Stem Cell Transplant vs MS Medications: What Patients Need to Know

Table of Contents

• Introduction: Understanding the Treatment Options
• Study Design and Methods
• Patient Characteristics
• Key Findings: Treatment Comparisons
• Safety Information
• Clinical Implications for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Understanding the Treatment Options

Autologous hematopoietic stem cell transplant (AHSCT) is a powerful treatment approach for highly active multiple sclerosis that involves using a patient's own stem cells to reset the immune system. This intensive procedure begins with chemotherapy to suppress the immune system, followed by transplantation of previously collected stem cells to rebuild a new immune system that may not attack the nervous system.

The treatment carries significant risks, including a 0.3% to 2% treatment-related mortality rate, though this risk has decreased in recent years due to better patient selection and increased center experience. Researchers designed this study to compare AHSCT against three established MS medications: fingolimod (a moderate-efficacy therapy), and natalizumab and ocrelizumab (both high-efficacy therapies).

Understanding how AHSCT compares to these powerful medications is crucial for patients and doctors making treatment decisions for highly active relapsing-remitting MS. This study represents one of the most comprehensive comparisons to date, involving nearly 5,000 patients from specialized centers around the world.

Study Design and Methods

This observational study emulated clinical trials by comparing AHSCT against the three medications using sophisticated statistical methods to ensure fair comparisons. Researchers collected data from May 2006 to December 2021 from six specialized MS centers with AHSCT programs and 94 centers across 27 countries participating in the MSBase international registry.

The study included 4,915 patients with relapsing-remitting MS who received either AHSCT (167 patients), fingolimod (2,558 patients), natalizumab (1,490 patients), or ocrelizumab (700 patients). All patients had at least two years of follow-up with multiple disability assessments. Researchers used propensity score matching, a statistical technique that helps ensure compared groups are similar in their clinical characteristics, making the comparisons more valid.

The AHSCT procedure followed specific protocols at each center. Patients typically received cyclophosphamide chemotherapy (2-4.5 g/m²) with granulocyte colony-stimulating factor to mobilize stem cells, which were then collected and cryopreserved. Approximately one-third of patients had their stem cells purified using CD34 selection. The transplant conditioning regimens included:

• BEAM protocol (carmustine, etoposide, cytarabine, and melphalan)
• Busulfan with cyclophosphamide
• Cyclophosphamide with antithymocyte globulin

Patients in the medication groups received standard dosing: fingolimod (0.5 mg daily orally), ocrelizumab (600 mg intravenously every 6 months), or natalizumab (300 μg intravenously every 4 weeks). The researchers analyzed outcomes including annualized relapse rates, freedom from relapses, and disability changes measured by the Expanded Disability Status Scale (EDSS).

Patient Characteristics

Before matching, the AHSCT patients tended to be younger and have greater disability than those in the medication groups. After statistical matching, the groups were well-balanced with similar characteristics:

The matched groups included:

• AHSCT vs fingolimod: 144 AHSCT patients vs 769 fingolimod patients
• AHSCT vs natalizumab: 146 AHSCT patients vs 730 natalizumab patients
• AHSCT vs ocrelizumab: 110 AHSCT patients vs 343 ocrelizumab patients

Across all groups, women represented 65-70% of patients. The average age ranged from 35.3 to 37.1 years, disease duration from 7.9 to 8.7 years, and EDSS scores from 3.5 to 3.9 (moderate disability). Patients had experienced 0.77-0.86 relapses in the year before treatment, indicating highly active disease.

Among AHSCT patients, the conditioning intensity varied: 26% received high-intensity, 29% intermediate-intensity myeloablative, 38% intermediate-intensity lymphoablative, and 7% low- to intermediate-intensity protocols.

Key Findings: Treatment Comparisons

The study revealed important differences in effectiveness between AHSCT and the three medications:

AHSCT vs Fingolimod (5-year follow-up)

AHSCT demonstrated substantially superior effectiveness compared to fingolimod. The annualized relapse rate was significantly lower with AHSCT: 0.09 (SD 0.30) versus 0.20 (SD 0.44) with fingolimod. This represents a 55% reduction in relapse rate that was highly statistically significant (P < 0.001).

The hazard ratio for relapses was 0.26 (95% CI, 0.18-0.36), meaning AHSCT patients had a 74% lower risk of experiencing relapses. While both treatments showed similar risk of disability worsening (HR 1.70; 95% CI, 0.91-3.17), AHSCT was associated with a significantly higher chance of disability improvement (HR 2.70; 95% CI, 1.71-4.26) - nearly three times more likely than with fingolimod.

AHSCT vs Natalizumab (5-year follow-up)

AHSCT showed marginal superiority over natalizumab. The annualized relapse rate was slightly lower with AHSCT: 0.08 (SD 0.31) versus 0.10 (SD 0.34) with natalizumab, a difference that was statistically significant (P = 0.03).

