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Figure 1.
Multiple Sclerosis (MS) Progression-Free Survival
Multiple Sclerosis (MS) Progression-Free Survival

The probabilities of Expanded Disability Status Scale progression-free survival after autologous hematopoietic stem cell transplantation (AHSCT) are shown by Kaplan-Meier analysis in the total cohort and in subgroups stratified according to the factors identified on multivariate analysis as affecting progression-free survival. A, The entire patient cohort. B, Quartiles according to age (P = .02 for trend). C, Patients with relapsing-remitting, secondary progressive, and primary progressive forms of MS (P = .007 for heterogeneity). D, Patients who received 1 to 2 or 3 or more previous disease-modifying treatments (P = .008 for heterogeneity). The gray shading represents 95% CIs for each Kaplan-Meier survival curve.

Figure 2.
Evolution of Expanded Disability Status Scale (EDSS) Scores Before and After Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Relapsing vs Progressive Multiple Sclerosis (MS)
Evolution of Expanded Disability Status Scale (EDSS) Scores Before and After Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Relapsing vs Progressive Multiple Sclerosis (MS)

The individual (colored) and integrated (solid black) curves show the evolution of EDSS scores in the subset of 111 patients who had longitudinal EDSS data both before and after transplantation and the date of EDSS assessment documented. The forms of MS at the time of transplantation were relapsing in 32 patients (A) and progressive in 79 patients (B). Rapid worsening of disability was observed before transplantation in both subgroups, as expected for patients with aggressive forms of MS who were selected for AHSCT. The integrated curve suggests that, on average, accumulation of disability was stopped in patients with relapsing MS during the first 2 years after transplantation.

Figure 3.
Overall Survival
Overall Survival

A, The probability of survival after autologous hematopoietic stem cell transplantation (AHSCT) is shown as Kaplan-Meier survival curves in the entire patient cohort. B, Because higher baseline Expanded Disability Status Scale (EDSS) score was found on multivariate analysis to be independently associated with worse survival (summarized in Table 2), we show the probabilities of survival after AHSCT in 3 strata of patients with different levels of disability at baseline assessment, which differed significantly for the highest EDSS score bracket (P = .004 for heterogeneity). The gray shading represents 95% CIs for each Kaplan-Meier survival curve.

Table 1.  
Demographic and Clinical Characteristics of Patients
Demographic and Clinical Characteristics of Patients
Table 2.  
Univariate and Multivariate Analyses of Factors Influencing Multiple Sclerosis (MS) Progression-Free and Overall Survival
Univariate and Multivariate Analyses of Factors Influencing Multiple Sclerosis (MS) Progression-Free and Overall Survival
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Krasulová  E, Trněný  M, Kozák  T,  et al.  High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience.  Mult Scler. 2010;16(6):685-693.PubMedGoogle ScholarCrossref
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Original Investigation
April 2017

Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis

Author Affiliations
  • 1Division of Brain Sciences, Imperial College London, London, England
  • 2Center for International Blood and Marrow Transplant Research, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee
  • 3Clinical Hematology, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 4Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington
  • 5Internal Medicine, Autoimmune and Vascular Diseases Unit, Unité Fonctionnelle 04, Assistance Publique–Hôpitaux de Paris Saint-Louis Hospital, Institut National de la Santé et de la Récherche Médicale Unité Mixte de Recherche 1160, Paris, France
  • 6Department of Hematology, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • 7Division of Neurology, Department of Medicine, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 8Fred Hutchinson Cancer Research Center and University of Washington, Seattle
  • 9Bone Marrow Transplantation Unit, San Martino Hospital, Genova, Italy
  • 10Bone Marrow Transplant Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil
  • 11Department of Neurology, First Medical Faculty, Charles University, Prague, Czech Republic
  • 12Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • 13Department of Internal Medicine and Haematology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic
  • 14Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genova, Italy
  • 15Department of Neurosciences, Careggi University Hospital, University of Florence, Firenze, Italy
  • 16Department of Clinical Medicine, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil
  • 17Colorado Blood Cancer Institute, Denver
  • 18Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 19Department of Hematology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
  • 20Hematology Service, Hospital Clinic and Neurology Service, Universitat de Barcelona, Barcelona, Spain
  • 21Hospital Clinic and Institut d’Investigació August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain
  • 22Department of Medicine, Charles University General Hospital, Prague, Czech Republic
  • 23Drum Tower Hospital of Nanjing Medical University, Nanjing, China
  • 24European Blood and Marrow Transplant Paris Office, Hôpital Saint Antoine, Paris, France
  • 25Biostatistics Unit, University of Genoa, Genova, Italy
  • 26Haematology Department, Careggi University Hospital, Firenze, Italy
JAMA Neurol. 2017;74(4):459-469. doi:10.1001/jamaneurol.2016.5867
Key Points

Question  What are the long-term outcomes after autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis?

