In patients with critical limb ischemia (CLI) and no good therapeutic options, treatment with autologous stem cells appears safe and may help stave off amputation, according to data from a small randomized trial published online November 27, 2012, ahead of print in Circulation: Cardiovascular Interventions.

For the multicenter phase I/IIa ACT34-CLI trial, investigators led by Douglas W. Losordo, MD, of Northwestern Memorial Hospital (Chicago, IL), randomized 28 patients with moderate or severe CLI who were poor or non-candidates for revascularization to either a low dose (1 x 10⁵ cells/kg; n = 7) or high dose (1 x 10⁶ cells/kg; n = 9) of autologous CD34+ cells, or a placebo (n = 12). After cell mobilization, all patients received intramuscular injections at 8 sites in the ischemic lower extremity.

The authors caution that the study was not powered to detect differences in efficacy among treatment groups. 

Trend Toward Leg Salvage 

Twelve months after injection, patients in both the low-dose and high-dose groups had experienced fewer total and major amputations than controls, although the difference did not reach statistical significance for either category (table 1).

Table 1. Amputation at 12 Months

 
Trends also emerged toward an increased probability of amputation-free survival in the low-dose and high-dose groups compared with controls during follow-up (log-rank P = 0.35). When the 2 cell-treated groups were combined, the probability of amputation-free survival was clearly lower with stem cell therapy (P = 0.013). In addition, estimated rates of major amputation-free survival were numerically lower for both individual and combined treatment groups (P = 0.414 and P = 0.294, respectively).

In the 11 patients who completed a 6-minute walk test, functional changes from baseline showed mixed results but no overall differences among the 3 groups at either 6 or 12 months. Similarly, no treatment-related trends were seen in surrogate markers including wound healing, leg pain, Rutherford score, and health-related quality of life at either time point.

Safety Profile

Over the 12-month follow-up period, 60 serious adverse events were recorded in 22 subjects, all but 1 of which occurred after injection. Most were considered unrelated to the treatment by the investigator. Possible exceptions were moderate hypotension experienced by 1 patient during cell mobilization and severe worsening of CLI in the target leg after injection; both required prolonged hospitalization.

Mostly modest and asymptomatic elevations in cardiac enzyme levels were seen over the cell mobilization and injection periods. During follow-up, elevated levels of troponin, CK-MB, and CK occurred in 5, 8, and 5 patients, respectively.

Study Lends Support to Particular Strategy

In a telephone interview with TCTMD, Warren Sherman, MD, of Columbia University Medical Center (New York, NY), noted that Dr. Losordo has embarked on 2 refractory angina studies, including the large RENEW trial, using the same therapy.

Explaining the hypothesized mechanism of action, Dr. Sherman said that CD34+ cells are widely accepted to be vascular progenitors, and although they are not necessarily incorporated into the vascular structure, they promote angiogenesis.

“This is really an ideal patient population to demonstrate the biological effect of angiogenesis,” Dr. Sherman observed, in part because amputation provides an objective measure of the progression of severe ischemia. The endpoint is more readily demonstrable than some used in cardiac cell-therapy studies, he added. For this reason, as well as the expectation of a similar effect and lower per-patient cost, peripheral disease is becoming the more attractive arena for testing angiogenic cell therapy.

According to Dr. Sherman, the safety profile in the study is “quite acceptable for this population, who are already fairly sick.” Reactions to cell mobilization with granulocyte-colony stimulating factor (G-CSF), as used here, have been seen in other studies. The number of patients is small, he cautioned, but there is nothing to suggest that larger studies should not go forward.

With regard to efficacy, the current findings echo the same signals seen in studies of other biologics, Dr. Sherman said. “So I would view this as a springboard and justification for moving on to a larger study.

“There are cost issues with this method of isolating and processing cells compared to off-the-shelf preparations,” he added. “Yet the purity and potency of having a higher population of CD34+ cells may provide an advantage. Unfortunately, we are a way off from comparing different biologics in this field.”

Study Details 

All participants underwent cell mobilization with G-CSF (5 µg/kg per day) administered subcutaneously for 4 or 5 days. The next day, the leukapheresis product was enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare, Deerfield, IL).

Baseline characteristics were similar among the 3 treatment groups. The study cohort consisted of 9 women and 19 men, with an average age of 67 years. All patients had undergone previous lower-extremity bypass surgery or PCI.

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