Information on the number of individuals screened and excluded was not available for all centers. Twenty-two patients receiving hematopoietic stem cell transplantation and 31 receiving cyclophosphamide (control group) experienced 1 event (death or persistent major organ failure) throughout follow-up (before October 31, 2013).aTwo patients had low diffusion capacity of the lung for carbon monoxide.bOne patient received the first cyclophosphamide pulse before randomization.
Hazard ratios (HRs) and 95% CIs were calculated by Cox regression. Hazard ratios were time-varying. The hazard (slope of the survival curve) in the hematopoietic stem cell transplantation (HSCT) group is initially high because of treatment-related mortality but gradually improves. At 1-year follow-up, the HR already favors the HSCT group, which leads to the crossing of the survival curves at 2 years’ follow-up. A, Three-month follow-up: HR, 2.01 (95% CI, 0.74-5.49); P = .17; 6-month follow-up: HR, 1.35 (95% CI, 0.62-2.96); P = .45; 1-year follow-up: HR, 0.52 (95% CI, 0.28-0.96); P = .04; 2-year follow-up: HR, 0.35 (95% CI, 0.16-0.74); P = .006; 3- through 10-year follow-up: HR, 0.34 (95% CI, 0.16-0.74); P = .006. B, Three-month follow-up: HR, 2.40 (95% CI, 0.75-7.67); P = .14; 6-month follow-up: HR, 1.50 (95% CI, 0.61-3.68); P = .38; 1-year follow-up: HR, 0.48 (95% CI, 0.25-0.91; P = .02; 2-year follow-up: HR, 0.29 (95% CI, 0.13-0.65); P = .002; 3- through 10-year follow-up: HR, 0.29 (95% CI, 0.13-0.64); P = .002.
eFigure 1. Post hoc Subgroup Analysis
eTable 1A. Transplant Group: Treatment Details
eTable 1B. Control Group: Treatment Details
eTable 2A. Causes of Death
eTable 2B. Major Organ Failure
eTable 3. Sensitivity Analysis: Treatment Responses in Clinical Outcome Variables, Change in the Area Under the Time Response Curve From Baseline to 2 Years’ Follow-up
eTable 4. Immunosuppressive Drugs Used Between 12 and 24 Months
eTable 5. Transplant Group: Treatment-Related Deaths
eTable 6. Viral Infections and Reactivations After Randomization
eAppendix. Analysis of the Time-varying Hazard Ratios
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, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DFP, Constans J, Tony H, 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, . Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic SclerosisA Randomized Clinical Trial. JAMA. 2014;311(24):2490-2498. doi:10.1001/jama.2014.6368
Copyright 2014 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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.
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.
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.
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.
isrctn.org Identifier: ISRCTN54371254
Quiz Ref IDSystemic sclerosis is a heterogeneous autoimmune connective tissue disease characterized by vasculopathy, autoantibody formation, low-grade inflammation, and fibrosis in skin and internal organs, with varying geographical prevalence (50-300 per million persons per year) and incidence (2.3-22.8 per million persons per year).1,2 Previous studies have shown that systemic sclerosis is amenable to treatment with autologous hematopoietic stem cell transplantation (HSCT).3- 9 Improvement of skin involvement and functional ability was consistently observed, although some studies showed that HSCT can also ameliorate vasculopathy, improve skin and lung involvement, and correct immune abnormalities.10- 13 The benefits of HSCT must be weighed against the risk of serious toxicities due to organ involvement in systemic sclerosis.14 It is still unclear whether HSCT prolongs survival in systemic sclerosis. We therefore conducted a randomized clinical trial called ASTIS (Autologous Stem Cell Transplantation International Scleroderma) to compare safety and efficacy of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide.