Findings  In this multicenter cohort study of 281 patients with predominantly progressive forms of multiple sclerosis who underwent autologous hematopoietic stem cell transplant between 1995 and 2006, transplant-related mortality was 2.8% within 100 days of transplant, and neurological progression-free survival was 46% at 5 years. Younger age, relapsing form of multiple sclerosis, fewer prior immunotherapies, and lower neurological disability score were significantly associated with better outcomes.

Meaning  The results support the rationale for further randomized clinical trials of autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis.

Abstract

Importance  Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

Objective  To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

Design, Setting, and Participants  Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

Exposures  Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

Main Outcomes and Measures  The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

Results  Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

Conclusions and Relevance  In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

Introduction

More than 2.3 million people in the world are affected by multiple sclerosis (MS).1 The disease typically manifests in young adulthood and can cause severe neurological disability, a major socioeconomic burden.2 Patients with an aggressive course of MS often fail to respond to several lines of disease-modifying treatment, and their condition deteriorates within a few years.

Autologous hematopoietic stem cell transplantation (AHSCT) is being investigated as a treatment for aggressive MS.3 The rationale of this approach is the use of high-dose immunosuppressive therapy to suppress the autoimmune inflammatory process. Infusion of autologous hematopoietic stem cells boosts bone marrow recovery and promotes immune reconstitution. The procedure has been shown to induce a degree of immune “resetting.”4,5 The treatment goals are to arrest the worsening of neurological disability, induce a prolonged medication-free interval, and potentially effect an improvement in neurological function. Early clinical trials established the proof of principle that AHSCT could invoke disease remission in patients with severe MS.6 Studies have shown that AHSCT is effective in suppressing disease reactivation as assessed clinically and on magnetic resonance imaging (MRI),7-9 can result in neurological improvement in patients with relapsing-remitting MS,7,8,10-12 and can halt all detectable central nervous system inflammatory activity for a prolonged period.13 However, outcome assessments in most studies were limited to a short follow-up, and longer-term outcomes have been reported only from small case series.14-16 Therefore, it is important to examine the course of MS after AHSCT in a large patient population and their rates of risks and complications over the longer term.

The primary objective of this study was to evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort by analyzing progression-free survival, evolution of neurological disability, overall survival, transplant-related mortality, and late effects, including new autoimmune and malignant disorders. A secondary aim was to examine the association of demographic and MS disease-related and treatment-related variables with long-term outcomes.

Methods
Study Design, Setting, and Data Sources

This study was a multicenter, observational, retrospective cohort study on AHSCT for the treatment of MS and was performed through collaboration between the Center for International Blood and Marrow Transplant Research (CIBMTR) Autoimmune Disease Working Committee and the European Blood and Marrow Transplant (EBMT) Group Autoimmune Disease Working Party. The CIBMTR is a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on consecutive marrow transplants to a statistical center located at the Medical College of Wisconsin, Milwaukee, and to the National Marrow Donor Program Coordinating Center, Minneapolis, Minnesota.17 The EBMT is a nonprofit organization comprising 640 transplant centers, mainly in Europe. All transplant centers are required to obtain written informed consent from all patients to report their data to the CIBMTR and the EBMT, in accord with the 1975 Declaration of Helsinki. Institutional review board approval for data collection and the use of data for research purposes was obtained locally by each center. Only fully anonymized data were transferred to the study database. After review by the study steering committee (P.A.M., M.P., H.L.A., J.D.B., D.F., A.F., M.S.F., E.H., T.K., G.L.M., R.A.N., S.P., A.S., M.P.S., and R.S.), the trial protocol (eAppendix in the Supplement) was approved by the CIBMTR Joint Affiliation Board and the EBMT Board of Association, in agreement with the rules for retrospective studies of both organizations. Multiple sclerosis data before transplant and during follow-up were prospectively obtained from participating transplant centers on disease-specific forms, which were harmonized between the 2 registries.18 For the purposes of this study, all bone marrow transplant centers that reported at least 1 AHSCT for MS to the CIBMTR or EBMT between January 1995 and December 2006 were sent an invitation to participate in the study together with a protocol summary. The centers that agreed to participate were asked to identify a transplant physician and a neurologist to oversee all patient data for the accuracy and completeness at each site. To better describe the disease activity before and after transplant and to extend the follow-up for our study, additional data collection was performed retrospectively. To this end, study team members (M.P. and M.B.) developed a supplemental data collection form that was preprinted with the previously reported data to facilitate additional data collection and concurrent verification of the accuracy of existing information. The overall completeness of enrollment in our study, calculated as the percentage of all procedures reported to the 2 registries during the study period, was 57.0% (281 of 493). A Consolidated Standards of Reporting Trials diagram of enrollment and screening of the cases potentially eligible for inclusion in the study is shown in the eFigure in the Supplement. Our study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (the checklist used is included in the eAppendix in the Supplement).

