Post-transplant cyclophosphamide increases risk for early cardiac events
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Post-transplant cyclophosphamide reduced incidence of graft-versus-host disease but led to higher incidence of early cardiac events after allogeneic hematopoietic stem cell transplantation, according to study results.
The findings, published in JACC: CardioOncology, also showed an association of cardiac events after HSCT with shorter OS.
“As a physician, I am deeply concerned by toxicity of the treatments I use to cure my patients. One of my main topics for research is to find ways to reduce the toxicity and to better understand the reasons why some patients may have severe toxicities and others do not,” Rémy Duléry, MD, researcher in the department of clinical hematology and cellular therapy at Saint-Antoine Hospital in Paris, told Healio.
Use of post-transplant cyclophosphamide has made feasible T cell-replete haploidentical (haplo) HSCT, which allows for quick identification of an available donor for the majority of patients, according to Duléry. With post-transplant cyclophosphamide, patients who undergo haplo HSCT do not have higher incidence of GVHD nor inferior survival outcomes compared with recipients of transplants from a matched-unrelated donor or umbilical cord blood donors, he said.
Post-transplant cyclophosphamide is now widely used for haplo HSCT and has been applied in other clinical settings, such as HLA-identical sibling, match-unrelated and mismatched-unrelated donor HSCT, Duléry added.
“However, when I started to treat my patients with haplo HSCT and post-transplant cyclophosphamide, an excess of cardiac toxicity was found, which led in some cases to patient deaths,” he said. “Related risk factors, clinical manifestations and incidence of early cardiac events are still poorly understood after HSCT.”
Duléry and colleagues assessed incidence and clinical features of early cardiac events among 136 patients with hematologic malignancies (median age, 53 years; range, 15-76; 63% male) who received post-transplant cyclophosphamide, and compared their clinical outcomes with those of 195 patients (median age, 56 years; range, 16-76; 58% male) who did not. They focused on the first 100 days after HSCT, and all patients received the same systemic cardiac monitoring.
Results showed cumulative incidence of early cardiac events of 19% among those who underwent post-transplant cyclophosphamide vs. only 6% among those who did not (P < .001).
Common early cardiac events after post-transplant cyclophosphamide included left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%) and acute coronary syndrome (2%). Researchers observed no association of cardiovascular risk factors with early cardiac events.
Results of a multivariable analysis showed associations of early cardiac events with use of post-transplant cyclophosphamide (HR = 2.7; 95% CI, 1.4-4.9), exposure to cyclophosphamide before HSCT (HR = 2.7; 95% CI, 1.5-5) a sequential conditioning regimen (HR = 2.6; 95% CI, 1.5-4.8) and older age (HR = 1.4; 95% CI, 1.1-1.7). Further, a history of cardiac events before HSCT (HR = 1.83; 1.26-2.65) and early cardiac events (HR = 2.7; 95% CI, 1.8-4.2) appeared associated with worse OS.
“These results may help to improve the selection of patients who are eligible to undergo HSCT with post-transplant cyclophosphamide, especially older adult patients and patients with previous exposure to cyclophosphamide,” Duléry said. “This is the first report on cardiac toxicity associated with post-transplant cyclophosphamide, which shows for the first time that the incidence of early cardiac events is significantly higher in those who received post-transplant cyclophosphamide vs. patients who did not.”
Duléry told Healio that research is ongoing to determine whether other pretransplant cardiovascular risk factors may be associated with post-transplant cardiac events.
“A cumulative maximum cyclophosphamide dose should be defined,” he said. “We are also evaluating whether reducing the post-transplant cyclophosphamide dose is feasible and could reduce the incidence of early cardiac events.”
The study has several strengths, including use of uniform data on post-HSCT echocardiography for each patient, in addition to data on several conventional and treatment-related cardiovascular risk factors as potential confounders, according to an accompanying editorial by Seth J. Rotz, MD, Patrick Collier, MD, PhD, and Betty K. Hamilton, MD, all researchers with Cleveland Clinic Foundation.
The editorial authors also noted limitations, such as the possible influence of other factors on cardiovascular events, and questions yet to be answered, including the role of pharmacokinetics and genetic predisposition.
“With the increasing use of post-transplant cyclophosphamide, the data remain limited on the relative contribution of cyclophosphamide to both early and late cardiotoxicity,” they wrote. “Additional studies defining pathogenesis, risk factors, biomarkers and potential preventive therapy, particularly in the HSCT setting, are critically needed.”
References:
Duléry R, et al. JACC CardioOncol. 2021;doi:10.1016/j.jaccao.2021.02.011.
Rotz SJ, et al. JACC CardioOncol. 2021; doi:10.1016/j.jaccao.2021.04.004.
For more information:
Rémy Duléry, MD, can be reached at Saint-Antoine Hospital, 184, rue du Faubourg Saint Antoine, 75012 Paris, France; email: remy.dulery@aphp.fr.
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