Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia

Abstract

BackgroundThe present study investigated factors associated with therapeutic benefits after autologous bone marrow cell (BMC) therapy in patients with “no-option” critical limb ischemia (CLI).Methods and resultsSixty-two patients with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were randomized to treatment with 40 ml of autologous BMCs (SmartPreP2) by local intramuscular (n = 32) or intra-arterial (n = 30) application. The primary endpoint was limb salvage and wound healing at 12 months. Seven patients (11 %) died during the follow-up from reasons unrelated to stem cell therapy. The BMC product of patients with limb salvage and wound healing (33/55) was characterized by a higher CD34+ cell count (p = 0.001), as well as a higher number of total bone marrow mononuclear cells (BM-MNCs) (p = 0.032), than that of nonresponders (22/55). Patients with limb salvage and wound healing were younger (p = 0.028), had lower C-reactive protein levels (p = 0.038), and had higher transcutaneous oxygen pressure (tcpO2) (p = 0.003) before cell application than nonresponders. All patients with major tissue loss at baseline (Rutherford 6 stage of CLI, n = 5) showed progression of limb ischemia and required major limb amputation. In the multiple binary logistic regression model, the number of applied CD34+ cells (p = 0.046) and baseline tcpO2 (p = 0.031) were independent predictors of limb salvage and wound healing. The number of administrated BM-MNCs strongly correlated with decreased peripheral leukocyte count after 6 months in surviving patients with limb salvage (p = 0.0008).ConclusionPatients who benefited from autologous BMC therapy for “no-option” CLI were treated with high doses of CD34+ cells. The absolute number of applied BM-MNCs correlated with the improvement of inflammation. We hypothesize that the therapeutic benefit of cell therapy for peripheral artery disease is the result of synergistic effects mediated by a mixture of active cells with regenerative potential. Patients at the most advanced stage of CLI do not appear to be suitable candidates for cell therapy.Trial registrationThe study was approved and registered by the ISRCTN registry. Trial registration: ISRCTN16096154. Registered: 26 July 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0379-z) contains supplementary material, which is available to authorized users.

Impact of severe diabetic kidney disease on the clinical outcome of autologous cell therapy in people with diabetes and critical limb ischaemia

“…The benefit of cell therapy on limb salvage has been proven by several randomized controlled trials [14,22,23] and metaanalyses in those with and without diabetes [24,25]. These studies showed lower amputation rates in the cell therapy groups compared to standard treatment or placebo, while no significant differences in pain scores and ischaemic variables were observed in the study by Pignon et al [23] in people who underwent bone marrow autograft for limb ischaemia.…”

Difference in Serum Endostatin Levels in Diabetic Patients with Critical Limb Ischemia Treated by Autologous Cell Therapy or Percutaneous Transluminal Angioplasty

“…Likewise, Dong et al, using purified CD34+ cells in CLI patients, did not report a correlation between improvement of clinical outcomes and low, medium, or high doses of injected CD34+ cells 37 . On the other hand, Madaric et al investigated factors associated with clinical benefits of ACT in patients with no-option CLI and discovered that the number of injected CD34+ cells was an independent predictor of limb salvage and wound healing 38 .…”

Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies

“…Updated in 2017, a similar meta‐analysis by Rigatto et al, included 19 RCT (837 CLI patients) concluded cell therapy modestly reduced the risk of amputation by 37%, improved amputation free survival by 18%, and improved wound healing by 59% . Finally, in an uncontrolled study, Madaric et al , analyzed the outcomes of 55 patients transplanted with BM MNC and concluded that responding patients with limb salvage and wound healing (33 of 55) at 1 year were transplanted with significantly higher MNC ( p = .032) and CD34+ cell dose ( p = .001) compared with nonresponders that required limb amputation (22 of 55). Therefore, in contrast to cell therapy trials for heart disease , the benefits of cell therapy for CLI are clearly evident, and considering up to 50% of CLI patients may not be candidates for revascularization therapies, cell therapy should be considered safe option for improving ABI, rest pain, and ulcer healing.…”