INDEX:

🔵 For Patients

Introduction

Clinical Studies

Immunological Evidences

🔵 For Healthcare Professionals

Introduction

Meta-Analysis

Systemic Review

RCTs

Observational Prospectives

Propensity Score

Observational Retrospectives

Case-Series

Expert Opinion

Immunological Evidences

Long-Term Benefits

Quality Of Life

Pharmacoeconomics

Tools to Understand Studies

On curems.net, all references to AHSCT (i.e., transplant) refer specifically to procedures performed using an intermediate-intensity conditioning regimen. References to AHSCT should therefore not be interpreted as encompassing other alternative conditioning intensities unless this is clearly specified. For more information on conditioning protocols click here.

For Patients

Introduction

How do we know if an MS treatment work?

When the patient is on treatment with a DMT (Disease Modifying Treatment) neurologists look at a few key signs to see if a treatment is helping, in particular an important measure is the evaluation if the patient is persistently in a condition called NEDA-3 (No Evidence of Disease Activity), that is the patient do not have:

  1. No relapses – the patient doesn’t have new clinical attacks.
  2. No worsening of disability – the ability to move, see, or think isn’t getting worse.
  3. No new MRI activity – brain scans don’t show new or enlarging damage.

Neurologists also check if the treatment is helping the patient feel better and improving their quality of life (QoL).

We at CureMS.net reviewed studies on AHSCT, focusing on patients with relapsing-remitting MS, and treated with an intermediate conditioning protocols such as BEAM-ATG or Cy-ATG.

Is the transplant more effective than the other therapies?

Ten years after transplant, 40–78% of patients were in a state of No Evidence of Disease Activity-3 (NEDA-3) continuously for 10 years without treatments (DMTs).

Among the studies presented above, those employing the BEAM + ATG conditioning regimen in RRMS, achieved NEDA-3 rates between 55% and 78%.

The table below presents a concise comparison of the effectiveness of AHSCT versus various disease-modifying therapies (DMTs) used to treat MS, as reported across 14 studies:

  • NEDA-3 – No Evidence of Disease Activity: means no relapses, no new MRI lesions, and no worsening of disability.
  • ARR – Annualized Relapse Rate: the average number of relapses a person has in one year.
  • MRI – Magnetic Resonance Imaging: a brain scan that shows if there are new or active lesions related to MS.
  • Less EDSS worsening – fewer people showed worsening of disability (based on the EDSS scale).
  • More EDSS improvement – more people showed improvement in their level of disability (based on the EDSS scale).
  • QoL – Quality of Life: how good and satisfying daily life feels, including physical, emotional, and social well-being.

The table above shows that none of the DMTs worked better clinically or radiologically than AHSCT.

What kinds of studies are done to assess whether a treatment is effective?

There are different types of studies, each providing evidence of varying strength.

CureMS.net adopts the study classification known as the “pyramid of evidence” (see figure below), which ranks studies according to the quality of their evidence.

Figure by openmd.com

This approach is rooted in evidence-based medicine (EBM), which is the practice of making medical decisions based on the best available scientific evidence. In this context, “quality of evidence” means that studies:

⬆️ at the top of the pyramid are more reliable because they use strong methods, large groups, and careful controls, while

⬇️ studies at the bottom rely on smaller or less controlled groups.

By following this hierarchy, EBM helps ensure that treatments and recommendations are grounded in solid research rather than anecdote or speculation.

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Clinical Studies

Meta-Analysis

This is when scientists combine the results of many studies on the same topic. By looking at all the data together, they can get a clearer picture of how well a treatment works and how safe it is.

From this large international analysis by Sormani et al., 2017 — combining data from 15 studies from 1995 to 2016, and over 700 people with severe MS with a follow-up of 5 years— the message is clear and encouraging:

AHSCT can dramatically slow or stop MS activity in many patients, especially those with aggressive RRMS.
Most people (about 8 out of 10) had no relapses, no new MRI lesions, and no disability worsening for years after treatment. NEDA patients at 5 years was 67%.
The procedure has also become much safer — treatment-related deaths have dropped from about 2% in older studies to less than 0.5% (post-2005). 

Between 2016 and 2025, treatment-related mortality (TRM) rates have declined to 0.2% in 2022 (see here). 

The best outcomes are seen in patients with active inflammation and lower disability before transplant. 

In simple terms:
– AHSCT can “reboot” the immune system and keep MS quiet for years. 

– It’s safest and most effective for people with relapsing MS who still have active inflammation but haven’t yet developed severe disability. 

– As indicated by the authors ”The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability”

🟢 Bibliography: Sormani et al., 2017

Systematic Review

A systematic review is like a careful “big-picture summary” of everything that’s been studied about a certain treatment.
Researchers look at all available studies, check their quality, and summarize what we can confidently say — and what we still don’t know.

These studies confirms that AHSCT is a powerful treatment option for multiple sclerosis when used in the right patients.

The Dos Santos Flora 2025 review shows that AHSCT can greatly reduce relapses, improve function, and even restore healthy immune balance — with lasting effects on inflammation and nerve protection. It’s effective and safe when done with proper patient selection and monitoring.

The Braun 2024 study finds that AHSCT works best for relapsing MS, while benefits in progressive MS are more variable. Some progressive patients, especially those with active inflammation, can still gain meaningful stability.

In simple terms:
AHSCT can “reset” the immune system and keep MS quiet for years. It’s safest and most effective for relapsing MS and for selected progressive cases with active disease.

🟢 Bibliography: Dos Santos Flora et al., 2025 | Braun et al., 2024

RCTs

In RCTs studies (Randomized Controlled Trials), people are randomly put into different groups. One group gets the treatment being tested (like AHSCT), and another group gets a different treatment or standard care (such as a common DMTs).
Because the groups are chosen at random, it helps make sure the results are fair and not influenced by outside factors.

These two RCTs demonstrate superior inflammatory suppression with AHSCT compared to standard therapies. 

MIST confirms clinical benefit (relapse and disability improvement), while ASTIMS reinforces radiological efficacy. Moreover MIST study confirms an improvement in QoL. Collectively, they support AHSCT as a highly effective option for aggressive or refractory MS.

🟢 Bibliography: MIST Trial | ASTIMS Trial

Observational Prospectives

In this type of study, researchers enroll MS patients before they undergo AHSCT and follow them for months or years to observe how the treatment affects disease activity, relapse rates, disability progression, and adverse events (AEs).

Among six studies conducted between 2010 and 2025 show that: AHSCT stands out as a powerful and increasingly safe treatment for people with highly active or treatment-resistant MS, especially the relapsing type.

  • Long-term control: Most patients stay free from relapses and new lesions for many years for 5 to 10 years. 
  • Improvement possible: Some patients can experience recovery, while the majority can maintain their physical and cognitive function.
  • Safer today: Over the years, treatment-related mortality has dropped (<0.5%) along with the overall risk of adverse events. 
  • Works best for active MS: Benefits are strongest when inflammation is still present.

In simple terms: AHSCT can “reset” the immune system and offer long-lasting remission — more effectively and durably than standard MS therapies.

🟢 Bibliography: Giedraitiene et al., 2025 | Braun et al., 2024 | Burt et al., 2022 | Häußler et al., 2021 | Nash et al., 2017 | Hamerschlack et al., 2010

Propensity Score

Propensity studies try to make two groups of patients as similar as possible — for example, those who got AHSCT and those who used a DMT — by matching them based on age, disease severity, and other factors.
This helps make the comparison fairer, even if people weren’t randomly assigned.

Across propensity-matched and real-world comparative studies, AHSCT consistently outperforms medium- and high-efficacy DMTs (fingolimod, natalizumab, anti-CD20s) in relapse suppression and disability improvement for highly active RRMS.

  • In progressive MS, results are more heterogeneous — while AHSCT provides stronger relapse control than conventional or low-intensity immunosuppression, its impact on disability progression remains modest, reflecting the neurodegenerative drive of later disease stages.
  • Safety profiles have improved substantially, with minimal or no recent treatment-related mortality, positioning AHSCT as the most potent immune reconstitution option for active RRMS and active SPMS, but with limited benefit in advanced, non-inflammatory SPMS.

In simple terms: 

AHSCT offers the strongest disease control available for inflammatory MS, but its advantage fades once inflammation gives way to neurodegeneration.

🟢 Bibliography: Kalincik et al., 2025 | Kalincik et al., 2024 | Boffa et al., 2023 | Kalincik et al., 2023 | Mariottini et al., 2022

Observational Retrospectives

In this type of study, researchers look at MS patients who already had AHSCT and review their medical records to analyze outcomes or complications.

Across the world — from the UK, Italy, Denmark, Sweden, and beyond — the evidence is remarkably consistent:

  • AHSCT can “reset” the immune system and stop MS activity for years.
  • It works best for relapsing MS with active inflammation.
  • It can improve disability, not just stabilize it.
  • Modern approaches are much safer, with very low treatment-related deaths (<1%).
  • Progressive MS or high disability reduces the benefit.

In simple terms:
AHSCT isn’t an experimental therapy anymore — it’s a powerful, one-time treatment that can give people with aggressive MS a second chance at long-term remission and stability. 

🟢 Bibliography: Muraro et al., 2025 | Kazmi et al., 2025 | Jespersen et al., 2023 | Boffa et al., 2021 | Das et al., 2021 | Zhukovsky et al., 2021 | Nicholas et al., 2021 | Boffa et al., 2020 | Muraro et al., 2017 | Burman et al., 2014

Case Series

A case series describes what happened to a small group of patients who all received the same treatment. It’s like a collection of personal stories from real patients — useful for learning early lessons, but not strong enough to prove cause and effect.

Effectiveness: Most patients treated with AHSCT stop having relapses. Many experience stable or improved disability, and brain changes often settle after the first few years.

Safety: AHSCT is generally safe when done in expert centers. Serious side effects are uncommon. Some patients may develop thyroid problems later, but severe infections are rare.

In simple terms:
AHSCT can strongly control aggressive or treatment-resistant MS by resetting the immune system. It works best in patients with active disease, especially earlier in the disease course. Research is ongoing to define its role as a standard treatment.

🟢 Bibliography: Ünsal et al., 2025, Patti et al., 2022

Expert Opinion

Sometimes, when research is limited, doctors rely on their experience and knowledge to guide treatment decisions. It’s helpful, but it’s the least strong kind of evidence because it’s based more on experience than data.

For people with highly active relapsing MS, the goal of treatment is often NEDA-3 —meaning no relapses, no worsening disability, and no new signs of disease on MRI. Standard therapies usually achieve this in only a minority of patients, and maintaining it over time is difficult.

  • AHSCT “resets” the immune system, stopping disease activity more effectively than standard treatments.
  • Around 78–83% of patients stay relapse-free and stable at 2 years, and 60–68% at 5 years—much higher than with typical therapies.
  • Even though patients receiving AHSCT usually have more aggressive disease, outcomes are better.
  • Serious risks are now low, with death related to the procedure occurring in only about 1% of patients, and safer treatment methods further reduce complications.

In simple terms:
AHSCT can provide long-lasting control of aggressive MS with a favorable safety profile. Ongoing research will clarify whether it should become a standard option for patients with highly active disease.

🟢 Bibliography: Sormani et al., 2017

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Immunological Evidences

Understanding Immune Reconstitution After AHSCT for MS

When you undergo AHSCT for MS, your immune system goes through a complete “reset.” Here’s how it works in simple terms:

A Helpful Analogy

Think of your immune system like a computer infected by a virus.

AHSCT is like wiping the hard drive and reinstalling a clean operating system.

It takes time to reinstall your programs (your immune cells), but once that’s done, your system runs cleanly and efficiently again—without the old autoimmune “bugs”.

Following the immune reconstitution timeline from day 0 to full recovery:

1. The Reset Phase (Day 0 – 2 weeks)

Before the transplant, you receive chemotherapy that wipes out most of your existing immune cells – including the “faulty” ones that have been attacking your nervous system.
Your own stem cells (collected earlier from your blood) are then returned to your body.
These stem cells travel to your bone marrow and start rebuilding your immune system from scratch (day 0). Read more about the procedure here.
Patient advice: For the first 2–3 weeks, you’ll stay in a protected hospital room (hematology unit). This controlled environment helps prevent infections while your new immune system begins to grow.
Focus on rest, gentle movement, balanced nutrition, and strict hygiene.

2. The Rebuilding Phase (Weeks to 12 Months)

This rebuilding happens gradually over 1–2 years, as different types of immune cells return and mature at different times. It’s a complex and slow process, and some stages may overlap.

Your body starts producing new immune cells.

  • Innate immunity (your first line of defense) recovers first: neutrophils, monocytes, and NK cells return in the first few weeks.

  • You remain more vulnerable to infections during this early period.

Patient advice: Once home, give your body time to heal. Avoid crowded places, limit close contact, and wear a mask if you need to go out or back to work.
Stay in touch with your medical team to plan vaccinations and monitor progress.

