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© 2001 American Society for Clinical Oncology Glutathione S-Transferase Polymorphisms and Outcome of Chemotherapy in Childhood Acute Myeloid LeukemiaFrom 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.
The glutathione S-transferases (GSTs) are a group of enzymes that add sulfur molecules (as glutathione) to a wide range of acceptor molecules (reviewed in1). Xenobiotic acceptors include halogenated and nitro compounds, organophosphates (including pesticides), alkylating agents, epoxides, and polycyclic aromatic hydrocarbons.2,3 The reaction is generally a detoxification, and the conjugate is degraded by the enzymes of the gamma-glutamyl cycle. The GST T1 (GSTT1) and the GST M1 (GSTM1) genes are polymorphic in humans, with the phenotypic absence of enzyme activity caused by a homozygous inherited deletion of the gene.4-6 The frequency of the GSTT1-negative genotype is approximately 15%, and the frequency of the GSTM1-null genotype is approximately 50% in United States and European studies (reviewed in7). Evidence indicates that GST expression plays an important role in determining the cytotoxicity of chemotherapeutic drugs, including alkylating agents such as chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, and thiotepa, intercalating agents such as doxorubicin, and mitomycin C and carmustine.8 In studies of laboratory cell lines, increased expression of GST has been shown to be associated with development of resistance to a range of cytotoxic drugs, including alkylating agents,9 anthracyclines,10 and nitrosourea.11 The role of GSTs in metabolism of other chemotherapy drugs, such as VP-16, is currently unclear. Because alkylating agents and anthracyclines are important drugs in the treatment of acute myeloid leukemia (AML) and are subject to detoxification by GST, it might be expected that GST genotype will be an important predictor of outcome in AML. In this study, we describe the impact of GST genotype on outcome of therapy in more than 300 children with AML. We show that genotype greatly influences outcomes and that the importance of genotype may vary with the intensity and timing of the chemotherapy regimen.
Patients The study population included 306 children with AML or myelodysplasia treated on Children’s Cancer Group therapeutic studies 2861 and 2891 between 1988 and 1994 and who participated in an epidemiologic study of AML, after the parent or guardian signed an institutional review board–approved informed consent document.12,13 Clinical data, including age, sex, WBC count at diagnosis, race, presence of chloroma, presence of CNS disease, and immunophenotype were collected prospectively. For GSTM1, 52 (33%) boys were positive and 105 (67%) null; 63 (43%) girls were positive and 84 (57%) null. For GSTT1, 117 (75%) boys were positive and 40 (25%) null; 122 (83%) girls were positive and 25 (17%) null. Distribution of GST genotypes by race is listed in Table 1; distributions did not differ significantly by race, but it should be noted that numbers are small in all categories other than white. It should also be noted that the frequency of the GSTM1 null genotype for the group as a whole is 63%, increased beyond the expected 50%. We have previously described increased risk of AML in association with the GSTM1 null genotype.14 Cases were classified on the basis of criteria established and revised by the French-American-British (FAB) Cooperative Study group by central pathology review.15 Of the 306 cases, 42 were M0 or M1, 74 were M2, 27 were M3, 64 were M4, 45 were M5, six were M6, 17 were M7, eight had refractory anemia with excess blasts, nine had refractory anemia with excess blasts in transformation, and 14 were not classified. All FAB categories were treated with the same chemotherapy regimens and were eligible for randomization.
Chemotherapy Treatment Regimen The chemotherapy treatment strategy has been described previously.16 Briefly, patients with AML were randomized at diagnosis to one of two induction approaches involving a 4-day cycle of five active chemotherapeutic agents (dexamethasone, cytarabine, 6-thioguanine, etoposide, and daunorubicin). The second cycle was administered either 10 days after the first cycle, despite low or dropping blood counts (intensive timing), or 14 days or later from the beginning of the first cycle, dependent on bone marrow recovery and degree of residual leukemia (standard timing). All patients achieving remission received a total of four cycles of induction therapy. They were then allocated to allogeneic bone marrow transplantation if a compatible family donor was present or randomized to aggressive nonmyeloablative chemotherapy (including the drugs listed above and high-dose cytarabine and L-asparaginase) or to myeloablative therapy with purged autologous bone marrow rescue. Allogeneic and autologous bone marrow transplant recipients received identical preparative therapy with the alkylating agents busulfan and cyclophosphamide before infusion of bone marrow stem cells.
