Long-Term Clinical Outcomes Survey of Bone Marrow-Derived Cell Therapy in Critical Limb Ischemia in Japan

Abstract

Background:The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan. Methods and Results:The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM-MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10-year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV.Conclusions: Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV.Key Words: Bone marrow-derived mononuclear cells; Critical limb ischemia; Therapeutic angiogenesis ORIGINAL ARTICLE Peripheral Vascular DiseaseAdvance Publication by-J-STAGE KONDO K et al.previous (5 years) or current history of neoplasms, diabetes with untreated retinopathy, age >80 years, the possibility of pregnancy, or the lack of informed consent. 6 We obtained written informed consent from all patients, and the ethics committees of the participating hospitals approved the protocol. Data CollectionWe developed a web-based database using FileMaker Pro (FileMaker, Inc., Santa Clara, CA, USA) and an electronic clinical record form (eCRF) to collect information about patient characteristics, previous medical history, adverse events, and outcomes on the last day on which the physician confirmed the patient's status. All patient data were stored and analyzed independently at the Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan. In 2015, 14 Japanese hospitals participated in this part of the TACT trial. Data were collected with the permission of the Ministry of Health, Labour, and Welfare.This study was retrospective, observational, and noncontrolled. The primary endpoints were the rates of overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS). AFS in this study included OS and major amputation. The safety of the therapy was assessed in the context of major adverse cardiovascular events (MACE; death, non-fatal myocardial infarctions, decompensated heart failure, and stroke) and all-cause adverse events during the 6-month follow-up period after ...

Thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) promote the effect of therapeutic angiogenesis in critical limb ischemia (CLI) of diabetic rats

“…The results confirmed that autologous BM-MNC treatment is clinically feasible and safe, especially in the case of TAO or CDV [22]. In China, a 10-year study on autologous BM-MNC treatment in CLI patients with thromboangiitis obliterans has shown that BM-MNC treatment is safe and effective.…”

Long-Term Clinical Outcomes of Autologous Bone Marrow Mononuclear Cell Implantation in Patients With Severe Thromboangiitis Obliterans

“…11 Therapeutic angiogenesis by means of gene therapy and cell therapy, including autologous BM-MNC transplantation, peripheral mononuclear cell transplantation, and endothelial progenitor cell transplantation, is being developed to provide options for effective revascularization. [12][13][14][15][16] Cell therapy for CLI patients was first reported in Japan in 2002 by Tateishi-Yuyama et al, who investigated the…”

“…11 In previous clinical studies, the trend for major amputation in patients with CLI after bone marrow mononuclear cell (BM-MNC) implantation decreased in patients with atherosclerotic PAD and patients with TAO. [12][13][14][15][16] Patients with TAO have less remarkable underlying medical complications. Hence, limb salvage and survival rates are significantly higher in patients with TAO after cell therapy.…”

“…13 Kondo et al investigated the long-term clinical outcomes in patients in the TACT trial with a median follow-up period of 31.7 months and concluded that therapeutic angiogenesis using autologous BM-MNC implantation is feasible and safe in patients with no-option CLI, particularly patients with CLI caused by TAO or collagen disease-associated vasculitis. 16 The mononuclear cell population in bone marrow includes hematopoietic progenitor cells, lymphoid cells, monocytes, endothelial progenitor cells, and cells of nonhematopoietic lineage. These cells are recruited to injured tissue throughout the circulatory system in response to large amounts of cytokines and growth factors from locations of affected tissue to prevent apoptosis, protect viable cells, elicit anti-inflammatory effects, and reduce fibrosis.…”

Therapeutic Angiogenesis Using Bone Marrow Mononuclear Cell Transplantation ― A New Standard Treatment for Thromboangiitis Obliterans? ―

“…In recent years, attempts have been made within Asia to investigate the use of other cells, such as adipose tissue-derived mesenchymal stem cells and peripheral blood mononuclear cells, for therapeutic angiogenesis in patients with TAO in addition to BM-MNCs, which have shown a certain degree of effectiveness (see Table). [4][5][6][7][8][9][10][11][12] Despite promising results from clinical trials, there are still many questions surrounding therapeutic angiogenesis, such as which stem cell types are most effective or efficient and whether hybrid treatment is desirable. Through further clinical studies, we hope that therapeutic angiogenesis through less invasive and more reliable cell transplantation…”