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."
Dr. Armenian will present this study in an oral presentation on Monday, December 10, at 2:45 p.m. EST at the Georgia World Congress Center in Room C108-C109, Level 1, Building C.
Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized Fralle 2000-A Protocol [Abstract 135]
New data demonstrate that omitting the chemotherapy drug daunorubicin from an initial treatment regimen for children with standard-risk acute lymphocytic leukemia (ALL) does not reduce survival outcomes, suggesting that these children may be able to achieve positive outcomes without having to endure a treatment associated with both short- and long-term toxicities.
ALL, the most common form of leukemia in children, is a fast-growing cancer of the white blood cells in which the bone marrow makes a large number of abnormal white blood cells that are unable to develop and fight infection. Important developments over the past 20 years have led to seminal insights about ALL in children, and today nearly 90 percent of children diagnosed with standard-risk ALL are cured. Some treatment regimens for standard-risk ALL include initial infusions of daunorubicin, a type of anthracycline. While effective, continual use of this therapy is associated with potential long-term heart damage, leading researchers to assess whether eliminating or reducing the dosage of daunorubicin during the initial one-month induction therapy period might provide the same level of efficacy as the standard treatment protocol with reduced long-term risk.
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