Use of Cyclophosphamide GVHD Prophylaxis, Prior Cardiac Disease May Increase Cardiac Toxicity After AlloHCT


Despite its infrequency, early cardiac toxicity may occur more often in patients who received cyclophosphamide-based graft-versus-host disease prophylaxis and those who have a prior history of cardiac disease.

GVHD, blood cancer

Although relatively infrequent following allogeneic hematopoietic transplant (alloHCT), post-transplant cyclophosphamide (PTCY)-based graft-versus-host disease (GVHD) prophylaxis and a prior history of cardiac disease appeared to increase the probability of cardiac toxicity presenting earlier on, according to study results presented at the EBMT 48th Annual Meeting.

Moreover, endothelial activation and stress index (EASIX), calculated based on the bloodwork done at the pre-transplant evaluation, appeared to be a predictor for early cardiac toxicity (defined as any adverse cardiac event diagnosed within the first 6 months after the stem cell infusion).

“It is important because endothelial dysfunction is a common type of mechanism with several severe infectious and noninfectious transplantation complications. And given that EASIX could be considered a surrogate marker of endothelial dysfunction, we hypothesize that it could potentially be helpful in predicting PTCY-associated cardiac toxicity, even the cyclophosphamide mechanism of action,” Amanda I. Perez-Valencia, MD, Institute of Hematology and Oncology, Hospital Clinic de Barcelona in Spain, said during a virtual presentation at the meeting.

At day +180, the cumulative incidence of early cardiotoxicity was 7.8% (95% CI, 5.2%-11.0%), with the most prevalent complications being heart failure (3.73%) and arrhythmias (1.86%).

Patients who received PTCY demonstrated a higher cumulative incidence of early cardiotoxicity compared with patients receiving other GVHD prophylaxis at day +180 (10.3% vs 3.8%, respectively; P = .03).

Using univariate and multivariate Cox regression analysis, results demonstrated that the use of PTCY-based GVHD prophylaxis (HR, 2.75; 95% CI, 1.03-7.30; P = .04), prior history of health technology assessment diagnosis (HR, 2.68; 95% CI, 1.21-5.94; P = .015), and prior history of cardiac disease (HR, 3.08; 95% CI, 1.25-7.57; P = .014) were significant risk factors for early cardiotoxicity after alloHCT.

Although high dose of total body irradiation (TBI) was not a significant risk factor (HR, 1.18; 95% CI, 0.40-3.44; P = .76), Perez-Valencia said, “it's remarkable that high-dose TBI was not found to be a risk factor.”

EASIX was a found to be a predictor for early cardiac toxicity (continuous Log2 EASIX: HR, 1.24; 95% CI, 1.05-1.47; P = .01); for example, patients with an EASIX score > 3.80, were 2.47 times more likely to develop early cardiotoxicity compared with patients with lower EASIX scores (HR, 2.56; 95% CI, 1.16-5.63; P = .01).

Lastly, simplified multivariate analysis confirmed the independent association between exposure to PTCY (HR, 2.81; 95% CI, 1.06-7.44; P = .038), prior history of cardiac pathology (HR, 2.70; 95% CI, 1.09-6.66; P = .031), and EASIX score > 3.80 (HR, 2.47; 95% CI, 1.12-5.45; P = .024) with early cardiotoxicity.

“With this information, we can conclude that early cardiac toxicity is a relatively infrequent adverse event after transplantation and PTCY-containing GVHD prophylaxis and prior history of cardiac disease increase the probability of presenting this complication,” Perez-Valencia said. “We can also conclude that EASIX calculated based on the blood work done at the pre-transplant assessment was found to be a predictor of early cardiac toxicity.”

The investigators aimed to investigate the incidence of early cardiotoxicity after alloHCT in patients who received PTCY, compared with those who did not; to identify risk factors associated with early cardiotoxicity after alloHCT; and to assess if EASIX evaluated in the pre-transplant phase can predict early cardiac complications.

“[Cyclophosphamide] has a special relevance in the transplant setting because of its use in the graft-versus-host disease prophylaxis with post-transplantation. Cyclophosphamide when administered, is rapidly metabolized into 2 main metabolites: phosphoramide mustard, which is an active neoplastic agent … and acrolein, which unfortunately is a toxic metabolite to the myocardium, cardiofibroblasts, and endothelial cells,” Perez-Valencia explained, adding that cyclophosphamide-associated cardiotoxicity out of the transplant setting ranges between 7% to 28%.

In total 334 adults underwent alloHCT at Hospital Clinic de Barcelona between January 2014 and March 2021, including 204 (61.1%) who received PTCY-based GVHD prophylaxis.

Cardiac events included arrhythmia, pericardial effusion, pericarditis, heart failure, and acute coronary syndrome.

Data was collected retrospectively and updated in November 2021.

Median age in the overall population was 53 years (range, 18-70). The majority of patients in the overall population were male (54.5%) and had received a diagnosis of acute myeloid leukemia (40.4%). A hematopoietic cell transplantation comorbidity index >3 was reported in 22.7% of patients and a Karnofsky Performance Status of 70% to 80% was reported in 24.4% of the population.

Of note, according to Perez-Valencia, all patients with haploididentical donor type received PTCY at the institution. Moreover, she added, 30 patients (14.7%) in the PTCY group received a high dose of TBI.

Cardiac risk factors in the PTCY and non-PTCY populations at baseline were hypertension (19.1% vs 13.1%, respectively), diabetes mellitus (6.9% vs 7.7%), dyslipidemia (11.8% vs 14.6%), and prior cardiac pathology history (9.3% vs 9.2%).


Perez-Valencia AI, Carbonell-Ordeig S, Charry P. Increased early cardiac toxicity in patients undergoing allogeneic hematopoietic cell transplantation combined with post-transplant cyclophosphamide. Presented at: EMBT 48th Annual Meeting; March 19-23, 2022; Virtual. Abstract OS05-01.

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