Risks, Rewards, and Unknowns: Advancing Cardiovascular Care in Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a cornerstone of management of a variety of malignant and non-malignant hematologic disorders, including leukemias, lymphomas, multiple myeloma, and some solid tumor malignancies, as well as bone marrow failure, hemoglobinopathies, and immune deficiencies.¹ The process of HSCT involves conditioning, or eradication of hematopoietic cells with chemotherapy and/or total body radiation followed by replenishment of bone marrow through patient-derived (autologous) or donor-derived (allogenic) cells. HSCT allows for high doses of cytotoxic cancer treatments that would otherwise be fatal. Additionally, allogenic transplant can result in beneficial graft vs tumor alloreactivity on residual cancer cells. HCST is associated with significant hemodynamic shifts as well as an intense systemic inflammatory response that can result in dysfunction in multiple organ systems, including both short- and long-term cardiotoxicity.² Refinement in HSCT technique over the past decade with reduced intensity of conditioning regimens has led to an expansion in the HSCT-eligible population, namely older patients with increased baseline cardiovascular risk.³ These patients may have pre-existing cardiovascular disease and are encountered in general and specialty cardiovascular clinics and procedure units. An understanding of HSCT and its associated cardiovascular risks is therefore relevant for both cardio-oncologists and the broader cardiology community. 

The cardiovascular risks of HSCT were highlighted by a 2011 study that showed a three-fold increased risk in long-term cardiovascular events in HSCT survivors as compared to the general population.⁴ This risk underlies the need for a comprehensive understanding of cardiac risk evaluation and mitigation in HSCT. A recognition of these risks spurred the inclusion of recommendations for HSCT assessment within the European Society of Cardiology (ESC) 2022 guidelines on Cardio-Oncology.⁵ Owing to a limited evidence base, these guidelines are largely driven by expert opinion, emphasizing the need for more refinement in evidence-based cardiovascular risk assessment and mitigation. In this setting, the Scientific Statement "The Cardiovascular Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: From Pre-Transplant to Survivorship" provides a useful summary of the current landscape of cardiovascular management of HSCT patients, from pre-transplant evaluation through survivorship, and outlines knowledge gaps and directions for future research. 

Pre-transplant evaluation 

In the pre-HSCT period, a thorough evaluation is needed to identify patients at high baseline risk of cardiovascular transplant. Inappropriate exclusion or inclusion of transplant candidates due to inadequate stratification of cardiovascular risk may lead either to inadequately aggressive treatment of hematologic disease or excess HSCT-related cardiac risk outweighing the benefit of transplant. For example, impaired left ventricular ejection fraction (LVEF) < 35% has been considered a contraindication to HSCT at many centers in the absence of compelling evidence that the risk of poor HSCT-related outcome in these patients is greater than the risk of less aggressive treatment of hematologic disease. To this end, limited evidence in this area suggests a low cardiovascular mortality rate in asymptomatic or minimally symptomatic patients with impaired LVEF receiving HSCT.⁶ Society guidelines are lacking in this area leading to eligibility criteria being largely driven by program-specific policies.

The Scientific Statement helps to clarify the pre-HSCT cardiovascular evaluation through a framework consisting of: (1) risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiac reserve. For risk stratification, the Hematopoietic Cell Transplantation-specific Comorbidity Index (HST-CI) score has been applied frequently as a comprehensive patient risk assessment prior to HSCT, but its utility in the evaluation of cardiovascular-specific risk has not been validated.⁷ The recently developed CARE-BMT score uses clinical risk factors including age, transplant type, baseline cardiovascular conditions, and routine laboratory assessment to identify those at intermediate or high cardiovascular risk with HSCT.⁸ This score may prove helpful as a tool to guide specialist referral prior to transplant. High-risk cardiovascular conditions are those considered to be lifespan-limiting, including severe valvular heart disease, multivessel and left main coronary artery disease, and advanced heart failure. These conditions may be contraindications to transplant if treatment such as valvular intervention or revascularization is not possible. Patients with well-compensated heart failure, including those with reduced LVEF, may tolerate HSCT. Recent data shows no difference in short-term and only a modest increase in long-term cardiovascular risk for HSCT recipients with an LVEF < 50% as compared to those with normal LVEF.⁹ It is important to note, however, that such cohort data is likely limited by clinical bias to select patients with better cardiovascular reserve and stability to undergo HSCT.

Criteria for evaluation of cardiac reserve are not standardized. Of the metrics used to assess cardiac reserve, including the ECOG and Karnofsky scores and the 6-minute walk test, the measurement of maximal oxygen consumption (VO2max) by cardiopulmonary exercise testing is among the best-validated measure of cardiovascular outcomes in HSCT recipients.¹⁰ One area of uncertainty highlighted by the Statement is the utility of "prehab" or physical conditioning prior to transplant to improve outcomes. A number of studies have demonstrated the safety of exercise therapy prior to or during transplant hospitalization but have not shown a clear benefit to cardiovascular or overall outcomes. Limitations to the existing literature include heterogeneity in physical conditioning protocols, small sample sizes, and short follow-up.¹⁰ 

Conditioning and short-term cardiovascular management 

For patients selected for HSCT, the conditioning period through transplant and the first 100 days of follow-up post-transplant are associated with unique challenges and considerations in cardiovascular management. 

