Results of a small randomised study presented at the Vascular Annual Meeting (Washington, DC, USA, June 2012) showed a trend toward improved major leg amputation-free survival with stem cell mobilisation therapy in patients with critical limb ischaemia. At 12 months, the major amputation rates were 50% for patients treated with mobilisation therapy and 83.3% in the control group (p=0.188).
Eric T Choi, associate professor of Surgery, chief, Section of Vascular Surgery, Temple University, Philadelphia, USA, told delegates that, in 1997, Jeffrey Isner’s lab in Boston discovered that a subset of bone-marrow-derived circulating cells was able to differentiate into endothelium and promote new blood vessel growth (Asahara et al. Science 1997; 275:964–7). He continued, “In 2006, Dan Link’s lab in St Louis showed that two types of such bone marrow-derived angiogenic cells are CD31, CD34, CD105 and CD144-positive endothelial progenitor cells (EPCs) and CD14, CD54-positive circulating angiogenic cells (CACS), as reported by Shepherd et al (Blood 2006; 108:3662–7).”
“Currently, there is no proven effective non-invasive treatment for critical limb ischaemia. We hypothesised that mobilisation of circulating angiogenic cells into the blood by subcutaneous injections of G-CSF may stimulate angiogenesis and result in a sustained improvement in blood flow in the lower extremities of patients with critical limb ischaemia,” Choi said.
Granulocyte colony-stimulating factor (G-CSF) is a drug that releases stem cells from the bone marrow into the blood.
The population at highest risk for impending leg amputation was identified as critical limb ischaemia patients (Rutherford category 5 or 6) with no surgical or endovascular revascularisation options, Choi said. After informed consent, patients were randomised (1:1) in a double-blinded fashion to treatment with daily subcutaneous injection of G-CSF (10μg/kg/day) or placebo for 10 days. Treatment failure was defined as an endpoint of major leg amputation at 12 months.
The investigatorsin the STEMPAD (Stem cell mobilisation to treat severe peripheral artery disease) studyenrolled 28 critical limb ischaemia patients; of which 24 have completed the 12-month follow-up (four patients did not finish the 10-day course of G-CSF or placebo). There were no significant differences between treatment and control groups in any of the demographic parameters.
At 12 months, the major amputation rates were 50% (six out of 12) for G-CSF group and 83.3% (10 out of 12) for control group (log-rank test, p=0.188). Choi said, “However, after four months, none of six remaining G-CSF treated subjects required a major amputation while three out of five remaining controlled subjects went on to have a major amputation suggesting that minimal effective duration of therapeutic angiogenesis from G-CSF treatment is four months. No adverse effects attributable to subcutaneous injection of G-CSF were reported.”
Choi stated that G-CSF is well tolerated in critical limb ischaemia patients and that 10μg/kg/day can mobilise EPCs and CACs effectively in these patients.
“We performed the first randomised, placebo-controlled, double-blinded study of C-GSF-induced angiogenic cell mobilisation to treat no-option critical limb ischaemia patients in the USA. This analysis was designed to demonstrate feasibility and safety of G-CSF treatment, and the preliminary data support a larger clinical trial to determine the effectiveness of G-CSF in critical limb ischaemia patients,” Choi said.