CD34-selected versus unmanipulated autologous haematopoietic stem cell transplantation in the treatment of severe systemic sclerosis: a post hoc analysis of a phase I/II clinical trial conducted in Japan

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Abstract

Background

The effectiveness of autologous haematopoietic stem cell transplantation (auto-HSCT) in treating severe systemic sclerosis (SSc) is established; however, the necessity of purified CD34+ cell grafts and the appropriate conditioning regimen remain unclear. This study aimed to compare the efficacy and safety of CD34-selected auto-HSCT with unmanipulated auto-HSCT to treat severe SSc.

Methods

This study was a post hoc analysis of a phase I/II clinical trial conducted in Japan. Nineteen patients with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilised with cyclophosphamide (4 g/m ²) and filgrastim (10 μg/kg/day). Following PBSC collection by apheresis, CD34+ cells were immunologically selected in 11 patients. All patients were treated with high-dose cyclophosphamide (200 mg/kg) monotherapy as a conditioning regimen and received CD34-selected ( n = 11) or unmanipulated auto-HSCT ( n = 8). Changes in skin sclerosis and pulmonary function were assessed over an 8-year follow-up period. Differences in the changes, toxicity, progression-free survival (PFS) and overall survival were compared between patients who had received CD34-selected auto-HSCT and those who had received unmanipulated auto-HSCT.

Results

Skin sclerosis progressively improved after transplantation over an 8-year follow-up period in both groups, and the improvement was significantly greater in the CD34-selected group than in the unmanipulated group. Forced vital capacity in the CD34-selected group continuously increased over 8 years, whereas in the unmanipulated group it returned to baseline 3 years after transplantation. Toxicity and viral infections, such as cytomegalovirus infection and herpes zoster, were more frequently found in the CD34-selected group than in the unmanipulated group. The frequency of severe adverse events, such as bacterial infections or organ toxicity, was similar between the two groups. No treatment-related deaths occurred in either treatment group. PFS of the CD34-selected group was greater than that of the unmanipulated group, and the 5-year PFS rates of the CD34-selected and unmanipulated group were 81.8% and 50% respectively.

Conclusions

CD34-selected auto-HSCT may produce favourable effects on improvement of skin sclerosis and pulmonary function compared with unmanipulated auto-HSCT. Use of CD34-selected auto-HSCT with high-dose cyclophosphamide monotherapy as a conditioning regimen may offer an excellent benefit-to-risk balance.

Electronic supplementary material

The online version of this article (10.1186/s13075-019-1823-0) contains supplementary material, which is available to authorized users.

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Most cited references 20

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Systemic sclerosis.

Christopher P. Denton, Dinesh Khanna (2017)

Systemic sclerosis, also called scleroderma, is an immune-mediated rheumatic disease that is characterised by fibrosis of the skin and internal organs and vasculopathy. Although systemic sclerosis is uncommon, it has a high morbidity and mortality. Improved understanding of systemic sclerosis has allowed better management of the disease, including improved classification and more systematic assessment and follow-up. Additionally, treatments for specific complications have emerged and a growing evidence base supports the use of immune suppression for the treatment of skin and lung fibrosis. Some manifestations of the disease, such as scleroderma renal crisis, pulmonary arterial hypertension, digital ulceration, and gastro-oesophageal reflux, are now treatable. However, the burden of non-lethal complications associated with systemic sclerosis is substantial and is likely to become more of a challenge. Here, we review the clinical features of systemic sclerosis and describe the best practice approaches for its management. Furthermore, we identify future areas for development.

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Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Keith M. Sullivan, Ellen A Goldmuntz, Lynette Keyes-Elstein … (2018)

Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

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Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution.

Daniel Douek, Robert A Vescio, Michael Betts … (2000)

The potential benefits of haematopoietic stem-cell transplantation are tempered by the depletion of T-cells accompanying this procedure. We used a new technique which quantifies the excisional DNA products of T-cell-receptor (TCR) gene rearrangement to measure thymic output directly in patients with multiple myeloma, and thus assessed the contribution of the thymus to immune recovery after transplantation. We studied 40 patients, 34-66 years of age, who had been randomly assigned myeloablative chemotherapy and autologous peripheral-blood haematopoietic stem-cell transplantation with unmanipulated grafts or grafts enriched for CD34 stem cells. CD4 and CD8 T-cell counts were measured, thymic output was estimated serially until 2 years after transplantation, and percentages of naive T-cells were measured. The production of substantial numbers of new naive T cells by the thymus could be detected by 100 days post-transplant; there was a significant inverse relation between age and recovery of new T cells. In the CD34-unselected group, numbers of TCR-rearrangement excision circles returned to baseline after 2 years, whereas in the CD34-selected group, numbers at 2 years were significantly higher than both baseline numbers (p=0.004), and 2-year numbers in the unselected group (p=0.046). Increased thymic output correlated with, and was predictive of, increased naive T-cell numbers and broader T-cell-receptor repertoires. Our results provide evidence that the adult thymus contributes more substantially to immune reconstitution after haematopoietic stem-cell transplantation than was previously thought, and therefore could be a target for therapeutic intervention.

