Autologous haematopoietic stem cell transplantation (AHSCT) in multiple sclerosis

Introduction: what is AHSCT and why interest in it is growing

Autologous haematopoietic stem cell transplantation (AHSCT) is a method of intensive immuno-reconstituting therapy in which the patient’s own stem cells are used to “reset” the immune system. The procedure includes temporary immunoablation (suppression of the pathologically active immune system) and subsequent restoration of haematopoiesis from previously collected stem cells.

Initially, AHSCT was used to treat onco-haematological diseases and severe autoimmune disorders (systemic sclerosis, vasculitis, severe forms of systemic lupus erythematosus). Experience with its use in multiple sclerosis (MS) began to accumulate in the late 1990s, when the hypothesis appeared that “rebooting” the immune system could stop the inflammatory cascade leading to demyelination and axonal damage.

History of the method and prevalence of AHSCT in MS

1995–2000 – the first small series of patients with severe, rapidly progressive MS. Predominantly high-intensity myeloablative regimens were used, which limited safety and made the results heterogeneous.

2000–2010 – transition to non-myeloablative and “moderate” conditioning regimens (BEAM–ATG, cyclophosphamide–ATG, etc.), which made it possible to significantly reduce toxicity and transplant-related mortality.

2010–2020 – formation of large national and international registries (EBMT, CIBMTR, programs in Sweden, Italy, Norway, Denmark, etc.), publication of meta-analyses and long-term observational studies.

2019 – the randomized MIST trial demonstrated the superiority of AHSCT over continuation of disease-modifying therapy in preventing disability progression.

2020–2025 – AHSCT has been included in the recommendations of the US National MS Society and ECTRIMS–EBMT as a possible treatment option for a strictly defined group of patients with aggressive disease course. Randomized trials STAR-MS and BEAT-MS have been launched to directly compare AHSCT with modern high-efficacy disease-modifying therapies (DMTs).

According to the European Society for Blood and Marrow Transplantation (EBMT) and CIBMTR, to date several thousand AHSCT procedures for MS have been performed worldwide (about 3,000–4,000 cases in total), and the annual number of transplants continues to grow. The largest programs operate in Europe, North America and a number of Asian countries.

Interest in AHSCT is growing for several reasons:

• accumulation of evidence showing more pronounced suppression of disease activity compared with DMTs;
• significant reduction in toxicity due to optimization of conditioning and patient management;
• the emergence of a group of patients with “pharmacoresistant”, highly active MS, for whom standard DMTs are insufficiently effective;
• better understanding of the concept of immuno-reconstituting therapy as an alternative to long-term immunosuppression.

Who is AHSCT indicated for in multiple sclerosis

According to modern ECTRIMS/EBMT and US National MS Society recommendations, AHSCT is considered primarily in patients with highly active relapsing MS (most often relapsing-remitting), in whom the disease remains active despite treatment with one or several high-efficacy disease-modifying therapies (high-efficacy DMTs such as natalizumab, alemtuzumab, ocrelizumab, ofatumumab, cladribine, etc.). Key selection criteria include:

• age, as a rule, up to 50 years;
• disease duration less than 10 years;
• preserved ability to walk independently (usually EDSS ≤ 6.0, optimally ≤ 5.5);
• frequent relapses and/or new contrast-enhancing lesions on MRI despite adequate high-efficacy DMT;
• absence of severe comorbid somatic pathology that substantially increases the risk of conditioning toxicity.

Patients with active secondary progressive MS (aSPMS) may be considered for AHSCT if clinical relapses and/or new MRI lesions are present despite high-efficacy DMT failure. In this group, the procedure generally leads to slowing of progression and stabilization; however, the frequency of neurological improvement is lower than in relapsing-remitting MS.

In primary progressive MS without signs of inflammation, the effectiveness of AHSCT is significantly lower; therefore such patients are usually not included in transplant programs. Overall, patients with pronounced inflammatory activity and still relatively reversible neurological deficit derive the greatest benefit.

