A phase II trial of autologous transplantation of bone marrow stem cells for critical limb ischemia: results of the Naples and Pietra Ligure Evaluation of Stem Cells study

Abstract

Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%-40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) transplantation performed in "no-option" patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Variation of blood perfusion parameters, evaluated by laser Doppler flowmetry or transcutaneous oximetry, was set as the primary endpoint at 12 months after treatment and amputation-free survival as the secondary endpoint. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates (75.2%) at 12 months after the treatment. This study provides further evidence that autologous bone marrow transplantation is well tolerated by CLI patients without adverse effects, demonstrating trends toward improvement in perfusion and reduced amputation rate, confirming the feasibility and safety of the procedure.

Figure 1.

Study enrollment diagram of the Naples and Pietra Ligure Evaluation of Stem Cells study. Abbreviations: LDF, laser Doppler flowmetry; TcPO₂, transcutaneous oximetry.

Figure 2.

Change in perfusion parameters in group 1: laser Doppler basal oxygenation flowmetry measurements at T0 (before transplantation), T6, and T12 (after transplantation) visualized as a box plot, including the median, the minimum, and the maximum data values (p = .008; repeated-measures analysis of variance). The black dots are the two outliers (patients 12 and 25), representing the minimum and the maximum of perfusion measurements. Abbreviations: PU, perfusion units; T, time in months.

Figure 3.

Change in perfusion parameters in group 2: transcutaneous oximetry measurements at T0 (before transplantation), T6, and T12 (after transplantation) visualized as a box plot, including the median, the minimum, and the maximum data values (p = .008; repeated-measures analysis of variance). Abbreviations: T, time in months; TcPO₂, transcutaneous oximetry.

Figure 4.

Amputation-free survival. The Kaplan-Meier curve describes the amputation-free survival after 12 months among all critical limb ischemia subjects enrolled (n = 50). Abbreviations: CI, confidence interval; std. err, standard error; surv, survival.