Response to glucocorticoids and toxicity in childhood acute lymphoblastic leukemia: role of polymorphisms of genes involved in glucocorticoid response.
BACKGROUND
Glucocorticoids (GCs) play a fundamental role in the treatment of pediatric acute lymphoblastic leukemia (ALL), but therapy with these agents often results in a number of severe side effects. The aim of our study was to evaluate the association between polymorphisms of genes encoding for proteins involved in the pharmacokinetics/pharmacodynamics of these drugs and the occurrence of side effects, in particular infections, in a small population of ALL children.


METHODS
Common polymorphisms of NR3C1, ABCB1, glutathione-S-transferase (GST)-M1, GST-P1, GST-T1, and IL-10 genes were analyzed in 36 pediatric patients with ALL, treated according to the AIEOP-BMF ALL 2000 study protocol. Toxicities occurring during the induction and reinduction periods were assessed and their association with genotypes was evaluated.


RESULTS
In univariate analysis, the risk of severe infections was increased in subjects with the GST-M1 null genotype, while patients with the GST-M1 normal genotype had significantly more moderate degree infections. The results were confirmed by multivariate analysis. Selection from the reference models of independent variables based on Akaike Information Criteria (AIC) scores maintained the GST-M1 genotype variable in the model to predict severe infections, and the ABCB1 C3435T and GST-M1 genotype variables in the model for moderate infections.


CONCLUSIONS
GST-M1 genotype may influence the severity of infections in ALL children during GC administration.
Marino
Sara
S
I.R.C.C.S Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy.
Verzegnassi
Federico
F
Tamaro
Paolo
P
Stocco
Gabriele
G
Bartoli
Fiora
F
Decorti
Giuliana
G
Rabusin
Marco
M
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000633:toxicity; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007223:Infant; D007239:Infections / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D011241:Prednisone / Q000008:administration & dosage
D003907:Dexamethasone; D005938:Glucocorticoids; D005982:Glutathione Transferase; D008727:Methotrexate; D011241:Prednisone