National and international experience (including Russian implementation programs of high-dose immunosuppressive therapy with AHSCT) demonstrate comparable efficacy and safety when selection criteria are followed and the procedure is performed in specialized centers.

Comparative effectiveness of AHSCT and high-efficacy DMTs

In recent years, large retrospective cohorts, meta-analyses and emulated “quasi-randomized” studies comparing AHSCT with high-efficacy DMTs (natalizumab, fingolimod, ocrelizumab, alemtuzumab, cladribine, etc.) have been published.

The key conclusions of these works are:

• in patients with highly active relapsing-remitting MS, AHSCT is associated with a significantly lower risk of clinical relapses compared with fingolimod, natalizumab and ocrelizumab;
• the annual relapse rate (ARR) after AHSCT decreases to about 0.04–0.05, which is lower than with most high-efficacy DMTs;
• the proportion of patients achieving NEDA (no evidence of disease activity: no clinical relapses, no new MRI lesions and no disability progression) is higher with AHSCT;
• the probability of improvement on the EDSS scale (not only stabilization) after AHSCT is significantly higher than on DMTs;
• the risk of confirmed disability progression in long-term follow-up with AHSCT is comparable to or lower than that with high-efficacy DMTs.

If we consider AHSCT among immuno-reconstituting strategies (IRT, including alemtuzumab, cladribine), data from large observational studies and meta-analyses indicate that AHSCT provides deeper and longer-lasting suppression of inflammatory activity and a higher probability of long-term NEDA than most other IRT approaches, with a comparable or more favorable profile of late autoimmune complications.

In several studies where AHSCT was compared directly with alemtuzumab, patients after AHSCT had fewer relapses and less MRI activity, experienced secondary autoimmune diseases less frequently, and a higher proportion of patients showed EDSS improvement. This further supports the concept of AHSCT as the most powerful variant of immuno-reconstituting therapy for aggressive MS.

Long-term outcomes and duration of AHSCT effect

Large observational studies and registry analyses (including EBMT data) make it possible to estimate how long the effect of AHSCT lasts.

The main trends are:

• in patients with highly active relapsing-remitting MS, 70–80% remain free from disability progression over a 5-year horizon after transplantation;
• about 30–40% of patients show a sustained EDSS reduction of ≥ 0.5–1.0 points or more compared with baseline;
• after 10 years of follow-up, approximately half of patients have no confirmed disability progression, especially when transplantation is performed at early disease stages and with low baseline EDSS;
• in some patients (around 20–30% in long-term series) disease activity may recur (new relapses, MRI lesions or slow disability accumulation), more often between the 3rd and 7th years after transplantation.

Overall, the body of data from meta-analyses and registries suggests that AHSCT provides prolonged remission lasting 5–10 years or more in a significant proportion of patients. The most favorable profile is seen in young patients with relatively short disease duration and pronounced inflammatory activity, in whom transplantation is performed within a “window of opportunity”, before the development of severe irreversible neurological deficit.

Management strategy when activity recurs after AHSCT

Recurrence of disease activity after AHSCT is relatively rare in the first 2 years and is more often observed between 3 and 7 years after transplantation. Two main approaches to management in this situation are discussed in the literature.

Repeat AHSCT

There are series of patients in whom repeat AHSCT was performed if disease activity recurred. It is assumed that a second immune “reboot” can again provide long-term remission, especially if the first transplantation produced a good effect. However, experience is limited, and the cumulative risk of toxicity from conditioning regimens (infections, haematological complications, impact on fertility, potential risk of secondary malignancies) increases.

ECTRIMS/EBMT recommendations consider repeat AHSCT as a possible option for strictly selected cases, to be performed in highly specialized centers after careful assessment of the risk–benefit ratio.

Switching to high-efficacy DMTs after AHSCT

A more common approach is to regard AHSCT as an immune system “reboot” and, in case of renewed activity, to switch to modern high-efficacy DMTs. Various registries and national cohorts describe strategies such as:

• prescribing anti-CD20 therapy (ocrelizumab, ofatumumab) when new relapses or MRI lesions appear;
• using natalizumab with a low JC virus risk;
• using oral immuno-reconstituting agents (for example, cladribine) after AHSCT.

