6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Through inhibition of purine de novo synthesis and enhancement of 6-mercapt opurine (6MP) bioavailability high-dose methotrexate (HDM) may increase the incorporation into DNA of B-thioguanine nucleotides (6TGN), the cytoxic me tabolites of 6MP, Thus, coadministration of 6MP could increase myelotoxicit y following HDM, Twenty-one children with standard risk (SR) and 25 with in termediate risk (IR) acute lymphoblastic leukemia (ALL) were studied. Durin g consolidation therapy they received either three courses of HDM at 2 week intervals without concurrent oral 6MP (SR-ALL) or four courses of HDM give n at 2 week intervals with 25 mg/m(2) of oral 6MP daily (IR-ALL). During th e first year of maintenance with oral 6MP (75 mg/m(2)/day) and oral MTX (20 mg/m(2)/week) they all received five courses of HDM at 8 week intervals. I n all cases, HDM consisted of 5000 mg of MTX/m(2) given over 24 h with intr aspinal MTX and leucovorin rescue. Erythrocyte levels of 6TGN (E-6TGN) and methotrexate (E-MTX) were, on average, measured every second week during ma intenance therapy. When SR consolidation (6MP: 0 mg), IR consolidation (6MP : 25 mg/m(2)), and SR/IR maintenance therapy (6MP: 75 mg/m(2)) were compare d, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count n adir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased sig nificantly with increasing doses of oral 6MP, Three percent of the HDM cour ses given without oral 6MP (SR consolidation) were followed by an ANC nadir <0.5 x 10(9)/l compared to 50% of the HDM courses given during SR/IR maint enance therapy. Similarly, only 13% of the HDM courses given as SR-ALL cons olidation induced a thrombocyte count nadir <100 x 10(9)/l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (beta = -0.017, P = 0.001), the average ANC level during maintenance therapy (beta = 0.82, P = 0.004), and E-6TGN (beta = -0 .0029, P = 0.02). The best-fit model to predict the thrombocyte nadir follo wing HDM during maintenance therapy included only mPLATE (beta = 0.0057, P = 0.046), In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of signi ficant myelotoxicity following HDM during maintenance therapy of childhood ALL.