Purpose: During maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX polyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN]) accumulate intracellularly, including in erythrocytes (E-MTX and E-6TGN) with large interindividual variations. In the present Nordic Society for Pediatric Hematology and Oncology (NOPHO) study, the relation of E-MTX and E-6TGN to relapse risk was explored.
Patients And Methods: Two hundred ninety-seven patients with non-B-cell ALL, aged 1 to 14 years, on oral MTX and 6MP had E-MTX and E-6TGN levels measured three to 35 (median, eight) and three to 75 (median, nine) times, respectively. For each patient, a mean of all E-MTX (mE-MTX) and E-6TGN (mE-6TGN) measurements was calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX-6TGN), since MTX and 6MP may have synergistic action.
Results: For patients in remission, the median mE-MTX and mE-6TGN values were 4.7 nmol/mmol hemoglobin (Hgb) (range, 0.4 to 10.3) and 173 nmol/mmol Hgb (range, 58 to 846). With a median follow-up duration of 66 months for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX-6TGN and sex to be the most significant parameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who had a mE-MTX-6TGN less than the product of the median mE-MTX and median mE-6TGN (813 [nmol/mmol Hgb]2) had a significantly poorer event-free survival (EFS) than did patients with higher values (5-year probability of EFS [pEFS5y], 0.70 v 0.86; P = .001).
Conclusion: 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.
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DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma.
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The Section for Pediatric Hematology and Oncology, Pediatric Clinic II, The Juliane Marie Center, The University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
Purpose: To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT).
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Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP.
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Section of Clinical Hematology and Oncology, Juliane Marie Center, University Hospital, Copenhagen, Denmark.
Purpose: To study the risk of non-B-cell acute lymphoblastic leukemia (ALL) relapse in relation to the routines of administration of oral methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN).
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