Stem Cell Transplantation Shows Significant Benefits for Active Secondary Progressive MS Patients

Table of Contents

• Introduction: Understanding Secondary Progressive MS and Treatment Challenges
• Study Methods: How the Research Was Conducted
• Key Findings: Detailed Results and Statistics
• Clinical Implications: What This Means for Patients
• Study Limitations: What the Research Couldn't Prove
• Recommendations: Actionable Advice for Patients
• Source Information

Introduction: Understanding Secondary Progressive MS and Treatment Challenges

Secondary progressive multiple sclerosis (SPMS) represents a challenging phase of MS where patients experience gradual worsening of neurological disability regardless of whether they have obvious relapses. This progressive disability accrual significantly impacts quality of life and daily functioning. While the exact mechanisms driving this progression aren't fully understood, recent evidence points to compartmentalized inflammation within the central nervous system (brain and spinal cord) that continues to drive nerve damage even without visible relapses.

Available disease-modifying therapies (DMTs) have shown only modest benefits for SPMS patients. In recent clinical trials, even the most effective medications have demonstrated limited impact, delaying disability progression by only about 19 days per year. This modest effect highlights the urgent need for more effective treatment approaches for this patient population.

Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment strategy for aggressive forms of MS. This procedure involves harvesting a patient's own blood-forming stem cells, then using intensive chemotherapy to essentially "reset" the immune system, before reinfusing the stem cells to rebuild a new immune system without the autoimmune abnormalities that drive MS.

Study Methods: How the Research Was Conducted

This Italian multicenter study compared outcomes between 79 patients with active SPMS who underwent AHSCT between 1997-2019 and 1,975 patients with SPMS treated with other DMTs extracted from the Italian Multiple Sclerosis Register. The researchers used sophisticated statistical methods to ensure fair comparisons between these groups despite not being a randomized trial.

Patients were included if they had started treatment after their SPMS diagnosis, had baseline Expanded Disability Status Scale (EDSS) scores recorded, and had at least one follow-up visit. The control group included patients treated with various DMTs: beta interferons (24%), azathioprine (13%), glatiramer acetate (13%), mitoxantrone (11%), fingolimod (9%), natalizumab (7%), methotrexate (6%), teriflunomide (6%), cyclophosphamide (6%), dimethyl fumarate (4%), and alemtuzumab (1%).

The transplantation procedure involved mobilizing stem cells from the blood using cyclophosphamide plus filgrastim. Most patients (64 out of 79) received the BEAM conditioning regimen (BCNU, cytosine-arabinoside, etoposide, and melphalan) plus antithymocyte globulin (ATG), while others received different conditioning protocols based on physician choice and patient characteristics.

Researchers used two different statistical approaches to minimize selection bias: propensity score matching (creating comparable groups based on patient characteristics) and overlap weighting (a method that includes all patients while statistically adjusting for differences). These methods accounted for factors including age, sex, baseline disability, previous treatments, relapse rate, disease duration, and treatment start year.

Key Findings: Detailed Results and Statistics

The study revealed dramatic differences between the treatment approaches across multiple outcome measures. The most significant findings include:

Disability Progression

Time to confirmed disability progression (CDP) was significantly longer in AHSCT-treated patients. The hazard ratio was 0.50 (95% CI: 0.31-0.81; p=0.005), meaning transplant recipients had a 50% lower risk of disability worsening compared to those on other DMTs.

At 3 years post-treatment, 71.9% of AHSCT patients remained free from disability progression (95% CI: 58.5-81.5%) compared to only 58.1% of patients on other DMTs (95% CI: 50.3-64.9%). At 5 years, this gap widened further with 61.7% of transplant patients progression-free (95% CI: 47.5-73.1%) versus 46.3% of those on conventional therapies (95% CI: 37.4-54.5%).

Disability Improvement

Perhaps the most remarkable finding was the significant disability improvement observed in AHSCT patients. The improvement rate was 4.21 times higher in transplant recipients compared to those on other DMTs (HR=4.21; 95% CI: 2.42-7.33; p<0.001).

At 1 year post-treatment, 30.2% of AHSCT patients had experienced measurable disability improvement (95% CI: 20.6-42.8%) compared to only 3.4% of those on other DMTs (95% CI: 1.6-7.0%). At 3 years, 38.8% of transplant patients maintained improvement (95% CI: 28.0-51.9%) versus just 7.8% of those on conventional therapies (95% CI: 4.6-12.7%).

Annualized Relapse Rates

The study found dramatically lower relapse rates in AHSCT patients. During the first two years of follow-up, the annualized relapse rate (ARR) was 0.024 (95% CI: 0-0.051) in the transplant group compared to 0.32 (95% CI: 0.24-0.39) in the other DMT group. This represents a 92.5% reduction in relapse risk (RR=0.075; 95% CI: 0.023-0.24; p<0.001).

Over the entire follow-up period, the ARR remained significantly lower in AHSCT patients at 0.020 (95% CI: 0.006-0.034) compared to 0.45 (95% CI: 0.36-0.55) in the other DMT group, representing a 95.6% reduction in relapse risk (RR=0.044; 95% CI: 0.021-0.091; p<0.001).

