The Influence of Thiopurine Methyltransferase Activity on Bone Marrow- and Hepato-toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia
High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6MP) may be
followed by myelotoxicity, which may necessitate treatment interruption and thus interfere
with the efficacy of the treatment of childhood ALL. Several studies have indicated that MTX
and 6MP act synergistically. It has previously been reported that the risk of significant
bone-marrow suppression is increased if oral 6MP is coadministered with HDM during
maintenance therapy and that reductions of the dose of concurrently given oral 6MP can
reduce the risk of significant myelotoxicity following HDM. MTX may increase the
bioavailability of 6MP through inhibition of xanthine oxidase, which catabolizes 6MP. In
addition, MTX may through inhibition of de novo purine synthesis enhance the availability of
6-thioguanine nucleotides (6TGN) that primarily exert the cytotoxic effect of 6MP.
The enzyme TPMT competes with the formation of 6TGN, as it methylates 6MP and thus create
relatively non-toxic metabolites. TPMT heterozygous patients with one wild type and one
low-activity allele have a higher risk of myelosuppression and treatment interruption
compared to patients with TPMT wild type. Furthermore, TPMT heterozygous patients have a
reduced risk of relapse and a higher risk of secondary malignancy compared to patients with
TPMT wild type.
Little has been published on the influence of both TPMT activity and 6MP dosage on myelo-
and hepatotoxicity following HDM.
Observational Model: Cohort, Time Perspective: Retrospective
Toxicity of treatment, degree of myelo- and hepatotoxicity
7-28 days after high-dose methotrexate
Kjeld Schmiegelow, M.D.
Denmark: Danish Medicines Agency
NOPHO ALL92 study HDM TPMT