Patients with left ventricular (LV) dysfunction fared just as well when treated with allogeneic mesenchymal stem cells (MSC) as they did when treated with autologous MSC, with no significant immune response to the treatment, according to a study presented Nov. 6 at the American Heart Association scientific sessions in Los Angeles. The study was simultaneously published online in the Journal of the American Medical Association.
Recent trials have shown that MSCs are effective in treating patients with ischemic cardiomyopathy (Circ Res 2011;108:792-796/Catheter Cardiovasc Interv 2005;65:321-329/J AM Coll Cardiol 2009; 54:2277-2286). The treating physician aspirates the patient's bone marrow and grows a culture of MSCs, which is then delivered to the patient's heart by transcardial injection (TESI). Bone marrow harvesting is difficult or not indicated in some patients, and there is a delay between aspiration and TESI while the culture is established. Allogeneic MSCs obviate the need for bone marrow aspiration and the attendant delay, but there is no data on the relative safety and efficacy of allogeneic MSCs in this treatment.
Joshua M. Hare, MD, of the University of Miami Miller School of Medicine, and colleagues enrolled 31 patients between April 2, 2010, and Sept. 14, 2011, in the Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells versus Allogeneic Mesenchymal Stem Cells in Patients with Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction (POSEIDON). Patients were eligible if they had a chronic ischemic LV dysfunction secondary to MI, LV ejection fraction (EF) of less than 50 percent and eligibility for cardiac catheterization within five to 10 weeks of screening.
The primary endpoint was any treatment-emergent serious adverse events—defined as the composite of death, nonfatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tampenade or sustained ventricular arrhythmia—within 30 days of TESI.
Patients were randomized 1:1:1 to receive doses of 20 million MSCs, 100 million MSCs, or 200 million MSCs. Each of these three groups was again randomized 1:1 to receive either allogeneic or autologous MSCs. The mean age of the patients was 62.8 years in the allogeneic group and 63.7 years in the autologous group. Males made up 86.7 percent of each group, and the groups were well-matched in all relevant factors.
Patients in the autologous group underwent bone marrow aspiration four to six weeks prior to the cardiac catheterization, and the autologous MSCs were cultured from the aspirate. Allogeneic MSCs were derived from the marrow of healthy donors.
All patients received MSCs via TESI to 10 sites in an infarcted myocardial region. Patients were hospitalized for four days post-procedure and observed for at least two weeks after catheterization, monthly for the next six months, and at 13 months.
One patient had to undergo repeat bone marrow aspiration because the cell culture became contaminated. One patient in each group had a treatment-emergent SAE within 30 days of TESI. At 30 days there were six adverse events in the allogeneic group and 17 AEs in the autologous group; three patients (20 percent) in the allogeneic group and nine patients (60 percent) in the autologous group experienced adverse events. No patients developed symptoms indicative of acute immunologic reactions.
At one year, there were no deaths, and there were 24 adverse events in 10 patients in the allogeneic group and 38 adverse events in 11 patients in the autologous group. There were no differences in the one-year incidence of major adverse cardiac events or heart failure.
Patients in both groups showed improvements in the New York Heart Association (NYHA) classification, six-minute walk test, and MLHFQ scores. Improvement in the six-minute walk test was significant only for the autologous group, however, and the autologous group showed more improvement in all these measures. Two patients in the allogeneic group and one patient in the autologous group had worsened NYHA class after 12 months. However, when data for both groups are combined, there was a statistically significant improvement across all three measures and no significant differences between the two groups.
At 13 months, patients in both groups experienced reverse LV remodeling, driven by a reduction in infarct size as measured by CT. Both groups experienced similar reductions. The researchers found that a larger infarct at baseline resulted in a larger reduction. Only the allogeneic group experienced a statistically significant reduction in LV end-diastolic volumes.
In both groups, EF, LV end-systolic volume, and early enhancement defect (EED) improvements were inverse to dose, with patients receiving 20 million cells showing significantly more improvement than patients receiving 200 million cells. The researchers postulated that this effect may be due to the concentration of cells, as the volume injected was the same in all patients.
"The increase in EF and decrease in EED in the 20 million cells group are remarkable for their large effect sizes, which are potentially meaningful and will require substantiation in larger trials," the authors wrote.
The authors pointed out that this was a small study without a placebo group and with an open label design. All are potential limitations, but the authors asserted that the results of this study, which demonstrated the safety and efficacy of allogeneic MSCs, merit confirmation through larger, double-blind, randomized, placebo-controlled trials.