RISK OF RELAPSE IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA IS RELATED TO RBC METHOTREXATE AND MERCAPTOPURINE METABOLITES DURING MAINTENANCE CHEMOTHERAPY

Purpose: During maintenance chemotherapy for childhood acute lymphobla stic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX po lyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN] ) accumulate intracellularly, including in erythrocytes (E-MTX and E-6 TGN) with large interindividual variations. In the present Nordic Soci ety 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, respective ly. 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, Re sults: 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 m onths for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX.6TGN and sex to be the most significant par ameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who h ad 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 probabilit y of EFS [pEFS(5y)], 0.70 v 0.86; P = .001). Conclusion: The pharmacok inetics of MTX and 6MP may have significant influence on the risk of r elapse. The value of dose adjustments by E-MTX and E-6TGN remains to b e determined.