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25Cellular Therapy and Transplantation (CTT). Vol. 11, No. 2, 2022 doi: 10.18620/ctt-1866-8836-2022-11-2-6-15 Submitted: 14 Мау 2022, accepted: 05 July 2022
High-dose immunosuppressive therapy with autologous hematopoietic stem cells transplantation for multiple sclerosis: Current view
Alexey Yu. Polushin, Evgeniya I. Lopatina, Yury R. Zalyalov, Alexander A. Tsynchenko, Natalia A. Totolyan, Alexander D. Kulagin
Pavlov University, St. Petersburg, Russia
Dr. Alexey Yu. Polushin, Pavlov University, 6-8 L. Tolstoy St., Phone: +7 (911) 816-75-59 197022, St. Petersburg, Russia E-mail: [email protected]
Citation: Polushin AY, Lopatina EI, Zalyalov YR, et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cells transplantation for multiple sclerosis: Current view. Cell Ther Transplant 2022; 11(2): 6-15.
Summary
Autologous hematopoietic stem cells transplantation (aHSCT) followed by high-dose immunosuppressive therapy is a promising and effective method of treating autoimmune diseases, including multiple sclerosis (MS). Over the past 15-20 years, frequency and severity of adverse events in aHSCT were decreased after reducing the intensity of conditioning regimens. Both better understanding of the immunological mechanisms of immune reconstitution and better approach to the selection of patients for this procedure also led to improved results.
In view of increased incidence of multiple sclerosis worldwide, as well as insufficient effectiveness of standard therapy, the introduction of autologous transplantation into clinical guidelines for the MS treatment could maintain quality of life in the workforce population.
Keywords
Multiple sclerosis, mobilization, apheresis, high-dose immunosuppressive therapy, autologous hematopoietic stem cells, transplantation, immunotherapy.
Introduction
Over recent decades, an increase in the incidence of multiple sclerosis (MS) was recorded worldwide [1-3]. Unfortunately, current medicamental treatment of MS is very expensive and is not efficient enough: it allows for relapse-free course only in a half of the cases. In this regard, European countries are already developing programs to include high-dose immu-nosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) into the standards of active MS treatment [4, 5]. In the Russian Federation, HDIT-AHSCT has been used for severe autoimmune diseases since the mid-1990s [6, 7] like as in the European transplant clinics [8; 9]. Hence, the purpose of this review is to analyze the scientific publications on the selection of optimal conditions and criteria for HDIT-AHSCT for multiple sclerosis.
Methods of data searching
The search for scientific publications in the databases "Pub-med", "Scopus" was carried out by the keywords "HDIT-AHSCT", "stem cells" and "multiple sclerosis".
Analysis and systematization of the data from scientific literature was based on the following issues: 1) algorithms and stages of the HDIT-AHSCT methodology; 2) immu-nopathgenic rationale for the HDIT-AHSCT in MS patients; 3) results of HDIT-AHSCT clinical trials (CT) in MS; 4) conditioning regimens in HSCT; 5) selection of MS patients according to the criteria for HDIT-AHSCT. Our analysis included publications with high levels of evidence: publication of the results of randomized and controlled experimental and clinical laboratory studies. The international consensus recommendations of expert groups were also considered.
The main stages of HDIT-AHSCT:
1. Mobilization of hematopoietic stem cells - the stimulation of the CD34+ hematopoietic stem cells (HSC) output from the bone marrow to peripheral blood aiming for subsequent apheresis and mononuclear cell collection. The granulocyte colony-stimulating factor (G-CSF) is used for CD34+ cell mobilization, either as a single drug, or in combination with cyclophosphamide (Fig. 1). The available studies have not been identified statistically significant differences between such approaches in terms of relapse-free clinical course [10]. There are also no significant differences when comparing the groups with or without CD34+ cells immunoselection, the latter technology has led to lower treatment costs [11]. Patient's age, individual features of bone marrow functioning, previous treatment modaliities are the factors that may affect efficiency of hematopoietic stem cell mobilization.
2. Apheresis means removal of CD34+ cells from peripheral blood for subsequent cryopreservation. The HSC apheresis may take 1-2 days for sufficient cell collection. The optimal number of CD34+ cells in the transplant should be 2-5x106/kg of recipient weight.
3. Cryopreservation of the transplant, i.e., storage of the transplant in liquid nitrogen with a cryoprotector (di-methylsulfoxide) is required for the time period of treatment and pre-transplant conditioning therapy.
4. Conditioning regimen (CR) includes high-dose immunosuppressive therapy (HDIT) in order to deplete autoreactive T- and B- lymphocytes. The AHSCT conditioning regimens are heterogeneous for their intensity, being 4 to 7 days long. Atkins H. et al. showed the effectiveness of high-intensity, i.e., myelo ablative regimens which include cyclophos-phamide and busulfan, even in the patients with progressive forms of MS [12]. However, the use of high-intensity conditioning has an adverse toxicity profile and may lead to increased therapy-associated mortality. Usage of low- and medium-intensity regimens often allows to avoiding significant toxicity and demonstrates high efficacy in patients with remitting MS. The issue of choosing of conditioning regimen still remains open in cases of progressive MS.
