C. The area under the concentration-time curve (AUC) of ara-C in plasma ranged from 302 to 20,298 microMh after the first dose of ara-C. The half-life of elimination (t1/2,el) of ara-C from plasma was 2.4 +/- 1.5 h in three patients with acute nonlymphoblastic leukemia (ANLL) and 4.78 +/- 4.1 h in 9 patients with acute lymphoblastic leukemia (ALL). The intracellular peak concentration of ara-CTP in circulating blast cells averaged 432.2 +/- 14.5 microM and 544.3 +/- 330 microM in patients with ANLL and ALL, respectively. The elimination kinetics of ara-CTP was monoexponential with t1/2,el of 3.30 +/- 0.8 h and 6.9 +/- 2.8 h in patients with ANLL and ALL. DNA synthetic capacity (DSC) of the blast cells was inhibited to between 24 and 64% of control after the first dose of ara-C and it declined further to between 1 and 32% after four doses of ara-C. The AUC of ara-CTP in leukemic cells ranged from 1,073 to 14,751 microMh and it was not related to the AUC of ara-C in plasma. The pharmacodynamic parameters of ara-CTP in circulating blast cells were more homogeneous in patients with ANLL than in patients with ALL. Four of six patients (67%) with ANLL and six of 14 patients (43%) with ALL achieved either complete remission or partial remission with high dose ara-C. We conclude that treatment of pediatric patients with leukemia in relapse with high dose ara-C is tolerable and moderately successful. Inhibition of DSC is positively correlated with the probability of having zero nadir peripheral blast cells. In turn there is a trend for a zero nadir peripheral blast cell count to be related to achievement of a response to therapy. This latter result is consistent with the results of larger studies in adults with leukemia.