Chemotherapy as a Double-Edged Sword: Figuring Out Who Pays the Price Later

N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome in Childhood Leukemia Survivors

NCT01913093

The Hospital for Sick Children, Toronto, Ontario, Canada

Canadian Institutes of Health Research (CIHR), Canadian Cancer Society Research Institute (CCSRI), C17 Council, Garron Family Cancer Center at the Hospital for Sick Children, Pediatric Oncology Group of Ontario

500 patients, estimated at 100 patients per year for five years from 2013 to 2018

The N-PhenoGENICS trial is a prospective observational case control study with a primary outcome measure to define neurocognitive and behavioral phenotypes of childhood leukemia survivors. The two cohorts will be leukemia survivors aged between eight to 20 years with or without treatment-related adverse neurocognitive effects (TRANCE) trait. The trial will focus on children with a past diagnosis of acute lymphoblastic leukemia (ALL) who had received their last treatment two years prior to enrolling on this study and who are in continuous complete remission. Patients who had undergone bone marrow transplantation or who had a Down Syndrome diagnosis are not eligible.

Chemotherapy for childhood ALL has been effective, but in some cases, it may lead to long-term adverse side effects including abnormal neurocognitive function and behaviorial problems, collectively classified as the “TRANCE” phenotype, in some survivors. The hypothesis underlying this study is that individual genetic variations in folate pathways and the metabolism of methotrexate are associated with the TRANCE phenotype. To explore these aspects, the study investigators will characterize the folate and vitamin B12 intakes of these children to establish whether there are significant differences that may influence folate-dependent pathways. To identify possible epigenetic mechanisms underlying this phenotype, DNA samples will be obtained from both study cohorts and analyzed for methylation patterns.

In the past few decades, the overall survival rate for children’s cancers has increased from 10 percent to nearly 90 percent, but long-term follow-up studies have revealed that this success has come with a price. Approximately 60 percent of children who remain in complete remission suffer devastating late effects such as secondary cancers, muscular difficulties, infertility, and neurocognitive abnormalities. This raises the question as to why only some children develop these adverse effects. Are there polymorphisms in critical genes that confer a protective effect? Could epigenetic phenomena play a role? What is the contribution of important nutrients such as folic acid and vitamin B12? To answer these questions, a new phase of research is required. The investigators in this study have chosen children who have survived ALL as a model to try and explain the selective development of detrimental side effects. They are embarking on the initial steps to identify differences between children with adverse events and those who have not developed any symptoms to uncover the underlying molecular characteristics driving this susceptibility. Their ultimate goal will be to find target molecules or pathways that may be amenable to therapeutic intervention. This will be the first step toward improving the long-term quality of life for children who have survived cancer.