5. The AHSCT procedure requires thawing and transfusion of the transplant to the patient (day 0). The duration of the procedure is less than half an hour. The primary goal of an autograft transfusion is to trigger fast recovery of the naive immunocompromised cell pool and to make cytopenic period shorter.
6. Immunotherapy includes usage of antithymocyte globulin (ATG) for additional exhaustion of T-lymphocytes in the transplant as well as lymphocytes in blood flow that survived after chemotherapy. In addition, ATG has an immunomod-ulating effect, due to increased expansion of T-regulatory cells, which, in turn, positively influences the processes of immunological tolerance [13].
7. The period of cytopenia is characterized by low leukocyte level in circulation. It is a regular complication of HDIT, but it is not the target when treating autoimmune disorders. In the framework of standard protocols, the massive accompanying anti-infectious therapy is carried out at this stage and, if necessary, transfusions of blood products are provided.
8. The period of hemopoietic recovery is achieved upon reconstitution of blood leukocytes to subnormal levels ("exit" from cytopenia). At this stage, G-CSF may be used to reduce the period of cytopenia by an average of 5-7 days. The patient can be discharged from the hospital after sustained hemo-poiesis recovery to >1x109/l leukocyte levels; neutrophils to >0.5x109/l; platelets to >20x109/l, does not require transfusions of blood components, in absence of toxic organ, infectious and hemorrhagic complications.
9. Consolidation is a feasible therapeutic option to maintain the HDIT effect (for example, in fast-progressing/aggressive MS). The consolidation treatment (remission support) may include complementary immunosuppressive therapy and is administered exclusively within the framework of internal protocols of specialized centers. To date, there is no consensus protocol for post-transplant management of patients with MS.
The HDIT-AHSCT stages are shown in Figure 1.
Hemopoiesis Transplantation recovery
Apheresis (AHSCT) (discharge)
HSC mobilisation G-CSF (+Cy) ■ an Conditioning regimen HDIT i_ .... Immut n lotherapy i
Day-5-2 DayO Day+1+3 14-20 days 12 month
n \f\ r r *
Lymphodepietion | Cytopenia | Immune reconstitution I
Figure 1. Steps of the high-dose intensive therapy (HDIT)-autologous stem cell transplantation (AHSCT)
Notes: G-CSF, Granulocyte Colony Stimulating Factor; HSC, Hematopoietic Stem Cells; HDIT, High-Dose Immunosuppressive Therapy; AHSCT, Autologous Hematopoietic Stem Cell Transplantation; Cy, Cyclophosphamide.
Immunopathogenic rationale of HDIT-AHSCT in MS
Multiple sclerosis is a promising disease for the potential HDIT-AHSCT application since it represents a classical autoimmune disease associated with impaired immuno-logical tolerance followed by a sequence of immunopatho-genic events directed against the nervous system, including altered antigen recognition and presentation, activation, proliferation and cell differentiation in the course of adaptive immune response. The notion that HSC in autoimmune diseases are intact, and the pathological process involves im-munocompetent cells at the early stages of differentiation, was suggested and confirmed by the efficacy of autologous and syngeneic bone marrow transplantation in experimental models for rheumatoid arthritis and experimental autoimmune encephalomyelitis using immunoablation with highdose cyclophosphamide and total body irradiation (TBI) [14-16].
Potential efficacy of HDIT preceding the AHSCT is based on a double effect upon immune system: a) elimination of pathogenetically significant autoreactive T- and B-lympho-cytes using high-dose immunosuppressive therapy followed by de novo repopulation of "naive" lymphocytes from the transfused autologous cells, and b) due to generation of im-munological tolerance to the disease-specific autoantigens [17-19]. The proof of concept for HDIT-AHSCT is based on 2 pre-requisites: (1) achievement of immune reconstitution after profound lymphodepletion and restoration of adequate balance between autoreactive cells, and (2) presumed effects of emerging immune cells responsible for immuno-suppression and immunoregulation. The expected effect also includes achievement of long-term immunological au-totolerance. The absence of radiological activity and clinical relapses after HDIT-AHSCT in patients with aggressive MS forms correlates with a decrease in circulating cell subpopulations of proinflammatory Th17 and dpTh1/Th17 [17].
Due to the intactness of stem cells, the autoimmune diseases (AID) do not require myeloablative conditioning. This concept allowed to eliminate highly intensive myeloablative conditioning, while maintaining the immunoablative action, thus providing total elimination of autoreactive clones of Tand B-cells [20, 21].
However, the use of a nonmyeloablative conditioning for experimental autoimmune encephalomyelitis without he-matopoietic stem cell support (only HDIT without AHSCT) did not result in long-term remission, suggesting possible immunomodulating effects of AHSCT [22]. Some studies have shown that the supposed diversification of immune cell repertoire (immunological reconstitution) may occur after AHSCT. One may also expect selective expansion of minor autoreactive T-lymphocyte clones that survived the conditioning treatment immediately after reinfusion of autologous stem cells. Moreover, the transplant itself also contains an admixture of T lymphocytes, which may be a cell substrate for subsequent immune reconstitution. Immunotherapy with ATG on the first days after AHSCT (D+1, D+2, D+3) leads to additional lymphodepletion and exhaustion of T-lympho-cyte subpopulations from MAIT (mucosal associated invariant), characterized by CD8+ phenotype, proinflammatory IL-17 and interferon-Y [23].