Traditional conditioning regimens lead to a high degree of physiologic stress and may be associated with specific cardiovascular risks, such as a risk of heart failure, pericarditis, and arrhythmias seen with high-dose cyclophosphamide.¹¹ Newer reduced-intensity conditioning regimens may have a lower inherent cardiovascular risk and expand the transplant-eligible population to include older patients and those with baseline cardiovascular comorbidities. Additionally, fewer patients in the contemporary HSCT population receive high-dose anthracycline treatment prior to transplant, a significant risk factor for cardiovascular complications after HSCT.^{9, 12} Despite these advances, the cardiovascular risk of transplant in published cohorts has remained largely constant over time, possibly due to increased transplantation in higher-risk candidates.  

Large-volume fluid resuscitation is common in the transplant period, given both routinely with conditioning agents and in treatment of hemodynamic instability in the peri-transplant period. This can lead to iatrogenic fluid overload and provoke decompensated heart failure that often requires aggressive diuretic treatment. Evidence to support preventative treatment for heart failure in HSCT is limited. A subset of the OVERCOME trial population consisted of 54 patients undergoing autologous HSCT for hematologic malignancy, showing a non-significant trend towards lower decline in left ventricular ejection fraction with preventative treatment with carvedilol and enalapril as compared to control.¹³ Larger trials, likely targeted to a high-risk population, would be needed to support routine use of preventative neurohumoral blockade to mitigate cardiovascular risk of HSCT. 

Another consideration in the short term after HSCT is the addition of post-transplant cyclophosphamide (PTCy) to many post-allogenic HSCT regimens, which has quickly become standard-of-care to prevent graft-versus-host disease. PTCy has been associated with an increased rate of cardiovascular events in the first 100 days after transplant, most commonly left ventricular systolic dysfunction and pulmonary edema.¹⁴ Patients with early cardiac events after PTCy may have a worse long-term outcome. Further studies are needed to better understand cardiac risk optimization for use of this addition to the HSCT regimen. 

Atrial arrhythmias are common in the short-term post-transplant period and are primarily managed with rate control due to conditioning-induced thrombocytopenia.⁹ Acute coronary syndromes are less common but are often difficult to manage due to thrombocytopenia precluding percutaneous coronary intervention and dual antiplatelet therapy. Additionally, drug-drug interactions with P450 and P-glycoprotein-metabolized agents are frequently encountered.¹⁵ The optimal management of acute coronary syndromes in the peri-HSCT setting is not yet understood and requires careful evaluation on a case-by-case basis. 

Long-term cardiovascular management 

For patients managed through the late post-transplant period after 100 days and long-term HSCT survivors, the Scientific Statement emphasizes the optimization of cardiovascular risk factors and cardiovascular surveillance with echocardiography in high-risk patients. Long-term survivors have an increased risk of hyperlipidemia, insulin resistance, and hypertension, as well as a greater incidence of cardiovascular events.¹⁶ In addition to the physiologic stresses of transplant, the use of long-term immunosuppression with corticosteroids and chronic GHVD in allogenic recipients may result in metabolic syndrome and accelerated atherosclerosis, with a corresponding increase in long-term cardiovascular risk as compared to autologous recipients.¹⁷ However, the optimal method of identifying patients at high risk for long-term complications is unknown and evidence for the optimal screen intervals is lacking in the adult population. There is no robust data to support routine biomarker screening in the asymptomatic post-transplant population. Cardiovascular risk scores may prove useful, but this remains to be studied. In contrast, for the pediatric population, society guidelines recommend echocardiographic surveillance for asymptomatic childhood cancer survivors determined by anthracycline and radiation dose thresholds.¹⁸ For symptomatic patients, yearly echocardiography in HSCT survivors has been recommended.¹⁹  

Conclusions and research needs

There are several points that clinicians should take from this Statement to apply to clinical practice. Clinicians should recognize that older patients with preexisting cardiovascular disease or cardiovascular risk are increasingly being evaluated for HSCT. Many patients with underlying cardiovascular disease can be safely managed through HSCT and so should be managed accordingly with an understanding of HSCT-specific cardiovascular considerations. Baseline risk factors as well as type of HSCT and the selected conditioning regimen all modulate patient-specific cardiovascular risk. Risk scores are most useful to identify patients at risk of complications from transplant but should not be used on their own as a basis to preclude patients from transplant. Not all cardiovascular events after HSCT are equally severe—the most common cardiac events are atrial tachyarrhythmias which can generally be managed through careful medical therapy through the transplant period.

A number of gaps in knowledge and guidelines for management of the HSCT population remain. More precise identification of patients who stand to benefit most from cardio-oncology referral prior to or after HSCT is needed. Application of existing clinical risk scores may prove helpful in this context. Additionally, protocols to increase recognition of and early intervention on modifiable cardiovascular risk factors may be helpful to mitigate long-term risks of heart failure and myocardial infarction this population. Finally, cost-effective strategies for cardiovascular surveillance in HSCT survivors to determine optimal testing candidates and screening intervals need to be developed.