More specialized immune cells gradually reappear and mature:

  • T cells and B cells slowly rebuild your adaptive immunity.

  • Regulatory T cells help restore immune balance and reduce autoimmunity.

 Patient advice: During this period, your immune system continues to stabilize. You can gradually return to social activities, according to your doctor’s advice.

3. Full Recovery (12–24 months)

By this stage, most people reach a “new normal”, where the immune system functions well and infection risk is low. Immune balance and tolerance are re-established.

  • Different types of T and B cells regain their normal numbers and function.

  • The immune system becomes capable of responding to new infections and vaccines.

  • Regulatory T cells help maintain long-term tolerance, keeping autoimmune activity under control.

Patient advice: You can fully return to normal life, including work, travel, and social activities — always maintaining healthy routines and regular check-ups.

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For Healthcare Professionals

Introduction

What are the indicators used to measure clinical evidence in MS?

To assess clinical evidences in MS field, NEDA-3, relapse-rate, EDSS score, QoL, and radiological data as valuable indicators.

CureMS.net screened PubMed and Google Scholar, along with AHSCT reviews. We pinpointed 22 studies that met the following criteria: the study had to involve AHSCT, include data on RRMS patients, and use an intermediate conditioning protocol.

The 10-year follow-up of RRMS patients who underwent AHSCT with an intermediate conditioning protocol shows that 40-78% of patients maintain NEDA-3 at 10 years post-transplant. Specifically, the four studies using BEAM and ATG reported 10-year NEDA-3 rates between 55% and 78%.

The total number of patients across these studies is 1145, though some patients appear in multiple studies.

The analysis of the results shows that no treatment, in any study, has been proven to be more effective, radiologically, clinically, immunologically, and pharmaco-economically, than AHSCT (i.e., transplant).

In the following table, we include the studies comparing AHSCT vs other DMTs.

Studies cited in the table above:

 

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Meta-Analysis

A meta-analysis statistically integrates findings from MS, combining qualitative evaluation of study features (e.g., methodology, data quality, potential bias) with quantitative synthesis of numerical results (ex.: pooling relapse-rate outcomes across several trials).
 

Sormani et al., 2017 “Autologous hematopoietic stem cell transplantation in multiple sclerosis. A meta-analysis”. Neurology.

🔹Background: MS is often aggressive and refractory to standard DMTs. AHSCT is investigated as an immune reset for severe MS.

🔹Aim: To summarize the evidence on AHSCT for severe and treatment-refractory MS by pooling data (1995–2016) to estimate Transplant-Related Mortality (TRM), disability progression, and No Evidence of Disease Activity (NEDA).

🔹Key Findings:

  • Pooled Data: 15 studies with 764 patients.
  • TRM: Pooled TRM was 2.1%. TRM was significantly lower in recent studies (0.3% post-2005) and in patients with RRMS and lower baseline disability.
  • Efficacy: Progression was 17.1% at 2 years and 23.3% at 5 years. NEDA status was achieved by 83% at 2 years and 67% at 5 years.

🔹Conclusions: AHSCT offers the best benefit/risk profile for patients with aggressive, Relapsing-Remitting MS and low disability. High NEDA rates are superior to most highly effective DMTs, and safety has significantly improved (TRM 0.3% post-2005).

Figure from Sormani et al. “Autologous hematopoietic stem cell transplantation in multiple sclerosis. A meta-analysis”. Neurology (2017)

 

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Systemic Review

A systematic review uses rigorous, standardized procedures to identify, select, and critically assess peer-reviewed evidence on a specific health question and does not necessarily include quantitative synthesis (ex.: screening all published trials on AHSCT for predefined eligibility criteria).
 

Dos Santos Flora et al., (2025) “Esperança na reconstituição imune: avanços do transplante de células-tronco na esclerose múltipla”. JMBR Medicine.

🔹Background: MS is a chronic autoimmune inflammatory disease of the central nervous system, characterized by clinical relapses and neurological progression. While DMTs have advanced, their therapeutic limitations remain evident, particularly in the aggressive and progressive forms of the disease. AHSCT has emerged as a promising alternative therapeutic strategy.

🔹Aim: This integrative review aimed to analyze the available scientific evidence regarding the efficacy, safety, and underlying immunological mechanisms associated with AHSCT in the treatment of MS.

🔹Key Findings:

  • The review analyzed 19 studies selected from the PubMed Central database.
  • Findings demonstrated significant clinical improvement, a marked reduction in relapse rates, and the normalization of key biomarkers of axonal damage and demyelination, such as Neurofilament Light Chain (NFL) and Myelin Basic Protein (MBP).
  • Long-lasting immunomodulatory effects were observed, including the suppression of pro-inflammatory cytokines and a beneficial modulation of the immune response to the Epstein-Barr virus (EBV).
  • Despite its efficacy, the procedure necessitates caution due to potential metabolic and reproductive adverse effects, underscoring the critical need for careful patient selection and intensive monitoring.

🔹Conclusions: When properly indicated and rigorously monitored, AHSCT represents an effective and safe strategy for patients with refractory MS. The procedure offers a durable immunological reset with the potential to significantly modify the clinical course of the disease.

Braun et al. “Exploring the therapeutic potential of autologous hematopoietic stem cell transplantation in progressive multiple sclerosis—a systematic review”. European Journal of Neurology.

🔹Background: Progressive Multiple Sclerosis (PMS), including PPMS and SPMS, is characterized by a shift towards chronic neurodegeneration with limited efficacy from current DMTs. AHSCT has shown promise in highly active RRMS, but its value in halting progression in PMS remains controversial.

🔹Aim: The aim was to determine the therapeutic value of AHSCT as an intervention for PMS by systematically reviewing the current literature and analyzing individual patient data.

🔹Key Findings:

  • Cohort: The review included 15 studies encompassing 665 PMS patients (74 PPMS, 591 SPMS). PMS patients presented with more severe disability at baseline compared to RRMS cohorts.
  • Transplant-Related Mortality (TRM): The pooled TRM for PMS patients was low, averaging 1.9% across the studies that reported separate data for this group.
  • Progression-Free Survival (PFS): PFS showed high variability among PMS cohorts, ranging from 0% to 78% at 5 years after treatment initiation. This range was lower than in RRMS cohorts (63% to 100% at 4 years).
  • NEDA-3: The percentage of patients achieving NEDA-3 at 5 years also ranged widely, from 0% to 75%.
  • Efficacy Comparison: One study showed that AHSCT maintained PFS in a significantly higher proportion of SPMS patients (61.7% at 5 years) compared to those treated with anti-inflammatory DMTs (46.3%). Furthermore, AHSCT achieved 100% relapse-free survival in some PMS cohorts.

🔹Conclusions: Based on the available data, AHSCT does not consistently halt progression in all people with PMS. However, there is strong evidence suggesting an improved outcome in selected patients, particularly those with active inflammatory disease (SPMS) and lower baseline disability. Due to significant heterogeneity in patient groups and reported outcomes, more comprehensive clinical trials are urgently needed for effective patient stratification.

 

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RCTs

RCTs allocate participants randomly to intervention or control groups to evaluate therapeutic or preventive strategies, providing the most robust form of causal inference in clinical research (ex.: comparing AHSCT versus DMTs with random assignment).

🔵 View supplementary definitions here.

RCTs completed

with published data

ASTIMS (2015) and MIST (2018) are completed RCTs demonstrating superiority of AHSCT over mitoxantrone or various DMTs, though they precede newer agents such as anti-CD20 therapies (ex.: interpreting MIST relapse-free survival outcomes).

Below, the table that summarizes ASTIMS and MIST trial.

Table from Cohen et al. “Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation”. Biol Blood Marrow Transplant (2019).

Mancardi et al., 2015 “Autologous hematopoietic stem cell transplantation in multiple sclerosis. A phase II trial”. Neurology.

🔹Background: For patients with severe MS who do not respond to standard treatments, intense immunosuppression followed by AHSCT has been proposed to reset the immune system.

🔹Aim: To compare the effect of AHSCT versus mitoxantrone (MTX) on MRI-measured disease activity in patients with severe MS.

🔹Key Findings: AHSCT reduced the number of new T2 MRI lesions by 79% compared to MTX. No patients in the AHSCT group developed new active (Gd+) lesions, compared to 56% in the MTX group. The relapse rate was also significantly lower with AHSCT. However, no significant difference was found in disability progression between the two groups.

🔹Conclusions: AHSCT is significantly superior to MTX in suppressing inflammatory MRI activity in severe MS. The results strongly support further studies to evaluate AHSCT’s effect on clinical endpoints.

Figure from Mancardi et al. “Autologous hematopoietic stem cell transplantation in multiple sclerosis A phase II trial”. Neurology (2015).

Burt et al., 2019 “Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis. A Randomized Clinical Trial”. JAMA

🔹Background: Standard DMTs are often insufficient for controlling highly active RRMS. AHSCT is a therapy designed to reset the immune system.

🔹Aim: To compare the effectiveness of nonmyeloablative AHSCT versus DMT on disease progression in patients with active RRMS.

🔹Key Findings: Disease progression occurred in 3 HSCT patients versus 34 DMT patients (Hazard Ratio, 0.07). In the first year, disability scores (EDSS) improved in the HSCT group but worsened in the DMT group. The relapse rate was 2% in the HSCT group versus 69% in the DMT group. No deaths or major toxicities occurred in the HSCT group.

🔹Conclusions: In patients with active RRMS, AHSCT was significantly more effective than DMT at preventing disease progression and improving disability. 

 

RCTs - Ongoing Trials

To date, there are 4 ongoing trials. For more information, please visit the following links: BEAT-MS, NET-MS, RAM-MS trial and STAR-MS.

For the section dedicated to trials on this website, click here and here for an overview.

RCTs - Terminated

Some trials do not reach publication due to operational, methodological, or recruitment constraints. COAST stopped due to low acceptance of the control arm, and MOST ended following the principal investigator’s sabbatical.

🔵 View supplementary definitions here.

The COAST trial (“Ocrelizumab or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis – a Phase-2 Randomised Controlled Trial”) was a multicenter controlled phase II trial aimed at comparing the efficacy and safety of ocrelizumab and alemtuzumab with AHSCT in patients with active RRMS.

Participants were randomized to receive either ocrelizumab, alemtuzumab, or AHSCT. The primary endpoint was time to treatment failure, defined by failure of NEDA (no evidence of disease activity), which includes no progression in EDSS, no relapse, no new T2 lesions, and no gadolinium-enhancing lesions.

This study was terminated due to lack of recruitment caused by low acceptance of the control arm.

This study highlights the difficulty of conducting randomized studies where one of the arms is AHSCT. Another difficulty in conducting these studies is the lack of sponsorship from pharmaceutical companies.

The MOST trial (“Maximizing Outcome of Multiple Sclerosis Transplantation”) Northwestern University (USA) was a “randomized study of autologous unmanipulated peripheral blood hematopoietic stem cell transplant (HSCT) comparing two regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).”

This study terminated due to sabbatical principal investigator. The last updated was on 2021-01-11.

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Observational Prospectives

These studies follow individuals forward in time to examine associations between exposures and subsequent outcomes without investigator intervention (ex.: monitoring patients post-AHSCT to document long-term disability trajectories).

Giedraitiene et al., 2025. “Disease modifying therapy after autologous haematopoietic stem cell transplantation in multiple sclerosis patients: 10-years follow-up data from Lithuania“. MSRD

🔹Background: AHSCT is an emerging treatment for highly active RRMS. However, there is limited evidence on the long-term role of DMTs after AHSCT.

🔹Aim: To evaluate long-term outcomes of MS patients treated with AHSCT in Lithuania from May 2014 to January 2025 and to explore treatment strategies, including the use of DMT, in those with disease activity after transplantation.

🔹Key findings: Forty-two RRMS patients underwent AHSCT with a median follow-up of 65 months. 65% achieved sustained NEDA-3, and 35% showed early and lasting improvement in disability. About 29% required additional DMT post-AHSCT, mostly ocrelizumab or siponimod, which proved effective in stabilizing disease in several cases. No treatment-related mortality occurred.

🔹Conclusions: AHSCT provided durable disease control and disability improvement in the majority of patients with highly active RRMS. For those with residual disease activity, high-efficacy DMTs remained a safe and effective option. These findings reinforce AHSCT as a strong therapeutic strategy, with DMTs serving as a valuable complement in selected cases.

Braun et al., 2024. “Benefits of AHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life”. Multiple Sclerosis and Related Disorders

This monocentric study provides an update of the data published in 2021 by Häußler et al.

🔹Background: MS often progresses despite DMTs. AHSCT is highly effective short-term, but long-term data on cognition and QoL are scarce. Alemtuzumab is another induction therapy with limited durability.