The second phase of T-cell reconstitution begins in the thymus, where immunological "learning", differentiation and maturation of T-lymphocytes occur. Thereafter, "naive" T cells circulate in the blood and peripheral lymphoid organs and, hence, participate in "reboot" of the immune system. Patients without signs of activity show early expansion of CD8+PD-1+ T-lymphocytes, and inversion of CD4/CD8 ratio. Over the first months after the procedure, the repertoire of CD8+ and (to a lesser extent) CD4+ T-cells undergoes sufficient expansion. It is also known that autologous CD34+ cells may be involved in differentiation of GFAP-producing reactive astrocytes. After 1-2 years, expansion of naive CD4+ and CD8+ thymic cells is observed, which exhibit wider clonal diversity. The regulatory pool of CD4+CD25+CD127 FoxP3+ T-lymphocytes (promoters of immunological tolerance) is also increasing with time [24].
The B-cell repertoire is also changing as seen by the profile of recovering B-lymphocytes after HDIT-AHSCT which differs from B lymphocytes prior to therapy. The peculiarity of post-transplant B-cell reconstitution is a predominance of "naive" phenotype (CD27-), whereas an imbalance towards proinflammatory profile was evident before AHSCT. For this reason, the reduced secretion of proinflammatory cytokines (FNO, IL-6, GM-CSF) was detected, and an increase of IL-10 was achieved [25]. These changes contribute to the recovery of immunological autotolerance, which may be long-lasting [26]. The changes of adaptive immune response persist for a long time after HSCT and the initial lymphocyte repopulation phase. This hypothesis confirms the concept of immune "reboot" [27].
Clinical Studies of HDIT-AHSCT in multiple sclerosis
According to the data of Autoimmune Diseases Working Party (ADWP), about 4000 SCT for autoimmune diseases (AID) have been performed and officially registered by the European Society for Blood and Marrow Transplantation (EBMT). [28, 29]. More than half of the HDIT-AHSCT were administered in cases of multiple sclerosis. The largest register of the Mexican group, where more than 1000 SCT for MS have been performed, is also known [30].
Despite the experience gained so far, the number of completed clinical trials is limited, and the data obtained are difficult to compare for the patient groups, procedure protocols (CR) and test endpoints (Table 1), and to perform proper statistical evaluation, due to their heterogeneity.
According to the HALT-MS study, the patients with active relapsing-remitting MS (RRMS) had sustained clinical remission in 77% of cases during the 5-year follow-up [32]. According to the ASTIMS study, the number of T2-lesions (MRI) was decreased in 79% of patients during 4-year follow up after HDIT-AHSCT [33]. High-intensity CR (Bu-Cy-ATG) showed full clinical and radiological remission in 84% of patients with long-term observation for an average of 6.7 years (3.9 to 12.7) [12].
Data on the efficiency of HDIT-AHSCT according to the NEDA (No Evidence of Disease Activity) criteria in different studies are compared to results of immunotherapy in
MS patients (Fig. 2). Absence of clinical exacerbation, progression of disability and physical activity according to MRI data (the summary NEDA estimate) during the three-year observation was observed in 70-94% of patients after HDIT-AHSCT compared to 22-48% following standard immunosuppressive therapy [12; 32; 34-36] with alemtuzum-ab (anti-CD52), ocrelizumab (anti-CD20) and daclizumab (anti-CD25) (different monoclonal antibody drugs from the group of "highly effective MS therapy") [37-39]. In this regard, interesting data were obtained at the most active transplant centers in Italy over the period of 1996 to 2016, where,
after HDIT-AHSCT protocol (BEAM-ATG) applied in 122 patients (59% relapsing-remitting MS (RRRS)), 3-year relapse-free outcomes were registered in 91% of patients with RRMS and in 62% of cases with progressive-type MS (p<0.001). One should note that clinical exacerbations are rarely observed in secondary-progressive MS (SPMS), extremely rare in primary-progressive MS (PPMS). According to the single-center study performed by Mancardi et al., the NEDA criteria were achieved in 72% of RRMS patients and in 55% of SPMS patients within 5 years after HDIT-AHSCT (p=0.07) [26].
Table 1. Trials for clinical efficiency and safety of HDIT-AHSCT for multiple sclerosis [31]
Name of trial NCT index Conditioning regimen Comparison group Phase
MIST 00273364 Cy-ATG DMT 2 II
BEAT-MS 04 047628 BEAM-ATG DMT 2 III
RAM-MS 03477500 Cy-ATG Alemtuzumab III
HALT-MS 00288626 BEAM-ATG DMT 2 II
MOST 03342638 Cy-ATG+i/v Ig - III
COAST - Cy-ATG Alemtuzumab/ Ocrelizumab II
NET-MS - BEAM-ATG PITERS 2 lines II
ACTiMuS 01815632 Early HDIT-AHSCT Late HDIT-AHSCT II
Immunoablation and AHST for aggressive MS 01099930 Bu-Cy-ATG DMT II
ASTIMS EudraCT 2007-000064-24 BEAM-ATG Mitoxantrone II
Notes: Bu - Busulfan; BEAM - Bis-chloroethylnitrosourea (BCNU), Etoposide, cytosine Arabinoside, (Ara-C; cytosine-arab-inozide), Melphalan; Cy - Cyclophosphamide, ATG - Antithymocyte immunoglobulin; DMT - Disease-modifying therapy; NCT - National Clinical Trials; AHSCT - autologous hematopoietic stem cell transplantation; CR - conditioning regimen.
