Research SummaryPersonalizing conditioning regimen in hematopoietic stem cell transplantation
Hematopoietic Stem Cell Transplantation (HSCT) is the only curative treatment for various hematological conditions. This procedure involves treating the patient with high dose chemo and or radiotherapy- called conditioning regimen in order to remove the defective cells and then infusion of donor stem cells, resulting in engraftment of donor stem cells in the patient and hence cure. However, HSCT is curative only in 50-90% of good risk patients. Conditioning regimen related toxicities (RRT) are the leading cause of early mortality upto 30-35% in high risk patients. In addition to age and other co-morbidities, the bioavailability of the drug if it is given oral, the transporters involved in drug influx or efflux, drug metabolism and ethnic variations in the genes encoding the enzymes and transporters are known to influence RRT. There is limited knowledge on these aspects for several drugs used in conditioning. The conditioning regimen act on the vascular endothelium and release circulating endothelial cells, resulting in serious early complications including toxicities and/or graft vs. host disease. The basis of the role of endothelial damage caused by different conditioning regimen in causing RRT among patients is not completely clear.
We propose to evaluate the dose-exposure-response relationship for the drugs used in conditioning as well as the genetic determinants responsible for this variation among individuals in order to personalize the conditioning regimen thereby avoiding RRT. We will also evaluate the damage to endothelial cells by different drugs used for conditioning in cell lines and animal models to identify targets that can reverse the damage.