🔹Aim: Compare long-term outcomes of AHSCT vs. alemtuzumab in highly active MS.

🔹Key Findings:

  • NEDA-3: Higher rates with AHSCT (75% at 5 years; 55% at 10 years) vs. alemtuzumab (40% at 5 years).
  • Relapses and MRI activity: Relapse-free survival and absence of new T2 lesions were significantly more frequent in the aHSCT group.
  • Cognition: AHSCT patients improved in 5/12 cognitive domains (attention, processing speed, verbal learning, divided attention), whereas alemtuzumab patients declined in 4/12 domains.
  • Quality of life: AHSCT maintained stable QoL for up to 10 years, with improved fatigue scores, while alemtuzumab patients reported deterioration.
  • EDSS: Similar progression overall, but more AHSCT patients showed confirmed improvements.
  • Safety: Both treatments carried risks, but adverse events were manageable; no treatment-related mortality was observed in the AHSCT cohort.

🔹Conclusions: AHSCT is superior to alemtuzumab in maintaining long-term disease inactivity, improving cognition, and preserving QoL for up to a decade. These findings support considering AHSCT as a strong therapeutic option for highly active MS, though larger controlled trials are needed.

Figures from Braun et al. “Benefits of AHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life”. Multiple Sclerosis and Related Disorders (2024)

 

Burt et al., 2022 “Real‐world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis”. Journal of Neurology.

🔹Background: AHSCT has shown efficacy in RRMS, but its role in SPMS and long-term real-world safety remain less clear.

🔹Aim: To report real-world outcomes of non-myeloablative AHSCT in 507 MS patients (414 RRMS, 93 newly diagnosed SPMS) treated at Northwestern University between 2003–2019.

🔹Key Findings:

  • Survival/safety: 5-year overall survival 98.8%; treatment-related mortality 0.19% (1 death from legionella pneumonia).
  • Secondary autoimmunity: 10 ITP cases (2–3% non-alemtuzumab vs. 11.5% with alemtuzumab), ~7% thyroid disorders.
  • Relapse-free survival (RFS): RRMS 80.1% at 5y; SPMS 98.1% at 5y.
  • Progression-free survival (PFS): RRMS 95% at 4y vs. SPMS 66% at 4y.
  • Disability (EDSS): RRMS improved from 3.87 to 2.19 at 5y (p<0.0001). SPMS improved slightly at 1y (5.09→4.85, p=0.04) but not sustained.

🔹Conclusions: Non-myeloablative AHSCT is a safe and highly effective one-time therapy for RRMS, producing durable relapse and progression control with significant EDSS improvement. Benefit in SPMS is limited, especially without active inflammation.

Figure from Burt et al. “Real‐world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis”. Journal of Neurology (2022)

The study by Braun et al., 2024 was based on an update of the data published in 2021 by Häußler et al. (“AHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis”) published in Annals of Clinical and Translational Neurology.

🔹Background: AHSCT can reset the immune system in MS and may be more effective than high-efficacy DMTs like alemtuzumab, but direct comparisons are scarce.

🔹Aim: To compare outcomes of AHSCT vs. alemtuzumab in MS patients regarding NEDA, disability, and cognition.

🔹Key Findings:

  • Cohort: 19 AHSCT vs. 21 alemtuzumab patients, mean follow-up 59 vs. 28 months.
  • NEDA: 62% with AHSCT vs. 40% with alemtuzumab (p=0.038).
  • EDSS: 37% of AHSCT improved vs. 0% with alemtuzumab (p=0.033).
  • Relapses/MRI: No relapses or MRI activity in aHSCT group; 51% alemtuzumab patients developed new T2 lesions.
  • Cognition: AHSCT improved attention/processing speed, while alemtuzumab patients declined across domains.
  • Safety: Mostly expected early infections; one death (CML, linked to prior mitoxantrone), isolated thyroid disease, polyarthritis, infertility.

🔹Conclusions: AHSCT more effectively suppresses inflammatory activity and supports disability and cognitive improvement compared to alemtuzumab. It appears safe and promising for highly active MS, especially in RRMS.

Nash et al. “High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS”. Neurology

🔹Background: The HALT-MS trial investigated if high-dose immunosuppressive therapy (HDIT) followed by AHSCT could reset the immune system to control active RRMS in patients who did not respond to standard therapies. 

🔹Aim: The study’s goal was to assess the 5-year safety and effectiveness of HDIT/HCT in inducing durable disease stabilization for patients with RRMS. The primary endpoint was event-free survival (EFS), defined as survival without death, disability progression, relapse, or new MRI lesions.

🔹Key Findings:

  • 24 patients underwent the procedure and were followed for a median of 62 months.
  • At 5 years, the event-free survival rate was 69.2%.
  • Progression-free survival was 91.3%, and relapse-free survival was 86.9%.
  • Surviving patients who completed the study showed neurological improvement, with a median EDSS score reduction of 0.5.
  • Adverse events were as expected for this type of procedure, and no deaths were attributed to the transplant.

🔹Conclusions: HDIT/HCT, as a one-time treatment without ongoing therapy, was effective in inducing long-term, sustained remission of active RRMS at 5 years. It represents a potential therapeutic option for patients with RRMS who fail conventional treatments.

Figures from Nash et al. “High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS”. Neurology (2017)

Hamerschlak et al.. “Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG”. BMT

🔹Background: AHSCT is an intensive immunosuppressive therapy used to prevent disease progression in patients with refractory MS. Controversy exists regarding the ideal conditioning regimen, particularly concerning the safety and efficacy of more intensive (myeloablative) versus less intensive (non-myeloablative) approaches.

🔹Aim: This prospective Brazilian study aimed to compare the toxicity and clinical outcomes of two different conditioning regimens used for HSCT in MS patients: an intermediate-intensity regimen (BEAM with horse ATG) and a non-myeloablative regimen (Cyclophosphamide with rabbit ATG)

🔹Key Findings:

  • The study included 41 patients, most of whom had secondary progressive MS (80.4%) and significant disability, with 78% having a baseline EDSS score of 6.0 or higher.
  • The protocol was changed from BEAM/horse ATG to CY/rabbit ATG after the first 21 patients because of an unacceptable mortality rate; three patients (7.5% of the total) died in the BEAM/ATG group, whereas there were no deaths in the CY/ATG group.
  • The BEAM/ATG regimen was significantly more toxic, resulting in more complications during transplantation (71.4% vs. 40%), longer hospital stays, and a greater need for blood and platelet transfusions compared to the CY/ATG regimen.
  • Despite the differences in toxicity, the efficacy was similar between the two groups. Overall, 63.2% of patients remained stable or improved. Event-free survival (EFS) showed no statistically significant difference between the BEAM group (47%) and the CY group (70%).
  • After transplantation, no new enhancing lesions were seen on MRI in any patient from either group.

🔹Conclusions: In this study, the non-myeloablative CY/rabbit ATG regimen was associated with significantly less toxicity and appeared to be as effective as the more intensive BEAM/horse ATG regimen. Although long-term follow-up is required for a full assessment, the CY/rATG regimen demonstrated a better safety profile for this patient population.

🔹Back to index.

Propensity Score

Retrospective observational studies may use propensity scores to balance measured covariates and reduce confounding, partially emulating randomization, while remaining limited by unmeasured factors (ex.: matching AHSCT patients to DMT-treated controls on baseline characteristics).

Mariottini et al., 2025. “Autologous haematopoietic stem cell transplantation affects long-term progression independent of relapse activity in aggressive multiple sclerosis: a comparative matched study“. J Neurol Neurosurg Psychiatry.

🔹Background: Progression independent of relapse activity (PIRA)—the gradual worsening of disability not linked to relapses—is a major cause of long-term disability in MS and is poorly controlled by standard disease-modifying treatments (DMTs). Since the chemotherapy used in AHSCT reaches the central nervous system, it may also act on the mechanisms driving PIRA.

🔹Aim: To To compare the long-term effects of AHSCT versus natalizumab (NTZ) and subsequent DMTs on PIRA in aggressive RRMS.

🔹Key Findings:

In a matched study of 30 AHSCT and 30 NTZ-treated patients (median follow-up 106 months), PIRA rates were similar during NTZ therapy but significantly lower after AHSCT over the full follow-up (10% vs 49% at 10 years, p=0.020). AHSCT also outperformed controls in reducing relapses, overall disability progression, and achieving no evidence of disease activity (NEDA-3). Conversion to secondary-progressive MS occurred in 7% after AHSCT versus 40% after NTZ. 

🔹Conclusions: AHSCT substantially reduced long-term disability progression unrelated to relapses (PIRA) in aggressive RRMS compared with DMTs. Early intervention targeting both peripheral and central nervous system inflammation may best prevent irreversible disease progression.

🔹Limitations: In this study, anti-CD20 were not compared with AHSCT.  

Kalincik et al., 2025. “Effectiveness of autologous haematopoietic stem cell transplant in comparison with anti-CD20 therapies in relapsing-remitting MS“. Poster ECTRIMS 2025.

🔹Background: AHSCT may offer stronger disease control for MS patients who respond suboptimally to high-efficacy immunotherapies (e.g. anti-CD20). Head-to-head evidence comparing these approaches is lacking.

🔹Aim: To emulate a comparative effectiveness trial of AHSCT versus anti-CD20 therapies (ocrelizumab, rituximab) in RRMS.

🔹Key Findings:

  • Cohort: The study included matched cohorts of 152 AHSCT-treated patients and 859 anti-CD20-treated patients (ocrelizumab 752 and rituximab 107 patients).
    . Both groups had highly active MS (79–82% with relapses in the prior 2 years) and moderate disability (mean EDSS > 3.5).
  • Relapse Suppression: AHSCT was associated with a significantly lower risk of relapses (Annualized Relapse Rate 0.04 vs. 0.09; p<0.0001) compared to anti-CD20 therapy.
  • Disability: AHSCT showed a similar risk of confirmed disability worsening but a higher probability of confirmed disability improvement (Hazard Ratio 1.91) than anti-CD20 therapy.
  • Safety: AHSCT was associated with a risk of infections, but no treatment-associated deaths (TRM) were reported in the AHSCT group.

🔹Conclusions: In patients with active RRMS and moderate disability, AHSCT outperforms anti-CD20 therapy (ocrelizumab, rituximab) in suppressing relapses and promoting recovery of neurological function, with comparable risk of disability worsening and acceptable safety in this cohort.

Kalincik et al., 2024. “Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis”. Journal of Neurology, Neurosurgery & Psychiatry.

🔹Background: Natalizumab has not demonstrated clear benefit in modifying disability progression in progressive forms of multiple sclerosis. AHSCT is proposed as an alternative, but comparative data are limited.

🔹Aim: To compare AHSCT with natalizumab in patients with primary or secondary progressive MS, specifically looking at relapse rates, disability worsening and improvement over follow-up of up to ~4 years.

🔹Key Findings:

  • Sample: 39 patients treated with AHSCT (mostly secondary progressive MS; mean age ~37; mean EDSS ~5.7; about 28% had recent disability progression) matched with 65 treated with natalizumab.
  • Pre-treatment relapse rate for the AHSCT group was high (~0.54/year), but during treatment both groups had low relapse rates (~0.08/year).
  • No significant difference between AHSCT and natalizumab in risk of confirmed disability worsening (HR ~1.49) or confirmed disability improvement (HR ~1.50).
  • Relapse activity while on treatment was similar for both (ARR ~0.08).
  • Safety: In the AHSCT group there were multiple complications (febrile neutropenia, serum sickness, ICU admissions, post-discharge complications), but no treatment-related deaths.

🔹Conclusions: In progressive MS patients with advanced disability and low relapse activity, AHSCT was not clearly superior to natalizumab in preventing disability worsening, promoting improvement, or reducing relapse frequency. Given risks, AHSCT is not supported over natalizumab in this subgroup.

 

Figures from Kalincik et al. ”Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis“. J Neurol Neurosurg Psychiatry (2024)

Boffa et al., 2023. “Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis”. Neurology

🔹Background: SPMS with residual inflammatory activity remains challenging to treat. While AHSCT has shown strong efficacy in relapsing-remitting MS, evidence in active SPMS is limited.

🔹Aim: To compare AHSCT with conventional DMTs in active SPMS using real-world data from the Italian BMT-MS Study Group and MS Register.

🔹Key Findings: 

  • Cohorts: 79 AHSCT (14 centers) vs 1,975 DMT-treated patients (IFN-β, GA, AZA, MTX, CYC, MITX, FTY, NAT, ALM, DMF, TER); matched subset: 69 vs 345. 
  • Relapses: ARR 0.02 vs 0.43 → ~95% reduction (p<0.001). 
  • Disability progression: HR 0.50 (95% CI 0.31–0.81; p=0.005) → half the risk of EDSS worsening (50% lower risk of sustained EDSS worsening). 
  • Disability improvement: HR 4.21 (p<0.001) → ~4× higher chance of EDSS recovery. 
  • Safety: One treatment-related death (1.3%). 
  • NEDA-3/QoL: not evaluated. 

