Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia

TY - JOUR

T1 - Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia

AU - Gregers, J

AU - Gréen, H

AU - Christensen, I J

AU - Dalhoff, K

AU - Schroeder, H

AU - Carlsen, N

AU - Rosthoej, S

AU - Lausen, B

AU - Schmiegelow, K

AU - Peterson, C

PY - 2015/8/25

Y1 - 2015/8/25

N2 - The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

AB - The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

KW - Acute Disease

KW - Adolescent

KW - Antineoplastic Agents

KW - Bone Marrow Diseases

KW - Child

KW - Child, Preschool

KW - Denmark

KW - Drug-Induced Liver Injury

KW - Genotype

KW - Haplotypes

KW - Humans

KW - Infant

KW - Male

KW - Methotrexate

KW - P-Glycoproteins

KW - Polymorphism, Genetic

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Predictive Value of Tests

KW - Recurrence

KW - Risk Assessment

KW - Treatment Outcome

U2 - 10.1038/tpj.2014.81

DO - 10.1038/tpj.2014.81

M3 - Journal article

C2 - 25582575

SN - 1470-269X

VL - 15

SP - 372

EP - 379

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 4

ER -