Small Trial Shows Promise of Cell Therapy in Critical Limb Ischemia

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Cell therapy produced positive effects in a small randomized trial of “no-option” patients with chronic critical limb ischemia (CLI), resulting in fewer amputations, less pain, and improved quality of life, according to results appearing online October 21, 2011, ahead of print in the Journal of Vascular Surgery.

Researchers led by Mark D. Iafrati, MD, of Tufts Medical Center (Boston, MA), looked at 48 patients with CLI marked by rest pain or mild/moderate tissue loss (Rutherford class 4-5) who were not candidates for surgical or endovascular revascularization. Patients were randomized to 40 percutaneous injections of autologous concentrated bone marrow aspirate in the affected limb (n = 34) or placebo injections (n = 14).

Cell therapy patients had 240 mL of marrow withdrawn and then processed using a proprietary point-of-care system (SmartPReP2, Harvest Technologies, Plymouth, MA) to concentrate the marrow, followed by 40 1-mL intramuscular injections under ultrasound guidance.

Improvements Seen Across the Board

The mean number of cells injected was 3.23 x 10⁹. At 3 months, there were no deaths or severe unexpected adverse events. Bone marrow aspiration was well tolerated with no complications. Renal function remained stable in both groups and no patient demonstrated inappropriate angiogenesis.

Though the numbers were too small to show statistically significant differences, cell therapy patients showed improvement in several categories, including major amputations, pain (on visual analogue scale), Rutherford class, and ankle brachial index (table 1).

Table 1. Three-Month Outcomes

In terms of quality of life, measured using the Rand-36 questionnaire, cell therapy patients demonstrated improvements compared with controls in 6 of the 8 domains, though only the physical function domain approached statistical significance (P = 0.06). In addition, among Rutherford class 5 patients at baseline, those receiving cell therapy underwent about half as many major amputations as controls at 3 months (26.1% vs. 57.1%; P = 0.18). More cell therapy patients also experienced “success,” defined as a composite comprising survival, no major amputation on the index limb, no worsening of Rutherford class or visual analogue pain scale, and improvement in either of those scales (50.0% vs. 21.4%; P = 0.11).

“Our pilot study supports the potential of bone marrow-derived cells as a regenerative medical intervention for CLI,” the researchers conclude. “This randomized, double-blinded controlled, pilot study . . . although not powered to prove efficacy, showed cell therapy to be feasible and safe in no-option patients.”

In addition, the authors note that the point-of-care marrow processing technique is “fast and easy,” and that “By not requiring dedicated laboratory facilities or personnel, this protocol may be feasible for a wide range of clinicians and patients.” They recommend that for future CLI trials, subjects should be stratified according to disease severity, and an endpoint encompassing pain and quality of life should be incorporated.

A Step Forward for the Field

“This is quite positive,” Warren Sherman, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview. “From the standpoint of the whole regenerative cardiovascular medicine field, this is very encouraging and lends full justification to moving on [to larger trials].”

“I think this is the next exciting step we may be taking in the area of cell therapy,” said Vincent J. Pompili, MD, of the Ohio State University (Columbus, OH), in a telephone interview with TCMTD. “Over the past several years we’ve watched the evolution of a number of phase I feasibility trials. Now we’re beginning to actually see randomized trials.”

According to Dr. Iafrati, since the study was designed as a small pilot trial, there was no thought to demonstrating significant differences in clinical outcomes. “But everything went in the right direction, so we were really surprised,” he told TCTMD in a telephone interview. “We went back to [the Centers for Medicare and Medicaid Services] and [the Food and Drug Administration] with the information and got feedback that this was in their opinion the best data they’d ever seen from a cellular therapy pilot study, so they were enthusiastic about letting us move forward with the pivotal study.”

Dr. Iafrati said a larger trial of the cell therapy is currently underway with a planned enrollment of 212 Rutherford class 5 patients.

‘Missing Link’ Misses the Point

He added that a key difference in the current trial, in his opinion, is the marrow aspirate that was used, as opposed to a more selected cell population. “In a lot of prior studies, investigators thought they could identify the particular cell type that was the most important—the ‘missing link,’” Dr. Iafrati said. “Some of them tried to grow out certain cell types in culture to try and concentrate them and then after hours or days, put them back into the patient as a refined product. But that may not have had all the parts we’re looking for.”

He explained that the point-of-care system used in the study is a simple centrifugation technique that removes much of the plasma and red blood cells, leaving the mononuclear cell component, “where we think all the action is,” Dr. Iafrati explained. “I think a big piece of the advantage we have is the platelets are going back in. We don’t take them out. The platelets are a really rich source of growth factor and other regulatory components.”

Dr. Sherman was not completely convinced. “It’s hard to say if these cells are equally, more, or less potent than other cells that have been used,” he said. “From a purely scientific standpoint, it’s not clear whether that’s the reason this study might separate itself from others.”

Point-of-Care System Creates New Model

Regardless, the cell preparation system does offer certain advantages. “There are a number of ways of getting cells from the same patient,” Dr. Sherman said. “Some of them involve more elaborate preparation and human handling. This is one of a small number of systems where the latter 2 issues, manipulation and human handling, are minimized.”

Dr. Pompili noted that such techniques may pave the way for a faster, more efficient system. “They’re creating a model for a point-of-care cell therapy delivery system that’s not dependent on cell numbers or cell therapy labs, where you can really be in a vascular surgery suite or in a surgeon’s office perhaps and pull the marrow and do the delivery,” he said.

 

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Source:
Iafrati MD, Hallett JW, Geils G, et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg. 2011;Epub ahead of print.

 

 

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