The ASTIS trial was an investigator-initiated, randomized, open-label, parallel-group trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation–registered transplant facility.15 Patients were eligible if they were between 18 and 65 years of age; had diffuse cutaneous systemic sclerosis according to American Rheumatism Association criteria,16 with maximum disease duration of 4 years; minimum modified Rodnan skin score (mRSS) of 15 (range, 0-51, with higher scores indicating more severe skin thickening); and involvement of heart, lungs, or kidneys (eAppendix in the Supplement). Prior treatment with cyclophosphamide was allowed up to a cumulative dose of 5 g intravenously or up to 2 mg/kg body weight orally for 3 months. Patients with severe major organ involvement including severe pulmonary arterial hypertension (PAH) (mean pulmonary artery pressure >50 mm Hg) or serious comorbidities were excluded. The protocol was amended in 2004 to allow inclusion of patients with disease duration of 2 years or less and no major organ dysfunction as defined above, provided they had an mRSS of at least 20 and an erythrocyte sedimentation rate greater than 25 mm in the first hour and/or hemoglobin less than 11 g/dL not explained by causes other than active scleroderma. The protocol was further amended in 2008 to make it compliant with the European Union Directive for Clinical Trials, to change the power calculation because of a lower than expected accrual and event rate, and to include guidance on monitoring and treatment of Epstein-Barr virus (EBV) reactivation after HSCT.
The study protocol was approved by the institutional review board at each site and complied with country-specific regulatory requirements. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
After registration, patients were randomly assigned in a 1:1 ratio by blocked randomization to receive HSCT or 12 intravenous pulses of cyclophosphamide (Figure 1). Block randomization was performed centrally by telephone at the study administration office according to a computer-generated randomization program for each site, with random block sizes (2, 4, 6). Treatment was allocated within blocks according to an optimum assignment procedure (minimization) to balance the investigational and standard treatment groups for age (≤40 years, >40 years) and disease duration (<2 years, ≥2 years) but included a 25% chance to be assigned to the nonoptimal group.
Quiz Ref IDThe protocol for HSCT was designed with the intention to achieve intensive lymphocyte ablation. Peripheral blood hematopoietic stem cells were mobilized with intravenous cyclophosphamide (a total of 4 g/m2 administered in equal amounts on 2 consecutive days) and filgrastim (10 µg/kg per day), harvested by leukapheresis, and enriched for CD34+ cells using immunomagnetic separation (CliniMACS, Miltenyi Biotec). The conditioning regimen consisted of intravenous cyclophosphamide (a total of 200 mg/kg intravenously over 4 consecutive days) and intravenous rabbit antithymocyte globulin (rbATG, Genzyme) (a total of 7.5 mg/kg administered in equal amounts over 3 consecutive days) administered with intravenous methylprednisolone (1 mg/kg) and hyperhydration, followed by reinfusion of peripheral blood autologous CD34+ stem cells (≥2 × 106/kg). Patients in the control group received 12 monthly pulses of intravenous cyclophosphamide (750 mg/m2). Crossing over was allowed after the second year. Concomitant medications or other treatments deemed necessary for patients’ supportive care and safety were allowed at the discretion of the investigators. Adherence to European Group for Blood and Marrow Transplantation guidelines was recommended.15 After 2008, guidance was provided on the monitoring of EBV load by polymerase chain reaction after HSCT. Investigators were advised to initiate prophylactic treatment with angiotensin-converting enzyme inhibitors in all patients enrolled.
Patients were seen every 3 months in the first 2 years, and yearly thereafter, for physical examination, full blood cell count, and urinalysis and for measurement of skin score, toxicity, and the Health Assessment Questionnaire Disability Index (HAQ-DI), for a total follow-up of 7 years. Patients and assessors were not blinded. Options for ethnic origin were predefined in the case record forms and determined by each investigator. Information on quality of life (36-item Short Form General Health Survey [SF-36] and EuroQol [EQ-5D]) was collected at 3 and 6 months and then every 6 months in the first 2 years and annually thereafter. Lung function tests, echocardiography or multiple-gated acquisition scan, and electrocardiography were performed yearly up to 7 years after enrollment. Survival and the absence of major organ failure among patients with follow-up longer than 7 years were ascertained by telephone calls or e-mails with the investigators.
Collected data were transferred to the study administration office, which stored, managed, and analyzed the data. An independent data and safety monitoring committee monitored efficacy and safety data.
