NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.

Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.

“About 30% of our patient population with critical limb ischemia have no options for the standard of care, such as surgical bypass, due to absence of a surgical target or chronic total occlusion, which mitigates an endovascular approach,” he said at the American Heart Association scientific sessions. “Thus, these no-option critical limb ischemia patients represent an unmet medical need for a novel agent that may promote limb salvage and prevent amputation and its associated disabilities.”

In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.

Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.

“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”

The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.

Lessons learned

A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.

“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.

“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”

“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.

Identifying patients who benefit

Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.

“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.

“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.

Trial details

Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).

They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.

Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.

The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).

“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.

Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.

The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.

Bone marrow cells prove limb-saving for some