This multicenter study investigates the incidence and predictors of CE following allo-HCT with PTCY-based prophylaxis in AML patients at risk for CVR-CVT. CE occurred in 67 (14.3%) patients post-allo-HCT within a median of 81 days, with ECE and LCE occurring at rates of 8.2% and 6.2%. Pre-existing HTN and DLP emerged as significant risk factors for post-transplant cardiac complications. Furthermore, the diagnosis of CE heightened the risk of mortality post-allo-HCT, underscoring the necessity for implementing post-transplant cardiac monitoring protocols to facilitate early detection and prevention of complications.
The observed incidences of ECE and LCE occurring after allo-HCT were 8.2% and 6.2%., for a global incidence of CE of 14.3%, with patients presenting a heterogeneous array of cardiac complications, and being arrhythmias, heart failure, and pericardial complications the most prevalent ones (2–9). The most relevant pathological mechanisms involved in Cy-induced cardiac toxicity are cardio-myocyte induced apoptosis, endothelial dysfunction, calcium deregulation, endoplasmic reticulum, and mitochondrial damage, translating into structural/mechanical, vascular, or electric-conduction cardiac disorders (23, 24). Additionally, the exacerbated activation of endothelial cells occasioned by rapidly proliferating alloreactive T-cells post-infusion of donor stem cells, the administration of PTCY itself, and the diagnosis of complications such as infections and GVHD can potentiate myocardial damage and contribute to the increased cardiotoxicity associated with PTCY (5, 9, 23–27).
These results were consistent with data from previous publications with incidences of ECE ranging from 7.4–19% (6–9), and of LCE from1 to 17%) (2–5). These results are considered relevant as this study includes patients with AML patients at risk for CVR-CVT. Nevertheless, caution regarding LCE incidences is recommended, as the follow-up of our patients might be short for the evaluation of LCE in HCT survivors (28, 29).
Interestingly, although the incidence of CE was higher in patients undergoing haplo-HCT than in the rest, the differences were not statistically significant. Infusing haploidentical products is considered a risk factor for ECE due to alloreactivity induced by the infusion of less HLA-compatible donor cells (6, 8, 9). However, studies reporting this association mainly included patients undergoing haplo-HCT with PTCY and patients undergoing allo-HCT from other donor types with and without PTCY. The design of these studies could have overestimated CE risk in haplo-HCTs considering the potential synergistic effect of stem cell alloreactivity and PTCY, but also underestimated the risk of CE in non-haplo-HCT groups (since some of the included patients did not receive PTCY). These observations together support that PTCY is an independent risk factor for CE regardless of donor type (6, 8).
As Cy-induced cardiotoxicity risk correlates with dose (2), recent HCT centers have implemented new GVHD prophylactic protocols including reduced doses of PTCY with other immunosuppressant agents particularly for older adults and patients with prior cardiac disease undergoing haplo-HCT (30–33). Results from these studies are encouraging, showing that reducing PTCY doses decreases ECE and provides comparable GVHD prevention (30–33). However, PTCY reduction might also be considered out of the haplo-HCT setting, as patients undergoing allo-HCT from other donor types can also experience cardiac toxicity. It's presumed, based on current knowledge, that future clinical practices will recommend reducing the PTCY dose in patients at increased risk for cardiac complications, regardless of donor type.
The diagnoses of HTN and of DLP were identified as risk factors for CE after allo-HCT. In contrast, older age, pre-existing cardiac disease, and Cy or TBI administration as part of the myeloablative preparative regimens were not predictors for CE in our analysis (28, 29, 34). The facts that, among the participant institutions, the majority of patients with cardiac morbidity underwent assessment and clearance by Cardiology departments before transplantation, and that older adults received more exhaustive monitoring during the HCT process due to their assumed higher risk for CVR-CVT, could had mitigated the potential risk for cardiac toxicity among these patients. Additionally, the reduced number of patients receiving Cy or TBI as part of the MAC regimens may justify our findings, as most prevalent conditioning regimens mainly consisted of Flu/Bu combinations. Overall, the results enhance the importance of implementing appropriate transplant monitoring programs in high risk patients.
Among the 64 patients with CE, the mortality rate was up to 10.9%, and increased to 15.6% and 23.4% on days + 30 and + 60 after allo-HCT due to the notable morbidity induced by CE in post-transplant patients. Similar to previous publications, the diagnosis of both ECE and LCE after allo-HCT negatively impacted NRM probability and, consequently, OS. These findings, along with the observed heterogeneity in cardiac monitoring practices among participating institutions, underscore the importance of treating cardiovascular risk factors when present (1, 9); they emphasize the necessity of implementing post-transplant cardiac monitoring protocols for patients (1, 35, 36); and they recommend the conduction of prospective studies exploring the effectiveness of reducing PTCY doses in high-risk patients.
The retrospective nature, lack of uniform methodology for post-transplant cardiac monitoring, and relatively short follow-up of transplant survivors are the main limitations of this study. These factors may have led to an underestimation of CE incidence, as only clinically symptomatic cases were captured in the analysis. Anthracycline cumulative dose was not recorded during data collection. However, the variable disease status was included in MVA for detecting predictors for CE to indirectly identify patients who might have received multiple lines of chemotherapy to achieve remission (most of them including anthracyclines), partially overcoming this limitation.
In conclusion, the global incidence of CE after allo-HCT in patients with AML treated with anthracyclines and standard doses of PTCY was 14.3%. Furthermore, the diagnosis of CE was associated with increased morbidity and significantly higher mortality risk. Considering the widespread adoption of PTCY-based prophylaxis in the HCT community (10–13), it is advisable to implement exhaustive control of HTN and DLP when present, along with cardiac monitoring protocols to for early detection of cardiac dysfunction. Additionally, conducting studies to explore the role of preemptive pharmacological strategies or the safety of decreasing PTCY doses in patients of high-risk of CE, regardless of donor type, will be valuable for increasing the safety of allo-HCT performed with PTCY in the future.