The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (X10 years) and 176 non-adolescents (o10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) o50 Â 10 9 /l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS 12y :0.71 vs 0.83, P ¼ 0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r S ¼ 0.36, P ¼ 0.02), which became nonsignificant for those who relapsed (r S ¼ 0.05, P ¼ 0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P ¼ 0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient ¼ 0.65, P ¼ 0.003) than for non-adolescents (coefficient ¼ 0.42, P ¼ 0.04). Adolescents had higher mean neutrophil counts (P ¼ 0.002) than nonadolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r S ¼ 0.38, P ¼ 0.02), which was not the case for those who developed a relapse (r S ¼ 0.15, P ¼ 0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Summary A population-based sample of acute childhood leukaemia cases in Sweden 1973-94 was analysed by a geographical information system (GIS) for spatial leukaemia distribution in relation to population density. The annual incidence rate for acute lymphoblastic leukaemia (ALL) was 3.6, and for acute non-lymphoblastic leukaemia (ANLL) 0.7, cases per 100 000 children. Incidence rates in population centres, constituting 1.3% of Sweden's land area and approximately 80% of the population, compared with the rest of Sweden showed a statistically significant excess of ALL [odds ratio (OR) 1.68; 95% confidence interval (CI) 1.44-1.95], but not ANLL (OR 1.13; 95% CI 0.98-1.32). An increasing trend, however not statistically significant, was found for ALL incidence with both increasing population density in parishes and increasing degree of urbanity in municipalities. These findings support the theories that some environmental factors associated with high population density, such as infectious agents, may be of aetiological importance for childhood acute lymphoblastic leukaemia.