NEW ORLEANS – Allogeneic stem cells appear to be a safe treatment option for nonischemic dilated cardiomyopathy and show somewhat greater efficacy than autologous stem cells, according to the results of the randomized POSEIDON-DCM trial.
“Nonischemic dilated cardiomyopathy is an incurable condition with significant genetic and immunologic underpinnings,” noted lead investigator Joshua M. Hare, MD, director of the Interdisciplinary Stem Cell Institute and professor of medicine at the University of Miami.
Dr. Joshua M. Hare
The phase I/II trial undertook a head-to-head comparison of allogeneic and autologous bone marrow–derived mesenchymal stem cells in 37 patients with nonischemic dilated cardiomyopathy.
Results presented at the American Heart Association scientific sessions and simultaneously published (J Am Coll Cardiol. 2016. doi: 10.1016/j.jacc.2016.11.009) showed that none of the patients in either group experienced a 30-day treatment-emergent serious adverse event, the trial’s primary endpoint.
The allogeneic group had a greater shift to a lesser inflammatory immune profile, and, at 12 months, a lower rate of major adverse cardiac events and more improvement in walk test distance. Additionally, half of patients in the allogeneic group no longer met the ejection fraction cutoff typically used to define dilated cardiomyopathy, compared with only about one-fifth of those in the autologous group.
“Immunomodulation may contribute to the efficacy of allogeneic human mesenchymal stem cells in nonischemic dilated cardiomyopathy, as we have shown suppression of immune activation to a greater degree with the allo versus auto cells,” Dr. Hare said.
“We argue that these data support the use of allogeneic mesenchymal stem cell therapy in future pivotal placebo-controlled clinical trials for this patient population, an important patient population with significant unmet need.”
Trial details
The patients enrolled in POSEIDON-DCM had left ventricular dysfunction due to nonischemic dilated cardiomyopathy and were randomized evenly to allogeneic or autologous stem cell therapy. Stem cells were delivered by transendocardial injection into 10 left ventricular sites using a catheter.
In the first 30 days after treatment, there were no treatment-emergent serious adverse events, defined as death, nonfatal myocardial infarction, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias. “The 30-day safety and tolerability was excellent in both groups receiving either allogeneic or autologous therapy,” Dr. Hare said.
At 12 months, the allogeneic group had lower rates than the autologous group of major adverse cardiac events (20.3% vs. 57.1%, P = .0186) and all-cause rehospitalizations (28.2% vs. 70.0%, P = .0447).
In terms of efficacy, ejection fraction at 12 months had improved by a significant 8.0 Units in the allogeneic group and a nonsignificant 5.4 Units in the autologous group (P not significant for difference between groups). Roughly half of patients in the allogeneic group had achieved an ejection fraction of greater than 40%, compared with only two patients in the autologous group. “This is meaningful because the clinical definition of dilated cardiomyopathy typically uses an ejection fraction cutoff of 40%,” he noted.
The 6-minute walk test distance increased by a significant 37.0 m for the allogeneic group and by a nonsignificant 7.3 m for the autologous group (P = .0168 for difference between groups). Scores on the Minnesota Living With Heart Failure Questionnaire fell significantly in the former group and nonsignificantly in the latter group (P not significant for difference between groups).
Patients in the allogeneic group were more likely to have an improvement from baseline in New York Heart Association class (66.7% vs. 27.3%, P = .0527).
“An issue of concern in this field has been the formation of ectopic tissue with mesenchymal stem cells, so patients received whole-body CT scanning over 12 months,” Dr. Hare reported. “There was no ectopic tissue formation or tumor formation in any patient.”
In terms of biologic endpoints, two measures of endothelial function known to be suppressed in the setting of circulatory failure – endothelial progenitor cell colony-forming units and flow-mediated vasodilation – had increased significantly at 3 months in the allogeneic group only. Tumor necrosis factor–alpha levels fell by roughly 70% with allogeneic therapy versus 50% with autologous therapy (P = .05).
Both groups had a lessening of the immunosuppression that is common in heart failure, but benefit in several markers, such as the percentage of switched memory B cells, was greater with the allogeneic therapy. Additionally, there was a trend toward greater reduction of early T-cell activation in the allogeneic group.
“Of importance in the field of allogeneic cell therapy is [whether] the allogeneic cells mount a panel-reactive antigen [PRA],” commented Dr. Hare, who disclosed that he has an ownership interest in and is a consultant or advisory board member for Vestion.
Results showed that one patient in the allogeneic group developed a high-risk PRA, compared with none in the autologous group. Another four patients in the former group developed a moderate-risk PRA, compared with one in the latter group (P less than or equal to .05).