The hazard ratio for relapses was 0.51 (95% CI, 0.34-0.74), indicating a 49% lower relapse risk with AHSCT. The risk of disability worsening was similar between treatments (HR 1.06; 95% CI, 0.54-2.09), but AHSCT again showed significantly better disability improvement outcomes (HR 2.68; 95% CI, 1.72-4.18).

AHSCT vs Ocrelizumab (3-year follow-up)

With the shorter available follow-up period, AHSCT and ocrelizumab showed remarkably similar effectiveness. The annualized relapse rates were comparable: 0.09 (SD 0.34) for AHSCT versus 0.06 (SD 0.32) for ocrelizumab, with no statistical difference (P = 0.86).

The hazard ratio for relapses was 0.75 (95% CI, 0.36-1.57), indicating no significant difference in relapse risk. Both treatments showed similar results for disability worsening (HR 1.77; 95% CI, 0.61-5.08) and disability improvement (HR 1.37; 95% CI, 0.66-2.82).

Safety Information

The study provided detailed safety data for the AHSCT patients. Among 159 matched AHSCT patients, researchers reported the following complications:

• Febrile neutropenia during mobilization: 23.3% (37 patients)
• Serum sickness: 11.3% (18 patients)
• Intensive care unit admission: 8.8% (14 patients)

After discharge following AHSCT, 82 serious adverse events occurred in 58 patients. The majority of these (59.8%) were infections, with viral infections representing 41.5% of all serious adverse events.

Tragically, one treatment-related death occurred (0.6% mortality rate) due to veno-occlusive disease of the liver following busulfan conditioning. This mortality rate falls within the expected range for AHSCT procedures and highlights the serious risks associated with this treatment.

Clinical Implications for Patients

This research provides valuable insights for patients considering treatment options for highly active relapsing-remitting MS. The findings suggest that AHSCT offers substantial benefits for reducing relapse activity compared to fingolimod and natalizumab, with similar effectiveness to ocrelizumab over the available follow-up period.

Perhaps most importantly, AHSCT demonstrated a significantly higher rate of disability improvement compared to both fingolimod and natalizumab. Approximately 30% of AHSCT patients experienced measurable recovery from disability, particularly during the first year after treatment. This finding is especially notable because natalizumab itself is known to have a relatively high rate (25%) of disability improvement shortly after treatment initiation.

The similar outcomes between AHSCT and ocrelizumab are particularly noteworthy, as ocrelizumab is considered one of the most effective currently available MS medications. However, the shorter follow-up period for ocrelizumab comparisons (3 years versus 5 years for the other medications) means longer-term comparisons are needed.

Study Limitations

While this study provides valuable information, patients should understand its limitations. As an observational study rather than a randomized controlled trial, there may be unmeasured factors that influenced the results despite sophisticated statistical matching.

The follow-up period for ocrelizumab was shorter (3 years) than for the other medications (5 years), which limits direct comparisons. Ocrelizumab is a newer medication, so longer-term data simply wasn't available yet.

Treatment decisions were made by doctors and patients rather than random assignment, which could introduce selection bias. Patients choosing AHSCT might have different characteristics or disease severity than those choosing medications, even after statistical adjustments.

The study didn't include magnetic resonance imaging (MRI) outcomes, which provide important information about disease activity that isn't always apparent through clinical measures alone.

Patient Recommendations

Based on this research, patients with highly active relapsing-remitting MS should consider the following:

1. Discuss all options with your neurologist, including AHSCT and high-efficacy medications like natalizumab and ocrelizumab
2. Consider AHSCT if you have highly active disease that hasn't responded adequately to other treatments
3. Understand the risks - AHSCT carries significant short-term risks including infection and rare mortality (0.6% in this study)
4. Consider timing - The disability improvement benefits of AHSCT were most pronounced in the first year after treatment
5. Seek specialized centers - AHSCT should only be performed at experienced centers with multidisciplinary teams
6. Factor in follow-up duration - While AHSCT showed similar effectiveness to ocrelizumab, we need longer-term data for complete comparison

This study provides strong evidence that AHSCT can be a highly effective treatment option for appropriate patients with highly active relapsing-remitting MS. The decision between AHSCT and high-efficacy medications should be made through detailed discussions with your healthcare team, considering your specific disease characteristics, personal preferences, and risk tolerance.

Source Information

Original Article Title: Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis

Authors: Tomas Kalincik, MD, PhD; Sifat Sharmin, PhD; Izanne Roos, MBChB, PhD; et al

Publication: JAMA Neurology

Publication Date: May 15, 2023

Volume and Issue: Vol. 80, No. 7

Pages: 702-713

DOI: 10.1001/jamaneurol.2023.1184

This patient-friendly article is based on peer-reviewed research originally published in JAMA Neurology. It maintains all significant findings, data points, and conclusions from the original study while making the information accessible to patients and caregivers.