Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children.

The prognostic value of systemic clearance of methotrexate (MTX) has been evaluated in 58 children with acute lymphoblastic leukemia, receiving altogether 380 MTX infusions in a dose range of 0.5 to 33.6 g/m2. The linear regression analysis of dose-steady state concentration relationship revealed that relapsed children had significantly lower steady state concentration of MTX (faster systemic clearance) than those who remained in continuous complete remission (CCR), whatever dosage of the drug was given. Relapsed children (n = 25) had a systemic clearance of MTX 122.5 +/- 55.5 ml/minute/m2 versus 71.8 +/- 25.8 ml/minute/m2 found in the CCR patients (n = 33) when the dosage of MTX was 0.5 to 1.0 g/m2. When the dose was 6.0 to 8.0 g/m2 the clearance values were 93.27 +/- 32.6 versus 61.8 +/- 24.5 ml/minute/m2, respectively. The differences are statistically significant (P less than 0.001). In 16 of 25 relapsed patients (64%) an increase of the systemic clearance has been observed during the consecutive treatments, but only 4/33 CCR patients (12%) has expressed such a phenomenon. The dose-independent prognostic relevance of systemic clearance of MTX as a possible sign of resistance to MTX is concluded.