PHARMACOKINETICS, DOSE ADJUSTMENTS, AND 6-MERCAPTOPURINE METHOTREXATEDRUG-INTERACTIONS IN 2 PATIENTS WITH THIOPURINE METHYLTRANSFERASE DEFICIENCY/

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and ph enotype. They were monitored with haematological parameters and red bl ood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and meth otrexate (E-MTX, including MTX polyglutamates), in relation to the dos es of 6-mercaptopurine (6MP) and methotrexate (MTX), during their main tenance chemotherapy. Both patients developed severe pancytopenia at t he standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold ab ove the population median, but without unacceptable bone-marrow toxici ty. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia follo wed high-dose MTX infusions. Due to the risk of fatal myelosuppression we recommend up-front determination of TPMT activity in patients trea ted with 6MP or azathioprine.