The peripheral blood mononuclear cells versus purified CD34+ cells transplantation in patients with angiitis-induced critical limb ischemia trial: 5-year outcomes and return to work analysis-a randomized single-blinded non-inferiority trial

Hao Liu, Tianyue Pan, Yifan Liu, Yuan Fang, Gang Fang, Xiaolang Jiang, Bin Chen, Zheng Wei, Shiyang Gu, Peng Liu, Weiguo Fu, Zhihui Dong, Hao Liu, Tianyue Pan, Yifan Liu, Yuan Fang, Gang Fang, Xiaolang Jiang, Bin Chen, Zheng Wei, Shiyang Gu, Peng Liu, Weiguo Fu, Zhihui Dong

Abstract

Backgrounds: Patients with AICLI constitute a considerable proportion of NO-CLI patients and cannot be treated with surgical or endovascular treatment. Although cell therapy has shown satisfactory results in treating AICLI, research comparing the efficacy of treatment with the 2 kinds of cell products is rare. The aim of this study was to report the 5-year outcomes of a randomized single-blinded noninferiority trial (Number: NCT02089828) on peripheral blood mononuclear cells (PBMNCs) and purified CD34+ cells (PCCs) transplantation for treating angiitis-induced critical limb ischemia (AICLI).

Methods: A randomized single-blinded non-inferiority trial (Number: NCT02089828) was performed. Fifty patients were randomized 1:1 to the PBMNCs and PCCs groups. Efficacy outcomes, safety outcomes and patients' work conditions were analyzed. The primary efficacy outcomes included major amputation and total amputation over 60 months.

Results: During the 60-month follow-up, 1 patient was lost to follow-up, 1 died, and 2 underwent major amputation. The major amputation-free survival rate (MAFS) was 92.0% (95% confidence interval [CI] 82.0%-100.0%) in the PBMNCs group and 91.7% (95% CI 81.3%-100.0%) in the PCCs group (P = 0.980). Compared with the PCCs group, the PBMNCs group had a significantly higher 5-year new lesion-free survival rate (100.0% vs. 83.3% [95% CI 69.7-99.7%], P = 0.039). All patients lost their ability to work before transplantation, and the 5-year cumulative return to work (RTW) rates were 88.0% in the PBMNCs group and 76.0% in the PCCs group (P = 0.085).

Conclusion: The long-term follow-up outcomes of this trial not only demonstrated similar efficacy and safety for the 2 types of autoimplants but also showed a satisfactory cumulative RTW rate in AICLI patients who underwent cell transplantation.

Trial registration: ClinicalTrials.gov, number NCT02089828. Registered 14 March 2014, https://ichgcp.net/clinical-trials-registry/NCT02089828 .

Keywords: CD34+; Cell transplantation; Critical limb ischemia.

Conflict of interest statement

All authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Protocol of the study. Legend: TAO, thromboangiitis obliterans; SLE, systemic lupus erythematosus; HES, hypereosinophilic syndrome; PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells
Fig. 2
Fig. 2
Longitudinal changes in pain relief, functional improvement and blood perfusion restoration. Legend: The assessments of pain were accessed based on a the Wong–Baker Faces Pain Rating Scale, the functional improvement was assessed based on b the pain-free walking time, and blood perfusion restoration was assessed with c the transcutaneous oxygen pressure, d the ankle-brachial index, and e, the toe-brachial index. The values are presented in linear graphs that show the means and SDs. * P < .05 vs. baseline; ** P < .01 vs. baseline. WBFPS, Wong–Baker Faces Pain Rating Scale; PFWT, pain-free walking time; TcPO2, transcutaneous oxygen pressure; ABI, ankle-brachial index; TBI, toe-brachial index; PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells
Fig. 3
Fig. 3
Kaplan–Meier curves showing the probabilities of a, major amputation-free survival and b, total amputation-free survival in both groups. Legend: PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells
Fig. 4
Fig. 4
The change in Rutherford classification and CLI-free ratio during the 5-year follow-up. Legend: Serial changes in Rutherford classification (0–6) proportions of the a PBMNCs and c PCCs groups and serial changes in the CLI-free ratio of the b PBMNCs and d PCCs groups. * P < .05 vs. baseline; ** P < .01 vs. baseline. PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells; CLI, critical limb ischemia
Fig. 5
Fig. 5
Title: Kaplan–Meier curves showing the probabilities of a recurrence-free survival and b new lesion-free survival in both groups. Legend: PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells
Fig. 6
Fig. 6
Quality of life at baseline and at 1 year, 3 years and 5 years after transplantation. Legend: Quality of life was assessed using the Short Form-36 (SF-36) scoring system (version 2) in the PCCs and PBMNCs groups. The SF-36 examines eight domains: a vitality, b social function, c physiological function, d mental health, e role-emotional, f role-physical g general health, and h bodily pain. * P < .05 (intragroup comparison with baseline, based on the Wilcoxon signed-rank test). PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells
Fig. 7
Fig. 7
Kaplan–Meier curves showing the probabilities of a cumulative RTW incidence in both groups and serial changes in work status proportions in the b PBMNCs and c PCCs groups. Legend: RTW, return to work; PBMNCs, peripheral blood mononuclear cells; PCCs, purified CD34+ cells; AICLI, angiitis-induced critical limb ischemia

