NEW YORK— In patients with critical limb ischemia (CLI), bone marrow-derived cell therapy appears safe and may delay adverse events including amputation, according to early results from a pair of randomized trials presented January 20, 2011, at the Sixth International Conference on Cell Therapy for Cardiovascular Disease. The findings also provide insight into which patients are more likely to benefit from the experimental treatment.

One set of data comes from a pilot trial in which investigators at 8 sites (7 in the United States, 1 in India) randomized 48 patients with CLI in a 2:1 ratio to intramuscular injection of autologous bone marrow concentrate (n = 34) or a placebo (n = 14). All patients had disease classified as Rutherford class 4 (characterized by rest pain) or 5 (characterized by minor tissue loss) and had exhausted all therapeutic options short of amputation. Treated patients were somewhat more likely than controls to be class 5 (67.6% vs. 50%) and to have diabetes (52.9% vs. 42.9%).

Bone marrow was aspirated from treated patients and processed using the point-of-care BMAC system (Harvest Technologies, Plymouth, MA), while peripheral blood was drawn from controls. Both groups then received a series of injections, all under conscious sedation.

According to presenter Thomas F. O’Donnell Jr, MD, of Tufts Medical Center (Boston, MA), there were no serious adverse events associated with the procedure.

A Question of Class

Rates of the primary endpoint (amputation-free survival) were similar between the 2 groups at 6 months (P = 0.123). However, Dr. O’Donnell pointed out, Rutherford class 5 patients clearly had worse outcomes: 47% underwent amputation vs. about 6% of class 4 patients (P = 0.0029).

On the other hand, among Rutherford 5 patients there was a strong trend toward delayed time to amputation out to 1 year in the treated vs. the placebo group (P = 0.067). In addition, the rate of amputation-free survival was numerically higher among treated class 5 patients.

At 6 months, 67% of class 4 patients had improved at least 1 Rutherford class, while only about 18% of class 5 patients showed similar improvement (P = 0.0013). Overall, there was a trend toward class improvement in treated vs. placebo patients (P = 0.08). When the comparison was limited to class 4 patients, treated subjects were significantly more likely to improve 1 class than placebo patients (82% vs. 43%; P = 0.0003).

In logistic regression analysis, only tissue loss predicted both amputation rate (OR 18.48; P = 0.01) and amputation-free survival (OR = 20.15; P = 0.008) at 6 months.

According to Dr. O’Donnell, an important lesson of the trial is that Rutherford class 5 patients clearly differ from class 4 patients. As a group, the former are more likely to undergo amputation and less likely to improve in Rutherford class in response to bone marrow cell therapy. This difference should be taken into account when designing future trials of cell therapy for no-option CLI patients, he argued.

Longer Time to Treatment Failure

Interim results of the multicenter, double-blind RESTORE-CLI (Use of Vascular Repair Cells in Patients with Peripheral Arterial Disease to Treat Critical Limb Ischemia) trial were presented by Sharon Watling, PharmD, of Aastrom Biosciences (Ann Arbor, MI). The analysis focused on 72 patients with CLI and no revascularization option who were randomized in a 2:1 ratio to injection with vascular repair cells (n = 48) or a placebo solution (n = 24). All patients had at least 6 months of follow-up.

The vascular repair therapy consisted of autologous bone marrow-derived cells aspirated from the patient and then selected and expanded using Aastrom proprietary technology.

Time to first occurrence of treatment failure (composite of major amputation of the treated leg, all-cause death, doubling of wound size, or new gangrene), the primary efficacy endpoint, was extended by 56% in the treated group vs. the placebo group (HR 0.44; 95% CI 0.22-0.86; P = 0.0132). Moreover, individual events were delayed in treated patients (table 1).

Table 1. Time to Treatment Failure

In addition, amputation-free survival was 24% higher in the treated group (HR 0.76, 95% CI 0.30-1.92), although the reduction did not reach statistical significance (P = 0.5541). Dr. Watling said the finding is not surprising since the study was underpowered to show a difference. She also noted that the event rates were consistent with those of an earlier interim analysis.

Overall, the cell therapy appeared safe, with similar serious adverse event rates for the treated vs. control groups (43% vs. 50%).

“Based on the clinically relevant endpoints, we are convinced we are seeing a treatment signal,” Dr. Watling said. Together with additional data from continuing follow-up, the findings provide support for design of a pivotal clinical trial, she added.

 

---

Sources:
1. O’Donnell TF. A randomized controlled double-blinded pilot trial of autologous bone marrow concentrate for no-option critical limb ischemia. Presented at: Sixth International Conference on Cell Therapy for Cardiovascular Disease; January 20, 2011; New York, NY.

2. Watling S. Tissue repair cells in patients with peripheral arterial disease to treat critical limb ischemia (RESTORE-CLI): Interim analysis results. Presented at: Sixth International Conference on Cell Therapy for Cardiovascular Disease; January 20, 2011; New York, NY.

 

 

Related Stories:

• Cell Therapy Shows Promise for Limb Ischemia Due to PAD, Buerger’s Disease
• Cell Therapy Linked to Long-Term Improvement for Chronic Limb Ischemia
• Gene Therapy Safe for Critical Limb Ischemia