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Authors: Polushin A.Yu.1,2, Zalyalov Yu.R.1, Gavrilenko A.N.1,2, Tsynchenko A.A.1, Lopatina E.I.1, Skiba I.B.1,2, Estrina M.A.1,2, Babenko E.V.1,2, Gotovchikov A.A.1, Prakhova L.N.3, Ilves A.G.3, Totolyan N.A.1, Kulagin A.D.1,2, Skoromets A.A.1
1 Pavlov First Saint Petersburg State Medical University (Pavlov University), Saint Petersburg, Russia
2 R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Saint Petersburg, Russia
3 N.P. Bekhtereva Human Brain Institute of the Russian Academy of Sciences, Saint Petersburg, Russia
Article type: Original research (single-center observational study; clinical approbation program)
DOI: 10.30629/2658-7947-2022-27-5-25-35
How to cite: Polushin A.Yu., Zalyalov Yu.R., Gavrilenko A.N., Tsynchenko A.A., Lopatina E.I., Skiba I.B., Estrina M.A., Babenko E.V., Gotovchikov A.A., Prakhova L.N., Ilves A.G., Totolyan N.A., Kulagin A.D., Skoromets A.A. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: preliminary clinical results of approbation of the method. Russian Neurological Journal. 2022;27(5):25–35. (In Russian). DOI: 10.30629/2658-7947-2022-27-5-25-35
Corresponding author: Polushin Alexey Yu. — alexpolushin@yandex.ru
Conflict of interest: The authors declare no conflicts of interest.
Funding: The study had no external funding / sponsorship. Patient care was provided within the clinical approbation program of the Ministry of Health of the Russian Federation.
Contents
Introduction. In 2018–2020, a study was conducted in the Russian Federation on the efficacy and safety of high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) in multiple sclerosis (MS).
Aim. To analyze preliminary data on the effectiveness and safety of HDIT-AHSCT in patients with MS who participated in a national clinical approbation program.
Materials and methods. Twenty-one patients were included in a single-center observational study at Pavlov University (Saint Petersburg, Russia). In 10 patients (47.6%), Expanded Disability Status Scale (EDSS) ranged from 1.0 to 4.0; in 10 patients, EDSS ranged from 4.5 to 6.0; one patient with primary progressive MS (PPMS) had EDSS 6.5. Conditioning regimen consisted of cyclophosphamide (200 mg/kg total dose) in combination with rituximab (1000 mg/m2). Neurological assessment (EDSS, SNRS, T25-FW, 9-HPT, PASAT, MoCA, HADS) and brain MRI were performed before therapy and at 12 months. Early and long-term complications were analyzed in detail.
Results. At 12 months after HDIT-AHSCT, improvement or marked improvement was observed in 10 patients (47.6%), stabilization in 8 (38.1%), and worsening/relapse or progression in 3 (14.3%). Lower clinical benefit was seen in patients with spasticity >3 points on the Modified Ashworth Scale (MAS). MRI at 12 months showed stabilization with no disease activity in 18 patients (85.7%), meeting No Evidence of Disease Activity (NEDA) criteria. Long-term complications included autoimmune thyroiditis (n=1) and amenorrhea in two women older than 38 years. No therapy-related mortality was recorded.
Conclusion. HDIT-AHSCT is an effective treatment option for selected patients with MS. The results of this clinical approbation program demonstrate acceptable safety and short-term effectiveness and may support broader access to this type of care in the Russian Federation.
Clinical approbation; high-dose immunosuppressive therapy; multiple sclerosis; hematopoietic stem cells; transplantation; immunotherapy; cyclophosphamide; rituximab; efficacy; complications.
Given the increasing prevalence of autoimmune diseases worldwide, recent years have seen a growing number of studies exploring expansion of indications for high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) in autoimmune conditions [1–5]. The first reports suggesting efficacy of this approach were presented in 1995 [6,7]. In the Russian Federation, early results of HDIT-AHSCT in severe autoimmune diseases were obtained in the late 1990s [8,9].
From 2018 to 2020, three transplant centers in the Russian Federation conducted a study on the efficacy and safety of HDIT-AHSCT in multiple sclerosis (MS) as part of a national clinical approbation program entitled “Provision of specialized medical care within the clinical approbation framework for patients with multiple sclerosis by applying high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation” [10,11].
