Impact of Ptcy on Early Cardiac Toxicity after HLA-Matched Allo-HCT in Patients with Acute Myeloid Leukemia. Study on Behalf of the Grupo Español De Trasplante Hematopoyético y Terapia Celular (GETH-TC)
Authors: Salas Maria Queralt , Cascos Enric , Pérez López Estefanía , Baile González Mónica , Martín-Rodriguez Carlos , Pascual Maria Jesús , Luque Marta , Esquirol Albert , Martin Calvo Carmen , Peña Felipe , Heras Inmaculada , Sáez Marín Adolfo Jesús , Oiartzabal Ormategui Itziar , Fernandez-Luis Sara , Dominguez Garcia Juan , Villar Sara , Fernandez de Sanmamed Girón Miguel , González Leslie , López Lorenzo José Luis , García Mañó Lucia , Gonzalez Ana Pilar , Torrado Tamara , Filafferro Silvia , Balsalobre Pascual , López Alberto , Orti Guillermo , Jurado Chacón Manuel 
Published: December 2024

INTRODUCTION
Acute myeloid leukemia (AML) is the primary indication for allo-HCT and these patients often receive anthracyclines-based induction regimens which potentially induce cancer treatment-related cardiovascular toxicity. Furthermore, using post-transplant cyclophosphamide (PTCY)-based prophylaxis has become increasingly prevalent in the allo-HCT Community secondary to its effective prevention of GVHD. Nevertheless, Cy is an alkylating agent associated with cardiac toxicity and for this reason concerns have arisen regarding the potential effect PTCY on early cardiac toxicity (first 100 days).
Considering that studies exploring the association between PTCY use and early cardiac events (ECE) have yield diverging results, especially in allo-HCT performed from HLA-matched related and unrelated donors, this retrospective and multicenter registry-based analysis conducted on behalf of the GETH-TC investigates the incidence and predictors for ECE in AML patients undergoing HLA-matched allo-HCT, with particular attention to the impact of PTCY on the likelihood of presenting this complication.
METHODS
Adult AML patients, treated with anthracyclines-based induction therapies, undergoing their first peripheral blood allo-HCT from HLA-matched related and unrelated donors between 2010 and 2022 in all participating centers were included. Retrospective data were updated in January 2024.
ECE encompassed any new episode of arrhythmia, heart failure, myocardial infarction/ischemia, and pericardial disease occurring during the first 100 days after allo-HCT. De novo hypertension (HTN) was not considered an ECE. Cumulative incidence (Cum.Inc) regression analyses for the estimation of ECE accounted for death and relapse as competing events. No ECEs occurring after relapse were accounted.
RESULTS
A total of 712 adults with AML were included. The median age was 55 (IQR: 44-62), with 384 (53.9%) patients being males. Before allo-HCT, 136 (19.4%) had HTN, 92 (13.2%) had dyslipidemia, 49 (7.0%) mellitus diabetes, and 81 (11.4%) had cardiac pathology history. A total of 415 (58.3%) adults received MAC regimens, 190 (26.7%) received PTCY (50mg/kg/24h x 2 doses in all cases), 381 (53.5%) adults received HLA-matched grafts from related and in 331 (46.5%) from unrelated donors.
Day +100 Cum.Inc of ECE was 3.2% (95% CI 2.1-3.7) (n=22 patients), occurring in a median of 11 (IQR: 7-21) days after the stem cell infusion. Among the 22 patients with ECE, arrhythmias (n=12, 54.5%), heart failure (n=4. 18.1%), and pericardial effusion or pericarditis (n=3, 13.6%) were the most prevalent complications in this order. According to CTCAE, 3 (22.0%) patients had a grade 3-4 ECE, and 1 (4.5%) patients died secondary to this complication. Overall, the day +30 and +60 mortality rates among patients with ECE were 4.5% (n=1) and 13.6% (n=3), respectively.
Notably, the observed Cum.Inc of ECE was higher in patients receiving PTCY than in the rest (Day +100 6.4% vs. 2.2%, P=0.007). The positive association between using PTCY and increased risk of ECE was further confirmed (HR 3.02, P=0.006) on a multivariate regression analysis controlling for age (≥65 years / younger) (HR 1.84, P=0.29), HTA (yes / no) (HR 1.09, P=0.87), DLP (yes / no) (HR 1.49, P=0.46), DM (yes / no) (HR 0.37, P=0.37), prior cardiac history (yes / no) (HR 1.09, P=0.880), disease status (CR1 / CR2 or more and refractory disease) (HR 0.75, P=0.65) and conditioning intensity (RIC / MAC) (HR 0.89, P=0.76)
Finally, the investigation of the impact of ECE (time-dependent) on transplant outcomes showed that ECE complication was associated with a lower overall survival (OS) (HR 1.78, P=0.04) and increased non-relapse mortality (NRM) (HR 2.87, P=0.005). With a median follow-up of 936 days, he 2-year OS was 51.8% for patients with ECE and 63.8% for patients without this complication (P=0.039). Similarly for 2-year NRM the proportions were 32.2% and 14.0%, respectively (P=0.003).
CONCLUSION
This study shows that the use of PTCY in AML patients undergoing HLA matched allo-HCT increases the likelihood of ECE. Since PTCY-based prophylaxis has been proved to be effective in preventing GVHD in the HLA-matched allo-HCT setting, these data will be useful for refining patient monitoring and exploring how to optimize its use for preventing ECE after allo-HCT.