The primary end point was event-free survival, defined as the time in days from randomization until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney), defined as left ventricular ejection fraction less than 30% by echocardiography (or multiple-gated acquisition scan), resting arterial oxygen tension less than 8 kPa (60 mm Hg) and/or resting arterial carbon dioxide tension greater than 6.7 kPa (50 mm Hg) without oxygen supply, or the need for renal replacement therapy. Each event (death or major organ failure) was reviewed and adjudicated in a nonblinded manner by the independent data and safety monitoring committee, which determined whether it was deemed treatment-related or attributable to disease progression.
The main secondary end points of the study were treatment-related mortality, toxicity, and changes in mRSS (minimally important difference, 3.2-5.3),17 organ function (heart, lung, kidney), HAQ-DI (minimally important difference, 0.10-0.14)17, body weight, SF-36 score, and EQ-5D score within 24 months following randomization. The need for immunosuppressive therapy between 12 and 24 months served as an additional end point.
We calculated that 75 patients were needed in each group, with a total study and follow-up period of 11 years, including at least 1-year follow-up of the last patient with an annual event rate of 9.5% (50 events in total), to detect a hazard ratio of 0.5, indicating that half as many patients in the intervention group had experienced an event as compared with the control group, assuming a 5% loss to follow-up after 8 years in both groups (α = .05 [2-sided]; power = .67 [1-sided]).
Data collected by October 31, 2013, were included in the analysis, consistent with a 4-year follow-up after the last participant was enrolled. Data for patients who survived and for those surviving event-free were censored at the date of the last follow-up visit. We analyzed all data by intention-to-treat (ITT) and report raw estimates without adjustment for baseline characteristics. In addition, per-protocol sensitivity analyses of secondary outcomes were performed.
Primary analyses compared event-free survival between the study groups by constructing Kaplan-Meier survival curves based on the time to the first event, ignoring additional failures, and by using the log-rank test and a Cox regression model. Because the survival curves crossed, the treatment × time interaction was modeled allowing a gradual change of the hazard of the transplant group crossing the hazard of the control group at 0.5 years and ending up as a constant after 2 years of follow-up. We analyzed, by ITT, the treatment responses in clinical outcome variables such as the mRSS, HAQ-DI, visceral involvement, body weight, SF-36 score, and EQ-5D score in patients still alive at 2 years using area under the time-response curve (AUC). We tested whether data were missing at random by comparing baseline characteristics between patients with missing values (cases with missings) and without missing values (complete cases) during the first 2 years in 2 scenarios: (1) inclusion of patients who died in the first 2 years of follow-up and (2) exclusion of nonsurvivors. Some baseline characteristics were statistically significantly different between complete cases and cases with missings when nonsurvivors were included in the analysis. Although there were no statistically significant differences between complete cases and cases with missings when nonsurvivors were excluded, for some parameters the P value was slightly greater than .05. We concluded that data were not missing at random. We therefore used the nearest observation in time for patients who survived the first 2 years or the poorest possible values when data were missing because of death. Areas under the curve were compared between the treatment groups by t test.
In a post hoc analysis, we used the Breslow-Day test for homogeneity of odds ratios to determine differences in the treatment effect across categories for subgroups of age (≤45 years, >45 years), sex, disease duration (<2 years, ≥2 years), smoking status (never smoked, ever smoked), pretrial use of cyclophosphamide, and baseline body weight (≤66.5 kg, >66.5 kg) at 2 years’ follow-up.
Ninety-five percent confidence intervals were computed where appropriate, with P values less than .05 (2-sided) considered statistically significant. Binary variables were analyzed by the Fisher exact test. Statistical analyses were performed using STATA version 12.0 (StataCorp).
From March 2001 to October 2009, 156 patients underwent randomization in 29 centers (28 in Europe and 1 in Canada). Seventy-nine patients were randomized to HSCT and 77 were randomized to cyclophosphamide (Figure 1). The number of individuals screened and excluded was not available for all centers. Baseline characteristics of the patients were similar between the 2 groups (Table 1).
Seventy-five patients in each group started treatment. Six patients did not receive the allocated treatment, whereas 71 (89.8%) and 57 (74.0%) completed treatment in the HSCT and cyclophosphamide groups, respectively (Figure 1). All 156 patients were included in the ITT population. The median follow-up of event-free survival of the ITT populations was 5.8 years (interquartile range, 4.1-7.8). Treatment-specific details are provided in eTable 1A and eTable 1B in the Supplement.