Objective. To analyze preliminary data on the effectiveness and safety of HDIT-AHSCT in patients with MS participating in the clinical approbation program.
This single-center observational study (Pavlov University; Saint Petersburg, Russia) included patients with confirmed eligibility for HDIT-AHSCT based on the conclusion of a neurological expert commission. Inclusion and exclusion criteria (developer: National Pirogov Medical and Surgical Center, Ministry of Health of the Russian Federation) were predefined in the clinical approbation protocol.
According to the protocol, patients underwent stage 1 evaluation at the Clinic of Neurology No. 1 (Pavlov University) and/or the N.P. Bekhtereva Human Brain Institute to confirm diagnosis and assess eligibility. At stage 2, patients were admitted to the R.M. Gorbacheva Research Institute for a 4-day stem cell mobilization procedure (CD34+) using granulocyte colony-stimulating factor (G-CSF) at 10 μg/kg/day.
After achieving peripheral blood CD34+ cell levels >10 × 106/L, apheresis of autologous hematopoietic stem cells was performed using an automated system (Spectra Optia 11), followed by cryopreservation (10% dimethyl sulfoxide solution; storage in liquid nitrogen at –180 °C until infusion). The number of apheresis sessions depended on CD34+ yield, targeting 2–4 × 106 cells/kg body weight (a detailed description of HDIT-AHSCT steps was published ранее [13]).
Conditioning consisted of high-dose cyclophosphamide 50 mg/kg on days –5, –4, –3, –2 (total dose 200 mg/kg). On day 0, thawed autologous stem cells were infused. Supportive care included antiemetics, electrolyte correction, antibacterial and antiviral therapy, and transfusion support as needed.
After hematopoietic recovery, B-cell-depleting immunotherapy with rituximab was administered at 500 mg/m2 on days +10 and +15. Patients were subsequently followed with scheduled visits. The assessment included standard clinical scales and questionnaires for depression and health-related quality of life. Brain MRI was performed according to a standard protocol (routine measures and morphometry were evaluated), and a set of clinical, biochemical, and immunological laboratory parameters was monitored.
This paper analyzes key clinical measures, selected standard MRI protocol parameters, and primary laboratory safety measures before therapy and at 12 months after HDIT-AHSCT. Neurological assessment was performed by two independent neurologists (blinded to pre-treatment data) and included disability (EDSS) and neurological status (SNRS).
Treatment response criteria followed the approbation protocol. Considering EDSS variability between raters, EDSS reduction ≥1.0 point versus baseline was interpreted as marked improvement; reduction by 0.5 point as improvement; no change as stabilization. Worsening was defined as EDSS increase ≥1.0 point if baseline EDSS ≤5.0, or increase by 0.5 point if baseline EDSS >5.0.
Statistical analysis was performed in SPSS 23.0. Distribution was assessed with the one-sample Kolmogorov–Smirnov test. Descriptive statistics included medians, quartiles, and proportions. Paired comparisons (before vs after AHSCT) were analyzed with the Wilcoxon test; p<0.05 was considered statistically significant.
The study was conducted in accordance with the Declaration of Helsinki [14]. The protocol was approved by the Ethics Committee of Pavlov University; all patients provided written informed consent.
Within the clinical approbation program, HDIT-AHSCT was performed in 21 patients (10 women, 11 men; median age at AHSCT 35 years [range 28–50]). Twelve patients (57.1%) were aged ≤35 years; two were older than 45 years. Median time from symptom onset to MS diagnosis was 3.0 years [0.5; 5.0], and from diagnosis to AHSCT was 8.0 years [6.0; 11.0]; in two cases, this interval was 18 and 27 years.
Sixteen (76.2%) patients had RRMS and four had SPMS, consistent with contemporary patient selection trends for AHSCT [15]. Median EDSS at AHSCT was 5.0 [2.0; 6.0]. Ten patients (47.6%) had EDSS 1.0–4.0, and ten had EDSS 4.5–6.0. The single PPMS patient had EDSS 6.5, considered the maximum acceptable threshold for AHSCT except in malignant, rapidly progressive cases [15].
All patients met MRI inclusion criteria. During the 12 months prior to selection, gadolinium-enhancing lesions were observed in 14 cases (66.7%), and new T2 lesions in 16 cases (76.2%).