Figure 2. Effectiveness of different therapies in MS, according to the NEDA criteria. Presented a comparative analysis of the results of clinical trials (12-24 months from the beginning of therapy) and HDIT-AHSCT (30-80.4 months from therapy) [12; 34-36; 40-46]
Notes: p1 - Phase 1 trial, NEDA - No Evidence of Disease Activity; IFNp-1a -interferon beta-1a.
The above data point to the effectiveness of HDIT-AHSCT, in advanced-stage MS patients. However, direct comparison of these results is not possible due to the differences in patient selection criteria, follow-up terms, and performance evaluation.
According to meta-analysis by Reston J.T. et al., the success rates of relapse-free period in MS after medium-intensity conditioning (BEAM/carmustine) may be higher than with high-intensity therapy including total body irradiation: 79.4% (69.9-86.5%) and 44.6% (26.5-64.3%) at the observation terms of 6-72 and 6-60 months, respectively [47].
In the MIST study, 110 patients were treated with HDIT-AHSCT (n=55) and with DMT (n=55). After a year of treatment, the disease progression with increasing neurological deficit (EDSS scale) was recorded in only 3 patients after HDIT-AHSCT versus 34 patients who received DMT. The total HDIT-AHSCT group showed an improvement by 1.02 points on the EDSS scale (decreased symptoms), and clinical worsening by 0.67 points in the DMT group (cross-group comparison, 1.7; 95% CI, 2.03 to 1.29; p<0.001). Despite the impressive results, it should be noted that the study had certain limitations, e.g., absence of patients in the group of DMT receiving high-efficiency treatment with ocrelizum-ab and alemtuzumab [48].
A long-term study of HDIT-AHSCT efficiency in MS from 1990 to 2000 was based on the inclusion of patients with a predominantly high disability levels (EDSS >6.5 points), and 20% of them were with PPMS. Relapse-free course was achieved in 60-80% of patients within 3 years of follow-up [43]. With a 10-year observation after treatment, 65% of SPMS patients had no MS symptoms, and 40% of PPMS patients showed a positive effect in terms of improved quality of life and cognitive functions [49, 50]. The limitations of this study relate to the issues of the outcome assessment, since, as noted above, the frequency of exacerbation for progressive forms of MS are difficult to evaluate in optimal manner.
Notes: BEAM - Bis-chloroethylnitrosourea (BCNU), Etoposide, cytosine Arabinoside, (Ara-C; cytosine-arabinozide), Melphalan; ATG - Antithymocyte immunoglobulin; ALG - Antilymphocyte immunoglobulin; Flu - Fludarabine; Mel - Melphalan.
According to the data of R.M. Gorbacheva Research Institute (Pavlov University, St. Petersburg), over the follow-up period of 19 to 7 years after HDIT-AHSCT only minimal progression of neurological deficit, i.e., 0.5±1.1 EDSS points was documented after treatment (the characteristics of the study group are presented in the Table 2).
The MSSS progression score at the time of HDIT-AHSCT was 76.5±21.36, compared to 62.43±25.05 after 13±2.5 years (p=0.015), which may indicate a delay of progression after treatment [51]. The obtained results (Fig. 3) show that HDIT-AHSCT allowed to influence the aggressive clinical course and to shift the average rank value of MSSS from the group "Fast Progressing Current 3B" to the group "Progressing Current 3A". In general, our results are in accordance with previously reported EBMT data [43, 52, 53].
Figure 3. Delayed MS progression after HDIT-AHSCT
Notes: MSSS - Multiple Sclerosis Severity Score [54].
Unresolved issues in conditioning regimens
As mentioned above, the conditioning regimes (CR/HDIT) differ in immunosuppressive effects: high-, medium- and low-intensity regimens. The most commonly used CRs are presented in Table 3.
Established variants of high-dose conditioning regimens depending on the level of immunosuppression [5, 8-10, 12, 20, 28, 32-36, 41, 43, 58].
As shown in Table 3, the high-intensity conditioning regimens were used predominantly in North America. The European transplant centers applied mostly reduced intensity protocols. Before 2010, high- and medium-intensity regimens were mainly used, followed by later shift towards the use of cyclophosphamide-containing regimens, thus enabling implementation of this approach even in younger MS patients with under 18 years [55].
Duration of the relapse-free course in MS as well as the severity of early and late HSCT complications is shown to depend on the intensity of conditioning regimen. In the report of the EBMT Registry (2005), a stable clinical response
Table 2. Characteristics of the patients who have undergone HDIT-AHSCT for multiple sclerosis in 2000-2012
Number 25
Age 33±6 y.o.