GST Genotyping
Statistical Analysis
Results of the randomized comparison of intensive versus standard timing of induction chemotherapy have been reported previously.16 Induction success and time to completion of induction chemotherapy were similar in the intensive and standard timing arms. However, a marked improvement in outcome was demonstrated in patients randomized to the intensive timing arm, irrespective of the postremission therapy to which they were allocated. As noted, the subset of patients enrolled onto this treatment study for whom GST genotyping is available were also enrolled onto an epidemiologic study of AML. Comparison of survival between those enrolled onto the therapeutic study for whom GST genotype was and was not available showed no difference in survival, indicating that this subgroup is probably representative of the study population as a whole. Analysis of the potential association of GSTT1 and GSTM1 genotypes with additional factors that might influence outcome of therapy for AML, such as WBC count at diagnosis (the most powerful predictor of prognosis in this therapeutic study16), age, and presence or absence of chloromas, showed no difference in distribution of genotypes within any of these categories that might confound the analysis. GSTT1 and GSTM1 genotypes were similarly distributed in each of the three postinduction arms (data not shown).
GSTT1 Genotype and Outcome
The frequency of death in remission was increased in GSTT1-negative cases (24% v 12%; log-rank P = .05) ( Fig 3). Further analysis showed that the frequency of death in remission was increased in GSTT1-null cases receiving intensively timed therapy (26% v 9% at 5 years; log-rank P = .05) but was similar in GSTT1-null and -positive cases receiving standard timed therapy (22% v 16%; log-rank P = .4). A multivariate model of death in remission adjusted for age, sex, WBC count, chloroma, and CNS involvement also showed an increased risk of death in the GSTT1-null cases (RR, 2.1; P = .08).
The frequency of relapse from end of induction at 5 years was similar in GSTT1-negative and GSTT1-positive cases (38% v 35%, log-rank P = .5 for the whole group). Relapse was nonsignificantly increased in GST-null cases receiving intensive timing (41% v 30%; log-rank P = .2) and was nonsignificantly decreased in GSTT1-null cases receiving standard timing (32% v 45%; log-rank P = .7) ( Fig 4). Multivariate analysis confirmed that there was no impact of GSTT1 genotype on relapse (RR, 1.3; P = .4).
Analysis of early events indicates similar frequencies of remission induction in GSTT1-positive and -negative cases (82% v 80%; P = .8). The frequency of death on induction was 4% in GSTT1-positive cases and 10% in GSTT1-negative cases (P = .11). Outcomes according to assigned therapy and GSTT1 genotype are listed in Table 2. Addition of race to all multivariate models showed that black race was associated with inferior outcome but that this was independent of GSTT1 or GSTM1 genotype.
GSTM1 Genotype and Outcome Patients with the GSTM1-negative genotype had similar survival compared with those possessing at least one GSTM1 allele (50% v 47% at 5 years; log-rank P = .9) ( Fig 5). Separate analyses of those who received intensively timed therapy and those who received standard therapy also showed no impact of GSTM1 genotype on overall survival. Similarly, frequency of death in remission was not different in GSTM1-positive and -negative cases. In contrast, disease-free survival from end of induction was reduced in GSTM1-positive compared with GSTM1-negative cases receiving standard timing therapy (33% v 59%; log-rank P = .05) but was not different in those receiving intensively timed therapy (62% v 59%; log-rank P = .7). A multivariate model adjusted for age, sex, WBC count, chloroma, and CNS involvement confirmed the improved disease-free survival in the GSTM1-negative cases (RR, 0.5; P = .05).
Analysis of early events indicates similar frequencies of remission induction (81% v 81.5%; P = not significant) and death on induction (5% v 6%; P = not significant) in GSTM1-positive and -negative cases. Outcomes according to assigned therapy and GSTM1 genotype are listed in Table 3.
GSTTI and GSTM1 Genotypes Combined and Outcome GSTT1 and GSTM1 combined genotypes (ie, GSTT1 negative/GSTM1 negative; GSTT1 negative/GSTM1 positive; GSTT1 positive/GSTM1 positive; GSTT1 positive/GSTM1 negative) were analyzed to determine whether the combined genotype affected outcomes. No significant effects on outcome were seen, although it should be recognized that numbers in each category might have been too small to detect a modest effect.
