Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Severe Auto-Immune Disease Adult Patients: Analysis of Outcomes from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGMT-TC) in Light of the European Society for Blood and Marrow Transplantation (EBMT) Activity
Authors: Guillaume-Jugnot Perrine , Marjanovic Zora , Labopin Myriam , Terriou Louis , Deligny Christophe , Lioure Bruno , Martin Thierry , Leblond Veronique , Pugnet Gregory , Blaise Didier , Peffault de Latour Régis , Yakoub-Agha Ibrahim , Snowden John A , Farge Dominique 
Published: October 2019

Abstract
Introduction
Autologous Hematopoietic Stem Cell transplantation (AHSCT) is used since 1994 worldwide to treat severe autoimmune disease (AD) refractory to standard therapy. Despite early release and regular update of the European Society for Blood and Marrow Transplantation (EBMT) practice guidelines (Snowden JA et al BMT 2012, Alexander T et al BMT 2014) along with 3 randomised Clinical trials (CTs) for Systemic Sclerosis (SSc) ASTIS, Crohn's Disease (CD) ASTIC and Multiple sclerosis (MS) ASTIMS, the uptake of this approach varies according to each ADs and between countries. We therefore design this retrospective study to evaluate patients (pts) outcomes as reported to the French Bone Marrow Transplantation Society registry (SFGMT-TC) in light of the other States activity published or reported to the EBMTregistry.
Materials and methods
All AHSCT for adult AD pts (> 18 years (yrs)) reported in France from 1997 to 2013 with at least one yr follow-up after AHSCT were included in the study. Primary data were derived from the EBMT registry (MED-A/B forms) with additional data obtained through a specific questionnaire (MED-C) for the study. Primary end point is overall survival (OS), defined as time since the day of transplant to death, irrespective of the cause. Secondary end points are Progression Free Survival (PFS), 100 day treatment related mortality (100-day TRM) and non-relapse related mortality (NRM). The probabilities were estimated using the Kaplan-Meier estimator for OS and PFS, cumulative incidence for NRM, relapse/progression being the competing event. All tests were two-sided. Statistical analyses were performed with IBM SPSS Statistics 22.0 and R version 3.1.2 (R Development Core Team, Vienna, Austria) software packages.
Results
96 adult pts (55% Female), median age 45 yrs [20-71], underwent a first AHSCT for ADs in 19 HSCT Units. Most of the ADs were rheumatological(72%) with 55 SSc, 7 polymyositis-dermatomyositis, 3 polychondritis, 2 Lupus Erythematosus, 1 Rheumatoid Arthritis (RA), 1 Ankylosing Spondylitis, or neurological (15%) with 14 MS, whereas the others were 5 CDs, 5 immune thrombocytopenic purpura, 1 hemolytic autoimmune anemia, 1 IgM neuropathy and 1 POEMS syndrome. Two pts had 2 simultaneous ADs (1 SSc and RA, 1 CD and RA). Median duration between AD diagnosis and AHSCT was 3.5 yrs [1-33]. With a median follow-up of 7 yrs [<1- 17], 5 yrs OS and PFS were 79.4% [95% CI: 70.8-88] and 49.3% [95% CI: 38.7-59.9] while 10 yrs OS and PFS were 70.2% [95% CI: 58.9-81.7] and 41.9 % [95% CI: 30.6-53.2], respectively. The 100 days NRM was 7.4% [95% CI: 3.2-13.9]. 5 and 10 yrs NRM was 9.6% [95% CI: 4.7-16.6] and 13.6% [95% CI: 6.9-22.7] respectively. At the end of follow-up, 28 pts (29%) had died, for whom the causes of death were: relapse or progression (n=12), AHSCT related cause (n=7 with 3 infections, 2 cardiac toxicity, 1 renal toxicity, 1 respiratory failure), secondary malignancies (n=3), aspiration pneumonia in polychondritis (n=1) or unknown causes (n= 5).
Conclusion
AHSCT for severe ADs, has progressively developed in France, allowing 5y OS equal to 79.4%, similar to UK (Snowden JA et al, BJH 2012) and EBMT data. In rapidly progressive severe SSc, where the proof of efficacy of AHSCT was obtained (Van Laar J and Farge D et al, JAMA 2014) and in MS (Pasquini MC et al BBMT 2010) where long-term responses are confirmed worldwide, the French and the EBMT registry activities have increased over the past 14 years, with sustained positive clinical results despite non negligible NMR, which remains lower than spontaneous AD evolution. Meanwhile, AHSCT activity has become exceptional in RA due to the availability of safe and effective biological therapies, and other indications remain rare, such as for CD or SLE where the risk of AHSCT in highly immunosuppressed patients has to be balanced with ADs severity. More than half of French pts were treated on an individual basis, outside CTs, underlying the need to evaluate national activity and to promote education of HSCT Unit members. At each French or other European state levels, like in the US, the indications for AHSCT in ADs remain low due to other competing therapies. Combined study using European and American data registry will allow analysis of a larger number of AD pts treated by AHSCT and would offer more clues to better understand the determinants of the response and to refine indications for each AD type.

Disclosures
Leblond: Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria. Snowden:MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau; Sanofi: Consultancy.