Genetic susceptibility to anthracycline-related congestive heart failure (CHF) in survivors of hematopoietic cell transp

The transplantation of blood-forming stem cells from the bone marrow, circulating blood, or umbilical cord blood is the primary treatment option for many patients with blood cancer who relapse after receiving standard front-line therapies. During the transplant, healthy stem cells replace damaged cells that caused the illness, effectively curing patients of their disease. Advances in transplant strategies have led to a growing number of long-term survivors of HCT. However, this growing population of survivors is at risk for developing life-threatening complications such as congestive heart failure, due in large part to their exposure to pre-HCT treatments with a class of chemotherapy drugs called anthracyclines. Transplant survivors tend to develop heart failure earlier than the general population, and the overall survival rate following diagnosis is less than 50 percent.

By analyzing transplant patient demographics such as age and gender, treatment strategy (i.e., pre-HCT chemotherapy and chest radiation), and presence of cardiovascular risk factors such as high blood pressure, diabetes, and high cholesterol, researchers have been able to create a clinical profile to determine which patients are likely to develop heart failure after transplant. However, this current profile is limiting, as it fails to accurately explain the wide variability in the risk of heart failure between individual patients. Importantly, it does not account for how individuals' genetic makeup can exacerbate their risk of developing heart failure.

Seeking additional insight into how genetics can influence the risk for developing heart failure later in life, researchers conducted a case-control study to identify the genetic pathways that may make certain transplant survivors more sensitive to the toxicities of pre-transplant chemotherapy and subsequently increase their risk of heart failure. In this study, the investigators evaluated specific genes responsible for the breakdown of anthracyclines into toxic byproducts (CBR1, CBR3, NQO1, MRP1, and MRP2), defense from oxidative stress, a condition that causes damage to healthy heart cells (NCF4, RAC2, CYBA, SOD), iron overload (HFE), and blood pressure and heart rate regulation (AGT, AGTR1, ACE and ADRB1, ADRB2) in 77 patients with leukemia, lymphoma, and myeloma who underwent a transplant at City of Hope between 1988 and 2007 and later developed congestive heart failure. Investigators matched the survivors with 178 controls (transplant survivors who did not experience heart failure).

After comparing the genetic makeup of the transplant survivors who developed heart failure to their controls, researchers found that patients who had variations in the MRP2, RAC2, and HFE genes had up to a three-fold higher risk of developing heart failure after transplant; these genes are responsible for key proteins that regulate the metabolism of anthracyclines and defense against oxidative stress. Females with two or more genetic variations were at the highest risk of developing the conditions when compared to males with one or none of these variations. The discovery of these genetic variations supplements previously identified clinical variables known to affect a transplant survivor's heart health.

"Following this study we now have a much better profile of those transplant survivors who are likely to develop heart failure," said Saro Armenian, DO, MPH, lead author and Assistant Professor in the Division of Outcomes Research and Medical Director of the Pediatric Survivorship Clinic in the Childhood Cancer Survivorship Program at City of Hope in Duarte, Calif. "Armed with these insights, we can now create better screening measures and perhaps even tailor intervention strategies based on a patients' genetic makeup, minimizing long-term transplant-related toxicity and making a tremendous difference in the long-term health of these patients."

Provided by American Society of Hematology