Patients who receive hematopoietic stem cell transplants (HCT) for leukemia, multiple myeloma, lymphoma, and similar disorders are at significantly increased risk of developing cardiovascular risk factors that only begin to emerge several years after treatment. That is the conclusion of a 10-year retrospective study now available online ahead of print in Blood (DOI 10.1182/blood-2012-06-437178).
The researchers, led by Saro H. Armenian, DO, MPH, Assistant Professor of Outcomes Research and Medical Director of the Pediatric Survivorship Center and Childhood Cancer Survivorship Program at City of Hope, found that the risk of developing hypertension, diabetes, and elevated cholesterol levels was markedly higher in HCT patients than the national rate. Moreover, those receiving donor cells rather than their own cells had notably higher rates of these conditions. The risks developed uncharacteristically soon after HCT and persisted for years after transplantation.
“We can use the information to better identify high-risk patients in order to screen and monitor them for cardiovascular risks factors over time,” he said in an interview. “Importantly, these are modifiable risk factors; more aggressive management of these conditions could result in a reduced burden of cardiovascular disease for these high-risk survivors.”
The researchers found that patients who underwent allogeneic HCT were at an especially high risk of developing cardiovascular disease risk factors, with 45.3 percent developing hypertension, 20.9 percent diabetes, and 50.5 percent high cholesterol over the study period.
The rates were lower for patients treated with autologous HCT: 32 percent, 15.9 percent, and 43.3 percent, respectively.
Rejection Drugs and GVHD
The use of immunosuppressant medications used to prevent or treat graft-versus-host disease (GVHD) largely contributed to the higher burden seen in allogeneic HCT patients, especially those who experienced acute GVHD shortly after HCT, Armenian noted. In these patients, 54.7 percent developed high blood pressure, 25.8 percent developed diabetes, and 52.8 percent developed high cholesterol over the 10-year study.
“Many allogeneic transplant patients must take immunosuppressant medications and these patients have a higher risk of developing conditions such as hypertension while one third will have multiple post-transplant cardiovascular risk factors,” Armenian said. “Post-transplant GVHD and the medications used to treat rejection appear to drive this risk.”
Another significant finding was that HCT conditioning with total body irradiation (TBI) was associated with a 1.5-fold increased risk of diabetes, and 1.4-fold increased risk of high cholesterol, regardless of HCT type.
“We do not have a good handle on why TBI increases the risk of developing these complications. Recent studies in other cancer populations have suggested that radiation-related injury to the pancreas or liver may impact the body's ability to regulate blood sugar or cholesterol levels,” he said.
Armenian and colleagues also found a linear relationship between the number of risk factors and the development of cardiovascular disease, including heart failure, coronary artery disease, myocardial infarction, and stroke.
A total of 115 patients out of the cohort of 1,885 developed cardiovascular disease. Those with no risk factors had a five percent risk over time; one risk factor increased the risk to seven percent, and two or more conditions increased the risk to 11 percent at 10 years.
Individuals who had received cardiotoxic treatments such as anthracycline chemotherapy or chest radiation prior to HCT had the highest risk—nearly one in five developed a life-threatening cardiovascular complication.
“We have shown that a significant number of patients develop cardiovascular risk factors in the years following HCT and, over time, these contribute to the overall health care burden in terms of stroke, heart disease, and heart failure,” he said.
Growing Body of Evidence
Asked for his opinion, Mohamad Mohty, MD, PhD, Professor and Head of the Department of Hematology at Saint-Antoine Hospital and the University of Pierre and Marie Curie and Chairman of the Acute Leukemia Working Party of the European Group for Blood and Bone Marrow Transplantation, said that data on long-term cardiac and cardiovascular complications after transplants are scarce, but it has become increasingly evident that long-term survivors are at risk for a variety of cardiac and cardiovascular late effects.
“This study sheds some light on this important topic. The authors should be praised for conducting such a well-designed and comprehensive analysis that can pave the way for future studies in the field,” he said.
Late cardiotoxicity after allogeneic bone marrow transplant (allo-BMT) includes cardiomyopathy, congestive heart failure, valvular dysfunction, and arrhythmia, with the total cumulative dose of anthracyclines being the main cause of cardiomyopathy, while mediastinal radiotherapy and subsequent fibrosis can contribute to the onset of restrictive cardiomyopathy and induce arrhythmias, autonomic dysfunction, and valvular defects, Mohty noted.
The link between cardiovascular events may be related to the decreased numbers of microvessels in the subcutaneous compartment and to endothelial injury, although such late cardiovascular events are likely influenced by other preexisting cardiovascular risk factors, such as diabetes, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, endocrine dysfunction, hypertension, and obesity.
“Compared with a general population, the risk of late death due to cardiac complications has been reported to be around two times higher after allo-BMT. However, one should consider these figures with caution, because cardiac complications may occur decades after treatment as very late events,” he said, noting that in terms of late cardiovascular complications, one study reported the incidence of an arterial event to be as high as 22 percent at 25 years.
Broader Education Needs
Also asked for his opinion for this article, Leslie E. Lehmann, MD, Clinical Director of Pediatric Stem Cell Transplantation at Dana-Farber and Children's Hospital Boston, and Assistant Professor of Pediatrics at Harvard Medical School, pointed out that it is only now that such long-term effects are becoming evident because there are more long-term HCT survivors. Eighty percent of recipients are now surviving for more than a year, and this represents an unprecedented and incremental increase in a cohort in which research on long-term associated risks is just beginning to emerge, she said.
“This is a new frontier that desperately needs more study. These findings are an example of some of the silent health issues that can take some time to appear, especially patients on long-term therapy for GVHD.”
There is a great need for more awareness of these potential long-term issues among health professionals who are not oncologists or transplant specialists, she continued, noting that a large number of survivors return to their primary care physicians.
‘Absolutely Need New Screening Paradigm for These Patients’
“Once patients are two or three years out from a transplant, they typically go back to their primary physician for insurance reasons, but primary care doctors and internists are not as up-to-date on the late complications of transplants. I doubt many of them will have read this paper. So there is absolutely a need for a new screening paradigm for these patients as well as more educational efforts directed at primary care doctors about long-term and often latent risk factors in transplant survivors.”
Routine blood pressure and cholesterol screening are not enough, she said. In order to diagnose more subtle cardiovascular issues, all survivors could need cardiac stress testing in addition to annual echocardiograms.
“Patients often feel that they have dodged the bullet after a successful transplant, but they need to be aware of emerging long-term risks. Monitoring cholesterol and blood pressure cannot diagnose coronary artery disease, and more sophisticated testing would allow early detection and intervention.”
The process of hematopoietic stem cell transplantation involves extracting multipotent stem cells from blood or bone marrow and storing them before they are transplanted after patients have been treated with high-dose radiation to kill any cancerous cells. These are either harvested from the patient (autologous) or a compatible donor (allogeneic). Many transplant patients have already undergone chemotherapy or radiation at some point in their disease but then later require HCT transplantation.