Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial
Jacob M van Laar, Dominique Farge, Jacob K Sont, Kamran Naraghi, Zora Marjanovic, Jérôme Larghero, Annemie J Schuerwegh, Erik W A Marijt, Madelon C Vonk, Anton V Schattenberg, Marco Matucci-Cerinic, Alexandre E Voskuyl, Arjan A van de Loosdrecht, Thomas Daikeler, Ina Kötter, Marc Schmalzing, Thierry Martin, Bruno Lioure, Stefan M Weiner, Alexander Kreuter, Christophe Deligny, Jean-Marc Durand, Paul Emery, Klaus P Machold, Francoise Sarrot-Reynauld, Klaus Warnatz, Daniel F P Adoue, Joël Constans, Hans-Peter Tony, Nicoletta Del Papa, Athanasios Fassas, Andrea Himsel, David Launay, Andrea Lo Monaco, Pierre Philippe, Isabelle Quéré, Éric Rich, Rene Westhovens, Bridget Griffiths, Riccardo Saccardi, Frank H van den Hoogen, Willem E Fibbe, Gérard Socié, Alois Gratwohl, Alan Tyndall, EBMT/EULAR Scleroderma Study Group, Klaus P Machold, Hildegard Greinix, René Westhovens, Eric Rich, Joël Constans, Noël Milpied, Pierre Philippe, Olivier Tournilhac, Christophe Deligny, Serge Arfi, Francoise Sarrot-Reynauld, Christophe Senturier, Frederic Garban, David Launay, Louis Terriou, Jean Marc Durand, Didier Blaise, Isabelle Quéré, Dominique Farge, Zora Marjanovic, Jérôme Larghero, Eliane Gluckmann, Gérard Socié, Thierry Martin, Bruno Lioure, Jean Sibilia, Daniel F P Adoue, Odile B Beyne-Rrauzy, Andrea Himsel, Axel Braner, Klaus Warnatz, Jürgen Finke, Hans Hartmut Peter, Stefan M Weiner, Alexander Kreuter, Roland Schroers, Christian Teschendorf, Ina Kötter, Marc Schmalzing, Jörg Henes, Hans-Peter Tony, Stefan Kleinert, Athanasios Fassas, Andrea Lo Monaco, Marco Matucci-Cerinic, Irene Miniati, Silvia Bellando-Randone, Serena Guiducci, Riccardo Saccardi, Nicoletta Del Papa, Alexandre E Voskuyl, Arjan A van de Loosdrecht, Peter C Huijgens, Annemie J Schuerwegh, Erik W Marijt, Willem E Fibbe, Jacob K Sont, Madelon C Vonk, Hanneke Knaapen, Anton V M B Schattenberg, Frank H van den Hoogen, Alan Tyndall, Thomas Daikeler, Paul Hasler, Peter Villiger, Michael Seitz, Alois Gratwohl, Paul Emery, Maya H Buch, Shouvik Dass, Rachel Kilding, Jacob M van Laar, Kamran Naraghi, Bridget Griffiths, Matthew Collin, John McLaren, Jacob M van Laar, Dominique Farge, Jacob K Sont, Kamran Naraghi, Zora Marjanovic, Jérôme Larghero, Annemie J Schuerwegh, Erik W A Marijt, Madelon C Vonk, Anton V Schattenberg, Marco Matucci-Cerinic, Alexandre E Voskuyl, Arjan A van de Loosdrecht, Thomas Daikeler, Ina Kötter, Marc Schmalzing, Thierry Martin, Bruno Lioure, Stefan M Weiner, Alexander Kreuter, Christophe Deligny, Jean-Marc Durand, Paul Emery, Klaus P Machold, Francoise Sarrot-Reynauld, Klaus Warnatz, Daniel F P Adoue, Joël Constans, Hans-Peter Tony, Nicoletta Del Papa, Athanasios Fassas, Andrea Himsel, David Launay, Andrea Lo Monaco, Pierre Philippe, Isabelle Quéré, Éric Rich, Rene Westhovens, Bridget Griffiths, Riccardo Saccardi, Frank H van den Hoogen, Willem E Fibbe, Gérard Socié, Alois Gratwohl, Alan Tyndall, EBMT/EULAR Scleroderma Study Group, Klaus P Machold, Hildegard Greinix, René Westhovens, Eric Rich, Joël Constans, Noël Milpied, Pierre Philippe, Olivier Tournilhac, Christophe Deligny, Serge Arfi, Francoise Sarrot-Reynauld, Christophe Senturier, Frederic Garban, David Launay, Louis Terriou, Jean Marc Durand, Didier Blaise, Isabelle Quéré, Dominique Farge, Zora Marjanovic, Jérôme Larghero, Eliane Gluckmann, Gérard Socié, Thierry Martin, Bruno Lioure, Jean Sibilia, Daniel F P Adoue, Odile B Beyne-Rrauzy, Andrea Himsel, Axel Braner, Klaus Warnatz, Jürgen Finke, Hans Hartmut Peter, Stefan M Weiner, Alexander Kreuter, Roland Schroers, Christian Teschendorf, Ina Kötter, Marc Schmalzing, Jörg Henes, Hans-Peter Tony, Stefan Kleinert, Athanasios Fassas, Andrea Lo Monaco, Marco Matucci-Cerinic, Irene Miniati, Silvia Bellando-Randone, Serena Guiducci, Riccardo Saccardi, Nicoletta Del Papa, Alexandre E Voskuyl, Arjan A van de Loosdrecht, Peter C Huijgens, Annemie J Schuerwegh, Erik W Marijt, Willem E Fibbe, Jacob K Sont, Madelon C Vonk, Hanneke Knaapen, Anton V M B Schattenberg, Frank H van den Hoogen, Alan Tyndall, Thomas Daikeler, Paul Hasler, Peter Villiger, Michael Seitz, Alois Gratwohl, Paul Emery, Maya H Buch, Shouvik Dass, Rachel Kilding, Jacob M van Laar, Kamran Naraghi, Bridget Griffiths, Matthew Collin, John McLaren
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.
Source: PubMed