A total of 53 events occurred during the study: 22 in the HSCT group (19 deaths and 3 irreversible organ failures; 8 patients died of treatment-related causes in the first year, 9 of disease progression, 1 of cerebrovascular disease, 1 of malignancy) and 31 in the control group (23 deaths and 8 irreversible organ failures [7 of these patients died later]; 19 patients died of disease progression, 4 of cardiovascular disease, 5 of malignancy, 2 of other causes) (eTable 2A and eTable 2B in the Supplement).
The hazard ratios for event-free survival and overall survival were time-varying (P = .04 and P = .03, respectively) (Figure 2). Patients treated with HSCT experienced more events in the first year but had better long-term event-free survival than those treated with cyclophosphamide. During the first year, there were 13 events (16.5%) in the HSCT group vs 8 (10.4%) in the control group (relative risk [RR], 1.59 [ 95% CI, 0.7-4.4]). After 2 years of follow-up there were 14 events (17.7%) in the HSCT group vs 14 (18.2%) in the control group (RR, 0.97 [95% CI, 0.5-2.0]). After 4 years of follow-up there were 15 events (19.0%) in HSCT group vs 20 (26.0%) in the control group (RR, 0.73 [95% CI, 0.4-1.3]). Corresponding time-varying hazard ratios for the primary outcome of death or major organ failure were 0.52 (95% CI, 0.28-0.96; P = .04) at 1-year follow-up; 0.35 (95% CI, 0.16-0.74; P = .006) at 2-year follow-up; and 0.34 (95% CI, 0.16-0.74; P = .006) at 4-year follow-up. Patients in the HCST group experienced higher mortality in the first year but had better long-term overall survival than those treated with cyclophosphamide. During year 1 there were 11 deaths (13.9%, including 8 treatment-related deaths) in the HSCT group vs 7 (9.1%, none treatment-related) in the control group (RR, 1.53 [95% CI, 0.4-5.4]). After year 2 of follow-up there were 12 deaths (15.2%) in the HSCT group vs 13 (16.9%) in the control group (RR, 0.90 [95% CI, 0.4-1.8]). After 4 years of follow-up there were 13 deaths (16.5%) in the HSCT group vs 20 (26.0%) in the control group (RR, 0.64 [95% CI, 0.3-1.1]). Corresponding time-varying HRs for mortality were 0.48 (95% CI, 0.25-0.91; P = .02) at 1-year follow-up, 0.29 (95% CI, 0.13-0.65; P = .002) at 2-year follow-up, and 0.29 (95% CI, 0.13 to 0.64; P = .002) at 4-year follow-up. The lower hazard ratios vs higher relative risks for event-free survival and overall survival at 1 year for the HSCT vs control group reflect a change in event rate in the HSCT group, because the majority of events are being observed in the first 6 months but the event rate in the HSCT group is already favorable at 1 year as compared with the relatively constant event rate in the control group.
No center effect was found, with 5 of 8 treatment-related deaths observed in 3 of the 4 most active autoimmune disease transplant centers in Europe.
The analysis of the AUC showed significant differences in the secondary outcome measures. Mean change from baseline until 2 years’ follow-up in mRSS was significantly better in the HSCT group (−19.9) than in the control group (−8.8) (difference, 11.1 [95% CI, 7.3 to 15.0]; P < .001), as were mean changes in forced vital capacity (6.3% predicted vs −2.8% predicted; difference, −9.1 [95% CI, −14.7 to −2.5]; P = .004), total lung capacity (5.1% predicted vs −1.3% predicted; difference, −6.4 [95% CI, −11.9 to −0.9]; P = .02), HAQ-DI (−0.58 vs −0.19; difference, 0.39 [95% CI, 0. 0.51 to 0.73]; P = .02), the physical component score of the SF-36 (10.1 vs 4.0; difference, −6.1 [95% CI, −10.9 to −1.4]; P = .03), and the EQ-5D index–based utility score (0.31 vs 0.03; difference, −0.29 [95% CI, −0.45 to −0.12]; P < .001) whereas mean change in creatinine clearance (mL/min) was significantly worse in the HSCT group (−12.1) than in the control group (−1.2) (difference, 10.9 [95% CI, 1.5-20.3]; P = .02) (Table 2). No statistically significant differences in left ventricular ejection fraction, residual volume, and the diffusion capacity of the lung for carbon monoxide were observed between the 2 groups.
