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

doi:10.1001/jama.2014.6368

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 KreuterChristophe 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,

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2490-8
Number of pages	9
Journal	JAMA - The Journal of The American Medical Association
Volume	311
Issue number	24
DOIs	https://doi.org/10.1001/jama.2014.6368
Publication status	Published - 25 Jun 2014

Keywords

Adult
Autografts
Cyclophosphamide
Female
Hematopoietic Stem Cell Transplantation
Humans
Immunosuppressive Agents
Male
Middle Aged
Scleroderma, Diffuse
Survival Analysis
Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

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10.1001/jama.2014.6368

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van Laar, J. M., Farge, D., Sont, J. K., Naraghi, K., Marjanovic, Z., Larghero, J., Schuerwegh, A. J., Marijt, E. W. A., Vonk, M. C., Schattenberg, A. V., Matucci-Cerinic, M., Voskuyl, A. E., van de Loosdrecht, A. A., Daikeler, T., Kötter, I., Schmalzing, M., Martin, T., Lioure, B., Weiner, S. M. (2014). Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA - The Journal of The American Medical Association, 311(24), 2490-8. https://doi.org/10.1001/jama.2014.6368

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title = "Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial",

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.",

keywords = "Adult, Autografts, Cyclophosphamide, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Male, Middle Aged, Scleroderma, Diffuse, Survival Analysis, Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't",

author = "{van Laar}, {Jacob M} and Dominique Farge and Sont, {Jacob K} and Kamran Naraghi and Zora Marjanovic and J{\'e}r{\^o}me Larghero and Schuerwegh, {Annemie J} and Marijt, {Erik W A} and Vonk, {Madelon C} and Schattenberg, {Anton V} and Marco Matucci-Cerinic and Voskuyl, {Alexandre E} and {van de Loosdrecht}, {Arjan A} and Thomas Daikeler and Ina K{\"o}tter and Marc Schmalzing and Thierry Martin and Bruno Lioure and Weiner, {Stefan M} and Alexander Kreuter and Christophe Deligny and Jean-Marc Durand and Paul Emery and Machold, {Klaus P} and Francoise Sarrot-Reynauld and Klaus Warnatz and Adoue, {Daniel F P} and Jo{\"e}l Constans and Hans-Peter Tony and {Del Papa}, Nicoletta and Athanasios Fassas and Andrea Himsel and David Launay and {Lo Monaco}, Andrea and Pierre Philippe and Isabelle Qu{\'e}r{\'e} and {\'E}ric Rich and Rene Westhovens and Bridget Griffiths and Riccardo Saccardi and {van den Hoogen}, {Frank H} and Fibbe, {Willem E} and G{\'e}rard Soci{\'e} and Alois Gratwohl and Alan Tyndall",

year = "2014",

month = jun,

day = "25",

doi = "10.1001/jama.2014.6368",

language = "English",

volume = "311",

pages = "2490--8",

journal = "JAMA - The Journal of The American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "24",

}

van Laar, JM, Farge, D, Sont, JK, Naraghi, K, Marjanovic, Z, Larghero, J, Schuerwegh, AJ, Marijt, EWA, Vonk, MC, Schattenberg, AV, Matucci-Cerinic, M, Voskuyl, AE, van de Loosdrecht, AA, Daikeler, T, Kötter, I, Schmalzing, M, Martin, T, Lioure, B, Weiner, SM, Kreuter, A, Deligny, C, Durand, J-M, Emery, P, Machold, KP, Sarrot-Reynauld, F, Warnatz, K, Adoue, DFP, Constans, J, Tony, H-P, Del Papa, N, Fassas, A, Himsel, A, Launay, D, Lo Monaco, A, Philippe, P, Quéré, I, Rich, É, Westhovens, R, Griffiths, B, Saccardi, R, van den Hoogen, FH, Fibbe, WE, Socié, G, Gratwohl, A, Tyndall, A 2014, 'Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial', JAMA - The Journal of The American Medical Association, vol. 311, no. 24, pp. 2490-8. https://doi.org/10.1001/jama.2014.6368

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. / van Laar, Jacob M; Farge, Dominique; Sont, Jacob K et al.
In: JAMA - The Journal of The American Medical Association, Vol. 311, No. 24, 25.06.2014, p. 2490-8.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis

T2 - a randomized clinical trial

AU - van Laar, Jacob M

AU - Farge, Dominique

AU - Sont, Jacob K

AU - Naraghi, Kamran

AU - Marjanovic, Zora

AU - Larghero, Jérôme

AU - Schuerwegh, Annemie J

AU - Marijt, Erik W A

AU - Vonk, Madelon C

AU - Schattenberg, Anton V

AU - Matucci-Cerinic, Marco

AU - Voskuyl, Alexandre E

AU - van de Loosdrecht, Arjan A

AU - Daikeler, Thomas

AU - Kötter, Ina

AU - Schmalzing, Marc

AU - Martin, Thierry

AU - Lioure, Bruno

AU - Weiner, Stefan M

AU - Kreuter, Alexander

AU - Deligny, Christophe

AU - Durand, Jean-Marc

AU - Emery, Paul

AU - Machold, Klaus P

AU - Sarrot-Reynauld, Francoise

AU - Warnatz, Klaus

AU - Adoue, Daniel F P

AU - Constans, Joël

AU - Tony, Hans-Peter

AU - Del Papa, Nicoletta

AU - Fassas, Athanasios

AU - Himsel, Andrea

AU - Launay, David

AU - Lo Monaco, Andrea

AU - Philippe, Pierre

AU - Quéré, Isabelle

AU - Rich, Éric

AU - Westhovens, Rene

AU - Griffiths, Bridget

AU - Saccardi, Riccardo

AU - van den Hoogen, Frank H

AU - Fibbe, Willem E

AU - Socié, Gérard

AU - Gratwohl, Alois

AU - Tyndall, Alan

PY - 2014/6/25

Y1 - 2014/6/25

N2 - 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.

AB - 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.

KW - Adult

KW - Autografts

KW - Cyclophosphamide

KW - Female

KW - Hematopoietic Stem Cell Transplantation

KW - Humans

KW - Immunosuppressive Agents

KW - Male

KW - Middle Aged

KW - Scleroderma, Diffuse

KW - Survival Analysis

KW - Clinical Trial, Phase III

KW - Comparative Study

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1001/jama.2014.6368

DO - 10.1001/jama.2014.6368

M3 - Article

C2 - 25058083

SN - 0098-7484

VL - 311

SP - 2490

EP - 2498

JO - JAMA - The Journal of The American Medical Association

JF - JAMA - The Journal of The American Medical Association

IS - 24

ER -

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

Abstract

Keywords

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