Pharmacogenetics of Outcome in Children with Acute Lymphoblastic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 Feb 17

PMID 15713801

Citations 57

Authors

Jose Claudio C Rocha

Cheng Cheng

Wei Liu

Shinji Kishi

Soma Das

Edwin H Cook

John T Sandlund

Jeffrey Rubnitz

Raul Ribeiro

Dario Campana

Ching-Hon Pui

William E Evans

Mary V Relling

Affiliations

Soon will be listed here.

Abstract

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.

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