These results were also confirmed by the sensitivity analysis, which showed similar point estimates of the effect size (differences in mean AUC) for all of the secondary end points; however, losing statistical significance for some end points because of the smaller number of patients in the analysis or using the poorest possible values (based on observed data in the whole trial population) when data were missing because of death (forced vital capacity, total lung capacity, HAQ-DI, and the physical component score of the SF-36) (eTable 3 in the Supplement). In the post hoc subgroup analysis, there were no statistically significant differences in the odds ratios of the treatment effect on the primary end point across categories of age, sex, disease duration, pretrial cyclophosphamide use, and baseline weight at 2 years’ follow-up (P ≥ .26). However, there was significant heterogeneity in the treatment effect across categories of smoking status (P = .02) (eFigure 1 in the Supplement). Eight patients in the control group received rescue HSCT after 2 years, 1 of whom died from treatment-related acute myeloid leukemia despite allogeneic HSCT. Two patients in the HSCT group received rescue intravenous cyclophosphamide therapy after 2 years. A smaller number of patients in the HSCT group as compared with the control group received immunosuppressive medication between 12 and 24 months (15 [22.4%] vs 28 [43.8%], P = .02) (eTable 4 in the Supplement).
Eight deaths (10.1% of ITT population), including 1 during mobilization and 1 during conditioning in the HSCT group, were deemed treatment-related by the independent data monitoring committee vs none in the control group (P = .007). Causes of treatment-related deaths included EBV, lymphoma, heart failure, myocardial infarction, and acute respiratory distress syndrome (eTable 5 in the Supplement). Seven of 8 patients who died from treatment-related causes were current or former smokers. Five (2 in the HSCT group and 3 in the control group) of 10 patients with PAH died before the cutoff date. Grade 3 or 4 adverse events occurred in 51 patients (62.9%) in the HSCT group and 30 (37.0%) in the control group (P = .002) (Table 3). Viral infections were detected in 22 patients (27.8%) in the HSCT group vs 1 (1.3%) in the control group (P < .001). Except for 1 patient in the control group with a primary herpes simplex virus infection, all infections with cytomegalovirus (9), EBV (6), herpes simplex virus (11), varicella zoster virus (3), and hepatitis B virus (1) occurred in the HSCT group (eTable 6 in the Supplement). Three patients in the HSCT group had cytomegalovirus/herpes simplex virus co-infection. Two of the patients with EBV developed EBV-positive lymphoproliferative disorder: 1 was successfully treated with rituximab, the other presented with fulminant disease with fatal outcome. Five patients with CMV infection received oral or intravenous antiviral treatment.
