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

Abstract

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.

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

“…Using concentration-guided individualized MTX dosing in 182 children, Evans et al 6 reduced the relapse incidence as compared to the conventionally dosed (by body surface area) group. Thus, although not unequivocal, these previous studies [2][3][4]6 have suggested that higher end-infusion MTX concentrations were related to lower risk for relapse. In the present study, such a relationship was found only in the SR group.…”

“…Most commonly, MTX is administered as a 24 h infusion with leucovorin (LV) administered after 36-42 h and continued until plasma MTX is below 0.1-0.25 mM. Several studies have indicated that the end-infusion MTX concentration is related to the chances of cure, [2][3][4] although this has been questioned by others. 5 Most convincingly, Evans et al 6 in a randomized study demonstrated that individual dose adjustment of MTX to obtain an MTX concentration within a target range increased the cure rate significantly for B-lineage ALL.…”

Mathematical model to predict methotrexate elimination in children with acute lymphoblastic leukemia

“…The relatively higher incidence of ALL in children with Down's syndrome is well known. Some observations suggest increased toxicity of MTX in these children (34).…”

The involvement of RNA and protein synthesis in programmed cell death (apoptosis) in human leukaemia HL-60 cells

“…Figure 1 shows the Scatchard plot of the binding of ['HIMTX by one of the leukaemia cell lysates. Analysis of the data [8] shows that one binder of MTX had an association constant ( K , , , ) P 5.3 x loh M-', whereas the other one had a K,,, GZ 3 x lo7 M-I. Immunological studies using monospecific antiserum to purified murine leukaemia DHFR 101 showed that the low-affinity binder of MTX in leukaemia cells may…”

“…Therefore, the direct binding of ['HIMTX by cell lysates could be used to quantify high-and low-affinity binders of this drug if these were present in certain cells. [3,41. Apoptosis, the physiological mode of cell death, is representative of an endogenous suicide mechanism which can be selectively triggered by the cell in response to as yet largely unknown stimuli.…”