HSCT activity in Progressive MS

Paolo A. Muraro, et al.Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017

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.


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.

If you cared to read the paper by ProfG and others members of TeamG on length dependent axonopathy (we hope that it will be open access soon) it suggests that it is not too late to benefit people with progressive MS, even with immunosupression. 

Therfore just as well wee havn’t given in progressive MS.

This study offers some support when analysis of people with MS undertaking HSCT was done. In this 80% of people had progressive MS and disability progression was stoped in about 50% of 5 people up to 5 years of analysis. It will take longer follow-up to see if this is sustained but based on the data below people continue to fail so at 10 years the progression free cohort only makes up about 30 percent. As you can see if you were relapsing verses progressive you were about two-three times as likely to see benefit.

So it says 50% of people progressed and tells me we need more than peripheral immunosuppression. I suspect you need to deal with inflammation in the brain. It also says that nearly 3% of people didnt make it, so it is not something you should do with your eyes closed. However in more recent studies this risk of mortality has reduced. 

As one of the readers says “Graph C (below) indicates that no-one with PPMS did not progress past 5 years so it sort of says do not expect miracles of anyone taking this treatment, given the risks is this really any better than other DMT?”

You need to be clear what the risks are and the competence and success of centres where you may undergo this . The types of HSCT was not all the same and (17.4% [49 of 281] low intensity, 63.7% [179 of 281] intermediate intensity, and 18.9% [53 of 281] high intensity treatment regimes. 

The 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. 

The incidence of new autoimmune disease was 5.0% (14 of 281), but considerably lower than after lymphocyte-depleting treatment with alemtuzumab, which approaches a risk of 50%.,

It is open access so have a read.

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  • So some benefit if most people survive the initial transplant, although the numbers are not brilliant. Again it looks like treat early and hard will provide the most benefit.

    But I think the biggest hurdle is the severity of the treatment, both in terms of mortality and impact during treatment.

  • Graph C indicates that no-one with ppmS did not progress past 5 years so it sort of says do not expect miracles of anyone taking this treatemnt, given the risks is this really anybetter than other DMY?

  • So really, these results indicate that AHSCT is effective in half of progressive, primarily SPMS patients. No other med can do this , certainly not ocrelizumab. I had HSCT done by Dr Saccardi in Italy , Muraros colleague , and may have crossed over to early SPMS. I'm 2.5 years post so time will tell. But if I progress, then what ? What med ? Do we go back to B cell depletion?

    • Getting rid of antibody secreting B cells (plasma cells) responsible for oligoclonal bands in the CNS, which IMO could be driving progression is a holy grail we haven't reached yet.

    • This study
      identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation
      in multiple sclerosis patients


  • Abstract The main objective of our work is to describe the
    long-term results of myeloablative autologous hematopoietic
    stem cell transplant (AHSCT) in multiple sclerosis patients.
    Patients that failed to conventional therapies for multiple sclerosis
    (MS) underwent an approved protocol for AHSCT,
    which consisted of peripheral blood stem cell mobilization
    with cyclophosphamide and granulocyte colony-stimulating
    factor (G-CSF), followed by a conditioning regimen of
    BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit
    Thymoglobulin. Thirty-eight MS patients have been
    transplanted since 1999. Thirty-one patients have been followed
    for more than 2 years (mean 8.4 years). There were 22
    relapsing-remitting multiple sclerosis (RRMS) patients and 9
    secondary progressive multiple sclerosis (SPMS) patients. No
    death related to AHSCT. A total of 10 patients (32.3%) had at
    least one relapse during post-AHSCT evolution, 6 patients in
    the RRMS group (27.2%) and 4 in the SPMS group (44.4%).
    After AHSCT, 7 patients (22.6%) experienced progression of
    disability, all within SP form. By contrast, no patients with
    RRMS experienced worsening of disability after a median
    follow-up of 5.4 years, 60% of them showed a sustained reduction
    in disability (SRD), defined as the improvement of 1.0
    point in the expanded disability status scale (EDSS) sustains
    for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical
    variable that predicted a poor response to AHSCT was a high
    EDSS in the year before transplant. AHSCT using the BEAMATG
    scheme is safe and efficacious to control the aggressive
    forms of RRMS.
    DOI 10.1007/s10072-017-2933-6

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