The data are still limited, but overall they indicate that DMTs can be used after transplantation and provide additional disease control, although they require particularly careful monitoring of infectious risks and immune reconstitution status.

The choice between repeat AHSCT and switching to DMTs in the event of recurrent activity remains open and is decided individually, taking into account the patient’s age, disease duration and phenotype, degree of disability, somatic status and patient preferences.

Safety and limitations of the method

Despite its high efficacy, AHSCT remains an invasive procedure with substantial early toxicity and a number of potential long-term risks.

Early toxicity and transplant-related mortality

In modern centers with sufficient experience, transplant-related mortality (TRM) for AHSCT in MS patients is generally less than 0.5–1.0%. The main early complications are associated with myelo- and immunoablation:

• severe cytopenias (neutropenia, thrombocytopenia, anaemia) requiring antibacterial and transfusion support;
• febrile neutropenia, bacterial and viral infections;
• mucositis, gastrointestinal toxicity, transient liver injury;
• marked asthenia, alopecia, the need for hospitalization in a specialized unit.

With adequate management, most of these complications are controlled and resolve as haematopoiesis and the immune system recover.

Late complications

Potential late effects of AHSCT include:

• reduced fertility, especially in women when more intensive conditioning regimens are used;
• premature ovarian failure and amenorrhoea in a proportion of female patients;
• secondary autoimmune diseases (autoimmune thyroiditis, cytopenias), usually less frequent and less diverse than with alemtuzumab therapy;
• a possible risk of secondary malignancies in a very long-term perspective (data are still limited and conflicting; longer follow-up is needed).

Limited availability and organizational complexity

AHSCT is performed only in a small number of specialized transplant centers with infrastructure for managing patients under profound immunosuppression. This limits the availability of the method, especially in countries with limited resources.

The procedure requires the participation of a multidisciplinary team (neurologists, haematologist-transplant physicians, infection control specialists, rehabilitation specialists), prolonged hospitalization and subsequent follow-up, which increases the organizational and economic burden.

Lack of large randomized trials

Although data from observational studies and meta-analyses are quite convincing, the number of large randomized controlled trials (RCTs) directly comparing AHSCT with modern DMTs is limited. The MIST trial showed a clear advantage of AHSCT over continued DMT in terms of risk of progression, but it preceded the widespread use of anti-CD20 agents and some modern immuno-reconstituting strategies.

Current RCTs (for example, STAR-MS, BEAT-MS) are aimed at direct comparison of AHSCT with alemtuzumab, ocrelizumab, ofatumumab and cladribine, but the results of these studies are still awaited. The difficulties in conducting RCTs are related to ethical aspects of randomizing patients with aggressive MS, logistics and the limited number of centers.

Conclusion: the place of AHSCT in modern MS therapy

Autologous haematopoietic stem cell transplantation is currently one of the most effective treatment strategies for highly active inflammatory multiple sclerosis. For carefully selected patients it provides:

• significantly more pronounced suppression of clinical relapses and MRI activity compared with most DMTs;
• a high proportion of patients with NEDA and long-term remission (5–10 years or more);
• a higher probability of neurological improvement (EDSS reduction) than with pharmacotherapy alone;
• a comparable or more favorable long-term risk profile for disability progression.

At the same time, AHSCT remains an invasive and potentially risky procedure that requires:

• strict patient selection and performance in specialized centers;
• patient readiness for intensive therapy and possible complications;
• consideration of organizational, economic and logistical limitations.

It seems optimal to use AHSCT as an early high-efficacy option for patients with aggressive relapsing-remitting MS not controlled by a single line of high-efficacy DMTs, as well as a possible option for carefully selected patients with active secondary progressive MS who retain walking ability and have marked inflammatory activity.

The issue of management when activity recurs after AHSCT (repeat transplantation or switch to DMTs) should be resolved individually based on a comprehensive assessment of risks and expected benefit.

References

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