Patients and Treatments

For each case included in the study, a minimum data set was required that comprised the following: (1) the MS disease subtype at baseline (relapsing-remitting, progressive relapsing, primary progressive, or secondary progressive); (2) the Expanded Disability Status Scale (EDSS) score at baseline, with 0 indicating no disability, 7 indicating wheelchair bound, and 10 indicating death from MS (details are listed in eTable 1 in the Supplement); (3) information on the administered conditioning regimen and graft manipulation; and (4) at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. Mobilization of peripheral blood stem cells was performed by the administration of a hematopoietic growth factor with or without chemotherapy; the type of growth factor and type of chemotherapy were sought for data-recording purposes. Graft manipulation to reduce the content of immune cells was also recorded. Conditioning regimens that included busulfan or total-body irradiation were classified as high intensity, while regimens that included cyclophosphamide alone or in combination with antithymocyte globulin or fludarabine phosphate were classified as low intensity. All other regimens were considered intermediate intensity.

Study End Points

Progression-free survival was defined as survival in the absence of progression of MS. Progression of MS was defined clinically as an increase of 1 point in the EDSS score confirmed at 12 months (0.5 points if the baseline EDSS score was ≥5.5) compared with the pretreatment baseline. The pretreatment baseline was defined as the last assessment before mobilization of peripheral blood stem cells (for peripherally mobilized autologous grafts) or before immunosuppressive conditioning (for bone marrow autologous grafts). The EDSS score increases that were detected at the last visit and thus could be confirmed were considered events according to a more conservative approach. A sensitivity analysis was performed censoring these last visit events. Death from any cause was considered MS progression in this analysis. Overall survival was considered time to death by any cause. For all patients who died after their AHSCT, the cause of death was examined. Early deaths that occurred within 100 days of transplant, which are considered treatment related, were described separately. Surviving patients were censored at the time of last follow-up. Information regarding the incidence of late effects was obtained, including malignant cancers and secondary autoimmune diseases.

Statistical Analysis

Data obtained from the CIBMTR and EBMT were summarized in descriptive tables of demographic information for the entire study population. Continuous variables were reported as medians and ranges or as means (SDs), while categorical variables were reported as absolute numbers and percentages of total patients. The probability of progression-free survival was calculated using the life-table estimator, and overall survival was calculated using the Kaplan-Meier estimator. A multivariate analysis assessing the association of baseline characteristics and transplantation methods with progression-free and overall survival was performed using multivariate Cox proportional hazards regression analysis models, adjusted for center. Proportionality of hazard was checked by plotting log-log transformation of the Kaplan-Meier survival curve as follows for each level of covariates: log-log(S[t]) vs time t, where S indicates the statistic. The assumption of proportional hazard is tenable if the difference between the 2 log-log Kaplan-Meier survival curves is constant over time.

Variables significantly associated with each outcome event on univariate analysis were included as covariates in the multivariate model, which selected the independent set of variables using a stepwise approach. For each patient having an EDSS assessment 1 year before and 1 year after transplant, the yearly EDSS score change before and after transplant was calculated. These changes were compared by a repeated-measures analysis of variance with 2 time points (change before vs change after transplant), also including disease subtype (relapsing vs progressive forms) and an interaction term (period of transplant × disease subtype) to evaluate whether the EDSS score change before and after transplant differed between patients with relapsing vs progressive disease.

A smoothing technique (locally weighted polynomial regression19) was applied to describe the EDSS score trend over time in patients with relapsing vs progressive disease for those individuals having the EDSS date of assessment reported. This technique is a nonparametric graphical tool to fit a smooth curve to the points in a scatterplot based on local weighted regression analyses.19

A 2-sided significance level of 5% was used. Analyses were performed using statistical software programs (R, version 3.2; The R Project for Statistical Computing and SPSS, version 19; SPSS Inc).