Per protocol criteria, patients had documented insufficient efficacy and/or safety/tolerability issues with prior disease-modifying therapies (DMTs). Nineteen of 21 patients (90.5%) had received two or more DMTs previously.
In 20 patients (95.3%), a single apheresis session yielded sufficient CD34+ cells; in one case (4.7%) two sessions were required. Median CD34+ dose was 4.0 × 106/kg [3.45; 4.70]. Mean hospital stay was 41 days (including hematopoietic recovery and subsequent rituximab infusions).
According to the approbation criteria, at 12 months after HDIT-AHSCT, improvement or marked improvement occurred in 10 patients (47.6%), stabilization in 8 (38.1%), and worsening in 3 (14.3%).
At 12 months, improvements were observed across key clinical parameters, including neurological deficit and disability (SNRS and EDSS), MSFC domains assessing lower-limb and upper-limb motor function and cognition, and depression (HADS). The EDSS decrease did not reach statistical significance (p=0.071), but was clinically meaningful in 10 patients (47.6%). The SNRS increase was statistically significant (p=0.028).
Time to complete the Timed 25-Foot Walk (T25-FW) improved in both attempts; 9-HPT time improved (dominant and nondominant hand in the second attempt); PASAT improved in the first attempt. A statistically significant reduction in HADS depression score was noted (p=0.011).
Based on combined clinical and MRI outcomes, 18 patients (85.7%) demonstrated stabilization with no evidence of disease activity at 12 months. One RRMS patient had a relapse (leg numbness/hypesthesia) and one new non-enhancing MRI lesion corresponding to symptoms; however, EDSS decreased by 1.5 points compared with pre-transplant evaluation during follow-up. Another RRMS patient with predominantly spinal manifestations developed a new gadolinium-enhancing cervical lesion (EDSS unchanged). The PPMS patient developed a new non-enhancing lesion with clinical progression and EDSS increase by 0.5 point.
Expected hematologic toxicity attributable to treatment mechanisms [16,17] occurred at the following rates: grade 3–4 anemia in 18 patients (85.7%), grade 4 thrombocytopenia in 12 (57.1%), and grade 4 neutropenia in all patients. Significant cytopenia typically developed by day +2 after AHSCT. Median duration of grade 4 neutropenia was 11 days (from day –1 to day +10 relative to AHSCT). All hematologic complications were managed during inpatient care.
Among clinically significant non-hematologic toxicities, febrile neutropenia occurred in all patients; grade 1–2 oropharyngeal mucositis in 6 (28.6%); grade 1–2 enteropathy in 2 (9.5%); grade 3–4 enteropathy in 1 (4.8%). Transient elevation of liver transaminases was noted in 19 cases (90.5%): grade 1–2 in 16 (76.2%) and grade 3 in 3 (14.3%). Cyclophosphamide-associated hemorrhagic cystitis occurred in 1 case (4.8%). Severe weakness during grade 4 neutropenia was reported by 16 patients (76.2%). Transient alopecia occurred in all patients.
Long-term complications included autoimmune thyroiditis (one case at 12 months after AHSCT) and amenorrhea in two women aged 38 and 43 years. No deaths were recorded during follow-up.
According to the Autoimmune Diseases Working Party (ADWP), by March 2022 approximately 4,000 HDIT-AHSCT procedures for autoimmune diseases had been performed and registered in the EBMT registry, with more than half conducted in patients with MS [18]. Based on global experience, HDIT-AHSCT can be considered a highly effective therapy for MS when applied in a timely manner—at a stage when active inflammation predominates over neurodegeneration.
In our study, patient selection aligned with contemporary EBMT criteria [18]: 16 of 21 had RRMS; 12 participants were younger than 35; 10 had mild-to-moderate disability (EDSS 2.0–4.0); MRI activity with gadolinium-enhancing lesions was documented in 14 patients within the 12 months preceding AHSCT. These factors support the rationale for a lymphoablative anti-inflammatory approach aimed at suppressing systemic and intrathecal inflammation.
Total lymphodepletion followed by re-diversification of naïve immune cell pools has the potential to provide durable suppression of autoimmune inflammation and maintain quality of life. In this cohort, median age at first MS symptoms was 23 years, indicating very early onset for an adult population. Reported median age of MS onset in the literature ranges from 21 to 40 years [19,20].