RRRS 4
Type of MS SPMS 10
PPMS 10
Total 6.0±1.0
EDSS 0-4.0 3
4.5-6.0 13
6.5-8.0 8
Conditioning BEAM-ALG/ATG 15
regimen Flu-Mel 9
Table 3. Predoninant conditioning regimens, according to the CIMBTR and EBMT data
Regimen CIMBTR EBMT
High-intensity CR
Cy-Alemtuzumab + -
TBI-Cy-ATG + -
Bu-Cy-ATG + -
Moderate-intensity CR
BEAM-ATG + +
BEAM - +
Thiotepa-Cy - +
Flu-Mel - +
Cy-ATG + +
Low-intensity CR
Flu-Cy (120 mg) - +
Cy-R + -
Cy - +
Notes: CIMBTR - Center for International Blood and Marrow Transplant Research; EBMT - European Society for Blood and Marrow Transplantation; TBI - Total Body Irradiation; BCNU -bis-chloroethylnitrosourea; Bu, Busulfan; BEAM - Bis-chloro-ethylnitrosourea (BCNU) and Melphalan; Cy - Cyclophosphamide; ATG - Antithymocyte immune globulin; Flu - Fludarabine; Mel - Melphalan; R - Rituximab.
was observed in 78% of patients who received high-intensity treatment, compared to 68% for medium- and 30% for low-intensity conditioning (p=0.0001) [56]. However, according to Reston et al. (2011), the patients with SPMS had a longer relapse-free course after medium-intensity conditioning than after high-intensity therapy (Bu-Cy, TBI-Cy, etc.) [47]. According to Arruda et al. the efficiency of conditioning regimen in MS depends more on lymphodepletion than on myeloablation, i.e., prolonged lymphopenia correlates with a longer period of relapse-free course [57].
Current principles of HDIT-AHSCT in MS
The basic principles of HDIT-AHSCT for MS are based on the recommendations of the European and American Societies for Blood and Bone Marrow Transplantation (resp., EBMT and ASBMT) [28, 58-61] being summarized as follows:
Level S/I (treatment standard/efficacy proven in at least one randomized CT):
1. HDIT-AHSCT should be offered to the patients with MS:
- with high clinical and MR-activity (at least two clinical exacerbations or one clinical exacerbation with signs of MR-activity in the form of accumulating contrast substance (Gd+) in post-concussive T1 or 1 new T2 lesions in the last 12 months);
- if one or more DMT are ineffective.
2. The factors of potential effectiveness are:
- the independence in moving (EDSS no more than 5.5);
- age under 45 years;
- the duration of the MS no more than 10 years.
Level CO/II (clinical option, no "corroborating" results of randomized CT/efficiency based on non-randomized CT data, cohort analytical studies):
1. Patients with aggressive MS (criteria: at least 2 clinical exacerbations or one clinical relapse with a centre accumulating contrast agent or a new T2 foci in the last 12 months) with disability in the last 12 months - are the candidates. In view of the potentially irreversible disability, such patients could be considered for HDIT-AHSCT before completing the full course of DMT;
2. Patients with SPMS should be considered for HDIT-AHSCT mainly with inflammatory activity (clinical relapses and Gd+/new lesions on T2 MRI) with documented progression in the previous 12 months;
3. Patients with PPMS should be considered for HDIT-AHSCT only with inflammatory activity (Gd+ and new lesions on T2 MRI) with documented apparent progression of disability in the previous 12 months;
4. Patients with MS under 18 years of age can be considered for HDIT-AHSCT only in case of aggressive MS with selection of less toxic protocols of CR;
5. The criteria for selecting patients are based on the aggressiveness of the disease, analysis of the patient's anamnesis and comorbidity, analysis of the risk-benefit ratio of the method, and from the personal and social aspects of the patient.
Conclusion
Critical evaluation of the world experience with HDIT-AHSCT in MS allows to consider this therapeutic option as highly effective treatment of multiple sclerosis if applied at early stages of the disease progression, at predominance of active autoimmune inflammation, but not at the stage of neurodegeneration prevalence. In the cases of progressive course of the disease, at a stage where neurodegenerative processes prevail, the method may have a certain delayed stabilizing effect. The selection criteria for HDIT-AHSCT in MS patients should include demographic factors, physical/social activity, type of disease and prognostic factors of adverse MS course as well as safety criteria based on present comorbidities and realistic expectations of the patient. Over last 10-15 years, taking into account the experience of multiple transplant centers, due to lower toxicity of conditioning regimes, we were able to reduce the severity of complications, however, keeping high clinical efficiency of AHSCT. Pathophysiology of multiple sclerosis, as well as in other neurological diseases, does not allow to compensate the irreversible pathomorphological changes that occurred in central nervous system before the therapy, but HDIT-AHSCT allows suppression of the current autoimmune process and, therefore, to avoid further damage and death of nervous tissues, accompanied by progression of irreversible neurological deficiency. When the desired long-term
relapse-free course is achieved, an obvious advantage of this approach may be a withdrawal of disease-modifying therapy, which complies with optimal principle of disease control using the "one-off disease control" therapy.
Conflict of interest
The authors state that there is no conflict of interest. The authors bear full responsibility for providing the final version of the manuscript to the press. All authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.
