Studies On Clinical Outcome And Concentrations Of High-dose Cytosine Arabinoside In Childhood With Acute Myeloid Leukemia

Objectives To study the pharmacokinetics of HD-Ara-C by determinating plasma concentration of Ara-C and Ara-U in childhood with newly diagnosed acute myeloid leukemia (AML) treated with 36g/m2 or 18g/ m2 cytosine arabinoside(Ara-C). In the meanwhile, we study the feasibility of such regimen in postremission AML by assessing therapy associated toxicities and overall outcome.Methods The peripheral blood samples were obtained from patients treated with HDAra-C (3g/m2) at the first and last infusion at indicated timepoints. The concentrations of Ara-C and its metabolite uridine arabinoside (Ara-U) in plasma were determined by high performance liquid chromatography and then calculated the maximum concentrations. In addition, the toxicity was evaluated, including complete blood count, level of alanine aminotransferase, creatinine, bilirubin, infections morbidity, nausea and vomiting, diarrhea and central nervous system.Results①Hematological toxicity: pancytopenia was occurred by an acute onset manner soon after the completion of HDAra-C. Patients treated with 36g regimen had a significantly longer duration of leucopenia, neutropenia and thrombocytopenia than 18g regimen patients. All patients who received 36g regimen had infections, more severe infections and an increased duration of febrile and antibiotics. Patients on 18g regimen had lower incidence and mild infection, then easier to tolerate than 36g regimen. But no difference of fatal infections between these two regimens was observed.②Non-hematologic toxicity: patients treated with 36g regimen were significantly more susceptible to nausea, vomit and diarrhea. These toxicities could generally be successfully managed. No kidney damage was recorded within both regimens and liver toxicity was mild (Grade 2) . There was no central neurotoxicity or peripheral neurotoxicity on both regimen.③One patient died from relapse after one course of 36g regimen and 3 courses of 18g regimen, others (10 patients) were followed up, the median survival was 68months (17to 124 months).④Concentrations of Ara-C and Ara-U increased after 30 minutes infusion and reached their peaks nearly at the end of infusion. The concentration of Ara-C decreased rapidly after infusion, otherwise the concentration of Ara-U decreased slowly. Figure 1. The first Ara-C and Ara-U concentrations of 36g regimen was higher than 18 regimen(P=0.009, P=0.000). The concentration of 18g regimen was relatively stable.⑤The average maximun concentration(Cmax) of Ara-C on both regimens were higer than the effective plasma concentration.Conclusion①As postremisson treatment in children with AML, the severe toxicity of 108g HDAra-C was hematological toxicity. There was no severe neurotoxicity and treatment-related mortality. Through intensive support treatment, the toxicities could be readily reversed.②1 08g HDAra-C as postremisson regimen could improve the overall survival.③T he plasma concentrations of Ara-C and Ara-U consistent with general pharmacokinetics.④Both regimen of HDAra-C could reach. effective leukemic cells killing concentration.⑤T he mean concentration of 36g regimen was higher than that of 18g regimen. Higher concentration of Ara-C could clear residual tumor cells in vivo more effectively.⑥The plasma concentrations of Ara-C and Ara-U were stable through administration intermittent on 18g regimen and could be used repeatedly.