Two-year results from the MOBILE (Marrowstim treatment of limb ischaemia in patients with severe peripheral arterial disease) trial indicate that injecting concentrated bone marrow aspirate (cBMA, Zimmer Biomet), vs. placebo, into patients with critical limb ischaemia is associated with a significant increase in amputation-free survival at two years. However, the results also suggest that diabetic/Rutherford 5 patients do not benefit from the therapy.
Katherin E Leckie (Division of Vascular Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, USA) presented the results of MOBILE trial at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA). She reported that the trial focused on the 30% of patients with critical limb ischaemia who have “no options for revascularisation”. She added the lack of revascularisation treatment options for these patients leads to 53,000 major amputations being performed in the USA each year, noting that—when all costs were considered—amputation was the “sixth most expensive operation” in the country and cost US$6 billion dollars per year.
In MOBILE, 152 patients (155 limbs) with Rutherford 4 or Rutherford 5 critical limb ischaemia were randomised to receive an injection of cBMA (119) or placebo (36). The cells used were mesenchymal stem cells, which Leckie explained can be taken from “bone marrow, the umbilical cord, adipose tissue, teeth, and the placenta” but were taken from bone marrow for this study. She said that a benefit of MOBILE, compared with previous stem cell trials, was that the extraction of cells from the bone marrow and subsequent injection back into the patient only involved one procedure for the patient.
The primary endpoint of the study was the rate of amputation-free survival (a combined endpoint of no amputation and no all-cause mortality) at 52 weeks, with a secondary endpoint being the rate of major amputation of the index limb. At one year, there was no significant difference in the rate of amputation-free survival between groups: 79.8% for cBMA vs. 69.5% for placebo (p=0.224).
However, Leckie and colleagues performed a post-hoc analysis to review the results at two years. This showed that there was a significant difference—76.5% for cBMA vs. 55.9% for placebo (p=0.028)—with a hazard ratio of 0.49 in favour of cBMA. Leckie reported that the separation between cBMA and placebo occurred at 56 weeks (i.e. after the primary endpoint).
Furthermore, with the post-hoc analysis, Leckie et al also looked at the effect of cBMA in certain subgroups—those with and without diabetes and those with Rutherford stage 4 vs. those with Rutherford stage 5. This part of the post-hoc analysis found that while cBMA did provide a significant benefit for patients without diabetes and Rutherford stage 4, it did not provide a benefit for diabetic patients and/or those with Rutherford stage 5.
According to Leckie, she and colleagues also found that the quantity of CD105+/CD34dim was relevant to the effect of cell therapy. The mean cell count in non-diabetic patients who did not have an amputation was significantly higher than non-diabetic patients who did have an amputation: 134.1 vs. 34.3 (p=0.0452). However, there was no significant difference in mean cell count between diabetic patients who underwent amputation and those who did not.
“Cell therapy becomes significantly effective at two years with a 50% reduction in death/major amputation, the quantity of CD105+/CD34dim is associated with freedom from amputation in non-diabetics, but the Rutherford 5 diabetic is unresponsive to autologous cell therapy,” Leckie concluded. She added that that MOBILE trial provides important information to inform future trials but it also raised questions such as is there a “more potent cell population” and whether such a population would benefit patients with diabetes.
Leckie told Vascular News: “The results of the two-year analysis indicate that the positive effect of cell therapy is later than we anticipated. In fact, it was at 56 weeks that the divergence between the cell treated and placebo groups in amputation free-survival became significant. This delay in therapeutic effect suggests that cell therapy may slow or halt the progression of disease from rest pain to tissue loss.” She adds that, with a NIH grant, she and her colleagues are now investigating the mechanisms “by which cell therapy, both autologous bone marrow derived cells and allogeneic mesenchymal stem cells, may prevent amputations”. “These studies are focusing on what the cells secrete after injection into ischaemic human skeletal muscle, how these secreted factors promote angiogenesis and muscle fibre regeneration, and ways to potentiate these effects using hydrogels and genetic modification of the cells,” Leckie notes.