This is the first report of GST genotype and outcome of therapy for AML, in which we describe inferior outcome for GSTT1 null individuals, caused largely by an increase in deaths in remission. Treatment of AML requires intensive myelosuppressive induction chemotherapy to achieve remission and continuing postremission treatment to maintain a durable long-term remission. More intensive induction and postremission chemotherapy improves overall survival but is associated with significant morbidity and mortality.20-25 The occurrence of a substantial number of deaths in remission caused by toxicity of therapy is an important limitation on success of treatment for AML.26 In this study, we have shown that absence of the GSTT1 gene is associated with increased toxicity of therapy for AML, particularly in those receiving the most intensive chemotherapy regimen. Absence of GSTT1 may reduce or delay metabolism of the chemotherapy drugs used for AML and might be expected to lead to a reduced relapse rate in addition to increased toxicity. However, the data in this study do not indicate any reduced frequency of relapse to counterbalance the increase in death in remission. It is possible that GSTT1 genotype influences production or excretion of drug metabolites that contribute to toxicity to a greater degree than it influences metabolites that have an antileukemic effect. The substrate specificity of GSTT1 remains unclear, making it difficult to determine which drug’s metabolism might be influenced by GSTT1 genotype. Interaction between GSTT1 genotype and sensitivity to the environmental carcinogen benzene has been reported.27 Similarly, a number of reports have described increased sensitivity to the genotoxic effects of the agent diepoxybutane in GSTT1-null individuals.28-32 Further studies of GSTT1 genotype and metabolism of chemotherapy drugs may clarify the relationship. Mu class GSTs are produced by a family of five genes (GSTM1-5), including the GSTM1 gene, which is the only member of the family to demonstrate a null allele.4,5 We found no effect of GSTM1 genotype on overall survival but do demonstrate an increased frequency of relapse (reduced disease-free survival) in GSTM1-positive children receiving standard timing therapy. Although this result needs to be confirmed in future studies, children receiving a less intense regimen who are able to metabolize drugs efficiently may receive an inadequate dose of cytotoxic therapy, leading to a higher relapse rate. A number of prior studies have examined GST protein levels and prognosis by using a variety of techniques, including immunochemistry, Western blotting, and high-performance liquid chromatography, with variable results. An immunohistochemical study of expression of GST mu in the blasts of children presenting with acute lymphoblastic leukemia (ALL) suggested a role for the mu class GSTs in outcome of treatment of this disease.33 Koberda and Hellmann34 conducted a study of GST activity in AML blasts from 30 adults by using 1-chloro-2,4-dinitrobenzene as a substrate and suggest that outcomes were poorer in those with increased activity. Wrigley et al35 have used immunochemistry and Western blotting to measure levels of GST pi, alpha, and mu in ovarian cancer, but they found no association between protein level and clinical outcomes, whereas other studies36,37 have reported both positive and negative correlations with levels of acidic GST levels in patients with ovarian cancer. Because protein expression studies measure pooled levels of a number of isoenzymes with different and overlapping substrate specificities, it is perhaps not surprising that these studies have not yielded clear-cut results. There have been few studies of GST genotype and outcome of therapy. A large study from St Jude Children’s Research Hospital showed no impact of GSTM1 genotype on incidence of childhood ALL.38 Although there was no impact of GSTM genotype on frequency of marrow relapse, there was a trend toward a higher incidence of CNS relapse in those with GSTM1-positive genotypes, in agreement with the higher frequency of relapse seen in GSTM1-positive individuals in this study. Because therapy for ALL depends largely on antimetabolite drugs such as methotrexate and vincristine, which are likely not metabolized by GSTs, this result is perhaps not unexpected. However, Howells et al39 have examined the impact of genotype on outcome of alkylating agent–based therapy for epithelial ovarian cancer. In this study of 148 women, there was no association between individual genotype and outcome, but women with both GSTM1-negative and GSTT1-negative genotypes demonstrated poorer survival and a shortened progression-free interval. Interestingly, the GSTM1/GSTT1 negative genotype was associated with chemotherapy unresponsiveness, in contrast to this study. The authors do not report frequencies of deaths from toxicity, perhaps because frequencies would be expected to be low in such a study, in contrast to the significant treatment-related mortality associated with therapy of AML. Although this study has focused on the impact GSTM1 and GSTT1 might have on treatment for AML, there are a number of other polymorphic genes involved in drug metabolism that have the potential to influence outcome of chemotherapy, eg, p450 enzymes, myeloperoxidase, and NQ01 (reviewed in40). In addition, variations in individual DNA repair capacity may also influence chemotherapy response and associated toxicity. Adding an extra level of complexity, changes within the leukemia cells themselves, such as overexpression of the multidrug resistance gene, can also importantly influence outcome of therapy.41-45 It is clear that identifying factors that predict outcome in AML can potentially involve a large number of factors, and studies are under way to analyze additional potentially important constitutional genes. In this study, we show that GSTT1-negative patients with AML treated with intensively timed chemotherapy have significantly increased treatment-related mortality, compared with patients with at least one GSTT1 allele. This was associated with inferior overall survival. The broader applicability of this finding to other chemotherapy regimens needs to be determined in future studies. If confirmed, the data have the potential to allow for modification of therapy in particular patient groups. This study shows that pharmacogenetic factors can influence the outcome of therapy, and particularly dose-intensive therapy. This is a variable that might need to be considered in the design of large-scale clinical trials, particularly those addressing dose intensification.
APPENDIX
APPENDIX (Cont’d) 
Supported by grant no. 5U10-CA13539 to S.M. Davies and by grant support from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Contributing Children’s Cancer Group investigators, institutions, and grant numbers are provided in the appendix.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistic or Fisher’s exact test. Survival estimates were based on the method of Kaplan and Meier.