🔹Conclusions: In active SPMS, AHSCT demonstrated statistically superior efficacy over conventional DMTs across all evaluated outcomes—marked relapse suppression, reduced disability progression, and increased probability of improvement.
 However, the study is observational (Class III), lacks modern comparators (e.g., ocrelizumab, siponimod), and carries higher procedural risk.
 AHSCT appears the most potent option for selected active-SPMS patients, but requires careful risk-benefit assessment and prospective validation.

Kalincik et al., 2023 “Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis”. American Medical Association

🔹Background: AHSCT is an intensive immune-reconstitution therapy for highly active RRMS when standard treatments are not enough.

🔹Aim: To compare effectiveness of AHSCT vs three disease-modifying therapies (fingolimod, natalizumab, ocrelizumab) in reducing relapses and/or improving disability in highly active RRMS.

🔹Key Findings:

  • AHSCT showed much lower relapse rates than fingolimod; slightly lower than natalizumab.
  • Disability improvement was greater with AHSCT vs fingolimod and natalizumab.
  • No clear difference between AHSCT and ocrelizumab over the shorter follow-up period.
  • Treatment-related mortality from AHSCT was low (~0.6%), though there were serious adverse events.

🔹Conclusions: AHSCT is more effective than fingolimod, and somewhat better than natalizumab, for relapse prevention and disability recovery in highly active RRMS. Its benefits vs ocrelizumab are uncertain given current follow-up. Though higher risk, its one-off nature may favour its use in selected patients.

Table from Kalincik et al. “Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis”. JAMA Neurology (2023)

Mariottini et al., 2022. “Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary–progressive multiple sclerosis”. European Journal of Neurology

🔹Background:

  • AHSCT has proven efficacy in relapsing–remitting MS, but its role in SPMS is less clear.
  • Low-dose immunosuppression with intravenous Cy is used as a treatment in SP-MS, particularly where high-efficacy options are limited.

🔹Aim: To compare the long-term effectiveness and safety of intermediate-intensity AHSCT vs low-dose immunosuppression with IV cyclophosphamide in patients with SP-MS, matched on baseline characteristics.

🔹Key Findings:

  • Sample: 93 SP-MS patients (31 AHSCT, 62 Cy), mean follow-up ~99 months for AHSCT, ~91 months for Cy.
  • Relapse-free survival (R-FS): At 5 years, 100% in AHSCT vs ~52% in Cy group. AHSCT fully suppressed relapses.
  • Disability progression (P-FS): No statistically significant difference at 5 years (≈70% AHSCT vs ≈81% Cy).
  • Other disability outcome (worsening confirmed) also similar between groups.
  • NEDA-2 (no evidence of disease activity type 2: no relapses + no confirmed EDSS worsening): no significant difference.
  • Safety: 1 cancer in AHSCT vs 2 in Cy; 2 deaths occurred in Cy group; none in AHSCT.

🔹Conclusions:

  • In SPMS, AHSCT is markedly superior to cyclophosphamide for suppressing relapses.
  • However, AHSCT did not show clear benefit over Cy in preventing disability accrual in this cohort.
  • This suggests that, in SPMS, disability progression may be driven more by neurodegeneration (less responsive to immunotherapy) than by active inflammation.

Mariottini et al. “Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary–progressive multiple sclerosis”. European Journal of Neurology (2022)

🔹Back to index.

Observational Retrospectives

Retrospective cohort studies reconstruct past exposures and outcomes using existing records, allowing researchers to explore associations without altering the clinical course (ex.: analyzing electronic health records to determine relapse history prior to AHSCT).

Kalincik et al., 2026: “Haematopoietic stem cell transplant versus immune-reconstitution therapy in relapsing multiple sclerosis“. Brain

🔹Background: AHSCT and immune-reconstitution therapies (IRTs) share mechanistic similarities and are used in highly active relapsing MS, but direct, head-to-head comparative clinical data were completely lacking.

🔹Aim: To compare the real-world clinical effectiveness of AHSCT versus the IRTs cladribine and alemtuzumab in relapsing-remitting multiple sclerosis (RRMS) patients using emulated pairwise trials from international registries.

🔹Key findings: AHSCT significantly reduced the annualized relapse rate compared to both cladribine (HR 0.24) and alemtuzumab (HR 0.52). While no significant differences were observed regarding confirmed disability worsening, AHSCT was markedly superior in facilitating 6-month confirmed disability improvement (HR 2.19 vs cladribine; HR 2.03 vs alemtuzumab). Delayed complications (mostly infections) affected 34% of the AHSCT cohort, but zero treatment-related deaths occurred. Sensitivity analyses confirmed the robustness of the cladribine comparison, whereas the alemtuzumab cohort was more susceptible to residual, unmeasured confounding.

🔹Conclusions:  In active RRMS with moderate disability, AHSCT surpasses both cladribine and alemtuzumab in suppressing clinical relapses and promoting short-term neurological recovery, without exposing patients to a higher risk of disability progression. The superior therapeutic value of AHSCT over established IRTs likely stems from the unique depth of immune ablation and qualitative immune reconstitution achieved during the transplantation procedure.

Muraro et al., 2025. “Effectiveness of Autologous Hematopoietic Stem Cell Transplantation versus Alemtuzumab and Ocrelizumab in Relapsing Multiple Sclerosis: A Single Center Cohort Study“. Annals of Neurology

🔹Background: Real-world comparative evidence for AHSCT against high-efficacy disease-modifying therapies (DMTs), particularly anti-CD20 agents, remains scarce due to small cohort sizes, heterogeneous protocols, and the lack of robust MRI data.

🔹Aim: To contrast long-term clinical and radiological outcomes of AHSCT against alemtuzumab and ocrelizumab in RRMS patients managed under standardized protocols at a single London tertiary center.
 
🔹Key findings: Over 5 years, AHSCT achieved significantly lower annualized relapse rates than both alemtuzumab and ocrelizumab, along with superior relapse-free survival against alemtuzumab. MRI lesion suppression was equivalent between AHSCT and ocrelizumab (~93% activity-free at 3 years) but significantly better than alemtuzumab. Disability accumulation did not differ across groups. AHSCT led to higher EDSS improvement probabilities and better NEDA-3 maintenance compared to alemtuzumab, with no difference found versus ocrelizumab. One treatment-related death was recorded (1.1% mortality).
 
🔹 Conclusions: AHSCT delivers superior relapse suppression compared to high-efficacy DMTs and yields radiological control comparable to ocrelizumab. The similar rate of disability accumulation across treatments likely stems from an advanced baseline disease severity within the AHSCT cohort. These strong real-world comparative outcomes justify and reinforce the necessity of ongoing randomized controlled trials (BEAT-MS, STAR-MS, RAM-MS).
 

Muraro et al. “Real-world effectiveness of autologous haematopoietic stem cell transplantation for multiple sclerosis in the UK“. J Neurol Neurosurg Psychiatry.

🔹Background: AHSCT is increasingly used as a potentially definitive, one-off disease-modifying therapy for aggressive forms of MS. This study reports the real-world effectiveness of AHSCT based on the nationwide experience in the UK.

🔹Aim: The objective was to report the real-world effectiveness of AHSCT by assessing long-term outcomes, including relapse-free survival (RFS), MRI activity-free survival (MFS), progression-free survival (PFS), and NEDA-3, in a large, unselected cohort of UK patients.

🔹Key Findings:

  • Cohort: The study included 364 patients treated between 2002 and 2023. Among those with adequate follow-up data (n=271), 62% had RRMS and 38% had Progressive MS (PMS). The median baseline EDSS score was 6.0, indicating significant disability.
  • Long-term Efficacy (at 5 years):
    • Relapse-Free Survival (RFS) was 88.6%.
    • MRI Activity-Free Survival (MFS) was 80.1%.
    • Progression-Free Survival (PFS) was 62.4%.
    • NEDA-3 was 46.2%.
  • Disability Status: RRMS patients had significantly higher rates of NEDA-3 and PFS than PMS patients. The prevalence of EDSS improvement was 20.4% at 5 years, with RRMS being a predictor of this improvement.
  • Safety: Treatment-related mortality (TRM), defined as death within 100 days, was 1.4% (n=5/364).

🔹Conclusions: In this large, real-world UK cohort, AHSCT led to durable remission of inflammatory activity and resulted in stabilization or improvement of neurological disability. The procedure proved particularly effective in patients with RRMS, supporting AHSCT as a highly effective option for aggressive MS. 

Kazmi et al., 2025. “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)“. B J Haem.

🔹Background: AHSCT has been developed since 1995 as an intensive immune “reset” therapy for MS. The UK is among the most active countries performing AHSCT for MS, but access remains uneven across regions.

🔹Aim: To describe national UK outcomes and safety of AHSCT for MS over 20 years (2002–2023) and identify factors influencing efficacy and complications.

🔹Key Findings:

  • Cohort: 364 patients (58% RRMS, 36% progressive MS); median age 40 years; median EDSS 6.0; median disease duration 10 years.
  • Efficacy: Progression-free survival (PFS) was 83.5% at 2 years and 62.4% at 5 years. RRMS patients had significantly better PFS than SPMS or PPMS (HR 1.69–2.07).
  • Safety: Transplant-related mortality (TRM) 1.4%, all in patients with advanced disability (median EDSS 6.5).
  • Complications: EBV reactivation in 76%, CMV in 21%; significant viral reactivation and higher ATG doses (>6 mg/kg) correlated with reduced PFS.
  • Long-term events: Secondary autoimmune diseases (7.9%), mostly thyroiditis; malignancies in 1.6%.
  • Geography: 88% of transplants occurred after 2016, mainly in London and Sheffield; limited access in other UK regions.

🔹Conclusions: AHSCT is an effective and increasingly safe one-off treatment for severe or refractory MS, yielding durable disease control, particularly in RRMS. Outcomes worsen with higher disability, progressive disease, and excessive ATG dosing. The study supports limiting ATG to ≤6 mg/kg and expanding equitable AHSCT access across the UK.

Jespersen et al., 2023 “Autologous hematopoietic stem cell transplantation of patients with aggressive relapsing-remitting multiple sclerosis: Danish nation-wide experience”. MSARD

🔹Background: AHSCT is an increasingly used treatment for aggressive RRMS. Despite strong efficacy signals, controlled data remain limited; therefore, national real-world experiences are valuable for assessing safety and effectiveness.

🔹Aim: To describe the Danish nationwide experience with AHSCT for aggressive RRMS regarding patient characteristics, safety, and efficacy.

🔹Key Findings:

  • Cohort: 32 RRMS patients (median age 36 years; median EDSS 3.5–5.0) treated from 2011–2021. Seven received BEAM/ATG, and 25 received cyclophosphamide (CY)/ATG.
  • Efficacy: At 2 years, relapse-free survival (RFS) was 77%, worsening-free survival (WFS) 79%, MRI event-free survival (MFS) 93%, and NEDA-3 69%. CY/ATG showed higher efficacy (NEDA-3 77%) than BEAM/ATG (43%).
  • Safety: No treatment-related mortality; most adverse events were mild to moderate. BEAM caused more acute and late AEs than CY.
  • Complications: Viral reactivations (EBV 24–43%, CMV <10%), thyroid autoimmunity (up to 28%), and herpes zoster (mainly post-prophylaxis). One unrelated death occurred 6 years post-transplant.
  • Regimen comparison: CY/ATG was equally or more effective than BEAM, with fewer severe AEs and lower toxicity.

🔹Conclusions: AHSCT is a highly effective and safe treatment for aggressive RRMS, achieving durable NEDA in most patients without mortality. The Danish experience supports CY/ATG as the preferred regimen due to similar efficacy and superior safety, while confirming the need for randomized trials versus high-efficacy DMTs.

 

Boffa et al., 2021 “Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis”. Neurology

🔹Background: Current DMTs for MS are often insufficient to prevent long-term disability progression. AHSCT has been investigated as an aggressive strategy to eliminate autoreactive immune cells and induce drug-free self-tolerance in patients with highly active MS. Long-term, real-world data confirming durable remission were needed.

🔹Aim: The objective was to determine, through the analysis of a large, multicenter cohort of aggressive MS patients, whether AHSCT is capable of inducing durable disease remission and preventing long-term disability worsening.

🔹Key Findings: The study included 210 MS patients (58% with RRMS) with a mean follow-up of 6.2 years.

  • Disability Worsening-Free Survival (DWFS): For RRMS patients, DWFS was 85.5% at 5 years and 71.3% at 10 years. Progressive MS patients had a lower DWFS (71.0% at 5 years; 57.2% at 10 years).
  • Disability Status: RRMS patients showed a significant reduction in EDSS score over time (p=0.001).
  • NEDA-3 Status: The probability of maintaining NEDA-3 in RRMS was 62.2% at 5 years and 40.5% at 10 years.
  • Conditioning Protocol: The BEAM + Anti-thymocyte globulin (ATG) protocol was independently associated with a significantly reduced risk of NEDA-3 failure in RRMS (HR 0.27, p<0.001).
  • Safety: Transplantation-related mortality was 1.4% (3 patients) and zero for patients transplanted after 2007.

