Donor, Autologous Stem Cells Equally Safe for Cardiomyopathy

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.