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JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368.

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.

Author information

1
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
2
Internal Medicine and Vascular Disease Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
3
Department of Medical Decision Making, Leiden University Medical Center, Leiden, the Netherlands.
4
Department of Rheumatology, The James Cook University Hospital, Middlesbrough, United Kingdom.
5
Service d'Hématologie Clinique et de Thérapie Cellulaire, AP-HP Hôpital Saint-Antoine, Paris 6 University, Paris, France.
6
Clinical Investigation Center in Biotherapies and Cell Therapy Unit, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
7
Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.
8
Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
9
Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
10
Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
11
Department of Biomedicine, Division of Rheumatology AOUC and Department of Experimental and Clinical Medicine, University of Florence, Florence.
12
Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands.
13
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
14
Department of Rheumatology, University Hospital Basel, Basel, Switzerland.
15
Department of Internal Medicine II, University Hospital, Tübingen, Germany.
16
Department of Clinical Immunology, Strasbourg University Hospital, Strasbourg, France.
17
Service d'Hématologie et d'Oncologie, Unité de Greffe de Cellules Souches Hématopoïétiques, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France.
18
2.Medizinische Abteilung Krankenhaus der Barmherzigen Brüder Trier, Trier, Germany.
19
Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, Oberhausen,Germany.
20
Service Médecine Interne, Hôpital Pierre Zobda Quitman, Fort-de France, Martinique.
21
Department of Internal Medicine CHU La Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
22
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.
23
Klinische Abteilung für Rheumatologie, Medizinische Universität, Vienna, Austria.
24
Pôle Pluridisciplinaire de Médecine, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
25
Division of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
26
Service Médecine Interne, Centre Hospitalier Universitaire Toulouse.
27
Service Médecine Interne et Médecine Vasculaire, Hôpital St-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
28
Department of Rheumatology and Clinical Immunology, University of Würzburg Medical Center, Würzburg, Germany.
29
Day Hospital Reumatologia, Ospedale G. Pini, Milan, Italy.
30
Department of Hematology, Cell and Gene Therapy Center, George Papanicolaou Hospital, Thessaloniki, Greece.
31
Department of Rheumatology, University Hospital Frankfurt, Frankfurt, Germany.
32
Service de Médecine Interne, Hôpital Claude-Huriez, Lille, France.
33
Section and Unit of Rheumatology, Department of Medical Sciences, University of Ferrara, Italy.
34
Service de Médecine Interne, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.
35
Department of Internal Medicine, Montpellier University Hospital, Montpellier, France.
36
Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
37
Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven, Rheumatology, University Hospitals, Leuven, Belgium.
38
Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
39
Department of Hematology, Careggi University Hospital, Florence, Italy.
40
Department of Rheumatology, Maartenskliniek, Nijmegen, the Netherlands.
41
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
42
Hematology/Transplantation, AP-HP Hôpital Saint-Louis, Paris 7 University, France.
43
Department of Hematology, University Hospital Basel, Basel, Switzerland.

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.

PMID:
25058083
DOI:
10.1001/jama.2014.6368
[Indexed for MEDLINE]
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