L-FOLINIC ACID VERSUS DL FOLINIC ACID IN THE RESCUE OF HIGH-DOSE METHOTREXATE THERAPY IN LEUKEMIC CHILDREN

Until now, folinic acid (FA) has been available the racemic mixture dl FA, whose biological activity is supported by natural l FA. The purpo se of this trial was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture dl FA with the pure l FA in the r escue of high-dose methotrexate (MTX) therapy. Eighteen children with acute lymphocytic leukemia (ALL) were entered in this trial planned wi th a cross-over design. Four cycles of MTX (5 g/m2, 24 h CVI) were adm inistered to each patient, with a 2-week interval between cycles. The rescue was achieved orally every 6 h, starting 12 h after the end of t he MTX infusion, at a dose of 12 mg/m2 for dl FA and 6 mg/m2 for pure l FA. dl FA and l FA rescues were alternated from one cycle to the nex t. d FA, l FA, and the active metabolite 5-methyltetrahydrofolate (5-M THF) were measured in plasma using a stereospecific HPLC assay. After administration of dl FA, the accumulation of d FA in plasma was confir med: mean residual concentrations were 420 and 652 nM after 2 and 6 in takes respectively. Total active folate concentrations (l FA + 5-MTHF) were similar between the two types of rescue: 92 and 100 nM respectiv ely for dl FA rescue and l FA rescue after two intakes, 186 and 184 nM respectively for dl FA rescue and l FA rescue after six intakes. Intr a-individual statistical analysis of total active folates (l FA + 5-MT HF) performed on 17 patients did not show any significant difference b etween dl FA rescue and l FA rescue. For both types of rescue, MTX ter minal half-lives were identical (average value 13.9 h). Considering ea ch type of toxicity (hematologic, hepatic, renal and digestive) there was no significant difference in the proportion of toxic cycles follow ing l FA rescue or dl FA rescue. In conclusion, the administration of the pure l FA, as compared with the administration of the racemic mixt ure, results in comparable blood profiles of active folates and MTX, a nd leads to equivalent treatment tolerance.