Given the improvements in diagnostic strategies, treatment, and supportive care, long-term survival is now an expected outcome for a large majority of patients with hematologic malignancies. Unfortunately, radiation therapy and anthracyclines, which form the backbone of front-line treatment, have well-established cardiotoxicity profiles.
“It’s not only the treatment with systemic therapies and potentially the radiation that drive the risk, but it’s also the de novo onset of new cardiovascular risk factors.”— Saro Armenian, DO, MPH
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During the 2021 American College of Cardiology (ACC) virtual conference on Advancing the Cardiovascular Care of the Oncology Patient, Saro Armenian, DO, MPH, of City of Hope Comprehensive Cancer Center, Duarte, California, and Eric Yang, MD, FACC, FASE, of UCLA Cardiovascular Center, discussed the many complications seen in this patient population, including cardiac dysfunction, heart failure, atherosclerosis, cardiac arrhythmia, and valvular disease.1
“Due to advances in treatment, it’s estimated there will be nearly 1.5 million survivors of hematologic cancers over the next 10 years,” said Dr. Armenian, who is a pediatric hematologist-oncologist. “These patients represent a fast-growing population at risk for cardiotoxicity during treatment and after completion of cancer-directed therapy.”
Eric Yang, MD, FACC, FASE
Drs. Armenian and Yang reported that nearly 200,000 individuals in the United States will be diagnosed this year with hematologic cancer, which includes Hodgkin and non-Hodgkin lymphoma, multiple myeloma, and acute and chronic leukemias. Cardiovascular disease impacts both the delivery of cancer-directed therapy and survivorship, said Dr. Armenian. In adolescents and young adults diagnosed with acute myeloid leukemia, for example, 5-year survival decreases by 15% among patients who develop left-ventricular systolic dysfunction during therapy,2 Dr. Armenian commented.
There’s also a dramatic increase in the incidence of atrial fibrillation in adults who undergo stem cell transplantation. According to Dr. Armenian, the difference in overall survival among patients who develop atrial fibrillation compared with those who do not is “quite striking.”
Dr. Armenian continued: “These data highlight the fact that, if you’re able to prevent these [cardiovascular] conditions or identify them early on, you may be able to substantially improve cancer-related outcomes.”
Cardiac Risk in Long-Term Survivorship
The risk extends beyond cancer treatment as well. Compared with their peers who do not develop cardiovascular disease, long-term survivors of lymphoma who develop complications such as congestive heart failure 1 to 2 years after completion of therapy have substantially worse overall survival, and the excess mortality continues to rise in the decades after treatment.3 The incidence of mortality and morbidity associated with cardiovascular disease is also significantly increased in patients with multiple myeloma and non-Hodgkin lymphoma.
“After adjusting for modifiable risk factors, we see anywhere from a 40% to 70% increased risk of morbidity in these long-term survivors,” said Dr. Armenian, who noted several well-established, dose-dependent risk factors that accelerate the risk of cardiovascular disease. “Heart failure is largely driven by anthracycline-based therapy as well as radiation delivered to or near the heart. Individuals who have exposure to both [types of therapy] have the highest incidence of heart failure.”
For coronary heart disease, said Dr. Armenian, the risk is primarily driven by radiation exposure to the heart and blood vessels. Similarly, with valvular disease, the greater the dose of radiation to the heart and its associated structures, the greater the incidence of valvular heart disease. Patients who have additional comorbidities, such as older age, preexisting left-ventricular dysfunction, and/or multiple cardiovascular disease risk factors, are also at high risk of developing cardiac disease and dysfunction in long-term survivorship and warrant special surveillance and monitoring, said Dr. Armenian.
Hematopoietic Cell Transplantation
Another group of patients at risk for cardiovascular disease are those who undergo bone marrow transplantation. As Drs. Armenian and Yang reported, more than 25,000 patients in the world will undergo stem cell transplants this year—a high-risk strategy that has been shown to be quite effective. In this unique population, however, there’s been a “striking increase” in the incidence of cardiovascular disease compared with their peers. This is largely driven by a marked increase in cardiomyopathy or heart failure risk, ischemic heart disease, and the incidence of stroke.4
Longitudinal analysis of patients after allogeneic stem cell transplantation has identified key variables that may be predictive of developing cardiac dysfunction. Age, development of graft-vs-host disease, hypertension, cumulative anthracycline dose, and abnormal global longitudinal strain prior to transplantation all contribute to a much higher risk of cardiac or left-ventricular dysfunction after stem cell transplant therapy, but modifiable risk factors play a role as well, noted the presenters.
“It’s not only the treatment with systemic therapies and potentially the radiation that drive the risk, but it’s also the de novo onset of new cardiovascular risk factors,” Dr. Armenian explained. “These individuals are at much higher risk of developing hypertension, renal disease, dyslipidemia, and diabetes after completion of therapy compared with the general population.”
Furthermore, Dr. Armenian reported a dose-dependent increase in the incidence of cardiovascular disease among survivors based on the cumulative burden of modifiable risk factors. Individuals who have hypertension and have been treated with high-dose anthracyclines (> 250 mg/m2), for example, have a greater than 30-fold risk of developing cardiac or -cardiovascular disease than those who have neither exposure.5 Based on these data, Dr. Armenian and -colleagues have developed risk calculators that take into account both modifiable and established risk factors from the general population as well as treatment-related risk factors. They are now using these scores to stratify individuals into high, intermediate, and low risk of developing cardiovascular disease.
Future Research
Despite the progress being made, however, Dr. Armenian emphasized that more longitudinal studies are needed to better characterize the phenotypes; biomarkers; and, increasingly, germline and somatic genetic changes that may be driving cardiovascular disease in patients with hematologic malignancies.
“We know that, for a large number of individuals, early screening and detection can substantially improve the likelihood of identifying significant cardiovascular disease and chronic health conditions. However, we really need to marry these efforts with ongoing evidence-based guidelines to evaluate cost-effective recommendations for population-based screenings,” explained Dr. Armenian.
“We increasingly need to think about new paradigms for monitoring long-term survivors and these patients,” he continued. “How do we integrate advances in imaging strategies as well as diagnostics from the general cardiology community into the cardio-oncology world? Ultimately, this is only going to be done through collaborative efforts to help translate the observational studies into interventional research.”
DISCLOSURE: Dr. Armenian and Dr. Yang reported no conflicts of interest.
REFERENCES
2. Getz KD, Sung L, Ky B, et al: Occurrence of treatment-related cardiotoxicity and its impact on outcomes among children treated in the AAML0531 clinical trial: A report from the Children’s Oncology Group. J Clin Oncol 37:12-21, 2019.
3. Armenian SH, Xu L, Ky B, et al: Cardiovascular disease among survivors of adult-onset cancer: A community-based retrospective cohort study. J Clin Oncol 34:1122-1130, 2016.
4. Chow EJ, Mueller BA, Baker KS, et al: Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation. Ann Intern Med 155:21-32, 2011.
5. Armenian SH, Sun CL, Vase T, et al: Cardiovascular risk factors in hematopoietic cell transplantation survivors: Role in development of subsequent cardiovascular disease. Blood 120:4505-4512, 2012.
