-
1.
Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party
Henes, J., Oliveira, M. C., Labopin, M., Badoglio, M., Scherer, H. U., Del Papa, N., Daikeler, T., Schmalzing, M., Schroers, R., Martin, T., et al
Haematologica. 2020
-
-
-
Free full text
-
Editor's Choice
Abstract
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
PICO Summary
Population
Adult patients with severe systemic sclerosis (n=80)
Intervention
Autologous haematopoietic stem cell transplantation with cyclophosphamide plus antithymocyte globulins conditioning
Comparison
None
Outcome
At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time. By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival. CD34+-selection was associated with better response.
-
2.
Autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease adult patients in France: analysis of the long-term outcome from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Guillaume-Jugnot, P., Badoglio, M., Labopin, M., Terriou, L., Yakoub-Agha, I., Martin, T., Lioure, B., Marjanovic, Z., Blaise, D., Nguyen, S., et al
Clinical rheumatology. 2019
-
-
-
Full text
-
Editor's Choice
Abstract
INTRODUCTION The use of autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease (AD) patients has increased progressively worldwide. We retrospectively analysed the long-term outcome of AHSCT for AD reported to the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). METHOD All French AD patients (≥ 18 years at transplant) with a first AHSCT between 1997 and 2013 were included. Primary data were derived from the European Society for Blood and Marrow Transplantation (EBMT) registry, and additional data were obtained through a specific questionnaire designed for the study. Primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS) and non-relapse mortality (NRM). RESULTS Ninety-four AD patients were included, of whom 71% suffered from rheumatologic diseases (n = 67, including 56 systemic sclerosis (SSc)), 16% from neurological disease (n = 15, including 14 multiple sclerosis (MS)) and 13% from various other AD (n = 12). After a median (interquartile range, IQR) follow-up of 83 months (38-130), OS at 5 and 10 years were 77% (95% CI 68.5-86.2) and 64% (95% CI 51.7-76.3), and for PFS 51% (95% CI 40.4-61.6) and 44% (95% CI 32.8-55.3), respectively. Overall, NRM was 8.7% (95% CI 4.0-15.5) at day 100, 9.8% (95% CI 4.8-16.9) at 5 years and 13.6% (95% CI 6.9-22.5) at 10 years. CONCLUSIONS This first SFGM-TC retrospective report shows long-term benefit of AHSCT in AD patients with acceptable toxicity.
PICO Summary
Population
Ninety-four adults suffering from autoimmune disease in France. Rheumatologic diseases (n=67), neurological disease (n = 15) or other AD (n = 12)
Intervention
Autologous haematopoietic stem cell transplantation
Comparison
None
Outcome
Overall Survival was 77% at 5 and 64% at 10 year. Non-Relapse Mortality was 8.7% at day 100, 9.8% at 5 years and 13.6% at 10 years.
-
3.
Allogeneic HSCT for Autoimmune Diseases: A Retrospective Study From the EBMT ADWP, IEWP, and PDWP Working Parties
Greco, R., Labopin, M., Badoglio, M., Veys, P., Furtado Silva, J. M., Abinun, M., Gualandi, F., Bornhauser, M., Ciceri, F., Saccardi, R., et al
Frontiers in immunology. 2019;10:1570
Abstract
Background: This retrospective study assessed the use and long-term outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe autoimmune diseases (ADs), reported to the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: Between 1997 and 2014, 128 patients received allogeneic HSCT for various hematological (n = 49) and non-hematological (n = 79) refractory ADs. The median age was 12.7 years (0.2-62.2). Donors were syngeneic for seven, matched related for 46, unrelated for 51, haploidentical for 15, and cord blood for nine patients. Results: The incidence of grades II-IV acute graft-vs.-host disease (GvHD) was 20.8% at 100 days. Cumulative incidence of chronic GvHD was 27.8% at 5-years. Non-relapse mortality (NRM) was 12.7% at 100-days. Overall survival (OS) and Progression-Free Survival (PFS) were 70.2 and 59.4% at 5-years, respectively. By multivariate analysis, age <18 years, males, and more recent year of transplant were found to be significantly associated with improved PFS. Reduced conditioning intensity was associated with a lower NRM. On a subgroup of 64 patients with detailed information a complete clinical response was obtained in 67% of patients at 1-year. Conclusions: This large EBMT survey suggests the potential of allogeneic HSCT to induce long-term disease control in a large proportion of refractory ADs, with acceptable toxicities and NRM, especially in younger patients.
-
4.
Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
Sharrack, B., Saccardi, R., Alexander, T., Badoglio, M., Burman, J., Farge, D., Greco, R., Jessop, H., Kazmi, M., Kirgizov, K., et al
Bone marrow transplantation. 2019
Abstract
These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
-
5.
Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes from the European Society for Blood and Marrow Transplantation
Brierley, C. K., Castilla-Llorente, C., Labopin, M., Badoglio, M., Rovira, M., Ricart, E., Dierickx, D., Vermeire, S., Hasselblatt, P., Finke, J., et al
Journal of Crohn's & colitis. 2018
Abstract
Background/Aims: Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe, treatment-refractory Crohn's disease (CD). The evidence base for AHSCT for CD is limited, with one randomised trial (ASTIC) suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe outside the ASTIC trial. Methods: We identified 99 patients in the European Society for Blood and Marrow Transplantation (EBMT) registry who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in 7 countries. Results: Median patient age was 30 years (range 20-65). Patients had failed or been intolerant to a median of 6 lines of drug therapy. 61/82 (74%) had had surgery. Following AHSCT, 53/78 (68%) experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months (range 6-174). 22/82 (27%) required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at last follow-up, 57% (24/42) achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at one year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% CI 1.14-4.83, p=0.02). One patient died due to infectious complications (CMV disease) at day +56. Conclusions: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.
-
6.
Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial
Lindsay, J. O., Allez, M., Clark, M., Labopin, M., Ricart, E., Rogler, G., Rovira, M., Satsangi, J., Farge, D., Hawkey, C. J., et al
The Lancet. Gastroenterology & Hepatology. 2017;2(6):399-406
Abstract
BACKGROUND The randomised controlled ASTIC trial showed no benefit of mobilisation and autologous haematopoietic stem-cell transplantation (HSCT) compared with mobilisation followed by conventional therapy using a stringent primary endpoint (steroid-free clinical remission for 3 months with no endoscopic or radiological evidence of intestinal inflammation) in patients with treatment-refractory Crohn's disease. We now assess HSCT in patients enrolled in the ASTIC trial using endpoints that are traditional for clinical trials in Crohn's disease, and identify factors that predict benefit or harm. METHODS Patients who underwent mobilisation and were randomly assigned to conventional therapy in the ASTIC trial were offered HSCT at 1 year and underwent complete assessment for a further year. We report analyses of the combined cohort of patients who underwent HSCT at any time during the ASTIC trial programme. The primary outcome for this analysis was 3-month steroid-free clinical remission at 1 year after HSCT (Crohn's Disease Activity Index [CDAI] <150). We also examined the degree of endoscopic healing at 1 year. Multivariate analysis was performed to identify factors associated with achieving the primary endpoint by using logistic regression, and factors associated with experiencing a serious adverse event using Poisson regression. Participants were not masked to treatment, but the adjudication panel that reviewed radiology and endoscopy was masked to allocation and visits. All patients who underwent HSCT and had data available at baseline and 1-year follow-up were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00297193. FINDINGS Between June 28, 2007, and Sept 1, 2011, 45 patients were enrolled in the ASTIC trial from 11 European transplant units. 23 patients were randomly assigned to immediate HSCT, and 22 patients were assigned to mobilisation followed by conventional care. After completion of the ASTIC trial, 17 patients from the conventional care group received HSCT. In the combined cohort, data were available for 40 patients at baseline and 38 patients at 1 year after HSCT (one patient died, one withdrew). At 1 year after HSCT, 3-month steroid-free clinical remission was seen in 13 (38%, 95% CI 22-55) of 34 patients with available data for the whole year. Complete endoscopic healting was noted in 19 (50%, 34-66) of 38 patients. On multivariate analyses, factors associated with the primary outcome were short disease duration (odds ratio [OR] 0.64, 95% CI 0.41-0.997 per year; p=0.048) and low baseline CDAI (0.82, 0.74-0.98 per 10 units; p=0.031). 76 serious adverse events occurred in 23 of 40 patients with available data. The most common serious adverse event was infection, most of which were treatment related. Smoking and perianal disease at baseline were independent factors associated with the number of serious adverse events (OR 3.07 [95% CI 1.75-5.38; p=0.0001] for smoking and 3.97 [2.17-7.25; p<0.0001] for perianal disease) on multivariate analysis. INTERPRETATION When assessed using endpoints traditional for clinical trials of conventional therapy in Crohn's disease, HSCT resulted in clinical and endoscopic benefit, although it was associated with a high burden of adverse events. The prognostic factors identified could allow the therapy to be targeted to patients most likely to benefit and not experience serious adverse events. FUNDING Broad Medical Research Program, National Institute for Health Research Senior Investigator Award, The University of Nottingham Medical School Dean's Fund, and The Nottingham University Hospitals NHS Trust Research and Development Fund.Copyright © 2017 Elsevier Ltd. All rights reserved.
-
7.
Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases
Snowden, J. A., Badoglio, M., Labopin, M., Giebel, S., McGrath, E., Marjanovic, Z., Burman, J., Moore, J., Rovira, M., Wulffraat, N. M., et al
Blood Advances. 2017;1(27):2742-2755
Abstract
Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10-5), relapse/progression (P < 10-5), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (>=23 transplants for AD, P = .001), learning (time from first HSCT for AD >=6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD. Conflict-of-interest disclosure: J.A.S. has received honoraria from Sanofi and Jazz for speaking at educational events. J.B. has received travel support and/or lecture honoraria from Almirall, Biogen, Genzyme a Sanofi Company, Hospira, and Merck Serono, and unconditional research grants from Biogen and Merck Serono. The remaining authors declare no competing financial interests.
-
8.
Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients?
Oliveira, M. C., Labopin, M., Henes, J., Moore, J., Papa, N. D., Cras, A., Sakellari, I., Schroers, R., Scherer, H. U., Cuneo, A., et al
Bone Marrow Transplantation. 2016;51(4):501-5
Abstract
This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials.