Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for 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.

Conflict of interest statement

Declaration of interests

PAM declares honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis. JB declares financial relationships as Consultant for Acorda Therapeutics, Biogen IDEC, Genzyme, Genentech, Pfizer/EMD Serono, Novartis, Teva Neuroscience; as speaker for corda Therapeutics, Biogen IDEC, Pfizer/EMD Serono, Novartis, Teva Neuroscience; and as recipient of Grant/Research support from Acorda Therapeutics, Alexion, Avanir, Biogen, EMD Serono, Genzyme, Glaxo Smith Kline, Medimmune, Novartis, Osmotica, Roche, Sanofi-Aventis, Synthon, Vaccinex, Xenoport; and as stock shareholder with Amgen. MSF received honoraria or consultation fees from BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva Canada Innovation; has been a member of a company advisory board, board of directors or other similar group for Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis; and participated in a speaker’s bureau sponsored by Genzyme. VKK received research funding from Janssen-Cilag, BIAL, EISAI, Biogen Idec and also honoraria for consultation from Novartis, Teva and Merck-Serono. GLM has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, Sanofi - Aventis, Merck Serono Pharmaceuticals, Novartis, Genzyme and Teva. Albert Saiz has received compensation for consulting services and speaking from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd and Novartis. All other co-authors declare no conflict of interest.

Figures

Figure 1. MS progression-free survival

Probabilities of EDSS progression-free survival after AHSCT are shown by Kaplan-Meier analysis (A) in the whole patient cohort and in subgroups stratified according to the factors identified by multivariate analysis as affecting progression-free survival, respectively: (B) in quartiles according to age (p = 0.022 for trend); (C) in patients with relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) forms of MS (p = 0.007 for heterogeneity); and (D) in patients who received 1–2 or 3 previous disease-modifying treatments (p= 0.008 for heterogeneity). The different shades of grey represent 95% Confidence Intervals for each K-M line.

Figure 2. Evolution of EDSS scores before and after AHSCT in relapsing and progressive MS

The individual (colored dotted) and integrated (solid black) lines depict the evolution of EDSS scores in the subset of patients who had both longitudinal pre-transplantation and post-transplant EDSS data and the date of EDSS assessment documented (n =111). These are subdivided in relapsing (A; n = 32) and progressive (B; n = 79) forms of MS at the time of transplant. Rapid worsening of disability was observed prior to transplant in both subgroups, as expected for patients with aggressive forms of MS who were selected for AHSCT. The integrated line suggests that on average the accrual of disability was stopped in relapsing MS patients during the first 2 years post-transplant.

Figure 3. Overall survival

The probability of survival after AHSCT is shown as Kaplan-Meier analysis in the whole patient cohort (A). Since higher baseline EDSS score was found by multivariate analysis to be independently associated with worse survival (see Table 2 for details) we show in (B) the probabilities of survival after AHSCT in three strata of patients with different levels of disability at baseline assessment (Expanded Disability Status Scale, EDSS brackets: 0–5.5; 6–6.5; ≥7), which differed significantly for the highest EDSS bracket (p = 0.004 for heterogeneity). The grey shades represent 95% Confidence Intervals for each K-M line.