References

    1. Kum S, Tan Y, Schreve M, et al. Midterm outcomes from a pilot study of percutaneous deep vein arterialization for the treatment of no-option critical limb ischemia. J Endovasc Ther. 2017;24:619–626. doi: 10.1177/1526602817719283.
    1. Dormandy J, Heeck L, Vig S. The fate of patients with critical leg ischemia. Semin Vasc Surg. 1999;12:142–147.
    1. Lawall H, Bramlage P, Amann B. Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg. 2011;53:445–453. doi: 10.1016/j.jvs.2010.08.060.
    1. Ohta T, Ishioashi H, Hosaka M, et al. Clinical and social consequences of Buerger disease. J Vasc Surg. 2004;39:176–180. doi: 10.1016/j.jvs.2003.08.006.
    1. Fang Y, Wei Z, Chen B, et al. A five-year study of the efficacy of purified CD34+ cell therapy for angiitis-induced no-option critical Limb Ischemia. Stem Cells Transl Med. 2018;7:583–590. doi: 10.1002/sctm.17-0252.
    1. Kawamoto A, Katayama M, Handa N, et al. Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells. 2009;27:2857–2864. doi: 10.1002/stem.207.
    1. Dong Z, Pan T, Fang Y, et al. Purified CD34 cells versus peripheral blood mononuclear cells in the treatment of angiitis-induced no-option critical limb ischaemia: 12-Month results of a prospective randomised single-blinded non-inferiority trial. EBioMedicine. 2018;35:46–57. doi: 10.1016/j.ebiom.2018.08.038.
    1. Liu H, Pan T, Fang Y, et al. Three-year outcomes of peripheral blood mononuclear cells vs. purified CD34 cells in the treatment of angiitis-induced no-option critical limb ischemia and a cost-effectiveness assessment: a randomized single-blinded noninferiority trial. Stem Cells Transl Med. 2021;10:647–659. doi: 10.1002/sctm.20-0033.
    1. Fukuhara S, Bito S, Green J, et al. Translation, adaptation, and validation of the SF-36 health survey for use in Japan. J Clin Epidemiol. 1998;51:1037–1044. doi: 10.1016/S0895-4356(98)00095-X.
    1. Fukuhara S, Ware JE, Jr, Kosinski M, et al. Psychometric and clinical tests of validity of the Japanese SF-36 health survey. J Clin Epidemiol. 1998;51:1045–1053. doi: 10.1016/S0895-4356(98)00096-1.
    1. Yoon Y, Park J, Tkebuchava T, et al. Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation. 2004;109:3154–3157. doi: 10.1161/01.CIR.0000134696.08436.65.
    1. You D, Waeckel L, Ebrahimian T, et al. Increase in vascular permeability and vasodilation are critical for proangiogenic effects of stem cell therapy. Circulation. 2006;114:328–338. doi: 10.1161/CIRCULATIONAHA.105.589937.
    1. Shintani S, Kusano K, Ii M, et al. Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI. Nat Clin Pract Cardiovasc Med. 2006;3(suppl 1):S123–S128. doi: 10.1038/ncpcardio0430.
    1. Mathiyalagan P, Liang Y, Kim D, et al. Angiogenic mechanisms of human CD34 stem cell exosomes in the repair of ischemic hindlimb. Circ Res. 2017;120:1466–1476. doi: 10.1161/CIRCRESAHA.116.310557.
    1. Dubsky M, Jirkovska A, Bem R, et al. Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. Diabetes Metab Res Rev. 2013;29:369–376. doi: 10.1002/dmrr.2399.
    1. Piazza G, Creager M. Thromboangiitis obliterans. Circulation. 2010;121:1858–1861. doi: 10.1161/CIRCULATIONAHA.110.942383.
    1. Sasajima T, Kubo Y, Inaba M, et al. Role of infrainguinal bypass in Buerger’s disease: an eighteen-year experience. Eur J Vasc Endovasc Surg. 1997;13:186–192. doi: 10.1016/S1078-5884(97)80017-2.
    1. Sahoo S, Klychko E, Thorne T, et al. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res. 2011;109:724–728. doi: 10.1161/CIRCRESAHA.111.253286.
    1. Kumar AH, Caplice NM. Clinical potential of adult vascular progenitor cells. Arterioscler Thromb Vasc Biol. 2010;30:1080–1087. doi: 10.1161/ATVBAHA.109.198895.
    1. Mathiyalagan P, Liang Y, Kim D, et al. Angiogenicmechanisms of human CD34(+) stem cell exosomes in the repair of ischemic hindlimb. Circ Res. 2017;120:1466–1476. doi: 10.1161/CIRCRESAHA.116.310557.
    1. Bachelier K, Bergholz C, Friedrich EB. Differentiation potential and functional properties of a CD34-CD133+ subpopulation of endothelial progenitor cells. Mol Med Rep. 2020;21:501–507.
    1. Brink E, Brändström Y, Cliffordsson C, et al. Illness consequences after myocardial infarction: problems with physical functioning and return to work. J Adv Nurs. 2008;64(6):587–594. doi: 10.1111/j.1365-2648.2008.04820.x.
    1. Rost K, Smith GR. Return to work after an initial myocardial infarction and subsequent emotional distress. Arch Intern Med. 1992;152(2):381–385. doi: 10.1001/archinte.1992.00400140121026.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する