asco@alo33:161479 JSONTXT

Background: Contemporary therapies produce high cure rates in HL. Hoever, complications of treatment produce substantial morbidity and mortality. Identification of individuals at high risk for toxicity is a goal for precision HL therapy. Methods: We conducted a nested case-control study of 953 intermediate risk HL patients enrolled on the Childrens Oncology Group AHOD0031 protocol, assessing associations beteen severe lung toxicity and clinical, demographic, x0026; genetic predictors. Chemotherapy included doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone. The frequency of 1936 variant alleles 1931 SNPs x0026; 5 CNVs in 225 drug metabolism enzyme and transporter genes ere compared beteen patients ith nomild n=929 x0026; severe n=24 lung toxicities. Significant polymorphisms plt0.005 ere combined into per-individual risk scores by summing risk alleles, and included in a predictive regression model ith significant covariates. Results: We found a significant association beteen severe lung toxicity and polymorphisms in 3 genes; NAT2, SLCO1B1x0026;ABCC1. Risk alleles ere summed across the 3 polymorphisms, generating an allelic risk score ranging from 0-5. A regression model for prediction of lung toxicity included allelic risk score and erythrocyte sedimentation rate ESR . The model identified a high-risk group ith severe lung toxicity prevalence of 9 percent, and a lo-risk group ith prevalence of 1.5 percent. Within the high-risk subset, a second-stage test of polymorphisms in GSTA4 and SLCO1B1 identified a subset ith a prevalence of 28 percent. Within the lo-risk subset, polymorphisms in CYP11B1, SLC7A8, and SLCO1B1 identified individuals ith a prevalence of 8 percent. To validate the results, e retested the model in 1000 bootstrapped data sets generated from the original data. Conclusions: A to-step algorithm combining genetic risk alleles in 8 polymorphisms, integrated ith ESR, identifies HL patients at lo lt1.5 percent and high 28 percent risk for severe pulmonary toxicities. These results suggest potential for genomic-guided therapy regimen assignment to avoid drugs eg bleomycin associated ith lung toxicity in high risk patients. This ork serves as a model for approaches to other HL toxicities.,J Clin Oncol 34, 2016 suppl; abstr 7522 00:00.0,Hematologic MalignanciesLymphoma and Chronic Lymphocytic Leukemia