Quiz Ref IDThis phase 3 study demonstrated that autologous HSCT using high-dose cyclophosphamide, rbATG, and reinfusion of CD34-selected cells was associated with early treatment-related deaths but better long-term event-free survival (the primary outcome measure) and better overall survival at a median of 5.8 (interquartile range, 4.1-7.8) years’ follow-up compared with intravenous pulse cyclophosphamide for patients with diffuse cutaneous systemic sclerosis.Quiz Ref IDThe long-term survival benefit of HSCT was particularly striking in those who had never smoked. Smoking has been shown to be associated with more severe systemic sclerosis and has been shown to influence the outcome after allogeneic HSCT in malignant diseases, in part through effects on pretransplant lung function.18- 20
HSCT was also more effective than intravenous pulse cyclophosphamide for the outcomes of skin score, functional ability, quality of life, and lung function, consistent with previous studies.4- 11 HSCT was associated with more grade 3 and 4 adverse events including respiratory distress, possibly due to rbATG and 10.1% treatment-related mortality, viral infections, and a modest decrease in creatinine clearance. The latter may be attributable to the nephrotoxic effects of medication used during conditioning (glucocorticoids, cyclophosphamide, rbATG). Of note, treatment-related mortality decreased from 17% in the first phase 1-2 multicenter study to 6% to 8.7% in 2 registry analyses of HSCT in autoimmune diseases that also reported evidence of a center effect.4,9,21,22 We did not find a center effect, but 7 of 8 treatment-related deaths occurred in current or former smokers. A recent retrospective study suggested that catheterization of the right side of the heart with fluid challenge and cardiac magnetic resonance imaging may identify patients at risk of treatment-related mortality.9 Another recent study demonstrated the clinical utility of left heart catheterization in addition to catheterization of the right side of the heart with fluid challenge by showing a high prevalence of left ventricular dysfunction in patients suspected of having PAH.23 Three of 8 treatment-related deaths in our study were attributed to a primary cardiac cause. To balance the potential risks of HSCT, our trial deliberately targeted patients with severe systemic sclerosis, including 10 patients with PAH, 5 of whom died. Quiz Ref IDA key problem in the management of systemic sclerosis is to identify patients at risk of disease progression and strike the right balance between the long-term benefits and upfront risks, including treatment-related mortality of an intensive treatment modality such as HSCT as opposed to standard immunosuppression currently recommended.24 Disease characteristics recently associated with premature mortality may be used to identify patients suitable for HSCT.25,26
Our study has limitations. First, wide confidence intervals for some secondary outcome measures are indicative of less certainty about results for these outcomes. Second, the unblinded assessments may have influenced our results. Third, the drop-out rate in the cyclophosphamide group was greater than 20% because of death, major organ failure, adverse events, or nonadherence.
Among patients with early diffuse cutaneous systemic sclerosis, HSCT was more effective than monthly intravenous pulse cyclophosphamide and, despite an early treatment-related mortality rate of 10.1% and an increase in serious adverse events, conferred a long-term survival benefit.
Corresponding Authors: Jacob M. van Laar, MD, PhD, Department of Rheumatology and Clinical Immunology, Room F.02.126, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands (email@example.com); Dominique Farge, MD, PhD, Assistance Publique-Hôpitaux de Paris; Saint-Louis Hospital; Internal Medicine and Vascular Disease Unit; INSERM UMRS 1160; Paris 7 Diderot University, Sorbonne Paris Cité 1 avenue Claude-Vellefaux, 75010 Paris, France (firstname.lastname@example.org).
Author Contributions: Drs van Laar and Farge had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs van Laar and Farge contributed equally to this article as first authors and Drs Naraghi and Marjanovic contributed equally as third authors.
Study concept and design: van Laar, Farge, Sont, Tyndall.
Acquisition, analysis, or interpretation of data: All authors
Drafting of the manuscript: van Laar, Farge, Tyndall.
Critical revision of the manuscript for important intellectual content: van Laar, Farge, Sont, Naraghi, Marjanovic, Larghero, Schuerwegh, Marijt, Vonk, Schattenberg, Matucci-Cerinic, Voskuyl, van de Loosdrecht, Daikeler, Kötter, Schmalzing, Martin, Lioure, Weiner, Kreuter, Deligny, Durand, Emery, Machold, Sarrot-Reynauld, Warnatz, Adoue, Constans, Tony, Del Papa, Fassas, Himsel, Launay, Lo Monaco, Philippe, Quéré, Rich, Westhovens, Griffiths, Saccardi, van den Hoogen, Fibbe, Socié, Gratwohl, Tyndall.
Statistical analysis: Sont, Naraghi.
Obtained funding: van Laar, Farge, Tyndall.