🔹Conclusions: AHSCT is effective in preventing long-term disability worsening and inducing durable clinical improvement, particularly in patients with RRMS. The BEAM + ATG conditioning protocol offers superior suppression of clinical and radiological inflammatory activity. The study supports AHSCT as a viable option for inducing long-term, drug-free remission in appropriately selected MS patients.Figures from Boffa et al. “Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis”. Neurology (2021)

Das et al., 2021. “Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with “aggressive” multiple sclerosis”. Multiple Sclerosis Journal.

🔹Background: AHSCT is a highly effective treatment for MS patients who have a very active disease course despite receiving standard DMTs. However, the optimal timing for offering AHSCT to patients with the “aggressive” MS phenotype, specifically whether it should be used as a first-line treatment, was unknown.

🔹Aim: The objective of this study was to explore the safety and efficacy of AHSCT when used as a first-line DMT in patients diagnosed with ‘aggressive’ multiple sclerosis.

🔹Key Findings:

  • Cohort: A total of 20 patients with aggressive MS were retrospectively identified from five international centers.
  • Baseline Status: The median time from diagnosis to AHSCT was very short (5 months). All patients had multiple poor prognostic markers, and the median pre-transplant Expanded Disability Status Scale (EDSS) score was 5.0 (range 1.5–9.5), indicating significant disability.
  • Efficacy: After a median follow-up of 30 months, the median EDSS score improved significantly to 2.0(p<0.0001).
  • Remission: No patient experienced further clinical relapses. After accounting for short-term post-transplant MRI activity, the cumulative NEDA (No Evidence of Disease Activity) rate was 100%.
  • Safety: The procedure was deemed safe, with no reported Grade 4 toxicities or treatment-related mortality.

🔹Conclusions: AHSCT is both safe and highly effective when utilized as a first-line DMT for inducing rapid and sustained disease remission and achieving a significant improvement in disability in carefully selected patients with aggressive MS. These findings support considering AHSCT early in the disease course for this specific, highly active phenotype.

 

Figures from Das et al. “Autologous haematopoietic stem cell transplantation as a first-line disease- modifying therapy in patients with “aggressive” multiple sclerosis”. Multiple Sclerosis Journal (2021)

Zhukovsky et al., 2021. “Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing–remitting multiple sclerosis: an observational study”. Journal of Neurology, Neurosurgery & Psychiatry.

🔹Background: AHSCT and alemtuzumab (ALZ) are both considered highly efficacious disease-modifying therapies (DMTs) for RRMS. Prior trials had compared AHSCT primarily to less potent DMTs, leaving a gap in real-world evidence comparing AHSCT head-to-head against a highly active agent like ALZ in terms of long-term efficacy and safety.

🔹Aim:  The objective was to compare the long-term efficacy and safety outcomes of AHSCT and ALZ in an observational cohort of patients with active RRMS.

🔹Key Findings:

  • Efficacy (NEDA-3): The primary outcome, the Kaplan-Meier estimate for NEDA-3 at 3 years, was achieved by 88% of patients treated with AHSCT, compared to 37% of patients treated with ALZ (p<0.0001).
  • Relapse Rate: The annualised relapse rate (ARR) was significantly lower after AHSCT (0.04) compared to ALZ (0.1) (p=0.03).
  • Disability Improvement: AHSCT resulted in a greater proportion of patients with confirmed disability improvement (57%) and fewer with confirmed disability worsening (1%) at last follow-up, compared to ALZ (45% improved, 12% worsened).
  • Early Safety (First 100 days): Adverse events (AEs) of Grade 3 or higher were much more frequent in the AHSCT group (48/69 patients), mainly due to manageable febrile neutropenia. No patients in the ALZ group experienced severe AEs during this period.
  • Late Safety (Autoimmunity): Late AEs, particularly autoimmune disorders, were more frequent with ALZ. The risk of developing thyroid disease at 3 years was significantly higher for ALZ (46%) compared to AHSCT (21%)(p=0.005).

🔹Conclusions: In this observational cohort, AHSCT was associated with a higher probability of maintaining NEDA and greater disability improvement than ALZ. While AHSCT has a greater risk of severe, short-term, acute adverse events, ALZ is associated with a significantly higher burden of long-term, autoimmune adverse events. AHSCT may be the preferred choice for patients willing to accept a high short-term risk for a higher probability of long-term, drug-free disease control. 

Figures from Zhukovsky et al. “Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing–remitting multiple sclerosis: an observational study”. J Neurol Neurosurg Psychiatry (2021)

Nicholas et al., 2021 “Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis. A Real-world Case Series”. Neurology

🔹Background: AHSCT has been shown in clinical studies to profoundly suppress MS activity and induce long-term clinical stabilization. However, data on its effectiveness and safety in a broader, real-world patient population, which often includes people with more severe or progressive disease, was needed.

🔹Aim: To examine the clinical efficacy outcomes and adverse events in a consecutive, real-world cohort of PwMS treated with AHSCT at two major transplant centers in London, UK, to see if real-world outcomes match those reported in highly selective clinical trials.

🔹Key Findings:

  • Cohort: The study included 120 PwMS; 52% had progressive MS (Primary or Secondary Progressive MS) and 48% had RRMS. The median baseline disability score (EDSS) was 6.0, and 90% of patients showed MRI activity prior to AHSCT.
  • Relapse-Free Survival: MS relapse-free survival was 93% at 2 years and 87% at 4 years overall. Relapses post-AHSCT occurred only in the RRMS subgroup.
  • MRI Activity: 90% of participants were free of new MRI lesions at 2 years, and 85% at 4 years.
  • Disability: EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. The RRMS subgroup showed a small average improvement in EDSS score at 12 months, while the progressive MS subgroup showed further deterioration.
  • Predictors: The presence of high monoclonal paraproteinemia was identified as a significant variable associated with worse EDSS score progression-free survival.
  • Safety: There were 3 transplantation-related deaths within 100 days (2.5%), all linked to fluid overload and cardiopulmonary complications.

🔹Conclusions: The efficacy outcomes of AHSCT achieved in this real-world cohort, which included a high proportion of patients with progressive MS, are similar to the profound disease suppression reported in more stringently selected clinical trial populations. However, the study suggests that the transplantation-related risks (mortality and morbidity) may be higher in this real-world setting, highlighting the need for careful patient selection and management of complications like fluid overload. 

 

Figure from Nicholas et al., 2021

Boffa et al., 2020 “Aggressive multiple sclerosis: a single-centre, real-world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab”. European Journal of Neurology

🔹Background: The ideal treatment for aggressive RRMS is unclear. Both AHSCT and alemtuzumab (ALZ) are potent immune-modulating therapies used for this phenotype. This study sought to provide real-world comparative data on their long-term effectiveness.

🔹Aim: The objective was to compare the efficacy in terms of disease control (NEDA-3) and the safety profiles of AHSCT versus alemtuzumab in a single-center cohort of patients with aggressive RRMS.

🔹Key Findings:

  • Cohort: 57 aggressive RRMS patients were included (AHSCT: n=25; ALZ: n=32). The AHSCT group had higher baseline disease activity (higher median EDSS, higher Annualized Relapse Rate, and more MRI lesions).
  • Efficacy (NEDA-3): NEDA-3 was achieved by 75% of the AHSCT group compared to 56% of the ALZ group at the end of follow-up.
  • Inflammatory Activity: AHSCT showed a significantly greater suppression of inflammation, with a reduced risk of relapse and new MRI activity compared to ALZ (P≤0.012 for both). The ARR at 36 months was much lower with AHSCT (0.05) than with ALZ (0.35).
  • Disability: AHSCT demonstrated a significant advantage in promoting EDSS improvement compared to ALZ (P=0.035).
  • Safety: Early adverse events (infections/cytopenia) were more frequent with AHSCT. However, late adverse events, particularly autoimmune disorders (e.g., thyroid disease), were significantly more common with ALZ (9 patients) than with AHSCT (1 patient).

🔹Conclusions: While both treatments are effective, AHSCT was superior to alemtuzumab in achieving NEDA-3 status and improving disability in patients with aggressive RRMS, suggesting better long-term suppression of inflammatory activity. The study highlights the trade-off: higher short-term risk with AHSCT versus higher long-term risk of secondary autoimmunity with ALZ. 

Figures from Boffa et al. “Aggressive multiple sclerosis: a single-centre, real-world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab”. European Journal of Neurology (2020)

 

Muraro et al., 2017. “Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis”. JAMA Neurology

🔹Background: AHSCT is a treatment option for aggressive MS that has failed standard therapies. However, most available data were limited to short-term follow-up. Long-term data from a large patient cohort were necessary to assess the long-term course, risks, and complications of MS after AHSCT.

🔹Aim: To evaluate the long-term outcomes in a large multicenter cohort of patients who underwent AHSCT for MS, specifically analyzing progression-free survival (PFS), overall survival, and transplant-related mortality.

🔹Key Findings:

  • Cohort and Follow-up: The study included 281 patients from 25 centers with a median follow-up of 6.6 years. The majority of patients (78%) had progressive forms of MS.
  • Progression-Free Survival (PFS): The overall probability of MS progression-free survival (PFS) was 46% at 5 years. The PFS rate was significantly higher for the relapsing MS subgroup, reaching 73% at 5 years.
  • Overall Survival (OS) and Safety: Overall survival was 93% at 5 years. Transplant-related mortality (TRM), defined as death within 100 days of transplant, was 2.8% (8 deaths).
  • Predictors of Better Outcome: Factors significantly associated with better long-term neurological outcomes included younger age, relapsing form of MS, fewer prior disease-modifying therapies, and lower baseline disability.

🔹Conclusions: In this large observational study, AHSCT was effective, with nearly half of the patients remaining free from neurological progression for 5 years. The procedure offers a clear benefit, particularly for patients with the relapsing form of MS. The findings underscore the importance of early intervention and careful patient selection to maximize the long-term benefit of AHSCT.

Figures from Muraro et al. “Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis”. JAMA Neurology (2017)

Burman et al.,2014. “Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience“. Journal of Neurology, Neurosurgery & Psychiatry.  

🔹Background: AHSCT is considered a viable treatment option for aggressive MS. Since no randomized controlled trials had been performed, systematic and sustained follow-up data were crucial to assess the safety and long-term efficacy of this procedure in a real-world setting.

🔹Aim: The objective was to describe the characteristics and outcome of all consecutive Swedish patients treated with HSCT for aggressive MS to provide important information on the treatment’s safety and efficacy.

🔹Key Findings:

  • Cohort and Follow-up: The study included 48 patients evaluated for safety, with 41 patients having at least 1 year of follow-up (mean follow-up: 47 months). Most patients (83%) had relapsing-remitting MS (RRMS), and the median EDSS score at the decision for HSCT was 6.0.
  • Efficacy at 5 Years:
    • Relapse-free survival was 87%.
    • MRI event-free survival was 85%.
    • EDSS score progression-free survival was 77%.
    • Disease-free survival (NEDA-3) was 68%.
  • Disability Improvement: The median EDSS score for RRMS patients improved from 5.5 at HSCT to 3.0 at 2 years. The median change in EDSS for RRMS patients was -1.5.
  • Prognostic Factor: The presence of gadolinium-enhancing (Gd+) lesions prior to HSCT was associated with a favorable outcome, resulting in a significantly higher disease-free survival rate (79% vs 46%; p=0.028).
  • Safety: There was no treatment-related mortality (TRM) recorded. The most common long-term side effects were herpes zoster reactivation (17%) and thyroid disease (8.3%).

🔹Conclusions: AHSCT with a low-to-intermediate intensity protocol is a highly effective treatment for inflammatory active MS, leading to long-term disease remission in the majority of patients. It can be performed with a high degree of safety at experienced centers. The study supports the principle that patients with evidence of active inflammation at baseline are the most likely to benefit.

 

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Case-Series

Case series describe multiple patients undergoing similar management, detailing demographics, clinical characteristics, treatments, and follow-up without a comparison group (ex.: summarizing outcomes of sequential patients treated with AHSCT at a single center).

Dy et al., 2026. “Clinical Outcomes of Autologous Hematopoietic Stem Cell Transplantation in Filipino Patients With Multiple Sclerosis: A Single-Center Retrospective Case Series“. Cureus

🔹Background: In the Philippines, access to high-efficacy disease-modifying therapies (DMTs) is limited.  AHSCT serves as a crucial escalation strategy for patients with ongoing disease activity despite treatment.

