Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial

Abstract

Background: Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM).

Objectives: The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM.

Methods: Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers.

Results: There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05).

Conclusions: These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625).

Keywords: endothelial function; heart failure; idiopathic dilated cardiomyopathy; immune biomarker; stem cell therapy.

Conflict of interest statement

Declaration of Interest: Dr. Hare and Dr. Heldman disclose a relationship with Vestion Inc that includes equity, board membership, and consulting. Dr. Hatzistergos and K. Valasaki disclose a relationship with Vestion Inc that includes equity. Vestion Inc did not participate in funding this work. Dr. Landin, Dr. Hare, A. Khan, and D. DiFede disclose a relationship with Longeveron LLC that includes consulting. Longeveron LLC did not participate in funding this work. D. DiFede discloses a relationship with BDS as consultant. The other authors report no conflicts.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Study Flow chart

Study screening, enrolment and randomization in detail showing 1:1 ratio of allo and auto with 30 day TE-SAEs and patients lost to follow up. TE-SAEs = treatment emergent serious adverse events.

Figure 2. Patient changes in Left Ventricular Structure and Function from baseline to 12-months Post-hMSC Injection after Allogeneic (denoted by: ●) and Autologous (denoted by ▲) hMSC therapy

(A) EF increased from baseline in allo but not in auto: 8 EF units (95%CI: 2.8–13.2 p=0.04). (B) Stroke volume was not significantly increased in either groups at 12-months. (C, D) Neither group showed significant improvement in EDV or ESV. (E) Structural remodeling was evident in the reduction in long axis diameter in allo from baseline to 12-months (p=0.03). * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. EF = ejection fraction, EDV = end diastolic volume, ESV = end systolic volume.

Figure 2. Patient changes in Left Ventricular Structure and Function from baseline to 12-months Post-hMSC Injection after Allogeneic (denoted by: ●) and Autologous (denoted by ▲) hMSC therapy

(A) EF increased from baseline in allo but not in auto: 8 EF units (95%CI: 2.8–13.2 p=0.04). (B) Stroke volume was not significantly increased in either groups at 12-months. (C, D) Neither group showed significant improvement in EDV or ESV. (E) Structural remodeling was evident in the reduction in long axis diameter in allo from baseline to 12-months (p=0.03). * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. EF = ejection fraction, EDV = end diastolic volume, ESV = end systolic volume.

Figure 2. Patient changes in Left Ventricular Structure and Function from baseline to 12-months Post-hMSC Injection after Allogeneic (denoted by: ●) and Autologous (denoted by ▲) hMSC therapy

(A) EF increased from baseline in allo but not in auto: 8 EF units (95%CI: 2.8–13.2 p=0.04). (B) Stroke volume was not significantly increased in either groups at 12-months. (C, D) Neither group showed significant improvement in EDV or ESV. (E) Structural remodeling was evident in the reduction in long axis diameter in allo from baseline to 12-months (p=0.03). * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. EF = ejection fraction, EDV = end diastolic volume, ESV = end systolic volume.

Figure 3. Global Ejection Fraction

Graphic representation of global EF from baseline to 12-months. In green allo shows 7 out of 15 patients increase above 40% or better at 12-months while in purple auto only 2 out of 9 patients had an increase of 40 or better at 12-months. EF = ejection fraction.

Figure 4. Cardiac Functional Outcomes and changes in endothelial function after Allogeneic (denoted by: ●) or Autologous (denoted by ▲) hMSC therapy

Graphic representation of estimated mean of the functional Outcomes (A) Allo but not auto therapy showed an improvement in the 6MWT (p=0.01 at six-months and p=0.04 at 12-months). (B) FEV1 improved by 0.11L (p=0.04) in allo compared to auto. (C) NYHA classification improved in 66.70% and 27.3% in allo and auto, respectively. (D) MLHFQ score improved in allo but not auto 12-months relative to baseline (p=0.002). (E) Allo but not auto show improvement in the FMD (p=0.0005) at 3-months relative to baseline. (F) The production of EPC-CFU was significantly greater (p=0.01) in allo compared to auto. * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. 6MWT = six-minute walk test, NYHA = New York Heart Association, MLHFQ = Minnesota Living with Heart Failure Questionnaire, FMD = Flow Mediated Vasodilation, EPC-CFU = Endothelial Progenitor Cell Colony Forming Unit.

Figure 4. Cardiac Functional Outcomes and changes in endothelial function after Allogeneic (denoted by: ●) or Autologous (denoted by ▲) hMSC therapy

Graphic representation of estimated mean of the functional Outcomes (A) Allo but not auto therapy showed an improvement in the 6MWT (p=0.01 at six-months and p=0.04 at 12-months). (B) FEV1 improved by 0.11L (p=0.04) in allo compared to auto. (C) NYHA classification improved in 66.70% and 27.3% in allo and auto, respectively. (D) MLHFQ score improved in allo but not auto 12-months relative to baseline (p=0.002). (E) Allo but not auto show improvement in the FMD (p=0.0005) at 3-months relative to baseline. (F) The production of EPC-CFU was significantly greater (p=0.01) in allo compared to auto. * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. 6MWT = six-minute walk test, NYHA = New York Heart Association, MLHFQ = Minnesota Living with Heart Failure Questionnaire, FMD = Flow Mediated Vasodilation, EPC-CFU = Endothelial Progenitor Cell Colony Forming Unit.

Figure 4. Cardiac Functional Outcomes and changes in endothelial function after Allogeneic (denoted by: ●) or Autologous (denoted by ▲) hMSC therapy

Graphic representation of estimated mean of the functional Outcomes (A) Allo but not auto therapy showed an improvement in the 6MWT (p=0.01 at six-months and p=0.04 at 12-months). (B) FEV1 improved by 0.11L (p=0.04) in allo compared to auto. (C) NYHA classification improved in 66.70% and 27.3% in allo and auto, respectively. (D) MLHFQ score improved in allo but not auto 12-months relative to baseline (p=0.002). (E) Allo but not auto show improvement in the FMD (p=0.0005) at 3-months relative to baseline. (F) The production of EPC-CFU was significantly greater (p=0.01) in allo compared to auto. * indicates p ≤ 0.05 within group, and † indicates between group p ≤ 0.05. 6MWT = six-minute walk test, NYHA = New York Heart Association, MLHFQ = Minnesota Living with Heart Failure Questionnaire, FMD = Flow Mediated Vasodilation, EPC-CFU = Endothelial Progenitor Cell Colony Forming Unit.

Central Illustration. Allogeneic Mesenchymal Stem Cell Therapy for Non-Ischemic Dilated Cardiomyopathy

(A) Cardiac computed tomography shows decreased global EF at baseline. (B) Global EF has significantly improved at 12-months post TESI. EF = ejection fraction, TESI = Transendocardial Stem Cell Injection.