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Bone marrow transplantation in multiple sclerosis

Evidence Summaries for Current Care Guidelines
5.2.2019
Raija Sipilä

Level of evidence: D

Stem cells transplantation might possibly decrease the number of new lesions in MRI and the number of relapses for patients with secondary progressive or relapsing-remitting multiple sclerosis, but the evidence is insufficient.

A phase II, randomized, controlled trial «Mancardi GL, Sormani MP, Gualandi F ym. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology 2015;84:981-8 »1 assessed the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) in multiple sclerosis (MS). The patients with secondary progressive or relapsing-remitting MS, with a documented increase on Expanded Disability Status Scale (EDSS) during the last year in spite of conventional therapy, and presence of at least one gadolinium enhancing lesion (GEL) were included. Patients were randomized to receive intense immunosuppression followed by AHSCT or intravenous mitoxantrone (MTX) 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years follow-up. Secondary endpoints were the cumulative number of GELs, relapse rate and disability progression. Adverse events were also reported. Intention to treat analysis was performed according to the last observation carried forward.

Twenty-one patients were randomized (AHSCT n=9, MTX n=12) and 17 had postbaseline evaluable MRI scans. Mean age was 35,5 years and median EDSS 6 (range 5,5-6,5).

The mean number of new T2 lesions was in the AHSCT group 2,75 (range 0-8) and in MTX group 12,75 (2-34), rate ratio 0.21 (95 % CI 0,10-0,48, p = 0.00016). The annualized relapse rate was 0,19 for AHSCT and 0,6 for MTX (RR 0,36, 95 % CI 0,15-0,88, p=0,026). No difference in the EDSS changes was observed between the groups.

  • Study quality: weak
  • Adaptability: high

Comment: The trial was planned as phase III trial, but the primary endpoint was switched from EDSS progression to cumulative number of new T2 MRI lesions due to recruitment problems. The number of patients was small and the method of randomization is not reported. The groups seem unbalanced at baseline.

A randomized, placebo-controlled cross-over phase II study «Llufriu S, Sepúlveda M, Blanco Y ym. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One 2014;9:e113936 »2 investigated the safety and efficacy of mesenchymal stem cells (MSCs) in MS. The patients unresponsive to conventional therapy, defined by at least 1 relapse and/or at least one GEL on MRI in past 12 months, aged 18 to 50 years, disease duration 2 to 10 years and EDSS 3.0-6.5 were included. Exclusion criteria were active or chronic infection, treatment with any immunosuppressive therapy within the previous 3 months or interferon-beta, glatiramer acetate or corticosteroids within 30 days prior to randomization. Patients were randomized to receive intravenous (IV) 1-2×10(6) bone-marrow-derived-MSCs/kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months.

The primary endpoints were safety and efficacy in terms of cumulative number of GELs on MRI between groups (6 months) and the reduction in the mean number of GELs (at the end). Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures.

At baseline 9 patients were randomized to receive MSCs (n=5) or placebo (n=4). At baseline median age was 41 years (range 23-48), media disease duration 9 years (4,31-10,00), median EDSS 3,5 (3,0-6,0) and median number of GELs 0 (0-22). One patient on placebo withdrew after having 3 relapses in the first 5 months. No serious adverse events were identified. At 6 months, mean cumulative number of GELs was 3.1 (95 % CI 1.1-8.8) for patients treated with MSCs and 12.3 (4.4-34.5) for placebo group (p=0,064). At the end of study mean change in GELs during the period of MSCs was -2.8±5.9 and during the placebo period 3±5.4 (p=0.075). No significant treatment differences were detected in the secondary endpoints.

  • Study quality: weak
  • Adaptability: high

Comment: There was a possibility for carryover effect and the number of patients was very small. The patient cohort consisted of clinically typical MS patients without a very aggressive disease course.

Comment: Some open-label studies have been conducted. It seems that the stem cells transplantation is associated with few serious or unexpected adverse events «Nash RA, Hutton GJ, Racke MK ym. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JA»3, «Cohen JA, Imrey PB, Planchon SM ym. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler 2018;24:501-511 »4, «Atkins HL, Bowman M, Allan D ym. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016;388:576-8»6. A cohort study «Muraro PA, Pasquini M, Atkins HL ym. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017;74:459-469 »5 evaluated the long-term (median follow-up 6.6 years) outcomes in patients who underwent AHSCT for the treatment of MS and eight deaths (2.8 %) were reported within 100 days from AHSCT and were considered AHSCT-related.

This document is linked to the following articles:

  • MS-tauti 1

References

  1. Mancardi GL, Sormani MP, Gualandi F ym. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology 2015;84:981-8 «PMID: 25672923»PubMed
  2. Llufriu S, Sepúlveda M, Blanco Y ym. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One 2014;9:e113936 «PMID: 25436769»PubMed
  3. Nash RA, Hutton GJ, Racke MK ym. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol 2015;72:159-69 «PMID: 25546364»PubMed
  4. Cohen JA, Imrey PB, Planchon SM ym. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler 2018;24:501-511 «PMID: 28381130»PubMed
  5. Muraro PA, Pasquini M, Atkins HL ym. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017;74:459-469 «PMID: 28241268»PubMed
  6. Atkins HL, Bowman M, Allan D ym. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016;388:576-85 «PMID: 27291994»PubMed
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