🔹Aim: To describe the clinical characteristics, safety profile, and short-term outcomes of six Filipino patients with MS who underwent AHSCT at St. Luke’s Medical Center between 2023 and 2025.

🔹Key Findings:

  • Cohort: Six patients (5 female, 1 male) with a median age of 44.5 years. Five patients had SPMS and one had RRMS, with a mean disease duration of 14.3 years.
  • Conditioning: Most (83.3%) received a regimen of carmustine, cytarabine, etoposide, melphalan, and ATG.
  • Adverse Events (AEs): Febrile neutropenia occurred in five patients (83.3%). Other AEs included one central line infection and one case of transient pulmonary congestion; all patients recovered.
  • Outcomes: Over a mean follow-up of 17.2 months, 100% of patients remained relapse-free with no disability progression. No patient required the resumption of DMTs.

🔹Conclusions: AHSCT was well-tolerated and provided short-term clinical stability. The findings support aHSCT as a viable option in resource-limited settings and suggest considering it earlier in the disease course to prevent irreversible disability.

Ünsal et al., 2025. “Results of Autologous Hematopoietic Stem Cell Transplantation in Refractory Multiple Sclerosis: Two Case Reports“. Hematol transfus cell ther

🔹 Background: Despite effective DMTs, a subgroup of PwMS continues to show disease activity. AHSCT aims to reset the immune system and control refractory disease. 

🔹 Aim: To report the outcomes of two MS patients with refractory disease treated with AHSCT in Istanbul, Turkey. 

🔹 Key Findings:

  • Two patients (one RRMS, one SPMS) underwent AHSCT after failing multiple high-efficacy DMTs. 
  • Stem cell mobilization, myeloablative conditioning regime and transplantation were successfully performed in both cases. 
  • During follow-up (3 months for RRMS, 8 months for SPMS), no relapses were observed and neurological status remained stable. 
  • The procedure was well tolerated, with no major complications reported. 

🔹 Conclusions: AHSCT is a safe and effective option, particularly in RRMS patients with high inflammatory activity refractory to standard therapies. Recent evidence shows durable disease control in over 60% of patients and low TRM, supporting AHSCT as a valuable therapeutic strategy in selected MS cases. 

Patti et al., 2022 “Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Patients: Monocentric Case Series and Systematic Review of the Literature”. Journal of Clinical Medicine

🔹Background: MS is often aggressive and refractory to standard DMTs. AHSCT, which works by immune reset, is a non-DMT option for these hard-to-treat patients.

🔹Aim: To report the short-term outcomes and safety of AHSCT in a monocentric case series (6 patients) and review the long-term data from the literature.

🔹Key Findings:

  • Case Series: All 6 patients achieved zero relapses. Disability (EDSS) either improved or stabilized. Only mild AEs were reported, with no severe toxicity (mean follow-up: 16.6 months).
  • Systematic Review Efficacy: Literature confirms AHSCT achieves relapse-free survival of 70–100%and NEDA rates of 68–78.5% at 5 years. Initial Brain Volume Loss (BVL) stabilizes after 2-3 years.
  • Systematic Review Safety: Transplant-Related Mortality (TRM) is low (0–2.8%). Late AEs mainly include thyroiditis (up to 26%). PML has not been reported after AHSCT in MS.

🔹Conclusions: AHSCT is safe and highly effective for achieving rapid and sustained remission, often leading to disability stabilization or improvement. The ideal candidate has early-stage disease with strong inflammatory activity. Final status as a “standard of care” for aggressive MS awaits results from ongoing RCTs.

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Expert Opinion

Expert opinion reflects the collective scientific judgment of designated specialists based on available evidence and professional evaluation (ex.: consensus statements from transplant experts on patient selection criteria).

Sormani et al. “NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs”. Multiple Sclerosis Journal.

🔹Background: NEDA—absence of relapses, disability progression, and MRI activity—is an emerging therapeutic goal in RRMS. With current DMTs, only 13–46% of patients reach NEDA after 2 years, and maintenance over time is uncommon.

🔹Aim: To assess how effectively AHSCT achieves NEDA compared with DMTs in highly active RRMS.

🔹Key Findings:

  • AHSCT induces an “immune reset” that can more effectively suppress disease activity.
  • In clinical studies, 78–83% of AHSCT-treated patients maintained NEDA at 2 years and 60–68% at 5 years—significantly higher than with any approved DMT.
  • This advantage is notable because AHSCT patients generally have more aggressive disease than those enrolled in DMT trials.
  • Transplant-related mortality has markedly decreased to ~1.3% since 2001, with no deaths reported in recent RRMS cohorts.
  • Nonmyeloablative conditioning regimens improve safety while preserving efficacy.

🔹Conclusions: AHSCT yields markedly higher and sustained NEDA rates than DMTs, with improved safety. A phase 3 randomized trial is warranted to confirm its efficacy and risk–benefit profile, potentially establishing aHSCT as a cost-effective therapy for highly active MS.

 

Figure from Sormani et al. “NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs”. Multiple Sclerosis Journal (2017).

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Immunological Evidences

How Does AHSCT Act on the Immune System?

Clinical data suggest that the immune reconstitution (IR) following transplant is associated with sustained therapeutic benefits (read “Clinical evidences” section). The precise mechanisms by which AHSCT provides therapeutic effects remain unclear (Massey et al., 2018), however immunological data indicates that AHSCT in MS involves a reset of the immune system through:

  1. Ablation (destruction) of pathogenic autoreactive immune cells
  2. Immune reconstitution from myeloid or lymphoid progenitor cells
  3. Fast recovery of innate immunity cells (neutrophils, macrophages, and NK cells), which return to baseline levels (few weeks after AHSCT)
  4. Slow recovery of adaptative immune cells (3-6 months)
  5. Slower recovery in regulatory cell levels (6-12 months)
  6. Normalization of immunological functions.

Additional insights can be found in the reviews Arruda et al., 2017, Cencioni et al., 2021 and Mariottini et al., 2023.

Figure from Arruda et al. “Section 15 Hematopoietic Cell Transplants for Non-Neoplastic Diseases. Autologous Hematopoietic Cell Transplants for Autoimmune Diseases: Specific Diseases and Controversies”. Cambridge University Press (2017).

Papers on Immune Reconstitution Post-AHSCT

Below, some recent papers on the impact on immune reconstitution post-transplant. Click on the authors’ name to read the abstract or the full article where available. This section currently is in progress.

Sandgren et al., 2025. “Lymphocyte Dynamics and the Emergence of Secondary Autoimmunity Following Immune Reconstitution Therapies in Multiple Sclerosis“. Neurol Neuroimmunol Neuroinflamm.

Background: Immune reconstitution therapies (IRTs) such as alemtuzumab (ALZ), AHSCT, and cladribine (CladT) effectively control MS but may trigger secondary autoimmunity (SAD). 

Aim: To compare lymphocyte subset dynamics after treatment with ALZ, AHSCT, and CladT, and to assess their associations with secondary autoimmunity and disease activity recurrence. 

Key Findings: 

  • 130 MS patients were followed for a median of 4.7 years (ALZ = 51, AHSCT = 20, CladT = 59). 
  • SAD occurred in 29% overall (ALZ 57%, AHSCT 15%, CladT 10%). 
  • AHSCT showed the fastest lymphocyte recovery; ALZ caused the most profound and sustained T-cell depletion; CladT showed the slowest B-cell repopulation. 
  • A low baseline CD4⁺ recent thymic emigrant (Trte):CD8⁺ Temra ratio, followed by a marked increase at 12–24 months, was associated with SAD development, particularly after ALZ. 
  • Lower baseline CD8⁺ T-cell counts were linked to a higher risk of disease activity. 

Conclusions: Lymphocyte depletion and repopulation patterns differ across IRTs and may explain variations in secondary autoimmunity risk. A dynamic imbalance between thymic output and effector T-cell expansion appears to predispose to SAD, especially after alemtuzumab. Further research should confirm these immunologic predictors to optimize IRT safety and monitoring.

Pavlovic et al., 2025. “The MMP-9/TIMP-1 Ratio and Concentrations of Osteopontin Are Elevated in Cerebrospinal Fluid of People With Multiple Sclerosis and Decrease After Autologous Hematopoietic Stem Cell Transplantation“. Annals of Clinical and Translational Neurology. 

Background: Blood–brain barrier (BBB) disruption drives inflammation in MS. Traditional CSF markers, such as the albumin quotient (QAlb)—an index measuring BBB integrity—are limited in sensitivity. The study focused on MMP-9 (an enzyme that breaks down the BBB), TIMP-1 (its inhibitor), their MMP-9/TIMP-1 ratio, and osteopontin (OPN), a protein linked to chronic inflammation. The MMP-9/TIMP-1 ratio and OPN may more accurately reflect BBB damage and disease activity.

Aim: To assess CSF MMP-9, TIMP-1, their ratio, and OPN in RRMS before and after AHSCT, and to assess their association with BBB integrity and disease activity. 

Key Findings:  In 43 pwMS and 32 controls, baseline MMP-9/TIMP-1 ratios and OPN levels were elevated, especially in patients with enhancing MRI lesions or on first-line therapies. Both declined markedly after AHSCT and remained low, while QAlb changed minimally. The MMP-9/TIMP-1 ratio predicted later disease activity. 

Conclusions: The MMP-9/TIMP-1 ratio and OPN are dynamic markers of BBB integrity and inflammation, decreasing after aHSCT and reflecting durable remission.

Gavasso et al., 2025. “High-dimensional Immune Profiling Following Autologous Hematopoietic Stem Cell Transplantation in Relapsing-Remitting Multiple Sclerosis“. PRE-PRINT.

Background: AHSCT is a highly effective treatment for RRMS, yet the precise mechanisms of immune reconstitution remain incompletely understood.

Aim: To characterize in detail the longitudinal remodeling of the immune system following AHSCT using mass cytometry (CyTOF) in RRMS patients.

Key Findings: Using high-dimensional immune profiling of over 100 million single cells across 25 RRMS patients, the study revealed that AHSCT induces profound and sustained immune remodeling over 24 months. Notably, it resulted in the long-term depletion of pro-inflammatory CD161⁺ T cells, alongside extensive reshaping of both innate and adaptive immune compartments.

Conclusions: AHSCT promotes a durable shift toward a less inflammatory and more regulated immune landscape, providing mechanistic insight into its long-term therapeutic efficacy in RRMS.

Müller et al., 2025.”Longitudinal immune profiling following autologous hematopoietic stem cell transplantation in multiple sclerosis: insights into immune reconstitution and disease modulation“. Frontiers in Immunology

Background: AHSCT is a potent therapy for aggressive MS, but the dynamics of immune reconstitution and their association with treatment outcomes are not fully understood.

Aim: To characterize longitudinal changes in immune cell subsets following AHSCT and identify immunological markers associated with post-treatment disease activity.

Key Findings: In 22 MS patients, AHSCT induced a marked shift in B-cell composition, with a dominance of naïve B cells and persistently low memory B cells. T-cell profiles transitioned from central to effector memory phenotypes, alongside sustained reductions in Th1/Th17 pro-inflammatory subsets. Importantly, patients with post-AHSCT disease activity had higher frequencies of switched memory B cells pre-transplantation.

Conclusions: AHSCT induces long-term immune remodeling that favors a less inflammatory state. Pre-transplant memory B-cell levels may serve as a predictive biomarker of treatment response.

Pavlovic et al., 2024. “Micro-RNA Signature in CSF Before and After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis”. Neurology.

Background: MicroRNAs (miRNAs) regulate gene expression and are dysregulated in people with multiple sclerosis (pwMS). AHSCT is an immune-ablative therapy for pwMS, but its impact on cerebrospinal fluid (CSF) miRNA levels is unknown.

Aim: To determine whether circulating miRNAs can distinguish pwMS from healthy controls (HCs) and to assess how AHSCT affects miRNA expression in CSF.

Key Findings:

  • Twelve miRNAs were significantly dysregulated in pwMS compared to HCs.

  • A cluster of 4 miRNAs (miR-16-5p, miR-21-5p, miR-150-5p, miR-146a-5p) showed strong correlations with disease activity and treatment response.

  • These 4 miRNAs were elevated in pwMS at baseline, especially in those with gadolinium-enhancing lesions or less effective prior treatments.

  • After AHSCT, expression levels of these miRNAs decreased and remained low for up to 5 years.

  • Pathway analysis linked these miRNAs to inflammation, cytokine production, and myelin maintenance.

Conclusions: CSF miRNAs are dysregulated in pwMS, particularly in those with active disease. A specific 4-miRNA signature reflects disease activity and responds to AHSCT, indicating potential as biomarkers for treatment monitoring.

Mariottini et al., 2024: “Thymic hyperplasia after autologous hematopoietic stem cell transplantation in multiple sclerosis: a case series“. Front. Neurol.

