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Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine. Human erythrocyte (RBC) TPMT activity is controlled by a common genetic polymorphism. On a genetic basis approximately one in every 300 subjects lacks TPMT activity, and 11% of subjects have intermediate activities. 6-Thioguanine nucleotides (6-TGN) are major metabolites of 6-MP and azathioprine in humans. RBC 6-TGN concentrations are correlated directly with risk for the development of leukopenia in patients treated with thiopurine drugs. Our studies were performed to determine whether there was a relationship between genetically controlled levels of RBC TPMT activity and RBC concentrations of 6-TGN. We found a significant negative correlation between RBC TPMT activity and 6-TGN concentrations in blood samples from 40 children with acute lymphoblastic leukemia receiving long-term therapy with 6-MP (rs = -0.474; P less than 0.005). In addition, RBC TPMT activities were significantly higher in blood samples from these patients than in blood samples from adult control subjects (P less than 0.0001) or children with acute lymphoblastic leukemia who were in remission but were not receiving drug therapy (P less than 0.0001). Finally, three adult patients were studied who developed very high RBC 6-TGN concentrations and thiopurine-induced leukopenia. Two of the three patients had no detectable RBC TPMT activity--presumably on a genetic basis. These results indicate that low TPMT activity may be a risk factor for the occurrence of elevated 6-TGN concentrations and for the development of severe leukopenia in patients treated with thiopurine drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Two children are described with acute leukemia in remission who both developed a swinging pyrexia and pathologically identical splenic necrotizing granulomata. No organisms were seen in, or isolated from, either spleen. After splenectomy, systemic symptoms persisted and did not resolve until steroids were given. The etiology of this syndrome remains unknown.

6-Mercaptopurine (6MP) pharmacokinetics and red blood cell 6-thioguanine nucleotide (TGN) concentrations were studied in 19 children receiving remission maintenance treatment for lymphoblastic leukemia. There was a high interpatient variation in all the pharmacokinetic parameters measured. The pharmacokinetic parameters measured in two children who subsequently had relapses were within the 95% confidence limits of the 17 other children. There was no difference in 6MP pharmacokinetic parameters with respect to neutropenia either after or before the study. The children who developed neutropenia 10 to 19 days after study had significantly higher TGN concentrations (U = 8; P less than 0.001) and had spent a longer time receiving reduced 6MP dosage in the 12 weeks before the study (U = 19.5; P less than 0.025). TGN concentrations are a better index of a child's ability to form active cytotoxic metabolites than 6MP dose or plasma concentrations.