Summary In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT)) during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT < 40 IU I -. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r > 0.70, P < 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk (Figure 1). One hundred and twenty-eight patients completed induction and consolidation therapy. Of these, 13 were excluded from this study due to major protocol violation during induction or consolidation therapy, refusal of MT by parents, AT not measured during MT, or lack of data (3, 1, 7 and 2 patients). Thus, 115 patients (67 boys and 48 girls) were eligible for analyses, with 56 cases of standard risk (SR), 39 cases of daily for 4 days); 6MP = oral 6-mercaptopurine (75 mg m-2 day-'); MTX = oral methotrexate (20 mg m-2 week-'); M = intrathecal methotrexate (12 mg m 2); pred/p = oral prednisone (60 mg m-2 day-'); -= 6-thioguanine (60 mg m 2 day-'); | / M = 500/1,000 mg MTX 24 h infusion with leucovorin rescue; V = vincristine (2 mg m2, max. 2 mg dose-'); XXXX = CNSirradiation (2,400 cGy).

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To explore the clinical significance of the concentration of methotrexate (MTX) in erythrocytes (E-MTX), 42 boys and 31 girls were studied during maintenance chemotherapy for childhood acute lymphoblastic leukemia for periods of 3-22 months (median, 8 months) at an unchanged dose of MTX. For each study period, a weighted mean of white cell counts (mWBC), absolute neutrophil counts (mANC), and serum aminotransferases (mAT) were calculated, using as weights the intervals from sampling until the next WBC, ANC, or AT determinations were done. In 17 patients who underwent at least six measurements of E-MTX during a period in which the MTX dose remained unchanged for up to 22-months, the median intraindividual coefficient of variation for E-MTX was 10% (range, 5%-22%). For each patient, a mean of all E-MTX values (mE-MTX) during a study period (range, 1-15 measurements; median, 3) was used as an index of the RBC accumulation of MTX at the prescribed dose of MTX. Among 42 patients receiving full-dose MTX (greater than 17.5 mg/m2), the mE-MTX ranged between 3.4 and 9.6 nmol hemoglobin (Hb) (interindividual coefficient of variation, 33%). The mE-MTX was significantly related to the MTX dose (r = 0.45, P = 0.00003). The mWBC and mANC were both significantly related to the mE-MTX (mWBC: r = -0.31, P = 0.004; mANC: r = -0.35, P = 0.02), but not to the dose of MTX (mWBC: r = -0.08, P = 0.25; mANC: r = -0.22, P = 0.08). Each of four patients with a persistent rise in AT above the upper normal limit (40 IU/l) and an mAT of greater than 80 IU/l had an mE-MTX of greater than 6.5 nmol/mmol Hb. Due to its low intraindividual variation, E-MTX may be useful for detecting persistent or intermittent failure of patient compliance. Its prognostic significance and its clinical value in MTX dose adjustment should be explored in prospective studies.

In a retrospective study of 84 children with standard-risk acute lymphoblastic leukemia diagnosed in 1981-1986, mean white cell count (mWBC) during maintenance chemotherapy (MT) was found to be significantly related to risk of hematological relapse, giving patients with the higher mWBC the poorer outcome. The only other significant relapse-related risk factor was white-cell count at diagnosis. mWBC was not significantly related to white cell count at diagnosis, sex, age, or dose of methotrexate or mercaptopurine. Patients with low mWBC also had relatively low white-cell counts after cessation of therapy when compared with patients with high mWBC.

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