Coronary artery calcification and its effect on cardiac events in patients undergoing allogeneic stem cell transplantation using nonmyeloablative conditioning

Abstract

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using non-myeloablative (NMA) conditioning has improved access for older, frail or medically unfit patients with high comorbidity index. The combination of fludarabine, cyclophosphamide, and low-dose total body irradiation (Flu/Cy/2Gy TBI) is safe, with added improvements in GVHD-related complications using post-transplant cyclophosphamide (PTCy) (Bolanos-Meade et al 2023). Coronary artery calcification (CAC), a marker of subclinical atherosclerosis, has been previously associated with increased mortality in myeloablative and reduced-intensity transplant settings following PTCy-based GVHD prophylaxis utilizing tacrolimus (Graham et. al, 2025). This study evaluates the effect of CAC on cardiac events following nonmyeloablative conditioning with PTCy, Sirolimus, and MMF. Methods: We evaluated 108 patients undergoing allo-HSCT between 2022 and 2025 using Flu/Cy/2Gy TBI. GVHD prophylaxis included PTCy on days +3 and +4, followed by sirolimus and mycophenolate mofetil (MMF) starting on days +5. All patients received peripheral blood stem cell grafts and had available non-contrast CT imaging performed within 30 days before transplant, assessing the presence or absence of CAC. CAC positivity was determined based on the presence of CAC in non-contrasted imaging (Hounsfield units >130). Cardiac events (CEs) included new-onset heart failure, arrhythmias, non-malignant pleural or pericardial effusions, and ischemic events. Early cardiac events (ECEs) were defined as those occurring before day +100. Results: Of 108 patients, 70 (65%) were CAC-positive (CAC+) and 38 (35%) were CAC-negative (CAC-). Cardiac events occurred in 47 patients, with 87% before day +100. The median age was similar in both groups (69 in CAC+ vs 63 in CAC-, p<0.001), with equal HCT-CI score <3 CAC (48.6% vs 44%, p=0.84). There was a higher preponderance of MDS in the CAC+ group (34% vs. 7.9%, p=0.0023), while AML was more common in CAC− patients (52% vs. 28%, p=0.013) with no difference in ALL or Lymphoma. The donor source (matched unrelated vs mismatched donors) was equal between groups. Cardiac Toxicity and CAC Status: CAC+ patients had significantly higher rates of ECEs (50% vs. 16%, p=0.00048) and overall CEs (57% vs. 18%, p=0.00016). The most common early cardiac events in CAC+ patients included newly diagnosed heart failure (CHF) (27%), atrial fibrillation (14%), pleural effusions requiring diuretics (14%), non-ST-elevation myocardial infarction (NSTEMI) (7%), and pericardial effusions (5.7%). One patient required a pericardial drain due to tamponade. For cardiac events occurring after D+100, but within one year of transplant, one patient developed a STEMI, one had an NSTEMI, two had CHF, and one had atrial fibrillation. In patients evaluable by HCT-CI cardiac scoring, CAC was associated with significantly more ECEs in patients who scored negative on HCT-CI (31% vs. 12%, p=0.032). In the CAC− group, ECEs included heart failure (13%) and pleural effusion (2.3%) with no events occurring after D+100. There was no statistically significant difference in the incidence of heart failure between CAC+ and CAC- (27% vs 13%, p=0.13), but there was a trend towards increased pleural effusions in CAC+ patients (12% vs 2.3%, p=0.09). In the CAC- group, no significant difference in ECEs existed across diagnoses or graft source (matched vs mismatched unrelated donor). Endothelial Dysfunction and CAC Status: Out of 108 patients, two developed veno-occlusive disease. Both patients had no history of cardiac disease, but were positive for CAC+. One patient with CAC+ developed an ischemic stroke. Disease Distribution and Outcomes: Despite frequent cardiac morbidity, there were no significant differences in relapse-free survival (51% vs. 60%), overall survival (76% vs. 79%), non-relapse mortality (NRM, 4.3% vs. 2.6%), aGVHD (33% vs 28%) or chronic GVHD rates (30% vs 36%). Discussion: Nonmyeloablative allo-HSCT using Flu/Cy/2Gy TBI with PTCy/sirolimus/MMF is associated with low non-relapse mortality and tolerable GVHD rates. However, CAC on pre-transplant imaging is strongly associated with early and overall cardiac events, with an increased incidence in patients without cardiac risk on HCT-CI. While CAC did not significantly impact survival in NMA conditioning HCT, high early cardiac morbidity stresses the need for improved cardiac risk assessment and medical interventions, such as lipid-lowering agents.