The median interval from diagnosis to AHSCT was 8 years. In the RRMS subgroup (n=16) this interval was 7±4.1 years; in the progressive MS subgroup (n=5) it was 10±2.8 years. Based on follow-up data and the literature [21], the greatest benefit is achieved when inflammation is controlled as early as possible through profound lymphodepletion and subsequent immune reconstitution.
The primary indication for AHSCT in program participants was insufficient control of disease on prior DMTs: 18 patients had received two or more DMTs, and one patient had received six first-line and escalation therapies. For the PPMS patient, DMT was not available due to administrative reasons, and intramuscular immunoglobulin had been used.
In medical records, the number of relapses in the year before AHSCT ranged from 1 to 4. At 12 months, clinical and instrumental data indicated stabilization in 18 patients; relapse or progression occurred in three.
At 12 months, improvement or marked improvement was seen in 10 patients (47.6%), stabilization in 8 (38.1%), and worsening in 3 (14.3%). Although EDSS reduction did not reach statistical significance (from 5.0 to 3.5; p=0.071), SNRS improved significantly (from 66.0 to 71.0; p=0.028), consistent with reports from international centers [22,23].
Despite the lack of statistical significance, EDSS changes may reflect clinically meaningful improvement for individual patients. At EDSS levels above 3.0, a 0.5-point decrease may correspond to improved daily functioning. MAS-based spasticity assessment reflects its impact on motor performance overall, influencing SNRS and EDSS. Severe spasticity is associated with higher disability and likely reflects spinal mechanisms of posture and gait maintenance in the context of impaired cortical control.
Nearly all patients with MAS ≥3 (2 with RRMS and 5 with progressive MS) did not show marked improvement at 12 months. In the subgroup without pronounced spasticity (MAS <3; n=14), mean SNRS before AHSCT was 72.5±11.1 (EDSS 3.25±1.7) and at 12 months was 79.5±14.8 (EDSS 2.0±1.78). In the subgroup with pronounced spasticity (n=7), SNRS/EDSS were 56.0±11.4 (EDSS 6.0±0.57) and 58.0±8.4 (EDSS 6.0±0.83), respectively.
We observed a statistically significant decrease in HADS depression score (p=0.011), which appears consistent with overall clinical improvement. MSFC suggested some improvement in motor (T25-FW, 9-HPT) and cognitive (PASAT) domains.
Using NEDA criteria [24,25], only three patients (14.3%) demonstrated combined clinical and radiological activity at 12 months. In one case (AHSCT in 2019; baseline EDSS 2.5), despite relapse and MRI activity (new enhancing lesion), EDSS decreased to 1.0 by year 2.
A noteworthy case involved a 33-year-old patient (AHSCT in 2019; RRMS duration 10 years; EDSS 6.0; >10 enhancing lesions on MRI). At 12 and 24 months, 5 and 3 enhancing lesions were detected, respectively, without clinical relapses and with disability improvement to EDSS 4.5 and 4.0, corresponding to independent walking without support for more than 500 meters.
These examples suggest that long-term effects of AHSCT may accumulate over time, likely mediated by immune reconstitution, particularly in patients with high baseline inflammatory activity and potentially reversible deficits. Thus, evaluation of effectiveness should not be limited to 12 months. Suboptimal response and resistance in aggressive MS must also be considered.
If disease activity persists beyond 2 years after AHSCT, DMTs may be reintroduced; in international practice, repeat AHSCT has been considered in select cases (up to three procedures have been reported). Standardized recommendations for managing post-AHSCT MS activity are lacking due to limited evidence regarding both efficacy and safety of DMTs after transplantation.
In our observations, for RRMS patients with relapse after immune reconstitution, resumption of immunomodulatory DMTs was recommended. For the PPMS patient, ocrelizumab was initiated as the only approved therapy for PPMS.
Predictable complications of AHSCT include thrombocytopenia, neutropenia, febrile neutropenia, transient transaminase elevations, transient enteropathy, asthenia, and alopecia. Early complications in our cohort were managed during hospitalization. Long-term complications were less frequent: one case of autoimmune thyroiditis and amenorrhea in two women over 38 years within 12 months.
Patients with autoimmune diseases who undergo AHSCT should be followed by a hematologist, endocrinologist, and gynecologist at least annually and should receive rehabilitation in specialized departments [26]. After discharge, prolonged antiviral prophylaxis is recommended; vaccination is possible no earlier than 3 months after AHSCT [27].