Study supervision: van Laar, Farge, Tyndall.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr van Laar reported receiving a research grant from Roche and honoraria from Genentech, Roche, Menarini, Bristol-Myers Squibb, Abbott, Novartis, Miltenyi, Tigenix, and Pfizer. Dr Vonk reported receiving research grants from Actelion and Therabel and serving as a consultant for Actelion, United therapeutics, and Pfizer. Dr Koetter reported receiving a grant from Novartis and personal fees from Abbvie, Roche, Pfizer, and UCB. Dr Emery reported receiving consulting and speakers fees from Abbvie, Bristol-Myers Squibb, Pfizer, UCB, Merck Sharp & Dohme, and Roche. Dr Warnatz reported receiving grants from Deutsche Forschungsgemeinschaft and Bundesministerium für Bildung und Forschung and speakers fees from Baxter, GlaxoSmithKline, CSL Behring, Pfizer, and the American Academy of Allergy, Asthma, and Immunology. Dr Adoue reported receiving honoraria from Amgen, GlaxoSmithKline, and Actelion. Dr Tony reported receiving speakers fees from and serving as a consultant for Abbvie, Bristol-Myers Squibb, Chugai, Merck Sharp & Dohme, Roche, and UCB. Dr Launay reported receiving honoraria from Actelion, GlaxoSmithKline, and Pfizer. Dr Westhovens reported receiving research grants from UCB and Roche; speakers fees from Bristol-Myers Squibb; and honoraria from Janssen and Galapagos. Dr Tyndall reported receiving grants from Imtex-Sangstat and Amgen. No other authors reported disclosures.
Funding/Support: The European Group for Blood and Marrow Transplantation (EBMT) and European League Against Rheumatism (EULAR) jointly supported the costs of the trial management and operations and approved submission of the manuscript. The Assistance Publique-Hôpitaux de Paris (AP-HP), French Ministry of Health Programme Hospitalier de Recherche Clinique (Ministère de la Santé–PHRC AOM 97030), Groupe Francophone de Recherche sur la Sclérodermie supported trial operations in French centres and approved submission of the manuscript. The Association des Sclérodermiques de France contributed to support of the trial in France. The National Institute for Health Research (NIHR) and NIHR Newcastle Biomedical Research Centre financially supported the Study Administration Office. Unrestricted grants were secured from Imtix-Sangstat and Amgen Europ; Miltenyi-Biotec supported the trial through provision of CD34-selection columns at a discount.
Role of the Sponsors: None of the commercial funders had any role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation of the manuscript; and decision to submit the manuscript for publication.
EBMT/EULAR Scleroderma Study Group Centers and Investigators: Medical University of Vienna, Vienna, Austria (Klaus P. Machold, MD, principal investigator; Hildegard Greinix, MD); Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU, Leuven; Rheumatology, University Hospitals, Leuven, Belgium (René Westhovens, MD, PhD, principal investigator); Service de Rhumatologie, Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada (Eric Rich, MD, principal investigator); CHU Bordeaux, Bordeaux, France (Joël Constans, MD, principal investigator; Noël Milpied, MD); CHU Clermont Ferrand, Clermont Ferrand, France (Pierre Philippe, MD, principal investigator; Olivier Tournilhac, MD); Hôpital Pierre Zobda Quitman, Fort-de-France, Martinique (Christophe Deligny, MD, principal investigator; Serge Arfi, MD); CHU Grenoble, Grenoble, France (Francoise Sarrot-Reynauld, MD, PhD, principal investigator, Christophe Senturier, MD, Frederic Garban, MD); CHRU Lille, Lille, France (David Launay, MD, PhD, principal investigator; Louis Terriou, MD); CHU La Conception, Marseille, France (Jean Marc Durand, MD, PhD, principal investigator; Didier Blaise, MD); CHU Montpellier, Montpellier, France (Isabelle Quéré, MD, PhD, principal investigator); AP-HP Hôpital Saint-Louis, Paris, France (Dominique Farge, MD, PhD, principal investigator; Zora Marjanovic, MD, Jérôme Larghero, PharMD, PhD, Eliane Gluckmann, MD, PhD, Gérard Socié, MD, PhD); CHRU Strasbourg, Strasbourg, France (Thierry Martin, MD, PhD, principal