Cancer Study Pinpoints Children at Greater Risk for Heart Damage from Leukemia Treatments

Children with high-risk leukemia who are successfully treated with doxorubicin suffer significantly more heart damage associated with the chemotherapy if they carry a specific genetic mutation for the most common iron disorder, according to a national Miller School study destined to guide individualized treatments for newly diagnosed cancer patients.

Published July 17 online in advance of print in Cancer, the official journal of the American Cancer Society, the multicenter study led by Steven E. Lipshultz, M.D., Director of the Batchelor Children’s Research Institute, showed that children with acute lymphoblastic leukemia who carry one of the gene variants associated with inherited hemochromatosis (HFE) have eight times more dead and dying heart muscle during their chemotherapy then children without a mutation for the disease in which too much iron builds up in the body. They also have more abnormal hearts two years later.

“We believe this report will help generate further research on the exact role this and other HFE genes play and on their usefulness as a screening tool to identify children at higher risk for doxorubicin-induced cardiotoxicity,” said Lipshultz, who is also professor of pediatrics and public health sciences and the George E. Batchelor Professor of Pediatrics. “If HFE gene mutations predict late cardiotoxicity, then patients with HFE mutations could be identified at diagnosis and be given cardioprotective agents to minimize their cardiac risk.”

Though a highly effective anti-cancer treatment, doxorubicin is a member of the family of anthracycline antibiotics that has long been associated with progressive and often deadly heart damage among long-term cancer survivors. The damage comes from iron and doxorubicin combining in the blood, and forming free radicals that injure DNA.

In previous studies, published in The New England Journal of Medicine in 2004 and in Lancet Oncology in 2010, Lipshultz and fellow researchers with the Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Consortium showed that some children with acute lymphoblastic leukemia (ALL), particularly girls, who were treated with doxorubicin had no heart damage five years later if they received dexrazoxane 30 minutes before chemotherapy. That finding led to the recommendations that dexrazoxane, which binds to and removes iron from the blood, become a new standard of clinical care.

For their latest study, “Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia,” the consortium researchers hypothesized that conditions leading to higher concentrations of iron in the blood favor the development of doxorubicin-induced cardiotoxicity, and set out to determine the frequency of two of the most common HFE genes, C282Y and H63D, in children diagnosed with acute lymphoblastic leukemia.

By testing the blood of 184 high-risk leukemia patients who had been successfully treated with doxorubicin without relapse in cancer centers across North America since 1991, the researchers found 24 percent carried the H63D gene and 10 percent the C282Y gene. They also found that two years after their treatments, these HFE mutation-carrying patients were significantly more likely to have lower cardiac function and less heart muscle due to doxorubicin-induced damage than those who didn’t, and that those with the C282Y mutation had the most cardiac injury – eight times more – during doxorubicin therapy than those who had no mutation.

“This is potentially of great importance, as it suggests that when a child is newly diagnosed with cancer, even before receiving any chemotherapy, they could be assessed for the presence of HFE gene mutations and, if one associated with anthracycline heart damage is present, another chemotherapy could be used, or higher amounts of the cardioprotectant dexrazoxane could be used,” Lipshultz said.

In addition to Lipshultz, other Miller School contributors to the study were Tracie L. Miller, M.D., professor of pediatrics and Director of the Division of Pediatric Clinical Research, and Vivian I. Franco, M.P.H., senior research associate in the Division of Pediatric Clinical Research.

Funded by the National Cancer Institute, the study was conducted by the Dana-Farber Cancer Institute Childhood ALL consortium, which is led by Stephen E. Sallan, M.D., Chief of Staff Emeritus at Dana-Farber, and Lewis Silverman, M.D., a Dana-Farber pediatric oncologist.

Also contributing were researchers at Brigham and Women’s Hospital, Boston Children’s Hospital and Harvard Medical School in Boston, the University of Rochester School of Medicine and Dentistry in Rochester, New York, McMaster University in Hamilton, Ontario, San Jorge Children’s Hospital in San Juan, Puerto Rico, Centre Hospitalier Universitaire de Quebec in Quebec City, Centre Hospitalaire Sainte-Justine Montreal in Montreal, Maine Children’s Cancer Program in Portland, Maine, and Columbia University in New York.

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