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Relling: Improving the drug therapy of childhood leukemia

The impetus for my research is the need to improve drug therapy of childhood leukemia by better understanding the contributions of and mechanisms underlying interindividual differences in pharmacokinetics and pharmacodynamics. Using currently available medications, acute lymphoblastic leukemia (ALL) is cured in the great majority of children. However, all of these medications may be associated with adverse effects. Why are most children cured with relatively few side effects, some are cured but endure serious adverse effects, and leukemia in some children is not cured at all with currently available therapy? We are studying the basis for interpatient variability in response to several of the most commonly used medications to treat leukemia, including methotrexate, mercaptopurine, asparaginase, and dexamethasone.

One mechanism underlying variability in response to all antileukemic medications involves polymorphisms (variations) in genes responsible for drug metabolism and response. These polymorphisms partly account for why individual patients differ from each other in many characteristics. We have active research projects studying genetic polymorphisms that affect response to antileukemic agents, and are part of a national network to study how genetics influence drug response ( For example, a common polymorphism in the enzyme thiopurine methyltransferase influences the dosage of 6-mercaptopurine patients can tolerate. Those with inactivating variations in the gene appear to be at lower risk of ALL relapse, but are at higher risk of adverse effects. In our program, all patients are prospectively tested for their thiopurine status, and dosages of thiopurines are adjusted based on that status. We use a genome-wide approach to identify other polymorphisms that are important for antileukemic drug effects: ones that may affect the chance for cure and ones that may affect the risk of adverse effects of chemotherapy.The main adverse effects that we study are asparaginase allergy and glucocorticoid-induced osteonecrosis.

We also have a major initiative to implement array-based pharmacogenetic testing into routine patient care (