Autologous bone marrow mononuclear cells in the treatment of chronic limb-threatening ischaemia: a proof-of-concept trial

Abstract

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): 1. Iniciativa Andaluza en Terapias Avanzadas 2. Fundación Progreso y Salud Background Chronic limb threatening ischaemia (CLTI) is a debilitating condition often leading to gangrene which necessitates amputation. Endovascular or surgical interventions remain the standard treatment, however, not all patients are suitable for such procedures. The aim of cell-based therapies is to harvest progenitor cells either from the patient (i.e., autologous) or other sources and re-administer them at a higher concentration near/at the ischemic site(s) to potentiate vasculogenesis. Aim The objective of this trial was to assess the efficacy, safety, and feasibility of treating CLTI with autologous bone marrow mononuclear cells (BM-MNC). Methods This multicentre, phase II, open-label, randomized clinical trial conducted between 2009 and 2011 consisted of adult diabetic patients with CLTI Rutherford grade II or III of at least one lower limb who were not suitable for surgical revascularization. Sixty eligible patients were randomly assigned to one of three treatment groups (1x108, or 5x108, or 1x109 BM-MNCs) or to the control group (standard of care treatment). The cell-product was prepared from the baseline bone marrow aspirate of the treated patients and injected intra-arterially proximal to the vessel occlusion under general anaesthesia <72 hours after bone marrow aspiration. The control patients did not undergo bone marrow aspiration. Ulcer healing and amputation variables were evaluated in all patients at baseline and months 1, 3, 6, 9 and 12. Results The sample demographics were similar in each arm. A total of 50 males and 10 females were enrolled into the trial, with mean age of 63.9 (SD=9.4) years, and mean body mass index of 27.8 Kg/m2 (SD=4.1). The average years living with diabetes was 18.6 years, and time since diagnosis of CLTI was 0.78 years (SD: 1.12 years). A clinically meaningful treatment effect was observable at 6 months, and at 12 months baseline ulcers in 75% of treated patients were completely healed, compared to 14% of control patients (P=0.0142). Furthermore, the ulcers of the treated patients were on average 19.66 mm smaller than those of the control patients (P<0.0001). These results corresponded to angiographical outcomes where vasculogenesis was observed in approximately half of the treated patients who improved in Rutherford Grade. There were no differences in amputation rates across arms. No pertinent covariates which might have impacted the outcomes were identified. No treatment-associated adverse events occurred in the trial. Conclusion Autologous BM-MNC is an effective therapeutic alternative in patients unsuitable for surgical or endovascular revascularization.