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Author and article information

Contributors

Masahiro Ayano: m-ayano@intmed1.med.kyushu-u.ac.jp

Hiroshi Tsukamoto: h-tsukamoto@shin-kokura.gr.jp

Hiroki Mitoma: mitoma@intmed1.med.kyushu-u.ac.jp

Yasutaka Kimoto: kimoty@beppu.kyushu-u.ac.jp

Mitsuteru Akahoshi: akahoshi@intmed1.med.kyushu-u.ac.jp

Yojiro Arinobu: yarinobu@cancer.med.kyushu-u.ac.jp

Toshihiro Miyamoto: toshmiya@intmed1.med.kyushu-u.ac.jp

Takahiko Horiuchi: horiuchi@beppu.kyushu-u.ac.jp

Hiroaki Niiro: hniiro@cancer.med.kyushu-u.ac.jp

Koji Nagafuji: knagafuji@med.kurume-u.ac.jp

Mine Harada: mharada@karatsu.saga.med.or.jp

Koichi Akashi: akashi@med.kyushu-u.ac.jp

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 22 January 2019

Publication date PMC-release: 22 January 2019

Publication date (Print): 2019

Volume: 21

Electronic Location Identifier: 30

Affiliations

[1 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Medicine and Biosystemic Science, , Kyushu University Graduate School of Medical Sciences, ; 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan

[2 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Cancer Stem Cell Research, , Kyushu University Graduate School of Medical Sciences, ; 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan

[3 ]ISNI 0000 0004 0642 121X, GRID grid.459691.6, Department of Internal Medicine, , Kyushu University Beppu Hospital, ; 4546 Tsurumibaru, Tsurumi, Beppu, 874-0838 Japan

[4 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Medical Education, , Kyushu University Graduate School of Medical Sciences, ; 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan

[5 ]GRID grid.415760.1, Present Address: Department of Rheumatology, , Shin-Kokura Hospital, ; 1-3-1 Kanada, Kokurakita-ku, Kitakyushu, 803-8505 Japan

[6 ]ISNI 0000 0001 0706 0776, GRID grid.410781.b, Present Address: Division of Hematology and Oncology, Department of Medicine, , Kurume University School of Medicine, ; 67 Asahi-machi, Kurume, 830-0011 Japan

[7 ]Present Address: Medical Center for Karatsu-Higashimatsuura Medical Association, 2566-11 Chiyoda-machi, Karatsu, 847-0041 Japan

Article

Publisher ID: 1823

DOI: 10.1186/s13075-019-1823-0

PMC ID: 6341635

PubMed ID: 30670057

SO-VID: 786f2a78-7db3-410d-a153-0f06536e1209

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 November 2018

Date accepted : 14 January 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;

Award ID: JSPS KAKENHI 16K19603

Award ID: JSPS KAKENHI 15K09527

Award Recipient : Masahiro Ayano Hiroshi Tsukamoto

Funded by: FundRef http://dx.doi.org/10.13039/501100003478, Ministry of Health, Labour and Welfare;

Award ID: H24-Jitsuyoka-Kokusai-004

Award Recipient : Koichi Akashi

Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Award ID: the Practical Research Project for Rare/Intractable Diseases

Award Recipient : Koichi Akashi

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: systemic sclerosis,scleroderma,haematopoietic stem cell transplantation,cd34

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ScienceOpen disciplines: Orthopedics

Keywords: systemic sclerosis, scleroderma, haematopoietic stem cell transplantation, cd34

CD34-selected versus unmanipulated autologous haematopoietic stem cell transplantation in the treatment of severe systemic sclerosis: a post hoc analysis of a phase I/II clinical trial conducted in Japan

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Abstract

Background

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Orthopedics

Most cited references 20

Systemic sclerosis.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution.

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