Thymic atrophy typically occurs with age; however, under specific conditions, thymopoiesis can be triggered by infections, burns, surgery, chemotherapy used in the treatment of malignancies, or during AHSCT.

Background: In MS, the thymus (a key immune organ) may age prematurely. AHSCT is known to reset the immune system, partly by reactivating the thymus to produce new T-cells (de novo thymopoiesis). However, this reactivation had not been previously documented with radiological imaging in MS patients.

Aim: To be the first to describe radiological evidence of thymic hyperplasia on chest CT scans in MS patients following AHSCT.

Key Findings:

  • In a case series of 15 MS patients (7 out of 15 were RRMS. All patients received DMTs before AHSCT), thymic hyperplasia was found in 20% of cases (3/15).

  • It occurred exclusively in females aged 30-40, detected on CT scans performed 1-3 months after AHSCT.

  • No significant association was found between thymic hyperplasia and patient characteristics or post-transplant clinical outcomes.

Conclusions: This study provides the first radiological proof of thymic hyperplasia after AHSCT in MS patients. The findings support previous immunological data, confirming that AHSCT promotes thymus reactivation and that de novo thymopoiesis is a cornerstone of immune reconstitution in this population.

Marchi et al., 2024 “Leptomeningeal enhancement in multiple sclerosis: a focus on patients treated with hematopoietic stem cell transplantation”. Front. Neurol. Sec. Multiple Sclerosis and Neuroimmunology.

Background: Leptomeningeal enhancement (LME) is a nonspecific MRI finding seen in various neurological diseases, including MS, and is linked to worse outcomes. It may reflect localized, compartmentalized immune activity in the CNS and is being explored as a biomarker of disease severity.

Aim: To assess the impact of  AHSCT on LME in MS, using a BEAM+ATG regimen.

Key Findings:

  • In one patient, an LME focus disappeared after AHSCT, suggesting potential disruption of CNS-compartmentalized inflammation.

  • A correlation was found between the number of LMEs and age at AHSCT, not age at MRI.

  • The results support the hypothesis that early, high-efficacy, CNS-penetrant therapies might reduce leptomeningeal inflammatory aggregates (e.g., ELFs) and limit inflammation compartmentalization.

Conclusions: AHSCT may halt or reverse LME in MS. Further long-term, prospective studies are needed to determine if LME can serve as a treatment response marker for therapies acting within the CNS.

Figure from Marchi et al. “Leptomeningeal enhancement in multiple sclerosis: a focus on patients treated with hematopoietic stem cell transplantation”. (2024) Front. Neurol. Sec. Multiple Sclerosis and Neuroimmunology.

Ruder et al., 2022 “Dynamics of T cell repertoire renewal following autologous hematopoietic stem cell transplantation in multiple sclerosis”. Science Translational Medicine.

Background: AHSCT is a potent treatment for MS, aimed at eliminating autoreactive immune cells and renewing the adaptive immune system. However, the behavior of surviving T cells shortly after AHSCT had not been fully explored.

Aim: To investigate the composition and renewal dynamics of the T cell repertoire in MS patients following AHSCT. 

Key Findings:

  • In 27 patients, early after AHSCT, naïve T cells were nearly absent, while effector memory (EM) CD4+ T cells reconstituted rapidly.

  • These early EM CD4+ T cells had shorter telomeres, higher senescence/exhaustion markers, and lower proliferation capacity compared to pre-AHSCT.

  • The TCR repertoire overlap between pre- and early post-AHSCT EM CD4+ T cells was about 26%, indicating significant survival of older clones.

  • By 12 months, this overlap dropped to 15%, and the naïve T cell repertoire was fully renewed.

  • Reactivity to MS-related antigens decreased, while reactivity to EBV increased post-AHSCT.

Conclusions: AHSCT leads to partial survival of older EM CD4+ T cells early post-transplant, followed by gradual replacement by newly generated, naïve T cells. Over time, this contributes to a renewed and reshaped T cell repertoire, reducing autoimmune potential.

von Niederhäusern et al., 2022 “B-Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis”. Neurology Neuroimmunol Neuroinflamm

Background: AHSCT aims to reset the immune system in MS. While T cell recovery has been studied, less is known about B-cell reconstitution and its role in long-term immune modulation and infection risk.

Aim: To characterize the kinetics and composition of B-cell reconstitution in MS patients following AHSCT.

Key Findings:

  • Total B-cell numbers recovered by 3 months post-AHSCT and rose above normal levels by 1 year, with a shift from transitional to naïve B-cell phenotypes.

  • Memory B cells recovered slowly, remained below normal levels, and showed reduced repertoire diversity at 1 year.

  • Isotype analysis showed an increase in IgG1 and a reduction in IgG2-expressing cells.

  • Highly mutated memory B cells and plasma cells may transiently survive conditioning, but repertoire analysis indicated renewal of the memory B-cell pool over time.

  • Patients with early CMV reactivation experienced delayed B-cell recovery.

Conclusions: AHSCT results in rapid expansion of naïve B cells but delayed and limited memory B-cell reconstitution, with reduced diversity and functional capacity. This may contribute both to reduced autoimmune activity and increased infection susceptibility, underlining a key mechanism of AHSCT’s therapeutic effect in MS.

Ruder et al., 2021 “NK Cells and Innate-Like T Cells After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis”. Front. Immunol. Sec. Alloimmunity and Transplantation

Background: While T and B cells are central in MS pathogenesis, other lymphocyte subsets like natural killer (NK) cells and innate-like T cells are also implicated. AHSCT is known to suppress MS disease activity by resetting the immune system, but its effects on these less-studied populations were unclear.

Aim: To analyze how AHSCT influences CD56^bright NK cells and innate-like T cells in MS patients.

Key Findings:

  • In 27 MS patients, CD56^bright NK cells increased significantly in both relative frequency and absolute numbers after AHSCT.

  • In contrast, all innate-like T cell populations (including MAIT and γδ T cells) showed a marked decline post-transplant.

  • These shifts suggest a move toward enhanced immune regulation via NK cells and reduction of proinflammatory innate-like T cells.

Conclusions: AHSCT not only eliminates autoreactive adaptive immune cells but also modulates innate immune cell subsets. The expansion of immunoregulatory NK cells and suppression of innate-like proinflammatory T cells may contribute to its sustained therapeutic efficacy in MS.

Cencioni et al., 2021. “Immune Reconstitution Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Review on Behalf of the EBMT Autoimmune Diseases Working Party”. Front Immunol

Background: MS is a CNS autoimmune disease driven by T and B cells, leading to inflammation and neurodegeneration. While disease-modifying therapies help some patients, others require autologous hematopoietic stem cell transplantation (HSCT), which can induce long-term remission by eliminating autoreactive cells and re-establishing immune tolerance.

Aim: To explore how HSCT resets immune memory, focusing on the roles of disease-promoting memory B cells and stem-like T cells involved in sustaining chronic inflammation.

Key Insights:

  • HSCT leads to TCR repertoire renewal, loss of proinflammatory T cells, and increased regulatory populations.

  • Memory B cells recover slowly, suggesting reduced autoimmune potential.

  • Stem-like T cells may influence long-term immune reconstitution.

  • Post-HSCT vaccination is essential for protection and may serve as a tool to assess immune recovery vs. suppression.

Conclusion: Studying B cell and memory T cell dynamics, along with vaccine responses after HSCT, may clarify the mechanisms behind immune resetting and durable remission in MS.

Massey et al., 2018 “Regenerating immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant”. Front Immunol

Background: MS is a chronic inflammatory disease of the CNS, marked by an aberrant adaptive immune response leading to progressive neurological disability. While current immunomodulatory treatments can mitigate inflammation to some extent, they fail to halt long-term disease progression. AHSCT, a more aggressive therapeutic strategy involving immune ablation, has emerged as a potential intervention during the inflammatory phase of MS to prevent irreversible disability.

Aim: To explore and review the immunological mechanisms by which AHSCT may induce long-term therapeutic benefit in MS patients, with a focus on how immune reconstitution (IR) post-AHSCT may reestablish immune tolerance.

Key Insights:

  • Immune Reconstitution and Tolerance: AHSCT appears to induce sustained immunotolerance through deletion of autoreactive immune clones via direct ablation and lymphopenia-driven mechanisms, such as replicative senescence and clonal attrition.

  • Restoration of Immune Regulation: Post-AHSCT, regulatory T cell populations show changes consistent with improved immune regulation, and transcriptional signatures normalize toward a state of immune homeostasis.

  • Thymic Rebooting: Evidence suggests AHSCT may reactivate thymic function, allowing for regeneration of a diverse naïve T cell repertoire that supports appropriate immune modulation against new antigens.

  • Mechanism Still Unclear: Despite these findings, the exact antigenic target(s) and the full mechanism of therapeutic benefit from AHSCT remain undefined.

Conclusions: AHSCT holds promise as a treatment capable of resetting the immune system in MS, promoting long-term disease stabilization through reestablishment of immunotolerance. While empirical data support its efficacy, further research is needed to elucidate the precise pathogenic targets in MS and the detailed mechanisms underlying immune reprogramming post-AHSCT.

Burt et al. “New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis”. Bone Marrow Transplantation

A part of this paper is dedicated to IR.

Figure Burt et al.“New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis”. Bone Marrow Transplantation

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Long-Term Benefits

The ECTRIMS/EBMT consensus statement (Muraro et al., 2025) posits that AHSCT should be presented as a therapeutic option to patients with RRMS who fail HE-DMTs.

In evaluating the risk/benefit profile of HE-DMTs and AHSCT, neurologists and patients must also consider the unique long-term benefits of AHSCT. Notably, over 50% of RRMS achieve NEDA-3 for more than 10 years without requiring further DMT.

In this section, we focus on the long-term benefits of AHSCT, defining “long-term” as the period beyond 1-year post-AHSCT:

An infographic by CureMS.net (2025) illustrating the long-term benefits.

Fatigue affects up to 90% of pwMS and it is often multifactorial, influenced by inflammation (chronic CNS inflammation is considered a key contributor), neurodegeneration, medications, sleep, depression, etc.

AHSCT, by halting the aberrant immune activity that drives ongoing CNS inflammation, has the potential to directly address one of the primary biological mechanisms underlying fatigue in MS.

Studies have begun to specifically investigate the impact of AHSCT on fatigue (Giedratiene et al., 2022 | Mariottini et al., 2023 | Volz et al., 2024), with emerging evidence suggesting a clinically meaningful improvement in this symptom, particularly in patients with highly active inflammatory disease.

These findings support the hypothesis that durable suppression of CNS inflammation through AHSCT may not only stabilize disability progression but also alleviate one of the most burdensome symptoms of the disease, significantly enhancing patients’ QoL.

AHSCT significantly enhances QoL in pwMS by addressing CNS inflammation, leading to lasting benefits across multiple dimensions.

Clinical evidence shows marked improvements in physical abilities, energy levels, and symptom relief, which contribute to better emotional health, greater autonomy, and improved social and professional engagement. More about QoL here. 

AHSCT has shown the potential to improve EDSS scores in some MS patients, particularly those with RRMS, indicating possible neurological recovery beyond disease stabilization. This is especially true when the procedure is performed early in younger patients with highly active disease and low baseline disability (Muraro et al., 2025 – EBMT/ECTRIMS Guidelines).

While MS does not impair fertility or pregnancy outcomes, DMTs can complicate family planning, as some are contraindicated during pregnancy and breastfeeding. AHSCT offers a treatment option that allows patients to plan future pregnancies without the ongoing influence of DMTs. 

The chemotherapy used in AHSCT may affect fertility; this risk is now routinely addressed through pre-treatment fertility preservation strategies for females such as mature oocyte cryopreservation, embryo cryopreservation or ovarian tissue cryopreservation or sperm cryopreservation for males (Mikulska et al., 2024 – Handbook of Clinical Neurology). See the fertility section here. 

There is not an official guideline specifying an exact timeframe for conception after AHSCT; however, clinical observations suggest that pregnancy can generally be considered safe from 12- and 24-months post-transplant, once the immune system has recovered and there is no longer interference from immunosuppressive therapies.

Fertility counseling and early consultation with specialists are strongly recommended before initiating the procedure.   

“Published guidance recommends that people who have undergone HSCT are considered as ‘never vaccinated’ and offered revaccination. Vaccination planning after AHSCT should follow national and international recommendations and be adapted to local practice.” (Muraro et al., 2025 | EBMT-ECTRIMS Consensus Statement). 

After the first year post-transplant, patients can receive future vaccinations with flexible timing, based on clinical need and patient preference. unlike with DMTs (for vaccination in patients on DMTs see Otero-Romero, et al., 2023 – ECTRIMS/EAN consensus on vaccination). 