Results
Patient Demographics and Procedures

Valid data were obtained from 25 centers in 13 countries for 281 patients. Demographic and clinical data at the time of AHSCT are summarized in Table 1. The median time from diagnosis of MS to AHSCT was 81 months (range, <1 to 413 months). At the time of AHSCT, 171 of 281 patients (60.9%) had received 2 or more prior MS treatments. At the assessment preceding mobilization of peripheral blood stem cells, the most represented disease subtype was secondary progressive MS, contributing 186 of 281 patients (66.2%), and the median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9), indicating moderately advanced disability on average.

A few differences existed between the subsets of patients reported to the CIBMTR and the EBMT, reflecting different patient selection practices in the 2 groups of countries. Compared with the CIBMTR cohort, the EBMT cohort (1) was younger (median age, 35 vs 40 years; P < .001), (2) more often had more than 2 MS treatments before transplant (51.7% [74 of 143] vs 32.1% [34 of 111], P = .002), (3) had fewer patients with secondary progressive MS (60.6% [103 of 170] vs 74.8% [83 of 111], P = .001), (4) had shorter time from diagnosis of MS to transplant (median, 77 vs 91 months; P = .04), and (5) had a greater proportion of patients who underwent transplant during the first half (1995-2000) of the 12-year period qualifying for inclusion in our study (41.8% [71 of 170] vs 21.6% [24 of 111], P < .01).

In total, 66.2% (186 of 281) of the patients underwent AHSCT during the second half (2001-2006) of the study. Details of mobilization of peripheral blood stem cells, graft manipulation, and conditioning regimens are also listed in Table 1. The proportions of patients who received high-intensity, intermediate-intensity, and low-intensity conditioning regimens were similar (approximately one-third each) in the CIBMTR cohort, whereas 88.8% (151 of 170) of patients in the EBMT cohort received an intermediate-intensity regimen, most commonly BEAM (carmustine, etoposide, cytarabine, and melphalan) plus antithymocyte globulin. The percentage of patients treated with high-intensity regimens was higher among patients with progressive MS (21.6% [47 of 218]) than among patients with relapsing MS (9.5% [6 of 63]) (P = .05). The median duration of follow-up after AHSCT was 6.6 years (range, 0.2-16 years).

Progression-Free Survival

Progression-free survival as assessed by the EDSS score was considered the primary neurological end point. In total, 239 of 281 patients (85.1%) with yearly EDSS assessments after transplant were eligible for this analysis. Multiple sclerosis progression-free survival in all evaluable patients was 46% (95% CI, 42%-54%) at 5 years after AHSCT (Figure 1A). Progression-free survival in the subgroup with relapsing MS was 82% (95% CI, 71%-93%) at 3 years, 78% (95% CI, 66%-91%) at 4 years, and 73% (95% CI, 57%-88%) at 5 years after AHSCT. Among patients with secondary progressive MS, the largest subgroup in our study, 33% (95% CI, 24%-42%) remained free from EDSS score deterioration at 5 years after AHSCT. When applying a multivariable Cox proportional hazards regression analysis, the assumption of proportional hazard was tenable. Factors associated with the risk of EDSS score deterioration as identified by univariate Cox proportional hazards regression analysis were age, progressive vs relapsing form of MS, and number of prior treatments (Table 2). The significance of these factors was confirmed on multivariate analysis (Table 2 and Figure 1B, C, and D). Younger age and relapsing forms of MS were independently associated with better progression-free survival rates (Figure 1B and C). There was no statistical difference in the risk of disease progression between patients with primary progressive MS and patients with secondary progressive MS (hazard ratio [HR], 1.09; P = .63) (Figure 1C). Patients who received 3 or more immunosuppressive or modulatory treatments before AHSCT had a higher probability of disease progression than those who received 1 to 2 treatments before AHSCT (Figure 1D). The results were unchanged when unconfirmed disease progressions at the last visits were considered censored observations.

EDSS Score Change in the Periods Before and After AHSCT

It was important to consider the evolution of neurological disability in patients before they underwent AHSCT. This information was available in a subset of patients in the study. There were 111 patients who met the minimum requirement for this evaluation, which was the availability of at least 1 EDSS score during the 3 years before and after AHSCT, including the respective dates of assessment. In the evaluable subgroup, the mean EDSS score increased by 0.94 points (95% CI, 0.77-1.11 points) during the 12 months before transplant compared with a mean decrease of −0.32 points (95% CI, −0.15 to −0.49 points) during the 12 months after transplant (P < .001). A test for interaction demonstrated that the EDSS score change before and after transplant was significantly different between patients with relapsing vs progressive MS (P < .001): for relapsing MS, the EDSS score change 1 year before transplant was +1.42 (95% CI, 0.98-1.86), and the EDSS score change 1 year after transplantation was −0.76 (95% CI, −1.08 to 0.34), while for progressive MS, the EDSS score change 1 year before transplant was +0.73 (95% CI, 0.59-0.87), and the EDSS score change 1 year after transplant was −0.14 (95% CI, −0.28 to 0.01). Figure 2 shows the evolution of EDSS scores recorded before and after AHSCT in the 111 patients with relapsing (panel A) and progressive (panel B) MS subtypes. This representation allows visualization of the rapid neurological deterioration occurring in both patient subgroups before AHSCT. After transplant, the integrated curve suggests a reduction in the rate of manifestation of disability in the subgroup with relapsing MS (Figure 2A).

