Late Cardiovascular Events in Survivors of Hematopoietic Cell Transplantation (HCT).

HCT is increasingly offered as a therapeutic option for hematological malignancies. Improvement in therapeutic and supportive care strategies has resulted in a growing population of long-term survivors. These survivors are at a substantial risk of morbidity, contributed to by therapeutic exposures, and development of comorbidities. For example, HCT survivors are potentially at increased risk of atherosclerotic disease of large and small vessels, due to the higher risk of dyslipidemia, diabetes, and hypertension in HCT survivors (Blood 2007;109:1765-72) as well as prior exposures to atherogenic therapeutic exposures (pre-HCT, during conditioning and post-HCT). However, cardiovascular disease (CVD) has not been well-characterized in HCT survivors, in part because of the long latency of clinically overt disease, requiring extended follow-up of large cohorts. The current report addresses this gap in literature by comprehensively evaluating the role of pre- and post-HCT therapeutic exposures (chemotherapy, radiation), transplant-related conditioning regimens, and comorbidities (pre- and post-HCT) in the development of late CVD after HCT.

Utilizing a nested case-control design, individuals with late CVD (diagnosed ≥1 year after HCT) were identified from a cohort of 3,287 1+ year survivors who underwent HCT at a single institution. This cohort formed the sampling frame for selecting controls (without CVD) matched for age and year of HCT, donor source (allogeneic vs. autologous), and length of follow-up. All episodes of CVD (cases) were clinically validated, and included coronary artery disease (CAD) or cerebrovascular events (stroke).

Sixty-three patients with late CVD were identified; 44 (69.8%) had CAD and 19 (30.2%) had stroke. Median age at HCT was 49.0 years (range, 18.6 to 78.9 years); median time to CVD was 4.1 years (range, 1.15 to 19.45 years); 66.7% received autologous HCT. Compared to matched controls (N=183), patients with late CVD were more likely to be male (68.3% vs. 51.6%; p=0.02), had greater body mass index at HCT (28.5 vs. 26.6 kg/m²; p=0.03), and were more likely to have multiple comorbidities after HCT (47.6% vs. 13.4%; p<0.01). Conditioning with total body irradiation (TBI), cyclophosphamide, and TBI + cyclophosphamide were associated with incremental increased risk (Odds Ratio [OR]=1.2, 2.5, 2.9, respectively; p for trend=0.04). Multivariate logistic regression revealed that having 2 of 4 cardiovascular risk factors (obesity, dyslipidemia, hypertension, and diabetes) was independently associated with a 5-fold risk of developing late CVD (OR=5.2; p<0.01). Multivariate analyses restricted to CAD cases and their matched controls revealed the following risk factors: pre-HCT exposure to mediastinal radiation (OR=9.3; p=0.04), and presence of 2 of 4 cardiovascular risk factors (OR=4.6, p=<0.01). No interactions were observed between therapeutic exposures and presence of comorbidities.

The current study represents the most comprehensive experience to date describing risk factors for late CVD following HCT, and demonstrates that mediastinal radiation and presence of comorbidities are primarily responsible for the risk of late CVD. These data form the basis for identifying high-risk individuals for targeted surveillance, as well as developing preventive strategies in the form of aggressive management of comorbidities.

No relevant conflicts of interest to declare.