Background Recent studies suggest that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine polymorphic variants of genes and relapse risk, toxicity, and drug dose delivery in standard risk ALL. Procedure We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children’s Cancer Group ALL study, CCG-1891. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually and clique-finding methodology was employed for detection of significant gene-gene interactions. Results After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR=1.94, p=0.047), MTHFR (HR=1.61, p=0.034), MTRR (HR=1.95, p=0.01), and TS (3R/4R, HR=3.69, p=0.007), were found to significantly increase relapse risk. One gene-gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons (p=0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes. Conclusions These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene-gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. childhood ALL therapy.

After completing this course, the reader will be able to:1. Identify children who may be at relatively higher risk of developing cardiotoxicity as a result of treatment with anthracyclines.2. Cite considerations for administering dexrazoxane prior to anthracycline treatment to mitigate anthracyclinerelated cardiotoxicity in children.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTAnthracyclines play a critical role in the treatment of a variety of childhood cancers. However, the cumulative cardiotoxic effects of anthracyclines limit the use of these agents in many treatment regimens. Dexrazoxane is a cardioprotectant that significantly reduces the incidence of adverse cardiac events in women with advanced breast cancer treated with doxorubicincontaining regimens. Clinical evidence for the efficacy of dexrazoxane as a cardioprotectant in children, especially from randomized clinical trials, is limited, but the available data support a short-term cardioprotective effect. Long-term follow-up in children treated with dexrazoxane has not been reported. Dexrazoxane's impact on the antitumor effect and toxicity profile of the anthracyclines and the role of dexrazoxane in the development of secondary malignant neoplasms in patients who received dexrazoxane are reviewed. Based on the available data, dexrazoxane appears to be a safe and effective cardioprotectant in children, and it does not appear to alter overall survival times in children with

2711 Purpose: Recent studies have suggested that polymorphisms in genes that encode enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric patients with acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine how frequency of polymorphism variants of certain drug metabolizing genes and gene pairs relate to relapse risk, toxicity, and drug dose delivery in standard risk ALL. Methods: We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children's Cancer Group ALL study, CCG-1891. These data were analyzed with outcome data obtained from CCG. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually by univariate analysis and clique-finding methodology was employed for detection of significant gene-gene interactions. Additionally, positive predictive value was calculated for those polymorphisms found to be statistically significant on univariate analysis. Results: After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR=1.94, p=0.047), MTHFR (HR=1.61, p=0.034), MTRR (HR=1.95, p=0.01), and TS (3R/4R, HR=3.69, p=0.007), were found to significantly increase relapse risk. However, the positive predictive value of these genotypes was not statistically significant. One gene-gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons (p=0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes. Conclusion: These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene-gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. Disclosures: No relevant conflicts of interest to declare.

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