The Use of Post-Transplant Cyclophosphamide Leads to Increased Cardiac Complications without Affecting Survival in Haploidentical Stem Cell Transplantation
Authors: Alfaro Tommy , Desai Nihar , Salas Maria Queralt , Chen Carol , Gerbitz Armin , Kim Dennis Dong Hwan , Kumar Rajat , Lam Wilson , Law Arjun , Lipton Jeffrey H. , Michelis Fotios , Novitzky-Basso Igor , Mattsson Jonas , Viswabandya Auro 
Published: December 2024

Post transplant cyclophosphamide (PTCY) has broadened the access to allogeneic stem cell transplantation. However, it is also associated with increased organ toxicity and infections in these patients. We intended to determine whether the occurrence of cardiac events (CE) after the use of PTCY has an impact in the outcomes of patients undergoing haploidentical transplantation (haplo-HCT).

We analyzed the outcomes of 157 patients who underwent peripheral blood haplo-HCT between August 2016 and December 2021 at Princess Margaret Hospital. All the patients received PTCY 50 mg/kg on D+3, +4 in combination with anti-thymocyte globulin (ATG) and cyclosporine, our standard GVHD prophylaxis regimen for recipients of haplo-HCT. We defined a CE as any new episode of arrythmia, heart failure, drop in the LVEF of more than 10% below 53%, myocardial ischemia, and pericarditis/pericardial effusion occurring after the stem cell infusion. Hypertension (HTN) was not considered a pre or post transplant CE.

The cumulative incidence (CumI) of CE was estimated accounting for death and relapse as competing events.

The median age for the cohort was 57 years (range: 18-73), and 67 (44%) patients were 60 years or older. Fifty patients had a diagnosis of HTN, 28 had diabetes mellitus, 36 had dyslipidemia, and 30 patients had prior cardiac history (pre-transplant arrhythmia, coronary artery disease, valvular disease or pericardial disease). Acute myeloid leukemia was the most prevalent baseline diagnosis (n = 79, 50.3%), and 38 (24.2%) patients received myeloablative conditioning regimens. Total body irradiation (TBI) was used in 126 patients, 12 received 12Gy and 114 received 200 cGy. Forty-six (30%) adults had a KPS ≤ 80%, 46 (30%) had an HCT-CI score &gt;3, and 34 (23.4%) had a high or very-high disease risk index.

Eighteen patients (12.7%) experienced a CE during their follow up, and in a median of 36 (range 1-623 days, interquartile range 20-63 days) days after haplo-HCT. Eight (5%) patients experienced arrhythmia, 7 (4.4%) experienced symptomatic heart failure or a drop in the LVEF &gt;10% to below 53%and 3 (1.9%) patients experienced pericardial effusions.

The CumI of CE was observed to be 8.3% (95% CI 4.6-13.3) at 100 days, 9.6% (95% CI 5.6-14.8) at 180 days, and 10.2% (95% CI 6.1-15.6) at 1-year. We analyzed the incidence of cardiac events between patients with a history of a pre-existing cardiac disorder and those without a cardiac history. The CumI was significantly higher in patients with a pre-existing cardiac condition, recorded at 17.6% (95% CI 8.9-35.6) at 180 days, compared to 7.3% (95% CI 3.6-12.8) in those without such issues (p = 0.007).

HTN had no impact on CE, no significant difference was found between hypertensive and non-hypertensive patients, with the CumI remaining similar across both groups (D+180 10% vs 10.2% respectively, p=0.9). Age did not appear to significantly affect the incidence of CE, with similar outcomes reported for patients over 60 years and those under 60 (D+180 10.3%, 95% CI 4.5-18.8 vs 9%, 95% CI 4.2-16.1, p=0.77). A trend towards higher CE incidence was observed in patients who received higher ATG dose (4.5mg/kg) when compared with patients receiving a lower dose of 2mg/kg (D+180 10.8% vs. 5.4, p=0.13). Furthermore, the role of TBI was explored, revealing a higher CumI of CE by D+180 in patients who received TBI (10.3%, 95% CI 5.8-16.4) compared to those who did not (6.5%, 95% CI 1.2-18.9), p=0.25. Fifteen cardiac events occurred in the group who received 2 Gy and 1 in the group who received 12 Gy.

Overall survival at 12 months was 55.6% (95% CI 30.5-74.8) for patients experiencing CE versus 59% (95% CI 50.3-66.6) for those without CE, p=0.92. Non-relapse mortality (NRM) did not significantly differ between the groups at 1 year, with NRM of 33.3% (95% CI 13.1-55.3) vs. 30.9% (95% CI 23.4-38.7) for patients who experienced a cardiac event vs those who didn't respectively, p=0.55.

Our study reports an incidence of CE of 12.7% following haplo-HCT with PTCY/ATG-based prophylaxis. Despite this, patients were successfully treated, and the diagnosis of this complication did not significantly impact transplant outcomes. Given the morbidity associated with these complications as noted in previous publications, the conduction of studies aimed at optimizing dosages and drug combinations when using PTCY-based prophylaxis will be desirable, especially for patients with a prior cardiac history.