Disability Trajectory

The longitudinal analysis of EDSS scores revealed strikingly different disability trajectories between the groups. AHSCT patients showed essentially stable disability with an estimated yearly EDSS change of -0.013 points per year (95% CI: -0.087 to 0.061), meaning no significant progression. In contrast, patients on other DMTs showed clear progression with an estimated yearly EDSS change of +0.157 points per year (95% CI: 0.117-0.196). The difference between these trajectories was highly statistically significant (p<0.001).

Clinical Implications: What This Means for Patients

These findings have profound implications for the treatment of active secondary progressive MS. The study provides the strongest evidence to date that AHSCT can significantly alter the natural history of SPMS by not only slowing disability progression but actually enabling neurological improvement in a substantial proportion of patients.

For patients with active SPMS who continue to experience relapses or MRI activity despite conventional treatments, AHSCT represents a potentially transformative treatment option. The dramatic reduction in relapse rates (over 90% reduction) and the significant disability improvement observed in more than one-third of patients suggests that early intervention with AHSCT in appropriate candidates might prevent irreversible neurological damage.

The stability of disability scores over time in transplant recipients compared to the steady progression in those on other DMTs suggests that AHSCT may provide long-term disease control that exceeds what is achievable with currently available medications. This is particularly important for SPMS patients, who typically experience gradual decline despite treatment.

It's important to note that seven patients (8.9%) in the transplant group required additional DMTs after AHSCT, beginning at a median of 2.2 years post-transplant. This suggests that while AHSCT provides robust and long-lasting benefits for most patients, some may still require additional therapy, highlighting the importance of continued monitoring even after transplantation.

Study Limitations: What the Research Couldn't Prove

While these results are compelling, several limitations must be considered when interpreting the findings. This was not a randomized controlled trial but rather an observational study comparing patients who received different treatments. Despite sophisticated statistical methods to minimize selection bias, unmeasured factors could still influence the results.

The study population was relatively small (79 AHSCT patients), and the treatment was performed across 14 different centers with some variation in transplantation protocols. While most patients received the BEAM+ATG regimen, some received alternative conditioning regimens, which could affect outcomes.

MRI data were not available for most patients in the control group, so the researchers could not fully account for MRI activity in their statistical adjustments. This is important because MRI activity might influence both treatment decisions and outcomes.

The follow-up duration varied between patients, and longer-term outcomes beyond 10 years are not yet available. Additionally, the study focused specifically on patients with "active" SPMS (those with recent relapses or MRI activity), so the results may not apply to patients with non-active SPMS.

Finally, as with all observational studies, there may be unmeasured confounding factors that influenced both treatment selection and outcomes that the statistical methods could not fully account for.

Recommendations: Actionable Advice for Patients

Based on these findings, patients with active secondary progressive MS should consider the following:

1. Discuss AHSCT with your neurologist if you have active SPMS with ongoing relapses or MRI activity despite conventional treatments. This may be particularly relevant for younger patients with more aggressive disease.
2. Seek evaluation at a specialized MS center with experience in both MS management and stem cell transplantation to determine if you might be a suitable candidate for this procedure.
3. Understand the risks and benefits - While AHSCT shows impressive efficacy, it carries significant risks including infection, infertility, and other treatment-related complications that must be carefully weighed against potential benefits.
4. Consider timing carefully - Earlier intervention during the active phase of SPMS may provide the greatest opportunity for preventing irreversible disability accumulation.
5. Maintain realistic expectations - While many patients experience significant benefits, results vary, and some patients may still require additional therapies after transplantation.
6. Participate in ongoing monitoring - Regular follow-up is essential even after successful transplantation to detect any potential disease reactivation or late complications.

This research represents an important step forward in the treatment of secondary progressive MS, offering hope for more effective disease modification beyond what conventional therapies can provide. As always, treatment decisions should be made collaboratively between patients and their healthcare teams based on individual circumstances, preferences, and risk tolerance.

Source Information

Original Article Title: Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis

Authors: Giacomo Boffa, MD; Alessio Signori, PhD; Luca Massacesi, MD; Alice Mariottini, MD, PhD; Elvira Sbragia, MD; Salvatore Cottone, MD; Maria Pia Amato, MD; Claudio Gasperini, MD, PhD; Lucia Moiola, MD, PhD; Stefano Meletti, MD, PhD; Anna Maria Repice, MD; Vincenzo Brescia Morra, MD; Giuseppe Salemi, MD; Francesco Patti, MD; Massimo Filippi, MD; Giovanna De Luca, MD; Giacomo Lus, MD; Mauro Zaffaroni, MD; Patrizia Sola, MD, PhD; Antonella Conte, MD, PhD; Riccardo Nistri, MD; Umberto Aguglia, MD; Franco Granella, MD; Simonetta Galgani, MD; Luisa Maria Caniatti, MD; Alessandra Lugaresi, MD, PhD; Silvia Romano, MD, PhD; Pietro Iaffaldano, MD; Eleonora Cocco, MD; Riccardo Saccardi, MD; Emanuele Angelucci, MD; Maria Trojano, MD; Giovanni Luigi Mancardi, MD; Maria Pia Sormani, PhD; and Matilde Inglese, MD, PhD

Publication: Neurology 2023;100:e1109-e1122. doi:10.1212/WNL.0000000000206750

Note: This patient-friendly article is based on peer-reviewed research from the Italian BMT-MS Study Group and the Italian MS Register involving 79 AHSCT patients and 1,975 patients treated with other disease-modifying therapies.