Overall Survival

Overall survival was 93% (95% CI, 89%-96%) at 5 years and 84% (95% CI, 78%-89%) at 10 years after transplant (Figure 3A). When applying a multivariable Cox proportional hazards regression analysis, the assumption of proportional hazard was tenable. Factors associated with worse overall survival on univariate Cox proportional hazards regression analysis were age, baseline EDSS score, high vs low intensity of the conditioning regimen, and progressive vs relapsing form of MS (Table 2). On multivariate analysis, only higher baseline EDSS scores remained significantly associated with greater risk of death over time, with an HR of 2.03 (95% CI, 1.40-2.95) per EDSS point. When stratifying by disability levels, Kaplan-Meier analysis revealed worse survival in patients with a baseline EDSS score of 7 or higher (mean [SE] 5-year mortality, 19% [6%]) than in patients with a baseline EDSS score of 6 to 6.5 (mean [SE] 5-year mortality, 4% [2%]) and in patients with a baseline EDSS score of 0 to 5.5 (mean [SE] 5-year mortality, 0% [0%]) (P = .004 for heterogeneity) (Figure 3B).

Mortality and Late Adverse Events

Overall, 37 deaths from any cause (treatment related or not) among 281 patients were reported during the entire follow-up. Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplantation and were considered transplant-related mortality. Data on factors associated with lower overall survival on univariate analysis are summarized in eTable 2 in the Supplement for the patients who died within and after 100 days of transplant compared with the entire cohort. Among the patients who died during follow-up, progressive form of MS and high-intensity conditioning regimen were overrepresented compared with the frequency of these factors in the entire cohort. However, the small number of events precludes a formal statistical evaluation. Individual causes of death and details on previous immunosuppressive or modulatory treatments for MS are listed in eTable 3 in the Supplement.

Late adverse events, including new onset of malignant cancers and autoimmune diseases, are listed in eTable 4 in the Supplement. In addition, 1 case of monoclonal gammopathy of unknown significance was reported. Of the 3 cases of myelodysplastic syndrome, 2 patients received a regimen based on total-body irradiation, and the third patient received cyclophosphamide plus antithymocyte globulin. Among the small number of events that occurred, there was no clear evidence to suggest the association of any of the late events with specific treatment regimens.

Discussion

Previous studies of AHSCT for the treatment of MS often reported detailed assessments, with some including MRI end points. However, most had a short duration of follow-up. For example, in a large published prospective study (n = 145), the median follow-up was 2 years.11 The few studies with long-term follow-up (ie, with outcomes at 5 years) comprised small numbers of patients, with the largest reporting on 35 patients during a median follow-up period of 11 years.15 We analyzed a large cohort of 281 patients undergoing AHSCT for the treatment of MS, with a median follow-up of 6.6 years. Compared with the largest previously published cohort in this patient setting by Burt et al,11 which included 118 patients (81.4%) with relapsing-remitting MS and 27 patients (18.6%) with secondary progressive MS, the proportions of MS subtypes differ in our study, with 63 patients having relapsing types (relapsing-remitting MS and progressive relapsing MS, totaling 22.4%) and 218 patents having progressive types (primary progressive MS and secondary progressive MS, totaling 77.6%). Therefore, this study provides additional information on outcomes after AHSCT in progressive MS, an area of unmet medical need.20 Burt and colleagues11 noted that their criteria selecting patients with active inflammation and excluding those with late secondary progressive MS may have prevented them from detecting associations that may exist between baseline EDSS score, older age, or prior number of immunosuppressive or modulatory treatments and a worse outcome. In our study, by not imposing any criteria to select a disease phenotype, we were able to demonstrate significant associations of these factors with worse outcomes. Previous studies focused on specific AHSCT protocols used at their respective centers. In our study, for the first time to our knowledge in a long-term cohort, we report outcomes after a wide range of regimens (ie, 17.4% [49 of 281] low intensity, 63.7% [179 of 281] intermediate intensity, and 18.9% [53 of 281] high intensity) and include conditioning regimen intensity as a variable in the statistical analyses.

