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Glutathione S-Transferase Polymorphisms and Outcome of Chemotherapy in Childhood Acute Myeloid Leukemia

From the Department of Pediatrics, University of Minnesota, Minneapolis, MN; South Carolina Cancer Center, Columbia, SC; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles; and the Children’s Cancer Group, Arcadia, CA.

Address reprint requests to S.M. Davies, MB, BS, PhD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email: davie008{at}tc.umn.edu

PURPOSE: Glutathione S-transferase theta (GSTT1) and mu (GSTM1) genes are polymorphic, the genes being absent in approximately 15% and 50% of the population, respectively. Because glutathione S-transferases may be involved in the metabolism of chemotherapy drugs, we hypothesized that presence or absence of the genes may influence the outcome of treatment for childhood acute myeloid leukemia (AML).

PATIENTS AND METHODS: We genotyped GSTT1 and GSTM1 in 306 children with AML receiving chemotherapy on Children’s Cancer Group therapeutic studies. Outcomes were compared in those with and without GSTT1 and GSTM1 genes.

RESULTS: Patients with the GSTT1-negative genotype had reduced survival compared with those with at least one GSTT1 allele (GSTT1 positive) (52% v 40% at 5 years; log-rank P = .05). A multivariate model of survival adjusted for age group, sex, WBC count, chloroma, CNS involvement, and French-American-British group confirmed the increased risk of death in the GSTT1-null cases (relative risk,AQ 1.6; P = .02). The frequency of death in remission was increased in GSTT1-negative cases compared with GSTT1-positive cases (24% v 12%, log-rank P = .05). The frequency of relapse from end of induction was similar in GSTT1-negative and GSTT1-positive cases (38% v 35%, log-rank P = .5).

CONCLUSION: Children who lacked GSTT1 had greater toxicity and reduced survival after chemotherapy for AML compared with children with at least one GSTT1 allele. If confirmed in further studies, GSTT1 genotype might be useful in selecting appropriate chemotherapy regimens for children with AML.

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