Evaluation of risk of acute lymphoblastic leukaemia treatment-related side-effects: the ERASE study

Treatment-related toxicities can be severe, life-threatening events that may impact on delivery of ALL therapy, and lead to reduction in quality of life. This work explored clinical and germline single nucleotide polymorphism (SNP) factors, to determine risk factors for selected toxicities; and to provide insights into pathogenesis and prevention. A systematic retrospective review of 1251 Australian children (1-18 years) treated on consecutive ALL protocols, between 1998-2013, was performed. Toxicities studied were venous thromboembolism (VTE), insulin-requirement, bone toxicity (osteonecrosis and fractures); neurotoxicity (central and peripheral) and multiple toxicities (≥ 2 of the selected toxicities). Multivariate logistic and cox regression were used to determine significant clinical risk factors. Genome-wide association studies (GWAS) were conducted on 707 Caucasian individuals. Clinical risk factors were identified for each toxicity (VTE, insulin requirement, MTX central neurotoxicity and multiple toxicities), and one SNP for multiple toxicity reached genome-wide significance (rs78342591, MUC16, P=2.42E-08). Children ≥ 10 years old had an increased risk of all toxicity types. Additionally, clinical risk factors for each toxicity correlated with more intensive therapy or more profound metabolic effects (such as raised hepatic enzymes, lower serum albumin) and/or weight at diagnosis. Clinical research highlights included development of a VTE risk algorithm to identify children at high-risk who may benefit from thromboprophylaxis; a two-fold risk of central nervous system relapse in children who had intrathecal MTX omitted after MTX neurotoxicity; and long-term effects including epilepsy and functional impairment in children following MTX neurotoxicity. Germline variant rs78342591 requires functional validation in relation to MUC16 expression and modulation of drug toxicity. Risk and protective SNPs that did not reach genome-wide significance levels (P