Stem Cell Transplantation for Multiple Sclerosis: A 20-Year UK Analysis of Safety and Effectiveness

Table of Contents

• Introduction: Understanding MS and Stem Cell Treatment
• How the Research Was Conducted
• Who Participated in the Study
• The Stem Cell Transplantation Procedure
• Detailed Results and Outcomes
• Safety Information and Complications
• Treatment Effectiveness Over Time
• What This Means for Patients
• Study Limitations
• Recommendations for Patients
• Source Information

Introduction: Understanding MS and Stem Cell Treatment

Multiple sclerosis (MS) is a chronic disease of the central nervous system that represents the main cause of disability in working-age adults. In the United Kingdom alone, more than 150,000 people live with MS, with approximately 3.6 new cases per 100,000 people each year. This autoimmune condition reduces life expectancy by an average of 7 years and increases overall mortality risk threefold compared to the general population.

MS typically presents as relapsing-remitting MS (RRMS) in about 85% of cases, beginning most often in a person's 30s with women affected 2.3 times more frequently than men. The remaining 15% develop primary progressive MS (PPMS), which usually starts in the 40s. Over time, many RRMS patients transition to secondary progressive MS (SPMS), characterized by steady disability progression without distinct relapse episodes.

Autologous haematopoietic stem cell transplantation (AHSCT) has been developed as a one-time treatment for MS since 1995. This procedure works by "resetting" the immune system through ablating (destroying) pathogenic immune cells and allowing reconstitution of a self-tolerant immune system. The United Kingdom has been one of the most active countries in Europe performing AHSCT for MS, with the treatment being commissioned through the NHS for severe MS since 2013.

How the Research Was Conducted

This study represents a comprehensive 20-year analysis of AHSCT activity and outcomes across the United Kingdom from 2002 to 2023. Researchers collected data from 14 participating transplant centers, including fully anonymized information on 364 patients with MS who underwent stem cell transplantation.

Patients were selected for transplantation by multidisciplinary teams including both neurologists and haematologists on a case-by-case basis according to established principles. Eligibility criteria included active disease despite disease-modifying therapies (DMTs), defined by continued relapses or MRI activity showing new lesions, or particularly aggressive disease in treatment-naive patients who were otherwise medically fit for the procedure.

The research team analyzed several key outcomes:

• Transplant-related mortality (deaths within 100 days of treatment)
• Treatment complications and adverse events
• Progression-free survival (maintaining stable disability levels) at 2 and 5 years
• Viral reactivations including Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
• Long-term effects including new autoimmune conditions and cancers

Statistical analysis was performed using specialized software, with survival outcomes calculated using Kaplan-Meier methods and comparisons between groups made through Cox regression analysis.

Who Participated in the Study

The study included 364 patients with multiple sclerosis who underwent stem cell transplantation between 2002 and 2023. The participant group had the following characteristics:

Basic Demographics: 210 patients (58%) were female, with a median age of 40 years at the time of transplantation (range: 18-66 years). This reflects the typical MS population where women are more frequently affected than men.

MS Types: The study included patients across the MS spectrum: - 209 patients (58%) had relapsing-remitting MS (RRMS) - 130 patients (36%) had progressive forms of MS (47 with primary progressive MS/PPMS, 83 with secondary progressive MS/SPMS) - 25 patients (6%) had unrecorded MS subtype

Disease Severity: Patients had significant disability at the time of transplantation, with a median Expanded Disability Status Scale (EDSS) score of 6.0 (range: 0-9). The EDSS is a standardized measure of disability in MS where higher scores indicate greater disability. A score of 6.0 means patients typically require a walking aid such as a cane or crutch to walk about 100 meters.

Disease Duration: Patients had lived with MS for a median of 10 years before undergoing transplantation (range: 4-34 years), indicating that most had tried multiple other treatments before considering stem cell transplantation.

Geographical Distribution: Treatment activity was concentrated around London and Sheffield, with many patients traveling significant distances for treatment. Notably, 15 patients came from the Republic of Ireland. The analysis revealed substantial geographical inequity in access to this treatment across different UK regions.

The Stem Cell Transplantation Procedure

The stem cell transplantation process followed established protocols across all 14 participating centers, which were all accredited by recognized international standards organizations.

Stem Cell Collection: Most patients (98%) received stem cells mobilized using cyclophosphamide (at doses of 2-4 g/m²) followed by G-CSF daily at 5-10 μg/kg starting 24 hours after cyclophosphamide for 7-10 days. A small number received G-CSF only mobilization if cyclophosphamide-based collection failed.

