Genes Predispose Some Anthracycline Patients to Heart Failure

Smita Bhatia, MD, MPH

Researchers have identified a genetic profile of the patients who are most likely to develop congestive heart failure after being treated with anthracyclines and then undergoing hematopoeitic stem cell transplant (HCT) for a range of blood cancers.

The results of the study, presented at the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), will help oncologists decide which blood-cancer patients are good candidates for anthracyclines, and which should either avoid the drugs or take them in combination with frequent heart screening and/or medication to prevent heart failure, said Smita Bhatia, MD, MPH, chair of the Department of Population Sciences at City of Hope in Duarte, California and a co-author of the paper.

“We all know that, first and foremost, we have to cure our patients,” Bhatia said. “But if we have to use anthracyclines in these patients, we may also consider using a cardio protectant.”

The study included patients with acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma who had undergone HCT. Transplant survivors tend to develop heart failure earlier than the general population, and the 5-year survival rate following diagnosis is less than 50%, Bhatia explained.

The patients selected were of particular interest because they had all been treated with anthracyclines, which, in previous studies, had been shown to increase the likelihood of heart failure, the doctor said. Because the study subjects had then undergone HCT—the transplantation of blood-forming stem cells from the bone marrow, circulating blood, or umbilical cord blood to replace disease-causing cells—they also faced a higher risk of developing diabetes, hypertension, or dyslipidemia, additional risk factors for heart failure, she said.

In conducting the study, lead author Saro Armenian, DO, MPH, and colleagues sought to explain the wide variability in the risk of heart failure among blood-cancer patients who receive anthracycline treatment followed by HCT by determining if some have a genetic susceptibility to the condition. It was an area previously unstudied in this population.

The investigators followed patients who had undergone HCT at City of Hope between 1988 and 2008 and survived at least one year. From that group, Bhatia said, the researchers chose 77 patients who developed heart failure and 178 who did not. The groups were equally matched when it came to amount of anthracyclines received, age at transplant, race, type of transplant (autologous vs allogeneic), and time followed since transplant. Using a statistical model, the doctor said, the researchers also adjusted for clinical factors with the potential to increase the risk of congestive heart failure, including type of diagnosis, gender, radiation to the chest, and the development of diabetes, hypertension, or dyslipidemia.

CBR1

CBR3

NQO1

MRP1

MRP2

CYBA

SOD

AGT

AGTR1

ACE

ADRB1

ADRB2

With the “playing field leveled,” the researchers compared the frequency with which certain genes, known to be associated with heart failure, were expressed in the subjects, Bhatia said. Specifically, they focused on genes responsible for the metabolism of anthracyclines (, , , , and ); defense from oxidative stress, a condition that causes damage to healthy heart cells (NCF4, RAC2, , ); blood pressure and heart rate regulation (, , and , ); and iron homeostasis (HFE).

MRP2

RAC2

HFE

“We found three genes that were independently associated with risk,” Bhatia said—specifically, , , and . “Then, we looked at them in combinations of two or more of the genes versus less than two genes. We found that, if the patient was female and had more than two of the genes, her risk of developing congestive heart failure was tremendously increased; it was 17-fold higher than for males with less than two of the genes.”

Combined with clinical factors, the gene signature makes it possible to predict with 79% certainty whether patients like those in the study will develop congestive heart failure, as compared to a 69% probability based on clinical factors alone, Bhatia said.

To increase predictive certainty to an ideal of about 95%, Bhatia said, researchers will first need to look for additional mutations to complete the gene signature for patients likely to develop heart failure after anthracyclines. “Once we have that signature,” she said, “we’ll try to replicate it in another population.”

If the findings are supported in that study, Bhatia said, oncologists will need to figure out ways to tailor therapies to cancer patients who might benefit from anthracyclines but face a high risk of heart failure if treated with that regimen.

“There has to be a multipronged approach,” she said. “In addition to considering alternative treatments, increasing the frequency of heart screenings, and prescribing a cardio protectant, a fourth option would be pharmacological intervention among those who have received anthracyclines to prevent the progression of the disease toward heart failure, a strategy Dr. Armenian is studying now.”

Reference

Armenian SH, Ding Y, Mills G III, et al. Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF) in Survivors of Hematopoietic Cell Transplantation (HCT). ASH 2012, Abstract 589.

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