title: Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.
abstract: Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.
authors: Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: J
authors: J
authors: Salazar
authors: A
authors: A
authors: Altés
authors: E
authors: E
authors: del Río
authors: J
authors: J
authors: Estella
authors: S
authors: S
authors: Rives
authors: M
authors: M
authors: Tasso
authors: A
authors: A
authors: Navajas
authors: J
authors: J
authors: Molina
authors: M
authors: M
authors: Villa
authors: J L
authors: JL
authors: Vivanco
authors: M
authors: M
authors: Torrent
authors: M
authors: M
authors: Baiget
authors: I
authors: I
authors: Badell
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000964:Antimetabolites, Antineoplastic; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate