Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial

Abstract

Context: Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared.

Objective: To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM.

Design, setting, and patients: A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up.

Intervention: Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites.

Main outcome measures: Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index.

Results: Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions.

Conclusions: In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling.

Trial registration: clinicaltrials.gov Identifier: NCT01087996.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hare reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, having equity interest in Vestion Inc, and being a consultant for Kardia. Mr Mendizabal is an employee of EMMES Corporation. Drs Rouy, Altman, and Wong Po Foo are employees of Biocardia Inc. Dr McNiece reported being a consultant and board member of Proteonomix Inc. Dr Heldman reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, and having equity interest in Vestion Inc. No other authors reported any financial disclosures.

Figures

Figure 1. Study Flow Diagram

MSCs indicates mesenchymal stem cells; LV, left ventricular.

Figure 2. Functional Outcomes of the Effect of Allogeneic and Autologous Mesenchymal Stem Cell (MSC) Transendocardial Stem Cell Injection on Patient Functional Capacity and Quality of Life

A, Autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test. When considering both groups combined, patients exhibited increased 6-minute walk test distance in both groups (P=.003 for analysis of variance with repeated measures; P=.004 vs baseline for all patients; and P=.21 for cell type × time interaction). B, Patients exhibited no change in peak exercise oxygen consumption per unit time ( V˙O2 max). C, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score improved in the autologous but not the allogeneic group. When considering both groups combined, MLHFQ scores improved (P<.001 for analysis of variance with repeated measures; and P=.54 for cell type × time interaction). D, Change in New York Heart Association classification from 12 months to baseline is shown as the proportion of patients who either improved, did not change, or worsened. Individual patient values for the 6-minute walk test, peak V˙O2, and total score of the MLHFQ are shown across time as gray lines with the corresponding cell type mean and 95% CIs indicated by bars and shaded across time. Within-group P values are noted as aP<.05 and bP<.01.

Figure 3. Computed Tomography (CT) Parameters Change From Baseline

MSCs indicates mesenchymal stem cells; EED, early enhancement effect. Mean changes from baseline to 13 months are noted by triangles and depict change in cardiac phenotype assessed by cardiac CT scan. Error bars indicate 95% CIs. Individual patient changes from baseline are shown as circles. Shown are changes in cardiac structural and functional parameters from baseline to 13-month follow-up in allogeneic, autologous, and combined patient groups. Within-group P values are noted as aP<.05, bP<.01, and cP<.001.

Figure 4. Improvement in Early Enhancement Defect (EED) After Transendocardial Allogeneic Stem Cell Injection

Upper panel, baseline early-phase short-axis multidetector computed tomography images in a representative patient with chronic myocardial infarction (EED total, 40.34 g). Lower panel, 13 months after transendocardial stem cell injection of allogeneic mesenchymal stem cells (100 million cells). There was a decrease of 34.68% in EED (26.35 g). The reduction of the myocardial defects was accompanied by decrease of end-diastolic volume from 433.68 mL to 365.81 mL, decrease of end-systolic volume from 371.83 mL to 277.38 mL, increase of ejection fraction from 14.26% to 24.17%, and improvement of sphericity index from 0.60 to 0.51. See Interactive of the patient’s 3D multidetector tomography scan reconstructions showing the EED before and after transendocardial stem cell injection.