Conditioning Regimen: The vast majority of patients (352/361, 98%) received a conditioning regimen consisting of cyclophosphamide and rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin). The specific regimens were: - Cyclophosphamide 200 mg/kg based on ideal body weight - Rabbit ATG at either 6.0 mg/kg or 7.5 mg/kg - 61% of patients (219/360) received the higher r-ATG dose of 7.5 mg/kg or more

A small minority (9/361, 2%) received a different conditioning regimen called BEAM-ATG (carmustine, etoposide, cytarabine, melphalan plus equivalent ATG dose).

Stem Cell Reinfusion: Patients received a minimum dose of 2.0 × 10⁶/kg CD34+ cells following a 24-hour washout period after conditioning. All patients successfully engrafted, with median time to neutrophil recovery of 11 days (range: 10-13 days).

Supportive Care: All centers provided comprehensive supportive care including platelet and red blood cell transfusions, antimicrobial prophylaxis, fever management, nutritional support, and physiotherapy according to established protocols.

Detailed Results and Outcomes

The study produced comprehensive data on both the safety and effectiveness of stem cell transplantation for MS over a 20-year period in the UK.

Treatment Activity Over Time: The researchers observed a significant increase in AHSCT activity after 2016, driven by increased awareness, commissioning guidance, and publication of supporting research. There was a temporary decrease in activity during 2021-2022 due to the COVID-19 pandemic.

Geographical Access Disparities: The analysis revealed significant inequity in access to treatment across different UK regions. Using patient postcode data, researchers calculated incidence rates of AHSCT per million population, confirming that some regions had markedly less activity compared to areas around London and Sheffield.

International Patients: The study included 15 patients from the Republic of Ireland who traveled to the UK for treatment, highlighting the international demand for this procedure.

Safety Information and Complications

The study provides detailed safety data that is crucial for patients considering this treatment option.

Early Complications: Where data was available (253/261 patients), 97% experienced some early complications, though most were manageable with standard medical care: - Fluid overload (more than 2% body weight gain) occurred in almost all patients (218/221, 99%) - Clinically significant fluid retention/weight gain occurred in 161/307 patients (52%) - High-grade fever during conditioning occurred in 86% of patients (225/261)

Treatment-Related Mortality: There were 5 deaths within 100 days of stem cell transplantation, representing a 1.4% mortality rate. All deaths occurred in patients with advanced baseline disability (median EDSS: 6.5). The causes were primarily toxicity from the conditioning regimen leading to cardio-respiratory failure or heart rhythm abnormalities. Two patients died before stem cell reinfusion could occur.

Among these five patients, two had PPMS and three had RRMS, though the RRMS patients had median disease duration of 9 years from first symptoms, suggesting they were likely transitioning to secondary progressive MS.

Late Deaths: Three additional deaths occurred beyond one year after transplant: - One due to MS progression - One due to COVID-19 - One with unknown cause (patient lost to follow-up) All these patients had significant advanced disease at transplantation (EDSS scores of 6, 6.5, and 7.5).

Late Effects: The study tracked long-term complications: - New malignancies developed in 5/315 patients (1.6%): skin cancers (2 patients), T-cell acute lymphoblastic leukemia (1), prostate cancer (1), and breast cancer (1) - Secondary autoimmune diseases developed in 24/305 patients (7.9%): predominantly thyroid disease (21 patients), immune thrombocytopenia (2), and celiac disease (1)

Viral Reactivations: Viral monitoring revealed important findings: - CMV reactivation occurred in 66/307 cases (21%), with clinically significant reactivation in 47/66 cases (15% of patients with data) - CMV reactivation was more common with higher r-ATG doses >6.0 mg/kg (29% vs. 8%, p = 0.0005) - EBV reactivation occurred in 76% of patients where monitoring was performed (235/311) - 15 patients (6% of those with EBV reactivation) required treatment with rituximab - No cases of clinically significant EBV disease occurred after 2019 when preventive rituximab treatment was implemented

Treatment Effectiveness Over Time

The study provides compelling evidence for the long-term effectiveness of stem cell transplantation in halting MS progression.

Overall Progression-Free Survival: The analysis showed excellent outcomes: - 83.5% of patients remained free from disability progression at 2 years post-transplantation - 62.4% remained progression-free at 5 years post-transplantation

Results by MS Type: Outcomes varied significantly based on MS type: - Patients with relapsing-remitting MS (RRMS) showed significantly better progression-free survival compared to those with primary progressive MS (PPMS) (hazard ratio 2.07) and secondary progressive MS (SPMS) (hazard ratio 1.69) - Even in the PPMS group, which typically has poorer responses to treatment, 46% of patients had no disability progression 5 years after transplantation

Impact of ATG Dose: Patients who received lower doses of r-ATG (≤6.0 mg/kg) had significantly better progression-free survival outcomes compared to those receiving higher doses (hazard ratio = 2.52, p = 0.0005). This effect was most pronounced in patients with RRMS.

