AML: 'Start as Oncology Patients, but Return With Heart Damage'

Nancy A. Melville

May 12, 2020

For many children with acute myeloid leukemia (AML) who undergo treatment and are cured, the toxicity of that treatment can leave them with severe health problems, often involving the heart.

"These patients start out as oncology patients," said Steven E. Lipshultz, MD, professor and chair of pediatrics at the University at Buffalo's Jacobs School of Medicine and Biomedical Sciences, in New York.

"But when they come back 20 years later, their hearts have been damaged, and I've been involved in probably more than 60 survivors of childhood cancer who required heart transplants," he said.

Lipshultz was approached by Medscape Medical News to comment on a new study of the cardioprotective agent dexrazoxane (multiple brands), which is used in pediatric AML. The study shows – for the first time – that the agent may reduce treatment-related mortality.

"If there is one population that really needs cardioprotection, it's the children with AML," Lipshultz told Medscape Medical News.

"Children with AML are initially treated with more than one heart-damaging chemotherapy, and for some, after they get their chemotherapy, they have to go on to receive a bone marrow transplant, and that is also associated with heart damage and heart failure," he explained.

In light of the evidence of the benefits of dexrazoxane, the fact that it is rarely used in pediatric AML is discouraging, Lipshultz noted. Studies from 2013 and 2015 suggest that fewer than 5% of AML patients in the United States are given the agent.

"I've done about a half a dozen prospective, randomized clinical trials, yet in spite of this, one of the most frustrating things has been how infrequently this is used outside of the protocols in multicenter studies," he commented.

"The evidence shows dexrazoxane doesn't interfere with treating cancer ― it may actually be beneficial ― and it definitely is associated with less heart damage," he said.

"This current study adds to that and supports that dexrazoxane should be used as part of routine care," Lipshultz said.

The new study was published in April in the Journal of Clinical Oncology.

"Our findings that dexrazoxane reduced the harmful cardiac effects of anthracyclines are consistent with prior studies," first author Kelly D. Getz, PhD, MPH, assistant professor of epidemiology at the University of Pennsylvania Perelman School, in Philadelphia, told Medscape Medical News.

"However, these data are, to our knowledge, the first to identify that dexrazoxane may be associated with a potential reduction in treatment-related mortality," he added.

The new study, with senior author Richard Aplenc, MD, PhD, professor of pediatrics at the Children's Hospital of Philadelphia, involved an analysis of results from the most recent trial from the Children's Oncology Group (COG) for de novo AML.

The COF AAML1031 study involved children with AML who were treated between 2011 and 2016.

Among the 1014 patients who were included in the analysis, 96 received dexrazoxane at every anthracycline course, and 918 were not treated with the drug.

Dexrazoxane was administered at the discretion of the treating physicians.

With a median follow-up of 3.5 years, patients who received dexrazoxane had significantly lower rates of left ventricular systolic dysfunction (LVSD) compared to those who did not (26.5% vs 42.2%; hazard ratio [HR], 0.55; P = .009).

Patients who received dexrazoxane had a 60% lower risk for LVSD of grade 2 or higher (11% vs 23%; HR = 0.40; P = .011), and the rate of LVSD of grade 3 or higher was 70% lower (3.8% vs 8.5%; HR = 0.30; P = .094).

The 5-year event-free survival was similar between the groups (49.0% vs 45.1%; P = .53), as were rates of overall survival (65.0% vs 61.9%; P = .61).

The difference in treatment-related mortality among those who did and those who did not receive dexrazoxane approached statistical significance (5.7% vs 12.7%; P = .06).

In an intent-to-treat sensitivity analysis, the lower treatment-related mortality in the dexrazoxane group did reach statistical significance (4.6% vs 12.6%; P = .024).

"We interpret our findings related to treatment-related mortality as suggesting that dexrazoxane may prevent acute, severe cardiac events that contribute to early deaths," Getz said.

Dexrazoxane may prevent acute, severe cardiac events that contribute to early deaths. Dr Kelly Getz

"These results provide very suggestive evidence that dexrazoxane provides cardioprotection during frontline treatment of pediatric AML," the authors conclude.

"Furthermore, these data support approval of dexrazoxane for cardioprotection in countries where its use is limited to anthracycline extravasation, " they add.

Prior Warnings May Drive Concerns

Reasons why clinicians may be reluctant to use dexrazoxane include concerns of the potential for secondary malignancies, which led to a black box warning from the European Medicines Agency in 2011 that prohibited its use in children, the authors note. Although that warning was later removed, concerns may linger, the authors comment.

There is increasing evidence of benefit from the use of the cardioprotective agent. A 2018 study by Getz's team showed a decrease in survival among pediatric AML patients who experienced on-therapy cardiotoxicity, a finding that underscores the need for increased use of dexrazoxane.

Their latest study adds to the evidence. Results suggest that therapy-related mortality is reduced in pediatric AML patients who receive dexrazoxane. The data have led the COG to "mandate dexrazoxane use for all patients randomized to standard chemotherapy" in an upcoming COG phase 3 AML trial that will test a liposomal anthracycline against standard chemotherapy, the authors note.

The research was supported by grants from the National Clinical Trials Network (NCTN) Operations Center and the NCTN Statistics and Data Center and by the St. Baldrick's Foundation, Alex's Lemonade Stand Foundation, and an NHLBI career development award. Getz and Lipshultz have disclosed no relevant financial relationships.

J Clin Oncol. Published online April 2020. Abstract

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