INTRACELLULAR RETENTION OF CYTOSINE-ARABI NOSIDE TRIPHOSPHATE IN BLAST CELLS FROM CHILDREN WITH LYMPHOBLASTIC-LEUKEMIA

Background Cellular uptake and intracellular phosphorylation to the nu cleotide cytosine arabinoside-triphosphate (Ara-CTP) is the preconditi on for the cytostatic effect of cytarabine. The pharmacokinetics of Ar a-CTP in leukemic cells was reported to be of clinical importance in a dult nonlymphoblastic leukemia. Therefore, the role of intracellular A ra-CTP formation and retention was investigated in blast cells from ch ildren with acute lymphoblastic leukemia (ALL). Patients and methods A t the time of diagnosis, peripheral or bone marrow blast cells from 41 children with ALL and 13 with relapsed ALL were incubated in Ara-C co ntaining medium (1 hour, 1 or 3 mu g/ml) followed by reincubation in A ra-C free medium (3 h). Intracellular Ara CTP formation and Ara-CTP re tention were determined. Main results Ara-CTP formation did not show m arked differences between the different immunological subtypes. Ara-CT P retention, however, was significantly lower in TALL (37 +/- 15%, n = 8) compared to non-T-ALL (67 +/- 25%, n = 33; p < 0,003). Ara-CTP ret ention was also significantly different in children with and without p ersistance of peripheral blast cells after one week of prednison treat ment (71 +/- 30%, n = 9 and 53 +/- 19%, n = 21; p = 0.031) as well as in children with and without complete bone marrow remission on day 15 of the ALL-BFM treatment protocol (66 +/- 17%, n = 19 and 43 +/- 18%, n = 11; p = 0,018). Ara-CTP retention was inversely correlated with th e risk groups defined by the ALL-BFM treatment protocols (standard 79 +/- 29, interme diate 59 +/- 25, high risk 37 +/- 21%). A trend toward s lower Ara-CTP retention was observed in relapsed leukemias (relapsed non-T-ALL 51 +/- 17%, p = 0.061). The difference in the probability o f event free survival (following risk group adapted treatment accordin g to ALL-BFM trials) between children with high (greater than or equal to 72%: 0,92 +/- 0,08) and low (< 72%. 0.58 +/- 0.15) Ara-CTP retenti on up to now did not reach statistical significance (p = 0.12). Conclu sions The more rapid decrease of cellular Ara-CTP in T-cell leukemia a nd children at higher clinical risk groups provide a pharmacokinetic r ationale for prolonged infusion duration as an alternative to the inte nsification by dose escalation alone.