Impact of Viral Reactivations: Patients with significant EBV viral reactivation (above 300,000 copies/mL) and those with CMV reactivations showed lower progression-free survival rates, suggesting that viral complications may affect long-term outcomes.

Time Period Analysis: Similar outcomes were noted in patients transplanted before and after 2013, indicating consistent results over the two-decade study period.

What This Means for Patients

This large UK study provides strong real-world evidence supporting the safety and effectiveness of stem cell transplantation for appropriate patients with multiple sclerosis.

For Patients with Treatment-Resistant MS: The results demonstrate that AHSCT can provide long-term disease control for patients who have not responded adequately to conventional disease-modifying therapies. The 62.4% progression-free survival rate at 5 years is particularly notable given that many patients had advanced disease and had failed other treatments.

Timing of Treatment: The better outcomes for RRMS patients compared to progressive forms suggest that earlier intervention during the relapsing-remitting phase may yield superior results. However, even patients with progressive forms showed meaningful benefits, with nearly half showing no disability progression at 5 years.

Safety Considerations: While the procedure carries risks (1.4% mortality rate in this study), these must be balanced against the risks of uncontrolled MS progression. The mortality rate has improved significantly from historical rates of 7.3% due to refinements in patient selection and treatment protocols.

Importance of Center Experience: The concentration of procedures at experienced centers in London and Sheffield likely contributed to the favorable safety profile observed. Patients should seek treatment at centers with substantial experience in MS stem cell transplantation.

Long-Term Monitoring: The findings highlight the importance of long-term monitoring for late effects including secondary autoimmune conditions and malignancies, though these occurred at relatively low rates (7.9% and 1.6% respectively).

Study Limitations

While this study provides valuable real-world data, several limitations should be considered:

Retrospective Design: As a retrospective analysis spanning 20 years, the study lacks the controlled conditions of a randomized trial. Treatment protocols evolved over time, and patient selection criteria may have varied between centers.

Missing Data: Some data points were missing for certain patients, particularly for longer-term follow-up. For example, EBV monitoring was not performed in 53 cases (14.5%), and some late effect data was incomplete.

Selection Bias: Patients selected for transplantation likely represented a specific subgroup with particular characteristics that made them suitable candidates, which may limit generalizability to all MS patients.

Lack of Control Group: Without a control group of similar patients who did not receive transplantation, it's difficult to determine exactly how much benefit was derived specifically from the procedure versus other factors.

Geographical Concentration: The concentration of procedures at specific centers may mean that outcomes reflect the expertise of those particular teams rather than what might be achievable more broadly.

Recommendations for Patients

Based on the findings of this comprehensive study, patients with MS considering stem cell transplantation should:

1. Seek evaluation at experienced centers with multidisciplinary teams including both neurologists and haematologists familiar with MS stem cell transplantation
2. Consider timing carefully - earlier intervention during the relapsing-remitting phase may yield better outcomes
3. Discuss the specific conditioning protocol with their medical team, particularly the ATG dose, as lower doses (≤6.0 mg/kg) were associated with better outcomes
4. Ensure comprehensive viral monitoring is part of their treatment plan, particularly for EBV and CMV
5. Plan for long-term follow-up to monitor for potential late effects including secondary autoimmune conditions and malignancies
6. Advocate for improved access to this treatment across all UK regions to address the current geographical disparities
7. Participate in ongoing research such as the STAR-MS study to help build the evidence base for this treatment

Patients should have realistic expectations about outcomes - while many experience long-term disease stabilization, individual results vary based on MS type, disease duration, disability level, and other factors.

Source Information

Original Article Title: Autologous haematopoietic stem cell transplantation for multiple sclerosis in the UK: A 20-year retrospective analysis of activity and haematological outcomes from the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT)

Authors: Majid Kazmi, Paolo A. Muraro, Varun Mehra, Ian Gabriel, Eleonora De Matteis, Gavin Brittain, Alice Mariottini, Richard Nicholas, Eli Silber, Julia Lee, Rachel Pearce, Ruth Paul, Maria Pia Sormani, Alessio Signori, Victoria Potter, Eduardo Olavarria, Ram Malladi, Basil Sharrack, John A. Snowden

Publication: British Journal of Haematology (2025), DOI: 10.1111/bjh.20199

Note: This patient-friendly article is based on peer-reviewed research published in a medical journal. It is intended to help patients understand the original scientific content but should not replace professional medical advice. Always consult with your healthcare team about treatment decisions.