Our primary neurological outcome was progression-free survival as assessed by systematic EDSS neurological disability scoring. In our cohort, 77.6% (218 of 281) of patients had primary progressive or secondary progressive MS, and the observed progression-free survival in the 85.1% (239 of 281) of evaluable patients was 46% at 5-year follow-up. Because long-term stability of neurological disability is not an expected feature of the natural course of aggressive forms of relapsing or progressive MS,21 these data raise the possibility that AHSCT may have reduced the risk of disease progression in the treated patients, yet demonstration is lacking in the absence of a control group.

However, neurological outcomes in our study were considerably better in patients with relapsing MS than in those with progressive MS, consistent with recent evidence of good efficacy in relapsing-remitting MS.7,11 Using multivariate analysis, we identified relapsing MS as a factor robustly associated with progression-free survival (HR, 2.33), which remained greater than 70% at 5 years after AHSCT in this patient subgroup. In total, 81.4% of the patients in the work of Burt et al11 had relapsing-remitting MS, and progression-free survival was 87% at 4 years. In the Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) trial,7 all patients had relapsing-remitting MS by the inclusion criteria, and progression-free survival was 90.9% at 3 years. Inclusion criteria that selected patients with early relapsing-remitting MS may explain the higher progression-free rates observed in those studies. Additional factors that were significantly associated with better progression-free survival in our study were younger age and less than 3 prior disease-modifying MS treatments. Some previous studies considered age in subgroup analyses,22 but none to our knowledge demonstrated significance through formal statistical evaluation. Furthermore, we analyzed in a subset of evaluable patients the trajectory of neurological disability as measured by the EDSS during the periods before and after AHSCT. The mean accumulation of disability during the 12 months before transplant(+0.94 EDSS points) was partially reversed after transplant (−0.32 EDSS points), and the reversal was significantly greater in the patients with the relapsing compared with the progressive MS forms. This comparison extends previous observations of improvement in EDSS scores after AHSCT in studies7,8,10,11 that included predominantly or exclusively patients with relapsing-remitting MS and in the subgroup of patients with relapsing-remitting MS in the Italian AHSCT database.12

We also examined the association of variables with overall survival. Univariate analysis identified age, baseline EDSS score, conditioning regimen intensity, and progressive vs relapsing form of MS as factors significantly associated with a lower overall survival rate. Of these factors, only baseline EDSS score was confirmed as significant on multivariable analysis, with an HR of 2.03 per EDSS point. However, the low rate of events limits the power to detect all variables underlying mortality on multivariate analysis, and we cannot conclude that factors such as conditioning regimen intensity or disease stage do not affect survival.

Transplant-related death is a major concern in a disease that is not immediately life threatening, such as MS. In the present study, the 100-day mortality (which in hematological practice is considered a surrogate of transplant-related death) was 2.8%, a high rate that likely reflects the early AHSCT experience captured in our study that only included transplants performed until December 31, 2006. Indeed, a retrospective analysis of the EBMT registry3 performed in 2007 found a decrease in treatment-related mortality from 7.3% in transplants for MS performed from 1995 to 2000 (inclusive) to 1.3% in transplants for MS performed from 2001 to 2007 (inclusive). In a 2010 update,23 the 100-day mortality in the entire registry was 2%, half of that in the 2005 report.24 The reduction over the years is likely related to improved selection of patients, with the exclusion of patients with advanced disability who are at higher risk of complications, and to the less frequent use of intensive conditioning regimens.22 As expected,22 the causes of death within 100 days in our study were partly related to the immunosuppression therapy, although the small number of events prevents a reliable analysis. Beyond day 100, the incidence of death is variable throughout the follow-up (Figure 3), and the causes can be attributed in large part to progression of MS disability and its attendant complications, which often include infection even in patients who have not been treated with immunosuppressant therapies. The conditioning regimen was more frequently a high-intensity one in the patients who died during follow-up than in the entire cohort, but nonrandom allocation of treatment and small numbers prevent us from making definitive conclusions about this association.