In large series, infectious mortality after AHSCT for MS may reach 0.2–1% [18,28–30]. Despite the wide range of potential complications, no deaths occurred in this cohort.
High-dose immunosuppression may affect ovarian function and reproductive health, potentially resulting in infertility, premature menopause, and long-term consequences of estrogen deficiency [31–33]. In this cohort, two women conceived 2 years after therapy and had uncomplicated pregnancies at the time of manuscript preparation; in one case, a healthy child was born 10 months after AHSCT (Apgar 9/9), with no change in MS status.
HDIT-AHSCT is an effective treatment option for patients with MS refractory to standard disease-modifying therapies. In recent years, complication rates have decreased substantially due to reduced intensity/toxicity of conditioning regimens, improved patient selection, and increasing center experience.
The spectrum of early complications necessitates inpatient management (often up to ~30 days). Mitigation of long-term risks is achieved through optimization of conditioning regimens, careful selection, and structured monitoring programs.
The clinical approbation results at Pavlov University demonstrate acceptable safety and short-term effectiveness. At 12 months, most patients showed reduced neurological deficit and stabilization of clinical and radiological MS activity.
Because neurodegenerative pathophysiology limits complete reversal of established morphological damage, timely suppression of inflammation followed by immune reconstruction is crucial. AHSCT may offer the potential to stabilize disease without the need for prolonged DMT administration; however, in aggressive disease courses, immunomodulatory therapy after immune reconstruction may be required if activity persists or recurs. Randomized trials are needed to confirm effectiveness of such strategies.
The results may support broader access to MS care involving AHSCT within the Russian Federation [34].
AHSCT (high-dose immunosuppressive therapy followed by infusion of autologous hematopoietic stem cells) is considered a treatment option for patients with aggressive or refractory MS in whom standard disease-modifying therapies (DMTs) do not adequately control disease activity. In the Russian Ministry of Health clinical approbation program conducted at Pavlov University (Saint Petersburg), HDIT-AHSCT demonstrated high effectiveness and an acceptable safety profile when strict selection criteria were applied and the procedure was performed in an experienced transplant center.
HDIT-AHSCT is a regimen of high-dose immunosuppressive therapy (e.g., cyclophosphamide 200 mg/kg total dose) followed by infusion of the patient’s own (autologous) hematopoietic stem cells. The goal is to “reset” the immune system, suppress autoimmune inflammation, and achieve durable control of MS activity.
AHSCT is considered in patients with highly active or aggressive relapsing MS and in a subset of patients with progressive MS (SPMS/PPMS) when there are signs of ongoing inflammatory activity clinically and/or on MRI. Key selection factors include relatively young age, moderate disability (EDSS), documented inadequate response to multiple DMT lines, and MRI activity (new lesions and/or gadolinium enhancement).
International studies and registry data show that AHSCT can enable a substantial proportion of patients to achieve NEDA (no clinical or radiological disease activity) in the medium to long term. In this clinical approbation program, most patients had reduced neurological deficit, stabilized MS activity, and decreased depressive symptoms at 12 months. In some patients with early aggressive disease, benefits can be durable; if needed, re-initiation of DMTs may be considered later.
AHSCT is a high-intensity intervention and must be performed in a specialized transplant center. Expected early complications include severe but manageable cytopenias (anemia, neutropenia, thrombocytopenia), febrile neutropenia, mucositis, transient liver enzyme elevations, transient alopecia, and marked weakness during hematopoietic recovery. Long-term complications may include autoimmune endocrinopathies (e.g., autoimmune thyroiditis), fertility impairment, and therapy-related mortality (TRM), which has decreased substantially in modern series with careful selection and experienced centers.
HDIT-AHSCT can affect ovarian reserve; pregnancy planning should be individualized, considering age, baseline fertility, and prior therapies. Successful pregnancies and deliveries after AHSCT have been reported in stable MS, but careful multidisciplinary risk assessment and long-term follow-up with a neurologist, hematologist, gynecologist, and endocrinologist are essential.
No. AHSCT is an option for carefully selected patients with highly active or aggressive MS refractory to DMTs. After immune reconstruction, if disease activity persists or recurs, DMT re-initiation or other treatment strategies may be required in line with international recommendations (EBMT, ECTRIMS, etc.).
Dr. Lidiia Prakhova