Purpose The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity. Methods The study population comprised 64 children with ALL/ML (age 1.6-16.8 years) who had received a total of 252 MTX courses (2-4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis. Results The population typical value of clearance was 7.43 L/h (inter-individual variability 43.9%), central compartment volume was 16.7 L (46.6%), peripheral compartment volume was 2.6 L (63.3%) and distribution clearance was 0.0952 L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A ) C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037-0.54] and SLC19A1 80A ) G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R ) 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039-0.61) and mucositis (OR 0.016, 95% CI 0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240). Conclusions A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.
COBISS.SI-ID: 3002737
The prediction of high-dose methotrexate (HD-MTX) toxicity is a key issue in the individualization of treatment in childhood acute lymphoblastic leukemia (ALL). Our aim was to evaluate the influence of MTX pathway polymorphisms on HD-MTX treatment outcome in children with ALL. In total, 167 children with ALLwere genotyped for methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G)A, methylenetetrahydrofolate reductase (MTHFR) 677C)T and 1298A)C, and thymidylate synthase (TYMS) 2R)3R polymorphisms. MTHFD1 1958A allele significantly reduced odds of hepatotoxicity (adjusted P=0.009), while TYMS 3Rallele significantly reduced odds of leukocytopenia and thrombocytopenia (adjusted P=0.005 and adjusted P=0.002, respectively). MTHFR polymorphisms didnot influence HD-MTX-related toxicity, but a significant effect of MTHFR 677C)T-TYMS 2R)3R and MTHFD1 1958G)A-MTHFR 677C)T interactions on HD-MTX-related toxicity was observed. None of the investigated polymorphisms influenced survival. Our study suggests an important role of polymorphisms andgene-gene interactions within folate pathway in HD-MTX-related toxicity in childhood ALL.
COBISS.SI-ID: 29379801
Treatment and long-term outcome in Slovenian children and adolescents, treatedfor acute lymphoblastic leukaemia (ALL) were evaluated, mainly considering diff erences between treatment regimens being evolved during time.From year 1967 through 2004, 394 patients (pts) were treated and six therapeutic schemes had been used. Retrospectively 5-year overall survival standard error (5yOS), relapse rate (RR) and second neoplasm (SN) were estimated according to treatment regimen, age, and where recorded, also according to BFM risk group, white blood cell count and disease subtype. For treatment regimens used after year 1992, 5-year eventfree survival standard error (5yEFS) was added to our observations. Among 75 pts enrolled in pre-POG treatment regimen, the probability of 5yOS was 25.3 5.0%, while no data for RR and SN analysis were available. For 91 pts treated according to POG derivedtreatment, the probability of 5yOS was 61.6 5.1%, with 64% RR and 5.5% occurrence of SN. Probability of 5yOS of 74.3 7.4%, RR of 37% and 8.5% occurrence of SN were reached for 35 pts enrolled in ALL-BFM 83 protocol. ALL-BFM 86 protocol included 62 pts with 69.4 5.9% probability of 5yOS, 33% RR and 3.2% occurrence of SN. For ALL-BFM 90 protocol the 5yEFS and 5yOS for 71 pts was 77.3 5.2% and 81.8 4.8%, respectively, with 17% RR and 1.5% occurrence of SN. Fifty-six patients enrolled in ALL-BFM 95 protocol reached 83.0 5.2% 5yEFS and 92.6 3.6% 5yOS, with 16% RR and 1.7% occurrence of SN.Stepwise rise of OS, decline in RR, reducing occurrence of SN and, for ALL-BFM 90 and ALL-BFM 95 protocol, improvements in EFS, were observed throughtime according to diff erent treatment regimens. General improvement regarding OS, RR and occurrence of SN was most obvious after the application of BFM regimen with evident continuous rise in OS and decline in RR and occurrence of SN thereafter.
COBISS.SI-ID: 29522649