After 1–2 years post-transplant, the immune system has reconstituted, and the revaccination program is complete. At this point, there is no evidence of an increased risk of infection, and the risk is presumably comparable to the pre-transplant period, whereas the continuous administration of DMTs increases the risk of infection (Langer-Gould et al., 2023 | Moiola et al., 2021)

AHSCT can induce long-term disease remission, eliminating the need for common DMTs. This translates into decreased psychological and logistical burden and a gradual reduction in routine monitoring—fewer blood tests, MRIs, and neurological evaluations. Here the indications of long-term monitoring post-AHSCT of the EBMT- ECTRIMS 2025 consensus:  

Immunological and Infectious monitoring following transplant: 

Neurological and Radiological monitoring following transplant: 

Emerging evidence suggests that AHSCT may offer benefits beyond MS disease control by positively influencing coexisting autoimmune conditions. In some cases, pwMS with immune-mediated comorbidities, such as psoriasis, have experienced remission or improvement after AHSCT, likely due to the immune system reset. However, while this therapeutic effect could be advantageous for individuals with multiple autoimmune disorders, it is also important to consider that AHSCT may occasionally be associated with the emergence of new autoimmune diseases, highlighting the need for careful patient selection and long-term monitoring.

BTK inhibitors will shortly enter the landscape of MS treatment (Naydovich et al., 2025). However, their concomitant use with another DMT may be problematic due to an increased risk of adverse events and conflicting mechanisms of action.

The use of BTK inhibitors in patients who underwent transplantation one year ago and are not using a DMT may therefore be safer.

 Following AHSCT MS patients in NEDA-3 without DMTs, are in optimal condition for testing neuroprotective strategies, such as Neural Stem Cells (Genchi et al, 2023) or NURR1 activators (Fox et al., 2024) or remyelinating therapies such as Lucid-31-302  (phase I trial, read more here), PIPE-307 (see more here) or dihydroartemisinin (link here).

Unlike DMTs, which require lifelong administration, AHSCT is a one-time treatment. This results in substantially lower long-term costs for national healthcare systems, insurance providers, and patients—especially in self-funded cases (for “AHSCT centers & costs”, click here).  

As outlined in the “Pharmacoeconomics section” (more here), AHSCT has shown superior cost-effectiveness compared to all available DMTs, whose cumulative and annually increasing costs continue to place a financial burden on healthcare budgets. Worth reading: Santoro et al., 2024 (An American Academy of Neurology Position Statement)

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Quality Of Life

WHO defines Quality of Life (QoL) as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns”.

Improvements in health-related QoL have consistently correlated with sustained clinical stabilization (Muraro et al., 2025) and represent the most meaningful outcome for patients, as they directly impact their daily lives.

In pwMS, QoL is affected in numerous ways and aspects, including their ability to work, perform daily activities, and execute everyday tasks (Rezapour et al., 2017).

Initially, only the physical disability caused due to MS was considered by clinicians, as the sole aspect of the disease. In order to obtain an overview on how MS impairs patients’ QoL both psychological aspects and physical aspects must be considered.

All three of the studies listed below, published between 2022-2025, and focused on QoL following AHSCT, have demonstrated a sustained improvement in QoL.

QoL according to FDA: a patient-report outcome

QoL can be considered as a patient-reported outcome (PRO). PROs are defined by the US FDA as the “measurement of any aspect of a patient’s health status that comes directly from the patient, without the interpretation of the patient’s response by a clinician or anyone else” (US Food and Drug Administration 2009) (EBMT handbook – Barata et al., 2024). Consequently, PROs describe the impact that AHSCT has on patients’ lives.

As reported in the EBMT handbook (2024) there are numerous measures for assessing QoL. These measures include both general and disease-specific assessments. Trials like STAR-MS, RAM-MS and NET-MS have included QoL as a secondary outcome, emphasizing that incorporating QoL alongside other measures in clinical and research settings offers a more comprehensive understanding of AHSCT outcomes.

Objective: To evaluate the impact of AHSCT on quality of life (QoL) in MS patients using MSIS-29 scores.

Patients & Methods: A retrospective cohort study of 96 RRMS patients treated with AHSCT in Sweden (2004–2019). QoL outcomes were analyzed using data from the Swedish MS registry.

Results:

  • After a median follow-up of 5.2 years, 58% improved physically and 63% psychologically.
  • Improvements occurred early (within one year) and were sustained.
  • Patients with No Evidence of Disease Activity (NEDA) reported better QoL.

Conclusion: AHSCT provides clinically meaningful, lasting QoL improvements, supporting its broader use in MS treatment. (Mitrache Desaga et al., 2025)

Objective: Compare long-term outcomes of AHSCT vs. alemtuzumab in MS patients, focusing on QoL, cognition, and disease stability.

Patients & Methods: 41 MS patients (20 AHSCT, 21 alemtuzumab); alemtuzumab group had longer disease duration (11.3 vs. 5.4 years, p = 0.002). Observational study (2007–2020) assessing NEDA-3, cognitive function, QoL (HAQUAMS), EDSS, and MSFC. The study was conducted at the University Medical Center Hamburg-Eppendorf, in Germany.

Results:

  • QoL: Stable up to 10 years in aHSCT; fatigue improved (p = 0.013). Alemtuzumab group worsened.
  • Cognition: AHSCT improved in 5/12 tests, alemtuzumab declined in 4/12.
  • Disease stability: Higher NEDA-3 in aHSCT (75% vs. 40% at 5 years, p = 0.012), no new T2 lesions vs. 35% in alemtuzumab (p = 0.002).

Conclusion: AHSCT is superior in maintaining QoL, cognition, and disease control for up to 10 years. (Braun et al., 2024)

Objective: To assess the impact of AHSCT on quality of life (QoL), fatigue, anxiety, and depression in MS patients.

Patients & Methods: A prospective study of 18 patients with highly active relapsing MS treated with AHSCT in Vilnius (Lithuania). QoL was measured using SF-36, fatigue, and psychological scales at baseline, 3, 12, and 24 months post-transplant.

Conclusion: AHSCT significantly improves QoL and reduces fatigue in MS patients, with benefits appearing earlier for QoL than fatigue. These findings support AHSCT as a valuable treatment option. (Giedraitiene et al., 2022)

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Pharmacoeconomics

Pharmacoeconomics is a specialized branch of economics that assesses the cost and value of pharmaceutical products and services. It examines their cost and the benefits they provide in terms of reducing disease progression, disability, and improving patients’ quality of life (QoL).

Pharmacoeconomics employs various methods, such as cost-effectiveness analysis, to evaluate these aspects. These studies are essential for all healthcare systems, given the increasing challenges in providing medications to all citizens.

Pharmacoeconomic studies has consistently shown that transplants offer greater benefits to patients at a lower cost (“more effective, less costly“) than traditional DMTs. These findings apply to both public healthcare systems (such as in Italy, Norway, and Poland) and private ones.

Figure from Mariottini et al. “Cost and effectiveness of autologous haematopoietic stem cell transplantation and high‐efficacy disease‐modifying therapies in relapsing–remitting multiple sclerosis”. Neurological Sciences (2024).

DMD, disease-modifying drugs (i.e., DMTs).

Figure from Orlewska et al. “Impact of Immunoablation and Autologous Hematopoietic Stem Cell Transplantation on Treatment Cost of Multiple Sclerosis: Real-World Nationwide Study”. Value in Health (2021)

Following studies or reports on pharmacoeconomic around the world comparing AHSCT vs. DMTs: 

Objectives: The study evaluates the cost-effectiveness of AHSCT compared to high-efficacy disease-modifying therapies (HE-DMTs) for RRMS in Italy (Mariottini et al., 2024).

Patients: RRMS patients treated with AHSCT or HE-DMTs (natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine). Costs and treatment outcomes were analyzed.

Results

  • Cost: AHSCT is initially similar in cost to HE-DMTs but becomes much cheaper over 5 years (€46,600 vs €93,800).
  • Effectiveness: AHSCT is more effective in achieving no evidence of disease activity (NEDA) at a significantly lower cost.
  • Healthcare Savings: AHSCT, as a one-time treatment, may reduce overall healthcare costs and improve access to care.

Conclusions: AHSCT is a highly cost-effective option for aggressive RRMS, offering both clinical and economic benefits for healthcare systems.

Objectives: This study by Gottschlich et al., 2024, evaluates the healthcare utilization and costs associated with AHSCT in Norwegian patients with RRMS. It aims to provide a detailed cost analysis using a micro-costing approach to assess the economic impact of AHSCT.

Patients: The study included 30 RRMS patients who underwent AHSCT at Haukeland University Hospital between 2015 and 2018. Data were extracted from medical records to estimate costs from pre-transplant screening to one year post-AHSCT.

Results

  • Total cost: The average total healthcare cost per patient for AHSCT was €66,304 (95% CI: €63,598 – €69,010).
  • Cost breakdown: Most expenses (€64,329) occurred during the treatment phase and first 100 days post-transplant.
  • Long-term savings: AHSCT may lead to significant cost reductions compared to high-cost disease-modifying therapies (DMTs), which range from €20,000 to €30,000 per year.

Conclusions: AHSCT represents a cost-effective treatment for selected RRMS patients with aggressive disease, offering long-term savings and potentially superior clinical outcomes compared to standard DMTs. Future research should include long-term cost-effectiveness studies to guide healthcare policy decisions.

Objectives: The study by Orlewska et al., 2021 examines the cost of AHSCT for MS within the Polish healthcare system, where AHSCT is exclusively performed by the Polish National Health Service (NHS). The study assesses treatment costs before and after AHSCT and its long-term financial benefits.

Patients: The study includes MS patients undergoing AHSCT in Poland, where the procedure is fully reimbursed by the NHS at a fixed rate of €12,000.

Results

  • Cost of AHSCT: The first-year cost after AHSCT was €13,180.9, including €12,000 for the procedure and €1,180.9 for inpatient care (ambulatory care, diagnostics, rehabilitation).
  • Cost Savings: The second-year cost dropped significantly to €410.6 per patient-year.
  • Reduction in Expenses:
    • Total treatment costs decreased by 82% within 12 months after AHSCT.
    • DMT therapy costs dropped by 97% post-AHSCT.
  • Break-even Point: The study estimates that AHSCT costs are recovered within 3.9 years, as total medical costs remain higher in the first year but decrease substantially afterward.

Conclusions: AHSCT in Poland drastically reduces treatment costs, making it a financially viable option for the healthcare system. The long-term cost-effectiveness suggests that AHSCT pays for itself within four years, reinforcing its economic and clinical benefits for MS treatment (Orlewska et al., 2021).

Objectives: The study by Burt et al. analyzes the costs of AHSCT for MS in the private American healthcare system. It compares AHSCT costs to disease-modifying therapies (DMTs) and evaluates the financial and clinical benefits of AHSCT.

Patients: The study includes 37 MS patients, with a mean age of 38 years, an Expanded Disability Status Scale (EDSS) score of 3.7, and a history of prior DMT use.

Results

  • AHSCT Cost: The average total cost for inpatient AHSCT in the U.S. is $150,000, though costs vary by patient and treatment plan. Uninsured patients typically face DMT costs of $86,000–$100,000 per year.
  • Cost Savings: Within five years, 85% of AHSCT patients remain relapse- and drug-free, leading to estimated savings of $292,400 per patient.
  • Clinical Benefits: AHSCT studies report greater improvements in NEDA (No Evidence of Disease Activity), disability progression, and quality of life (QoL) compared to DMTs.
  • Economic Impact: High DMT costs and the loss of employment due to MS may further increase the financial burden on patients, particularly those who lose insurance coverage.

Conclusions: AHSCT appears to be a cost-effective alternative to long-term DMT use, offering both financial savings and superior clinical outcomes. The study suggests that AHSCT may be a “win-win” solution, reducing overall healthcare costs while improving patient health. However, insurance coverage limitations remain a significant barrier to access.

The National Institute for Health and Care Excellence (NICE) provides guidance to improve health and social care in England, ensuring high standards within the NHS and other healthcare providers.

According to a 2018 NICE report, around 18,800 people in the UK could be eligible for AHSCT, a one-time treatment for MS costing £30,000 per person. If only 1% of eligible individuals undergo treatment, the total cost would be about £6 million. Unlike the recurring costs of DMTs for MS, AHSCT involves a one-off cost.

In the UK, AHSCT administered through clinical trials or the NHS does not have any financial cost for the recipient. 

As of July 2024 (see here the official notice) the NICE website indicates that the evaluation of AHSCT has been put on hold due to insufficient information, suggesting there is still limited interest in the topic.

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Tools to Understand Studies

Tools to Understand

Studies

Clinical evidences are information and data collected through scientific studies and clinical observations that demonstrate the efficacy, safety, and effectiveness of treatments or procedures.

To obtain clinical evidences, various types of studies are conducted (e.g., randomized controlled trials, cohort studies, case-control studies, etc.). Each of these studies provides evidence of different strengths.

Click on these links for additional informational about how clinical evidences are collected, phases of clinical trials or class of evidences (Source: Neurology).

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