Childhood leukaemia: a relationship between intracellular 6‐ mercaptopurine metabolites and neutropenia.

Abstract

1 6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. 2 We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 3 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P < 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. 4 Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. 5 Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P < 0.01; n = 90 and r = -0.3; P < 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. 6 Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P < 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was > 210 pmol/8 x 108 RBCs. 7 The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Clinical pharmacology of inflammatory bowel disease therapies

“…Higher concentrations of 6-thioguanine nucleotides have been reported in patients with leukopenia [28,29]. For this reason, a baseline assessment of thiopurine methyltransferase activity (phenotype) or genotype may be clinically useful to "tailor" the drug dose in order to reduce the frequency of leukopenia.…”

Optimizing immunomodulator therapy for inflammatory bowel disease

“…Research on the clinical utility and interpretation of 6-MP metabolite concentrations and TPMT activity measurements was initiated in childhood acute lymphoblastic leukemia [26,35,36]. Subsequently, the relationship between 6-TGN, TPMT, and thiopurine safety and efficacy was examined in pediatric IBD patients.…”

Thiopurine S‐Methyltransferase Pharmacogenomics: Protein Misfolding, Aggregation, and Degradation

“…1). Since these metabolites are critical for the therapeutic effect of thiopurines, 6-TGN concentrations have been used as an index of the therapeutic and toxic effects of these drugs [23][24][25]. For example, in children taking identical doses of 6-MP there are wide interindividual variations in RBC 6-TGN concentrations [23], and high concentrations of 6-TGNs are associated with profound bone-marrow suppression, the primary life-threatening thiopurine-induced toxicity [23,25].…”

“…Since these metabolites are critical for the therapeutic effect of thiopurines, 6-TGN concentrations have been used as an index of the therapeutic and toxic effects of these drugs [23][24][25]. For example, in children taking identical doses of 6-MP there are wide interindividual variations in RBC 6-TGN concentrations [23], and high concentrations of 6-TGNs are associated with profound bone-marrow suppression, the primary life-threatening thiopurine-induced toxicity [23,25]. Clinical studies have demonstrated that genetically determined levels of RBC TPMT activity are inversely correlated with RBC 6-TGN concentrations [23,26,27], supporting the hypothesis that an inherited decrease in TPMT activity might shift the balance among thiopurine metabolic pathways toward the formation of 6-TGNs.…”