Randi Nygaard

Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia - results from the NOPHO ALL-92 study

Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

Variability in methotrexate serum and cerebrospinal fluid pharmacokinetics in children with acute lymphocytic leukemia: relation to assay methodology and physiological variables

Methotrexate (MTX) steady state concentrations were evaluated in 42 children who had received high-dose infusions (6-8 g/m2) for acute lymphocytic leukemia. Concentrations in serum and cerebrospinal fluid (CSF) measured by immunoassay were found to be highly variable. Reanalysis by a reference high-pressure liquid chromatography method ruled out analytical factors as a source of this variability. The correlation coefficient between the analytical methods was 0.77 for the serum data and 0.88 for the CSF data. The variability of serum and CSF concentrations was higher in younger patients (serum; P = 0.05 and CSF; P = 0.18), and the CSF concentration decreased with decreasing age and in later courses. Body surface area, body mass index, weight, and gender were not significantly related to MTX variability. We conclude that the pronounced pharmacokinetic variability seen during MTX infusions remains largely unexplained.

Evaluation of Serious Adverse Events in Patients Treated with Protocols Including Methotrexate Infusions

During the period 1979 to 1992 we treated 141 children for various malignant diseases with protocols including methotrexate (MTX) infusions in doses ranging from 0.5 to 33.6 g/m2. During a total of 922 courses, there were no fatal complications associated with MTX treatment. Serum MTX concentration and pharmacokinetic data were monitored continuously during the infusions. In this study, we evaluated the occurrence of serious untoward reactions to MTX infusions. Impaired renal function with delayed drug elimination was seen in seven patients, all boys, especially after short infusion times. All recovered completely without any serious clinical symptoms. In three leukemia patients who later died from resistant disease, we observed late neurological disturbances and computer tomography (CT) brain scan abnormalities. Pharmacokinetic data from the patients with complications are described and confirm that serial MTX concentration monitoring is the most important early indicator of renal toxicity.

On the prognostic value of systemic methotrexate clearance in childhood acute lymphocytic leukemia

The prognostic value of systemic methotrexate clearance (ClMTX) during high-dose therapy was evaluated in a cohort of 42 children with acute lymphocytic leukemia (ALL). As part of an extensive chemotherapy protocol, they had received a total of 293 methotrexate (MTX) infusions in the 6-8 g/m2 dose range. At the termination of the study, when they had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in ClMTX during the eight courses was up to six-fold. In 67% of the patients, the maximum level of ClMTX reached at least twice the minimum value. The coefficients of variation for the intra- and interindividual variability in ClMTX were 9-57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients with a high ClMTX during the initial treatment course, but the difference was not significant on a 5% level. There was no significant relationship between high individual median ClMTX and subsequent relapse of ALL. However, ClMTX during the initial infusion, the time-dependent mean for ClMTX, and the individual patients median ClMTX, were significant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokinetic variability and unpredictable values of ClMTX in subsequent courses after standardized administration of MTX to paediatric patients with ALL. In spite of the association between ClMTX and prognosis shown by some of the analyses, estimates of ClMTX rates may not necessarily be related to disease outcome in a way that can be exploited to the benefit of the individual patient.

Thyroid Function in Children after Cytostatic Treatment for Acute Leukemia

Sixty-one children were examined for thyroid dysfunction as an adverse late effect after cessation of antileukemic treatment. The aim of the study was to contribute to clarifying which types of therapy can cause this endocrine disorder. Our treatment protocols do not include cranial irradiation as CNS prophylaxis, but we give relatively intensive intrathecal methotrexate treatment. The results indicate that this cytostatic regimen alone does not cause thyroid dysfunction as an adverse late effect.

Structural chromosome aberrations in lymphocytes from children with one to five years of total remission after chemotherapy of acute lymphoblastic leukaemia

Cytogenetic studies were made of 25 children (11 girls and 14 boys) with acute lymphoblastic leukaemia treated successfully with cytostatic agents and a reference group of children matched for age, sex and residence. The cytostatic treatment involved vincristine, prednisone, 1-asparaginase, methotrexate, 6-mercaptopurine for two to three years, and in a few cases cyclophosphamide, daunomycin and cytosine-arabinoside. No irradiation was given. Chromosome breakage and sister chromatid exchange (SCE) were not increased at one to five years after end of therapy. More cells with cytologically stable aberrations (translocations, deletions) were found among the patients, although an unexpected number of aberrant cells was also observed in the reference group.

Methotrexate infusions as central nervous system prophylaxis in children with acute lymphocytic leukemia: The Norwegian experience

This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).