Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia: dose adjustments by white cell counts or by pharmacokinetic parameters?

Abstract

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were ≥1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective 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×6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (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 2.7×10⁹/l (range, 1.4–4.8×10⁹/l). In a multivariate regression analysis, the best-fit model to predict the mWBC_shift included mE-MTX×6TGN, age at drug withdrawal, and mWBC in the order given [mWBC_shift=4.3+0.00089×(mE-MTX×6TGN)−0.097×age−0.41×mWBC_on; globalr _s=0.66,P=0.0002]. Thus, the patients with higher mE-MTX×6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronouced 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 intensity than do the WBCs alone.