METHOTREXATE AND 6-MERCAPTOPURINE MAINTENANCE THERAPY FOR CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - DOSE ADJUSTMENTS BY WHITE CELL COUNTS ORBY PHARMACOKINETIC PARAMETERS

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were greater than or equal to 1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therap y was analyzed in relation to the erythrocyte concentration of MTX pol yglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respe ctive major cytotoxic metabolites of MTX and 6MP). For each patient, E -MTX and E-6TGN levels were measured 2-15 (median, 6) and 2-17 (median , 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX x 6TGN). The degr ee of myelosuppression was registered as the mean WBC determined follo wing cessation of the therapy minus the mean WBC measured during the t herapy (mWBC(shift)). The mean WBCs measured on therapy (mWBC(on)) and off therapy were highly correlated (r = 0.48, P = 0.009). The median mWBC(shift) was 2.7 x 10(9)/I (range, 1.4-4.8 x 10(9)/l). In a multiva riate regression analysis, the best-fit model to predict the mWBC(shif t) included mE-MTX x 6TGN, age at drug withdrawal, and mWBC in the ord er given [mWBC(shift) = 4.3 + 0.00089 x (mE-MTX x 6TGN) - 0.097 x age - 0.41 x mWBC(on); global r(s) = 0.66, P = 0.0002]. Thus, the patients with higher mE-MTX x 6TGN values, the younger patients, and the patie nts with the lowest WBC during therapy had the most pronounced degree of myelosuppression as measured by mWBC(shift). These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment i ntensity than do the WBCs alone.