investigator; Bruno Lioure, MD, Jean Sibilia, MD); CHU Toulouse, Toulouse, France (Daniel F. P. Adoue, MD, principal investigator; Odile B. Beyne-Rrauzy, MD, PhD); University Clinic Frankfurt, Frankfurt, Germany (Andrea Himsel, MD, principal investigator; Axel Braner); University Hospital Freiburg, Freiburg, Germany (Klaus Warnatz, MD, principal investigator; Jürgen Finke, MD, Hans Hartmut Peter, MD); Ruhr-University Bochum, Bochum, Germany (Stefan M. Weiner, MD, principal investigator; Alexander Kreuter, MD, Roland Schroers, MD, Christian Teschendorf, MD); University Clinic Tübingen, Tübingen, Germany (Ina Kötter, MD, PhD, principal investigator; Marc Schmalzing, MD, Jörg Henes, MD); Department of Rheumatology and Clinical Immunology, University of Würzburg Medical Center, Würzburg, Germany (Hans-Peter Tony, MD, principal investigator; Stefan Kleinert, MD); George Papanicolaou Hospital, Thessaloniki, Greece (Athanasios Fassas, MD, principal investigator); University of Ferrara and Azienda, Ferrara, Italy (Andrea Lo Monaco, MD, PhD, principal investigator); University of Florence, Florence, Italy (Marco Matucci-Cerinic, MD, PhD, principal investigator; Irene Miniati, MD, Silvia Bellando-Randone, MD, Serena Guiducci, MD, Riccardo Saccardi, MD); University of Milan, Milan, Italy (Nicoletta Del Papa, MD, PhD, principal investigator); VU University Medical Center, Amsterdam, the Netherlands (Alexandre E. Voskuyl, MD, PhD, principal investigator; Arjan A. van de Loosdrecht, MD, PhD, Peter C. Huijgens, MD, PhD); Leiden University Medical Center, Leiden, the Netherlands (Annemie J. Schuerwegh, MD, PhD, principal investigator; Erik W. Marijt, MD, PhD, Willem E. Fibbe, MD, PhD, Jacob K. Sont, PhD); Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (Madelon C. Vonk, MD, PhD, principal investigator; Hanneke Knaapen, MD, Anton V. M. B. Schattenberg, MD, PhD, Frank H. van den Hoogen, MD, PhD); University Hospital Basel, Basel, Switzerland (Alan Tyndall, MD, principal investigator; Thomas Daikeler, MD, Paul Hasler, MD, Peter Villiger, MD, Michael Seitz, MD, Alois Gratwohl, MD); University of Leeds, Leeds, United Kingdom (Paul Emery, MD, principal investigator; Maya H. Buch, MD, Shouvik Dass, MD, Rachel Kilding, MD); The James Cook University Hospital, Middlesbrough, United Kingdom (Jacob M. van Laar, MD, PhD, principal investigator; Kamran Naraghi, MD); Freeman Hospital, Newcastle upon Tyne, United Kingdom (Bridget Griffiths, MD, principal investigator; Matthew Collin, MD, PhD, John McLaren, MD).
Previous Presentations: Presented in part at the 13th Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Germany; the 2012 Annual Meeting of the American College of Rheumatology; November 10-14, 2012; Washington DC; and the 54th Annual Meeting of the American Society of Hematology, December 8-11, 2012; Atlanta, Georgia.
Additional Contributions: We thank Professor Ronald Brand, PhD (EBMT Office, Leiden, the Netherlands), for lending his expertise with the statistical analyses and owe gratitude to the participating patients and their families, as well as the research nurses, trial coordinators, and operations staff for their contributions; the investigators whose patients were enrolled in the ASTIS trial; and the members of the Independent Data Monitoring Committee (Jane Apperley, MD [Imperial College London, United Kingdom], Daniel Furst, MD [UCLA, Los Angeles, California], Frank Wollheim, MD [Lund University, Sweden]). We also acknowledge the following for administrative, technical, or material support: University Hospital Basel, Basel, Switzerland (Iris Gerber, MD; Chiara Tyndall, PhD); Leiden University Medical Center, Leiden, the Netherlands (Ingeborg de Jonge, Annemiek J.M.S. Versluys-van Duinhoven); Hôpital St Louis, Paris, France (Sylvie Parlier, Homah Keshmandt, Mébarka Bettar); The James Cook University Hospital, Middlesbrough, United Kingdom (Susan Hales); EBMT Clinical Trial Office, London, United Kingdom (Liz Clark, MSc, Ruzena Uddin, MSci, Janette Zarev, MSc, Kim Champion, PhD, Zoë Doran). None of the persons listed in the above sections not listed as authors received compensation.