The analysis of late events included malignant cancers and new onset of autoimmune disease. With regard to malignant cancers, 1.1% (3 of 281) of patients had a myelodysplastic syndrome, a disorder associated with prior treatment with cytotoxic drugs. The other neoplasms observed in this cohort are usually not associated with previous chemotherapy. The incidence of new autoimmune disease was 5.0% (14 of 281), in line with a survey administered by the EBMT25 but considerably lower than after lymphocyte-depleting treatment with alemtuzumab, which approaches a risk of 50%.26

Limitations

The main limitation of our study is its partially retrospective nature. Although some of the data were obtained retrospectively from clinical records, we took many steps to optimize the analysis. As with most database studies, the reported outcomes mirror the practice for MS treatment in many countries. The raters of EDSS assessments were not masked to clinical information, and assessments were not systematically performed for the duration of follow-up in every patient. Therefore, we limited the analysis of progression-free survival to the large 85.1% (239 of 281) subset of patients who had yearly EDSS assessments after transplant. The number of patients with enough data points for the different analyses was variable and sometimes low, which reduced statistical power. In a retrospective study, incomplete reporting and loss to follow-up may result in underestimating the frequency of late adverse events. Another limitation is that, although our analysis included 57.0% (281 of 493) of the transplants registered with the CIBMTR and the EBMT during the study period, more than one-third of the activity was not captured by our study. However, the reason for the 78.3% (166 of 212) of unavailable cases was that the centers where the patients were treated declined to participate in the study. Seventy-four percent (43 of 58) of centers that did not join the study had performed fewer than 3 transplants, and lack of incentive for the clinicians to contribute few cases to a large study was stated in many centers’ responses. Based on this information, we do not expect that the unavailability of those cases could represent a significant source of bias.

Conclusions

In this large observational cohort of patients with MS with predominantly progressive forms of MS treated with AHSCT and followed up long term, almost half of them survived free from neurological progression for 5 years after transplant. Taken together, the multivariate statistics indicate that the profile of a patient who is more likely to survive without neurological progression is that of a younger individual with relapsing MS who has failed no more than 2 disease-modifying treatments and has not reached high levels of disability. These associations strengthen the case for an evaluation of safety and efficacy of AHSCT in a randomized clinical trial against approved therapies of high efficacy as first-line or second-line treatment in patients with highly active relapsing MS, as suggested by expert consensus.27 Furthermore, our results raise the question whether AHSCT may attenuate the progression of disability in patients with progressive forms of MS, a possibility that is more plausible in patients with MRI evidence of central nervous system inflammatory activity before transplant8,12,15 and that could be addressed in a randomized trial of AHSCT controlled against standard care.

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Article Information

Accepted for Publication: December 8, 2016.

Corresponding Author: Paolo A. Muraro, MD, Division of Brain Sciences, Imperial College London, 160 Du Cane Rd, Burlington Danes Building, Fourth Floor, London W12 0NN, England (p.muraro@imperial.ac.uk).

Published Online: February 20, 2017. doi:10.1001/jamaneurol.2016.5867

Author Contributions: Drs Muraro and Sormani 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.

Study concept and design: Muraro, Pasquini, Saccardi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Muraro, Pasquini, Sormani, Saccardi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Sormani.

Obtained funding: Muraro, Pasquini, Farge.

Administrative, technical, or material support: Massacesi, Badoglio, Zhong.

Study supervision: Muraro.

Conflict of Interest Disclosures: Dr Muraro reported receiving honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis. Dr Bowen reported having financial relationships as a consultant for Acorda Therapeutics, Biogen Idec, Genzyme, Genentech, Pfizer/EMD Serono, Novartis, and Teva Neuroscience; as a speaker for Acorda Therapeutics, Biogen Idec, Pfizer/EMD Serono, Novartis, and Teva Neuroscience; as a recipient of grant or research support from Acorda Therapeutics, Alexion, Avanir, Biogen Idec, EMD Serono, Genzyme, GlaxoSmithKline, MedImmune, Novartis, Osmotica, Roche, Sanofi-Aventis, Synthon, Vaccinex, and Xenoport; and as a stock shareholder with Amgen. Dr Freedman reported receiving honoraria or consultation fees from Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffmann-La Roche, Sanofi-Aventis, and Teva Canada Innovation; reported being a member of a company advisory board, board of directors, or other similar group for Actelion, Bayer HealthCare, Biogen Idec, Hoffmann-La Roche, Merck Serono, Novartis, Opexa, and Sanofi-Aventis; and reported participating in a speakers bureau sponsored by Genzyme. Dr Havrdrova reported receiving honoraria for speaking and consulting activities from Actelion, Biogen, Celgene, Merck, Novartis, Sanofi, Genzyme, Roche, and Teva and reported being supported by the Czech Ministry of Education (project PRVOUK-P26/LF1/4). Dr Kimiskidis reported receiving research funding from Janssen-Cilag, Bial, Eisai, and Biogen Idec and reported receiving honoraria for consultation from Novartis, Teva, and Merck Serono. Dr Mancardi reported receiving honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering Pharma, Biogen Idec, Sanofi-Aventis, Merck Serono, Novartis, Genzyme, and Teva. Dr Massacesi reported receiving honoraria for speaking at scientific meetings or participating in advisory boards from Genzyme, Biogen, and Roche and reported receiving travel support from Merck Serono, Biogen, Teva, Genzyme, and Novartis. Dr Saiz reported receiving compensation for consulting services and speaking engagements from Bayer Schering Pharma, Merck Serono, Biogen Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, and Novartis. Dr Sormani reported receiving consulting fees from Merck Serono, Biogen, Novartis, Roche, Genzyme, Teva, GeNeuro, and Vertex. No other disclosures were reported.

