Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial | Stem Cell Transplantation | JAMA | JAMA Network
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Original Investigation
June 25, 2014

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

Author Affiliations
  • 1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
  • 2Internal Medicine and Vascular Disease Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France
  • 3Clinical Investigation Center in Biotherapies and Cell Therapy Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France
  • 4Hematology/Transplantation, AP-HP Hôpital Saint-Louis, Paris 7 University, France
  • 5Department of Medical Decision Making, Leiden University Medical Center, Leiden, the Netherlands
  • 6Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
  • 7Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands
  • 8Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
  • 9Department of Rheumatology, The James Cook University Hospital, Middlesbrough, United Kingdom
  • 10Service d’Hématologie Clinique et de Thérapie Cellulaire, AP-HP Hôpital Saint-Antoine, Paris 6 University, Paris, France
  • 11Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
  • 12Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
  • 13Department of Biomedicine, Division of Rheumatology AOUC and Department of Experimental and Clinical Medicine, University of Florence, Florence
  • 14Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands
  • 15Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands
  • 16Department of Rheumatology, University Hospital Basel, Basel, Switzerland
  • 17Department of Hematology, University Hospital Basel, Basel, Switzerland
  • 18Department of Internal Medicine II, University Hospital, Tübingen, Germany
  • 19Department of Clinical Immunology, Strasbourg University Hospital, Strasbourg, France
  • 20Service d'Hématologie et d'Oncologie, Unité de Greffe de Cellules Souches Hématopoïétiques, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France
  • 212.Medizinische Abteilung Krankenhaus der Barmherzigen Brüder Trier, Trier, Germany
  • 22Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, Oberhausen,Germany
  • 23Service Médecine Interne, Hôpital Pierre Zobda Quitman, Fort-de France, Martinique
  • 24Department of Internal Medicine CHU La Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France
  • 25Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
  • 26Klinische Abteilung für Rheumatologie, Medizinische Universität, Vienna, Austria
  • 27Pôle Pluridisciplinaire de Médecine, Centre Hospitalier Universitaire de Grenoble, Grenoble, France
  • 28Division of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
  • 29Service Médecine Interne, Centre Hospitalier Universitaire Toulouse
  • 30Service Médecine Interne et Médecine Vasculaire, Hôpital St-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  • 31Department of Rheumatology and Clinical Immunology, University of Würzburg Medical Center, Würzburg, Germany
  • 32Day Hospital Reumatologia, Ospedale G. Pini, Milan, Italy
  • 33Department of Hematology, Cell and Gene Therapy Center, George Papanicolaou Hospital, Thessaloniki, Greece
  • 34Department of Rheumatology, University Hospital Frankfurt, Frankfurt, Germany
  • 35Service de Médecine Interne, Hôpital Claude-Huriez, Lille, France
  • 36Section and Unit of Rheumatology, Department of Medical Sciences, University of Ferrara, Italy
  • 37Service de Médecine Interne, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France
  • 38Department of Internal Medicine, Montpellier University Hospital, Montpellier, France
  • 39Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada
  • 40Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven, Rheumatology, University Hospitals, Leuven, Belgium
  • 41Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, United Kingdom
  • 42Department of Hematology, Careggi University Hospital, Florence, Italy
  • 43Department of Rheumatology, Maartenskliniek, Nijmegen, the Netherlands
JAMA. 2014;311(24):2490-2498. doi:10.1001/jama.2014.6368
Abstract

Importance  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.

Design, Setting, and Participants  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.

Interventions  HSCT vs intravenous pulse cyclophosphamide.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  isrctn.org Identifier: ISRCTN54371254

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