Stanulla M et al. (2005) Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293: 1485–1489

Mercaptopurine is an important component of treatment protocols for childhood acute lymphoblastic leukemia (ALL). The drug is inactivated by thiopurine methyltransferase (TPMT), a ubiquitously expressed, cytosolic enzyme that is subject to genetic polymorphism. Patients with intermediate or low TPMT activity—resulting from mutations in one or both copies of the TPMT gene—tend to achieve better event-free survival than those with normal TPMT activity. Stanulla et al. have recently investigated the effect of TPMT genotype in children receiving mercaptopurine during early treatment for ALL.

This ongoing study uses minimal residual disease analysis at two follow-up points, to facilitate risk-adapted treatment stratification in ALL patients aged 1–18 years. In the current analysis, 814 consecutive patients underwent TPMT genotyping and received a 4-week cycle of mercaptopurine.

Four patients were homozygous for a mutant TPMT allele and were excluded from the analysis. Of the remainder, 55 patients were heterozygous for allelic TPMT variants that resulted in lower activity of the enzyme. On day 78, these children showed a significantly lower rate of minimal residual disease positivity than the 755 children with homozygous wild-type alleles (9.1% vs 22.8%, P = 0.02). This corresponded to an approximately 3-fold reduction in risk for heterozygous individuals.

Concluding that TPMT genotype has a significant effect on response to mercaptopurine treatment, the authors emphasize the important role of minimal residual disease analysis in this setting.