Funding/Support: This work was supported by grant 938/10 from the Multiple Sclerosis Society UK (Dr Muraro), by the Center for International Blood and Marrow Transplant Research (CIBMTR), and by the European Blood and Marrow Transplant Autoimmune Disease Working Party. The CIBMTR acknowledges support by grant/cooperative agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; by grant/cooperative agreement 5U10HL069294 from the NHLBI and NCI; by contract HHSH250201200016C with the Health Resources and Services Administration; and by grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research. The CIBMTR also acknowledges grant support from the following: Actinium Pharmaceuticals; Allos Therapeutics, Inc; Amgen, Inc; an anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc; Gamida Cell Teva Joint Venture Ltd; Genentech, Inc; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc; HistoGenetics, Inc; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck & Co, Inc; Millennium: The Takeda Oncology Company; Milliman USA, Inc; Miltenyi Biotec, Inc; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Osiris Therapeutics, Inc; Otsuka America Pharmaceutical, Inc; Perkin Elmer, Inc; Remedy Informatics; Roswell Park Cancer Institute; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc; St Baldrick’s Foundation; StemCyte–A Global Cord Blood Therapeutics Company; Stemsoft Software, Inc; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc; Therakos, Inc; University of Minnesota; University of Utah; and Wellpoint, Inc.

Role of the Funder/Sponsor: The funding sources had no role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication.

Group Information: The Multiple Sclerosis–Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group investigators were Eva Krasulova, PhD, Charles University and Faculty of Medicine and General University Hospital, Prague, Czech Republic; Ivana Stetkarova, PhD, Charles University and Third Faculty of Medicine, Prague, Czech Republic; Maria Pia Amato, MD, and Massimo Di Gioia, MD, Careggi University Hospital, Firenze, Italy; Bonaventura Casanova-Estruch, MD, and Miguel A. Sanz, MD, University Hospital La Fe and University of València, València, Spain; Giancarlo Comi, MD, Università Vita-Salute San Raffaele and Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy; Fabio Ciceri, MD, IRCCS San Raffaele Scientific Institute, Milano, Italy; A. Lugaresi, PhD, Università “G. d’Annunzio” of Chieti-Pescara, Chieti-Pescara, Italy; Paolo Di Bartolomeo, MD, Ospedale Civile, Pescara, Italy; Claudio Gasperini, MD, and Ignazio Majolino, MD, San Camillo Forlanini Hospital, Rome, Italy; Maria Carmen Calles Hernández, MD, Hospital Universitari Son Espases, Palma de Mallorca, Spain; Antonia Sampol Mayol, MD, Hematología Hospital Universitari Son Espases, Palma de Mallorca, Spain; Letizia Mazzini, MD, Eastern Piedmont University, Maggiore della Carità Hospital, Novara, Italy; Daniela Cilloni, Centro Trapianti Metropolitano di Torino, San Luigi Hospital, Orbassano, Italy; Paolo Immovilli, MD, and Daniele Vallisa, MD, G. da Saliceto Hospital, Piacenza, Italy; Fredrik Piehl, PhD, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Hans Hägglund, PhD, Uppsala University Hospital, Uppsala, Sweden; Basil Sharrack, PhD, and J. Snowden, PhD, Sheffield Teaching Hospitals National Health Service Foundation Trust and University of Sheffield, Sheffield, England; Jeffrey Andrey, MD, Scripps Health, La Jolla, California; George Carrum, MD, Baylor College of Medicine, Houston, Texas; Afonso C. Vigorito, MD, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil; and Yvonne S. Loh, MD, and Goh Yeow Tee, MMed, Singapore General Hospital, Singapore.

Disclaimer: The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, the Health Resources and Services Administration, or any other agency of the US government.

Additional Contributions: We acknowledge Julio Voltarelli, MD (in memoriam), for his contributions to the field of hematopoietic cell transplantation for autoimmune diseases. We thank the patients who participated in this study.

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