Dominique Farge

MD, PhD, Head of Unit of Internal Medicine
Autoimmune and Vascular Diseases, Saint-Fouis- Lariboisiere Hospital, Paris, France
Dominique Farge
Assistance Publique-Hopitaux de Paris, (AP-HP) France St Louis Hospital
Internal Medicine, Autoimmune Diseases and Vascular Pathology Unit, UF 04 INSERM UMRS 1160, University Denis Diderot, Paris 7 France
35 years of medical experience and hospital-university practice in France 25 years of international academic research
Majors: Internal medicine and vascular diseases (CNU 53-01); competency: oncology Knight of the National Order of the Fegion of Honor (2010),
Knight of the National Order of Merit (2001)

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Autologous Stem Cell Transplantation in Systemic Sclerosis
the EBMT
Experience after 20 Years
What is the Next Step?

Sharing the Experience at International Conference in Moscow, Russia, November 2019
Systemic Sclerosis (SSc) is an immune mediated rare AD disease (prevalence 50-300 per million persons), characterized by progressive fibrosis in the skin and internal organs (1) and no standard treatment has yet demonstrated any efficacy in this diseases. According to the extent of heart, lung and kidney involvement in rapidly progressive diffuse cutaneous SSc, the respective 5 year (2) and 10 year (3 mortality rates are up to 30% and 50%. In this context, since the first EBMT consensus in 1997, the use of autologous hematopoietic stem cell transplantation has progressively increased with more than 4000 patients treated by AHSCT worldwide for an AD alone. Among the 3000 patients treated by AHSCT recorded until July 2019 in the EBMT registry, more than 600 patients have been treated for SSc (4). Results analysis from the early phase I-II trials showed that AHSCT in SSc induced major regression of clinical and histological dermal fibrosis (5) with and regression on lung fibrosis son CT scan (6, 7) which had never been previously observed with any other treatment in SSc. Prolonged follow-up of patients up to 7 years confirmed sustained improved functional status, fall in

skin score and stabilisation of lung function, whereas death from disease progression was lower compared to the 5-year mortality rate estimated at 30% in such severe SSc patients (8). The number of indications have increased (4) since three randomized clinical trials (ASSIST, in 2011 (7), ASTIS in 2014 (9 ) and SCOT in 2018 (10) successively demonstrated that AHSCT allows better overall survival and event free survival as compared to cyclophosphamide iv for early rapidly progressive SSc with significant gains, both at 1 and 2 years until 7 years after aHSCT. The mechanisms of action are related to intense initial immunosuppression, that allows eradication of the patient s autoimmune activated cells, and during the immune reconstitution process after aplasia, the capacity to reset the immune response as evidenced by subsequent thymic reprocessing or increased regulatory T-cell activity after AHSCT in SSc patients (11, 12). While gaining experience in the field with increased activity over the years, patient selection and center activity were shown to be important determinant of the observed responses (8). Patient selection directly affects transplant outcomes (13). In SSc patients, specific attention should be given for careful pretransplant evaluation of SSc-cardiac involvement, which requires not only echocardiography, but cardiac magnetic resonance, right heart catheterization with fluid overload, and 24-hour cardiac rhythm registration (Holter) (14). In conclusion, the use of aHSCT in severe and rapidly progressive SSc patients has shown impressive clinical results, with significant improvement in patients quality of life (15) and survival (7, 8, 9).

Worldwide collaboration using shared protocols and common data reporting and analysis will allow to improve patient care and to build the next international trials, so that the AHSCT procedure can be safer (16), while treating SSc patients at an earlier stage of their disease, after careful pretransplant evaluation in accredited expert center, where both disease experts and hematologists have agreed to work in tandem.
2013 classification criteria for systemic sclerosis: an American College of Rheumatology/ European League against Rheumatism collaborative initiative Arthritis Rheum. 2013 November; 65(11): 2737- 274

Fransen Jl, Popa-Diaconu D, Hesselstrand R Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres. Ann Rheum Dis. 2011 Oct;70(10): 1788-92.

Elhai M, Meune C, Boubaya M, Avouac J et al; EUSTAR group. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017 Nov;76(ll):1897-1905. doi: 10.1136/annrheumdis2017-211448

Snowden JA, Badoglio M, Labopin et al Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017 Dec 20;l(27):2742-2755.

Verrecchia F, Laboureau J, Verola O, et al. Skin involvement in scleroderma—where histological and clinical scores meet. Rheumatology (Oxford). 2007;46(5):833-841.

Launay D, Marjanovic Z, de Bazelaire C, et al. Autologous hematopoietic stem cell transplant in systemic sclerosis: quantitative high resolution computed tomography of the chest scoring. J. Rheumatol. 2009;36(7): 1460-1463.

Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haematopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomized phase 2 study. Lancet. 2011 Aug 6;378(9790):498-506

Farge D, Labopin M, Tyndall A, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. Haematologica. 2010;95(2):284-292.

van Laar JM and Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al, Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial JAMA. 2014;311:2490-8.

Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(l):35-47.

Farge D, Henegar C, Carmagnat M, et al. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum. 2005;52(5):1555-1563.

Farge D, Arruda LC, Brigant F, Clave E, et al Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. J Hematol Oncol. 2017 Jan 19; 10(1 ):21.

Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2012 Jun;47(6):770—90.

Farge D, Burt RK, Oliveira MC, et al. Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transplant. 2017 Nov;52(ll):1495-1503.

Puyade N, Maltez N, Lansiaux P, Pugnet G, Roblot P, Colmegna I, Hudson M, Farge D Healthrelated quality of life in systemic sclerosis before and after autologous hematopoietic stem cell transplant - a systematic review Rheumatology (Oxford). 2019 Aug 27. P

Burt RK, Farge D.Systemic sclerosis: Autologous HSCT is efficacious, but can we make it safer? Nat Rev Rheumatol. 2018 Apr;14(4):189-191.