The Influence of Thiopurine Methyltransferase Activity on 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.

Inclusion criteria

• included in the NOPHO ALL92 protocol
• available TPMT phenotype
• treated at least once with HD-MTX 5.0 g/m2 (+- 10%) during maintenance therapy
• at least one available measurement on blood counts or alanine aminotransferase levels 28 days after HD-MTX

Exclusion criteria

• HR ALL
• children with Down Syndrome
• Events during maintenance therapy
• TPMT deficiency