Acknowledgements
We acknowledge the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) for its support in providing updated registry data and all EBMT member centers and their clinicians, data managers and patients for their valuable contributions to the EBMT registry. The authors confirm that they followed the Declaration of Human Rights with persons involved into the study.
References
1. Sumelahti ML, Tienari PJ, Wikstrom J, Palo J, Hakama M. Regional and temporal variation in the incidence of multiple sclerosis in Finland 1979-1993. Neuro epidemiology. 2000 Mar-Apr;19(2):67-75. doi: 10.1159/000026241
2. Alonso A, Jick SS, Olek MJ, Hernan MA. Incidence of multiple sclerosis in the United Kingdom: findings from a population-based cohort. J Neurol. 2007; 254:1736-1741. doi: 10.1007/s00415-007-0602-z
3. Fromont A, Binquet C, Sauleau E, Fournel I, Despalins R, Rollot F, et al. National estimate of multiple sclerosis incidence in France (2001-2007). Mult Scler. 2012;18(8):1108-1115. doi: 10.1177/1352458511433305
4. Laureys G, Willekens B, Vanopdenbosch L, Deryck O, Selleslag D, D'Haeseleer M, et al. A Belgian Consensus Protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Belg. 2018;118(2):161-168. doi: 10.1007/s13760-018-0905-0
5. Burman J, Tolf A, Hogglund H, Askmark H. Autologous haematopoietic stem cell transplantation for neurological diseases. J Neurol Neurosurg Psychiatry. 2018;89(2):147-155. doi: 10.1136/jnnp-2017-316271
6. Sizikova SA, Lisukov IA, Kulagin AD, Kriuchkova IV, Gilevich AV, Chernykh EP et al. Vysokodoznaia immuno-suppressivnaia terapiia s autologichnoi transplantatsiei st-volovykh krovetvornykh kletok pri autoimmunykh zabole-vaniiakh. Terapevticheskii Arkhiv. 2002;74(7):22-26. (In Russian). PMID: 12181829
7. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasyev BV, Lisukov IA, Kozlov VA, et al. Autologous transplantation of hematopoietic stem cells in multiple sclerosis: results of a study of the Russian cooperative cell therapy group. Neurological Journal. 2008. Vol. 13. No. 2. pp. 11-18. (In Russian).
8. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakel-lari I, Kimiskidis V, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997; 20(8):631-638. doi: 10.1038/sj.bmt.1700944
9. Gavriilaki M, Sakellari I, Gavriilaki E, Kimiskidis VK, Anagnostopoulos A. Autologous hema-topoietic cell transplantation in multiple sclerosis: changing paradigms in the era of novel agents. Stem Cells Int. 2019; 2019:5840286. doi: 10.1155/2019/5840286
10. Currö D, Mancardi G. Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience. Neurol Sci. 2016;37(6):857-865. doi: 10.1007/s10072-016-2564-3
11. Moore J, Brooks P, Milliken S, Biggs J, Ma D, Handel M, et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum. 2002;46(9):2301-2309. doi: 10.1002/art.10495
12. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoi-etic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016; 388(10044):576-585. doi: 10.1016/S0140-6736(16)30169-6
13. Feng X, Kajigaya S, Solomou EE, Keyvanfar K, Xu X, Raghavachari N, et al. Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro. Blood. 2008;111(7): 3675-3683. doi: 10.1182/blood-2008-01-130146
14. Karussis DM, Slavin S, Lehmann D, Mizrachi-Koll R, Abramsky O, Ben-Nun A. Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation. J Immunol. 1992; 148(6): 1693-1698. PMID: 1541813
15. Karussis DM, Vourka-Karussis U, Lehmann D, Ovadia H, Mizrachi-Koll R, Ben-Nun A, et al. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest. 1993; 92(2):765-772. doi: 10.1172/JCI116648
16. Van Gelder M, Kinwel-Bohré EP, van Bekkum DW. Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant 1993;11: 233-241.
17. Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, et al. Canadian MS/BMT Study Group. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann Neurol. 2013; 73(3):341-354. doi: 10.1002/ ana.23784
18. Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol. 2017; 189(3):268-278. doi: 10.1111/cei.12985
19. Massey JC, Sutton IJ, Ma DDF, Moore JJ. Regenerating immunotolerance in multiple sclerosis with autologous hematopoietic stem cell transplant. Front Immunol. 2018; 9:410. doi: 10.3389/fimmu.2018.00410
20. Polushin AYu, Zalyalov YuR, Totolyan NA, Kulagin AD, Skoromets AA. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: a modern view of the method (review of literature). Scientific Notes of Pavlov University. 2021;28(4):9-21. (In Russ.). doi: 10.24884/1607-4181-2021-28-4-9-21
21. Oh S, Cudrici C, Ito T, Rus H. B-cells and humoral immunity in multiple sclerosis. Implications for therapy. Immunol Res. 2008;40(3):224-234. doi: 10.1007/s12026-007-8009-6
22. Meng L, Ouyang J, Zhang H, Wen Y, Chen J, Zhou J. Treatment of an autoimmune encephalomyelitis mouse model with nonmyeloablative conditioning and syngeneic bone marrow transplantation. Restor Neurol Neurosci. 2011; 29:177-185. doi: 10.3233/RNN-2011-0590
23. Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013; 136(Pt 9):2888-2903. doi: 10.1093/brain/awt182
24. Arruda LC, Lorenzi JC, Sousa AP, Zanette DL, Palma PV, Panepucci RA, et al. Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients. Bone Marrow Transplant. 2015; 50(3):380-389. doi: 10.1038/bmt.2014.277
25. Cencioni MT, Genchi A, Brittain G, de Silva TI, Shar-rack B, Snowden JA, et al. Immune re-constitution following autologous hematopoietic stem cell transplantation for multiple sclerosis: a re-view on behalf of the EBMT Autoimmune Diseases Working Party. Front. Immunol. 12:813957. doi: 10.3389/fimmu.2021.813957
26. Mancardi G, Sormani MP, Muraro PA, Boffa G, Sac-cardi R. Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. Mult Scler. 2018 Mar;24(3):245-255. doi: 10.1177/1352458517742532. Epub 2017 Nov 10. PMID: 29125439
27. Snowden J, Sharrack B, Akil M, Kiely D, Lobo A, Kazmi M, et al. Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases - a guide for the generalist. Clin Med (Lond). 2018 Aug; 18(4): 329-334. doi: 10.7861/clinmedi-cine.18-4-329
28. Sharrack B, Saccardi R, Alexander T, Badoglio M, Bur-man J, Farge D, et al. European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE). Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint
Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020 Feb;55(2):283-306. doi: 10.1038/ s41409-019-0684-0. Epub 2019 Sep 26. PMID: 31558790; PMCID: PMC6995781
29. Alexander T, Greco R. Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2022 May 16:1-8. doi: 10.1038/s41409-022-01702-w. PMID: 35578014; PMCID: PMC9109750
30. Murrieta-Álvarez I, Cantero-Fortiz Y, León-Peña AA, Olivares-Gazca JC, Priesca-Marín JM, Ruiz-Delgado GJ, et al. The 1,000th Transplant for Multiple Sclerosis and Other Autoimmune Disor-ders at the HSCT-México Program: A Myriad of Experiences and Knowledge. Front. Neurol. 12:647425. doi: 10.3389/fneur.2021.647425
31. https://clinicaltrials.gov/ct2/show/
32. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 2015; 72(2):159-169. doi: 10.1001/jamaneurol.2014.3780
33. Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E, et al. ASTIMS Haemato-Neurological Collaborative Group, On behalf of the Autoimmune Disease Working Party (ADWP) of the European Group for Blood and Marrow Transplantation (EBMT); ASTIMS Haemato-Neu-rological Collaborative Group On behalf of the Autoimmune Disease Working Party ADWP of the European Group for Blood and Marrow Transplantation EBMT. Autologous he-matopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015; 84(10):981-988. doi: 10.1212/ WNL.0000000000001329
34. Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, et al. Multiple Sclerosis-Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term outcomes after autolo-gous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017;74(4):459-469. doi: 10.1001/ jamaneurol.2016.5867
35. Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gun-narsson M, Nilsson P, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014 Oct;85(10):1116-21. doi: 10.1136/jnnp-2013-307207. Epub 2014 Feb 19. PMID: 24554104
36. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppres-sive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017 Feb 28;88(9):842-852. doi: 10.1212/ WNL.0000000000003660. Epub 2017 Feb 1. PMID: 28148635; PMCID: PMC5331868
37. Jones JL, Coles AJ. Mode of action and clinical studies with alemtuzumab. Exp Neurol. 2014 Dec;262 Pt A:37-43. doi: 10.1016/j.expneurol.2014.04.018
38. Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017 Oct;14(4):835-841. doi: 10.1007/s13311-017-0557-4
39. Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017 Feb;23(2):201-204. doi: 10.1177/1352458516645670. Epub 2016 Jul 11. PMID: 27207454
40. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910. doi: 10.1056/NEJMoa044397
41. Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, et al. Autologous non-myeloablative hae-mopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009 Mar;8(3):244-53. doi: 10.1016/S1474-4422(09)70017-1. Epub 2009 Jan 29. Erratum in: Lancet Neurol. 2009 Apr; 8(4):309. Stefosky, Dusan [corrected to Stefoski, Dusan]. PMID: 19186105
42. Giovannoni G, Comi G, Cook S, Rammohan K, Rieck-mann P, Soelberg Sorensen P, et al. CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010; 362(5):416-426. doi: 10.1056/NEJMoa0902533
43. Hamerschlak N, Rodrigues M, Moraes DA, Oliveira MC, Stracieri AB, Pieroni F, et al. Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Bone Marrow Transplant. 2010 Feb;45(2):239-48. doi: 10.1038/bmt.2009.127. Epub 2009 Jul 6. PMID: 19584827
44. Conway DS, Miller DM, O'Brien RG, Cohen JA. Long term benefit of multiple sclerosis treatment: an investigation using a novel data collection technique. Mult Scler. 2012;18(11):1617-1624. doi: 10.1177/1352458512449681
45. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovanno-ni G, Selmaj K, et al. DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-1107. doi: 10.1056/NEJMoa1114287
46. Kappos L, O'Connor P, Radue EW, Polman C, Hohlfeld R, Selmaj K, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015; 84(15): 1582-1591. doi: 10.1212/ WNL.0000000000001462
47. Reston JT, Uhl S, Treadwell JR, Nash RA, Schoelles K. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult. Scler. 2011; 17: 204-213.
48. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of Nonmyeloablative He-matopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized
Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/ jama.2018.18743. PMID: 30644983; PMCID: PMC6439765
49. Fassas A. On the evolution of high-dose immunosup-pressive therapy with autologous stem cell transplantation in multiple sclerosis. Cell Ther Transplant. 2010;2:e.000060.01. doi: 10.3205/ctt-2010-en-000060.01
50. Saccardi R, Mancardi GL, Solari A, Bosi A, Bruzzi P, Di Bartolomeo P, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005 Mar 15;105(6):2601-2607. doi: 10.1182/blood-2004-08-3205. Epub 2004 Nov 16. PMID: 15546956
51. Polushin AY, Zalyalov YR, Vinokurova AN, Skiba IB, Estrina MA, Kulagin AD, et al. Effectiveness of high-dose immunosuppressive therapy with subsequent autologous hematopoietic stem cell transplantation in progressive types of multiple sclerosis: the experience of the R.M. Gorbacheva Research Institute of Hematology and Transfusiology. Russian journal of Hematology and Transfusiology (Gema-tologiya i Transfusiologiya). 2020; 65(1):202. (In Russian).
52. Fassas A, Kimiskidis VK, Sakellari I, Kapinas K, An-agnostopoulos A, Tsimourtou V, et al. Long-term results of stem cell transplantation for MS: a single-center experience. Neurology. 2011;76(12):1066-1070. doi: 10.1212/ WNL.0b013e318211c537
53. Cull G, Hall D, Fabis-Pedrini MJ, Carroll WM, Forster L, Robins F, et al. Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS. Mult Scler J Exp Transl Clin. 2017; 3(1):2055217317700167. doi: 10.1177/2055217317700167
54. Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, et al. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005;64(7):1144-1151. doi: 10.1212/01. WNL.0000156155.19270.F8
55. Kirgizov KI, Skorobogatova EV, Bembeeva RT, Vol-kova EY, Bologov AA, Pilia SV, Maschan AA, Rumyantsev AG. Autologous hematopoietic stem cell transplantation in children with severe refractory forms of multiple sclerosis. Current Pediatrics. 2013;12(1):149-152. (In Russian). doi: 10.15690/vsp.v12i1.572
56. Gratwohl A, Passweg J, Bocelli-Tyndall C, Fassas A, van Laar JM, Farge D, et al. Autoimmune Diseases Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2005; 35(9):869-879. doi: 10.1038/sj.bmt.1704892
57. Arruda LCM, de Azevedo JTC, de Oliveira GLV, Scor-tegagna GT, Rodrigues ES, Palma PVB, et al. Immunolog-ical correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation. Clin Immunol. 2016;169:47-57. doi: 10.1016/j.clim.2016.06.005
58. Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and
Marrow Transplantation and the European Charcot Foundation. BMT-MS Study Group. J Neurol. 2000;247(5):376-382. doi: 10.1007/s004150050605
59. Afanasyeva KS, Barabanshchikova MV, Bondarenko SN, Bykova TA, Vlasova YY, Gevorgian AG, Golubovskaya IK, et al. Indications for hematopoietic stem cell transplantation. 2nd Edition. Based on EBMT Recommendations of 2019. 2019; 8(4). Cell Ther Transplant 8(4):101-145. doi: 10.18620/ ctt-1866-8836-2019-8-4-101-145
60. Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, et al. European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid
tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019; 54(10):1525-1552. doi: 10.1038/s41409-019-0516-2
61. Cohen JA, Baldassari LE, Atkins HL, Bowen JD, Bredeson C, Carpenter PA, 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;25:845-854. doi: 10.1016/j.bbmt.2019.02.014
Резюме
Высокодозная иммуносупрессивная терапия с ауто-логичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, включая рассеянный склероз. За последние 15-20 лет уменьшились частота и тяжесть нежелательных явлений при ВИСТ-ТГСК, что было достигнуто при помощи снижения интенсивности режимов кондиционирования. Также привели к улучшению результатов более глубокое понимание иммунологических механизмов восстановления иммунитета и смена тактики отбора пациентов на процедуру. Учитывая возросшую заболеваемость
рассеянным склерозом во всем мире, а также недостаточную эффективность стандартной терапии, введение аутологичной трансплантации в клинические рекомендации по лечению рассеянного склероза могло бы сохранить качество жизни молодым пациентам.
Ключевые слова
Рассеянный склероз, мобилизация, аферез, высоко-дозная иммуносупрессивная терапия, гемопоэтиче-ские стволовые клетки, трансплантация, иммунотерапия.
Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: современный взгляд на проблему
Алексей Ю. Полушин, Евгения И. Лопатина, Юрий Р. Залялов, Александр А. Цынченко, Наталья А. Тотолян, Александр Д. Кулагин
Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
