Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia.
BACKGROUND
Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients.


METHODS
Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records.


RESULTS
The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose.


CONCLUSIONS
Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.
Department of Child Health, Graduate School of Comprehensive Human Sciences.
Ryoko
R
Suzuki
Departments of Child Health.
Hiroko
H
Fukushima
Genetics.
Emiko
E
Noguchi
Department of Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki.
Masahiro
M
Tsuchida
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
Nobutaka
N
Kiyokawa
Department of Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki.
Kazutoshi
K
Koike
Clinical Trial and Clinical Epidemiology and.
Enbo
E
Ma
Epidemiology, Faculty of Medicine, University of Tsukuba.|School of Medicine, Information Management and Statistics, Fukushima Medical University, Fukushima, Japan.
Hideto
H
Takahashi
Departments of Child Health.
Chie
C
Kobayashi
Department of Pediatrics, University of Tsukuba Hospital, Tsukuba.
Ryoko
R
Nakajima-Yamaguchi
Department of Child Health, Graduate School of Comprehensive Human Sciences.
Aiko
A
Sakai
Departments of Child Health.
Makoto
M
Saito
Departments of Child Health.
Atsushi
A
Iwabuchi
Department of Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki.
Keisuke
K
Kato
Department of Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki.
Tomohei
T
Nakao
Department of Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki.
Ai
A
Yoshimi
Departments of Child Health.
Ryo
R
Sumazaki
Departments of Child Health.
Takashi
T
Fukushima
D000293:Adolescent; D000483:Alleles; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics* / Q000378:metabolism; D060046:Maintenance Chemotherapy / Q000379:methods*; D008297:Male; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013997:Time Factors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human
6-mercaptopurine; SLCO1B1; childhood; leukemia; methotrexate; polymorphism