title: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.
abstract: OBJECTIVE
  High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials.
  
  
  OBJECTIVE
  To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide.
  
  
  METHODS
  The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013.
  
  
  METHODS
  HSCT vs intravenous pulse cyclophosphamide.
  
  
  METHODS
  The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure.
  
  
  RESULTS
  A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years.
  
  
  CONCLUSIONS
  Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit.
  
  
  BACKGROUND
  isrctn.org Identifier: ISRCTN54371254.
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Jacob M
authors: JM
authors: van Laar
authors: Internal Medicine and Vascular Disease Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
authors: Dominique
authors: D
authors: Farge
authors: Department of Medical Decision Making, Leiden University Medical Center, Leiden, the Netherlands.
authors: Jacob K
authors: JK
authors: Sont
authors: Department of Rheumatology, The James Cook University Hospital, Middlesbrough, United Kingdom.
authors: Kamran
authors: K
authors: Naraghi
authors: Service d'Hématologie Clinique et de Thérapie Cellulaire, AP-HP Hôpital Saint-Antoine, Paris 6 University, Paris, France.
authors: Zora
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authors: Marjanovic
authors: Clinical Investigation Center in Biotherapies and Cell Therapy Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
authors: Jérôme
authors: J
authors: Larghero
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Annemie J
authors: AJ
authors: Schuerwegh
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Erik W A
authors: EW
authors: Marijt
authors: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors: Madelon C
authors: MC
authors: Vonk
authors: Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors: Anton V
authors: AV
authors: Schattenberg
authors: Department of Biomedicine, Division of Rheumatology AOUC and Department of Experimental and Clinical Medicine, University of Florence, Florence.
authors: Marco
authors: M
authors: Matucci-Cerinic
authors: Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Alexandre E
authors: AE
authors: Voskuyl
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Arjan A
authors: AA
authors: van de Loosdrecht
authors: Department of Rheumatology, University Hospital Basel, Basel, Switzerland.
authors: Thomas
authors: T
authors: Daikeler
authors: Department of Internal Medicine II, University Hospital, Tübingen, Germany.
authors: Ina
authors: I
authors: Kötter
authors: Department of Internal Medicine II, University Hospital, Tübingen, Germany.
authors: Marc
authors: M
authors: Schmalzing
authors: Department of Clinical Immunology, Strasbourg University Hospital, Strasbourg, France.
authors: Thierry
authors: T
authors: Martin
authors: Service d'Hématologie et d'Oncologie, Unité de Greffe de Cellules Souches Hématopoïétiques, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France.
authors: Bruno
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authors: Lioure
authors: 2.Medizinische Abteilung Krankenhaus der Barmherzigen Brüder Trier, Trier, Germany.
authors: Stefan M
authors: SM
authors: Weiner
authors: Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, Oberhausen,Germany.
authors: Alexander
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authors: Kreuter
authors: Service Médecine Interne, Hôpital Pierre Zobda Quitman, Fort-de France, Martinique.
authors: Christophe
authors: C
authors: Deligny
authors: Department of Internal Medicine CHU La Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
authors: Jean-Marc
authors: JM
authors: Durand
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
authors: Paul
authors: P
authors: Emery
authors: Klinische Abteilung für Rheumatologie, Medizinische Universität, Vienna, Austria.
authors: Klaus P
authors: KP
authors: Machold
authors: Pôle Pluridisciplinaire de Médecine, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
authors: Francoise
authors: F
authors: Sarrot-Reynauld
authors: Division of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
authors: Klaus
authors: K
authors: Warnatz
authors: Service Médecine Interne, Centre Hospitalier Universitaire Toulouse.
authors: Daniel F P
authors: DF
authors: Adoue
authors: Service Médecine Interne et Médecine Vasculaire, Hôpital St-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors: Joël
authors: J
authors: Constans
authors: Department of Rheumatology and Clinical Immunology, University of Würzburg Medical Center, Würzburg, Germany.
authors: Hans-Peter
authors: HP
authors: Tony
authors: Day Hospital Reumatologia, Ospedale G. Pini, Milan, Italy.
authors: Nicoletta
authors: N
authors: Del Papa
authors: Department of Hematology, Cell and Gene Therapy Center, George Papanicolaou Hospital, Thessaloniki, Greece.
authors: Athanasios
authors: A
authors: Fassas
authors: Department of Rheumatology, University Hospital Frankfurt, Frankfurt, Germany.
authors: Andrea
authors: A
authors: Himsel
authors: Service de Médecine Interne, Hôpital Claude-Huriez, Lille, France.
authors: David
authors: D
authors: Launay
authors: Section and Unit of Rheumatology, Department of Medical Sciences, University of Ferrara, Italy.
authors: Andrea
authors: A
authors: Lo Monaco
authors: Service de Médecine Interne, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.
authors: Pierre
authors: P
authors: Philippe
authors: Department of Internal Medicine, Montpellier University Hospital, Montpellier, France.
authors: Isabelle
authors: I
authors: Quéré
authors: Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Éric
authors: É
authors: Rich
authors: Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven, Rheumatology, University Hospitals, Leuven, Belgium.
authors: Rene
authors: R
authors: Westhovens
authors: Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors: Bridget
authors: B
authors: Griffiths
authors: Department of Hematology, Careggi University Hospital, Florence, Italy.
authors: Riccardo
authors: R
authors: Saccardi
authors: Department of Rheumatology, Maartenskliniek, Nijmegen, the Netherlands.
authors: Frank H
authors: FH
authors: van den Hoogen
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors: Willem E
authors: WE
authors: Fibbe
authors: Hematology/Transplantation, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
authors: Gérard
authors: G
authors: Socié
authors: Department of Hematology, University Hospital Basel, Basel, Switzerland.
authors: Alois
authors: A
authors: Gratwohl
authors: Department of Rheumatology, University Hospital Basel, Basel, Switzerland.
authors: Alan
authors: A
authors: Tyndall
mesh_terms: D000328:Adult; D064592:Autografts; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D045743:Scleroderma, Diffuse / Q000188:drug therapy*; D016019:Survival Analysis
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide