CLINACAL STUDIES
CELLULAR THERAPY AND TRANSPLANTATION (CTT JOURNAL)
VOL.10, NO.2, 2021 DOI:10.18620/CTT-1866-8836-2021-10-2-45-53
SUBMITTED: 25 JUNE 2021
ACCEPTED: 30 JULY 2021
VOL.10, NO.2, 2021 DOI:10.18620/CTT-1866-8836-2021-10-2-45-53
SUBMITTED: 25 JUNE 2021
ACCEPTED: 30 JULY 2021
AHSCT with
Low-Intensity conditioning regimens
in RRMS
Low-Intensity conditioning regimens
in RRMS
Clinical outcomes and quality of life
SUMMARY
The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians' and patients' perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.
INTRODUCTION
Multiple sclerosis (MS) is a severe inflammatory and demyelinating autoimmune disease of the central nervous system
(CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient's QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].
At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T - and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].
At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediateintensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients' selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient's QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].
Thus, we aimed to evaluate the effect of AHSCT with low- intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.
(CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient's QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].
At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T - and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].
At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediateintensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients' selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient's QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].
Thus, we aimed to evaluate the effect of AHSCT with low- intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.
PATIENTS AND METHODS
All the patients underwent AHSCT in the Transplantation Unit, Department of Haematology and Cellular Therapy, Pirogov National Medical and Surgical Centre (Moscow) from October 2006 to October 2018. The study was conducted according to the principles of Helsinki Declaration, and was approved by the Institute Research Board and local Ethics Committee before initiation. All the patients had given their written informed consent. The patients were eligible if they were >15 years old and met the Poser and McDonald criteria for clinically defined MS [32]. Other criteria for patients' selection included normal mental status and absence of severe concomitant diseases. The vast majority of patients was refractory to 2-4 different lines of conventional treatment including interferons, copaxone, mitoxantrone, cladribine, monoclonal antibodies therapy, azathioprine, intravenous immunoglobulin, glucocorticosteroids etc.
Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 ig/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0x106 CD34+ cells/kg.
Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m2, Etoposide 100 mg/m2, Ara-C 100 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m2) on D+11-12 (one infusion).
G-CSF (5 ig/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.
Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 plate- lets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].
The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.
For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar's test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.
Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 ig/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0x106 CD34+ cells/kg.
Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m2, Etoposide 100 mg/m2, Ara-C 100 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m2) on D+11-12 (one infusion).
G-CSF (5 ig/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.
Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 plate- lets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].
The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.
For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar's test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.
RESULTS
General characteristics:
A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.56.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients' chara
A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.56.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients' chara
Table 1. Characteristics of the patients with multiple sclerosis
Abbreviations: EDSS, Expanded Disability Status Scale score; ND, no data.
Abbreviations: EDSS, Expanded Disability Status Scale score; ND, no data.
SAFETY
The procedure of autologous HSCT was well tolerated by the patients. There were no cases of transplantation-related mortality. Mobilization was successful in all cases with median number of 2.1x106/kg (range 2-10.9x106/kg) collected CD34+cells; no major clinical adverse events were observed during this phase.
The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).
Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) - 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.
The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).
Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) - 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.
CLINICAL OUTCOMES
Median follow-up after AHSCT was 30 months (3.7-110.9). The vast majority of patients (99%) responded to treatment. The decrease of EDSS score from median 2.0 to 1.5 was observed at 12 months after AHSCT, and it remained at this level during the follow-up of more than 60 months (Fig. 1). The EDSS score improved significantly for the entire group (P <0.001) at all the time intervals, as compared with baseline. EDSS changes in patients with RRMS prior to and at different time-points after AHSCT are presented in Table 2. The proportion of patients with change of >1.0 in EDSS score was 36% (86 patients) with index of improvement at 12 months, and 0.4% (1 patient) with an index of the disease progression. At 2 years post-transplant, 47 (32%) patients showed improvement, 1 patient (0.7%) became worse, and others presented with stable disease. At 3 years posttransplant, improvement was observed in 23 (25%) patients, worsening - in 1 (1.1%) patient, the others were in stable clinical state. At 4 years posttransplant, the majority (83.1%) of patients were stable, there was no further worsening, and 10 patients (16.9%) exhibited improvement. Hence, the vast majority of patients was stable during the continuous follow-up; clinical deterioration took place in 6% of patients.
Figure 1.
EDSS medians in patients with RRMS before and at different time-points after AHSCT
EDSS medians in patients with RRMS before and at different time-points after AHSCT
After AHSCT, the vast majority of patients with RRMS were relapse-free (245 out of 258). The mean term until relapse was 30.4 months (95% CI 18.24-42.52). Estimated relapse-free survival (RFS) at the median follow-up of 29.5 months was 95% (95% CI: 92.3-97.7) (Fig. 2A).
Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3%
Table 2.
EDSS changes in patients with RRMS before and at different time-points after AHSCT
Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3%
Table 2.
EDSS changes in patients with RRMS before and at different time-points after AHSCT
Figure 1.
Relapse-free (a)
and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT
Relapse-free (a)
and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT
(95% CI: 71.3-95.3). Estimated progression-free survival (PFS) at the follow-up of 36 months was 98% (95% CI: 95.6100.0), at the follow-up of 60 months, 91.2% (95% CI: 81.9100.0), at the follow-up of 84 months, 86.2% (95% CI: 73.199.3), as seen from Fig. 2B.
Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed. Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAMlike group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig
Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed. Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAMlike group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig
Figure 3.
Relapse-free survival Kaplan-Meyer curves for patients who received BEAM-like vs who received high-dose Cyclophosphamide+Rituximab
Table 3.
Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT
Relapse-free survival Kaplan-Meyer curves for patients who received BEAM-like vs who received high-dose Cyclophosphamide+Rituximab
Table 3.
Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT
Notes: *Wilcoxon test
Abbreviations: RRMS, relapsing-remitting multiple sclerosis; AHSCT, autologous hematopoietic stem cell transplantation; SD, standard deviation; PF, physical functioning; RPF, Role physical functioning; BP, Bodily pain; GH, General health; V, Vitality; SF, Social functioning; REF, Role emotional functioning; MH, Mental health; IQoLI, Integral QoL Index.
Abbreviations: RRMS, relapsing-remitting multiple sclerosis; AHSCT, autologous hematopoietic stem cell transplantation; SD, standard deviation; PF, physical functioning; RPF, Role physical functioning; BP, Bodily pain; GH, General health; V, Vitality; SF, Social functioning; REF, Role emotional functioning; MH, Mental health; IQoLI, Integral QoL Index.
Figure 4.
QoL changes in RRMS patients at 12 months
after AHSCT as compared to baseline (before ASCT)
QoL changes in RRMS patients at 12 months
after AHSCT as compared to baseline (before ASCT)
Figure 5.
QoL changes in RRMS patients at long-term follow-up
after AHSCT as compared to baseline (before ASCT)
QoL changes in RRMS patients at long-term follow-up
after AHSCT as compared to baseline (before ASCT)
PATIENT-REPORTED OUTCOMES
Mean QoL values in RRMS patients before AHSCT and 12 months after AHSCT (n=78) are presented in Table 3. QoL changes (Д) of scores according to all the SF-36 scales in 12 mo after AHSCT were compared to the baseline levels (Fig. 4).
We have also performed analysis of QoL changes at longterm follow-up after AHSCT (>18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Д) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).
Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).
AHSCT was accompanied by a significant improvement in patient's QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.
We have also performed analysis of QoL changes at longterm follow-up after AHSCT (>18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Д) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).
Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).
AHSCT was accompanied by a significant improvement in patient's QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.
Figure 6.
Prevalence of common MS symptoms before and at 12 months posttransplant
Prevalence of common MS symptoms before and at 12 months posttransplant
DISCUSSION
We have analyzed a cohort of 258 patients with RRMS undergoing AHSCT, with a median follow-up of 30 months. Low-intensity conditioning regimens based on BEAM and cyclophosphamide were applied. Outcomes of AHSCT were evaluated both from physician's and patient's perspective. Transplantation procedure was well tolerated by the patients. There were no cases of transplantation-related mortality. In our cohort, the vast majority of patients responded to treatment and exhibited clinical improvement, or were stable during the entire period of follow-up. Significant decrease of EDSS score was observed after transplantation; the EDSS score improved (decreased by >1.0 point), with 32% and 17% of patients demonstrating improvement at 2 years and 4 years, respectively. In our cohort, relapse-free survival and progression-free survival at 7-year follow-up were 83% and 86%, respectively. These results are in line with previously published data by R. Burt [18, 19].
Moreover, AHSCT was accompanied by significant improvement in patient's QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient's perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient's QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.
For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.
On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.
This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for >4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can't be made.
Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.
Moreover, AHSCT was accompanied by significant improvement in patient's QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient's perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient's QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.
For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.
On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.
This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for >4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can't be made.
Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.
CONFLICTS OF INTEREST
None reported
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4. Hafler DA. Multiple sclerosis. J Clin Invest. 2004; 113(6):788-794. doi: 10.1172/JCI21357
5. Visser, LA, Louapre, C, Uyl-de Groot CA, Redekop WK. Health-related quality of life of multiple sclerosis patients: a European multi-country study. Arch Public Health 79, 39 (2021). doi: 10.1186/s13690-021-00561-z
6. Lucchetta RC, Tonin FS, Borba HHL, Leonart LP, Ferreira VL, Bonetti AF, et al. Disease-modifying therapies for relapsing-remitting multiple sclerosis: A network meta-anal- ysis. CNS Drugs. 2018;32(9):813-826. doi: 10.1007/s40263- 018-0541-5
7. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72(2):152-158. doi: 10.1001/jamaneurol.2014.3537
8. Burt RK, Cohen B, Rose J, Petersen F, Oyama Y, Stefoski D et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005; 62(6):860-864. doi: 10.1001/archneur.62.6.860
9. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005
10. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
11. 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; 23(2):201-204. doi: 10.1177/1352458516645670
12. Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman 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;55(2):283-306. doi: 10.1038/s41409-019- 0684-0
13. Gavriilaki M, Sakellari I, Gavriilaki E, Kimiskidis VK, Anagnostopoulos A. Autologous hematopoietic cell transplantation in multiple sclerosis: Changing paradigms in the era of novel agents. Stem Cells Int. 2019; 2019:5840286. doi: 10.1155/2019/5840286
14. 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 autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017; 74(4):459-469. doi: 10.1001/jaman- eurol.2016.5867
15. Miller AE, Chitnis T, Cohen BA, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis: recommendations of the National Multiple Sclerosis Society. JAMA Neurol. 2021;78 (2):241-246. doi:10.1001/jamaneu- rol.2020.4025
16. Tolf A, Fagius J, Carlson K, Akerfeldt T, Granberg T, Larsson EM, Burman J. Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurol Scand. 2019; 140(5):320-327. doi:10.1111/ane.13147
17. 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(5):845-854. doi: 10.1016Zj.bbmt2019.02.014
18. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015; 313(3):275-284. doi: 10.1001/ jama.2014.17986
19. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC et al. 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. 2019; 321(2):165-174. doi: 10.1001/jama.2018.18743
20. Zhukovsky C, Sandgren S, Silfverberg T, Einarsdottir S, Tolf A, Landtblom A-M, et al. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2020. doi: 10.1136/ jnnp-2020-323992
21. Bertolotto A, Martire S, Mirabile L, Capobianco M, De Gobbi M, Cilloni D. Autologous hematopoietic stem cell transplantation (AHSCT): standard of care for relapsing-remitting multiple sclerosis patients. Neurol Ther. 2020;9(2):197-203. doi:10.1007/s40120-020-00200-9
22. Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hi- epe F et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006; 54(12):3750- 3760. doi: 10.1002/art.22256
23. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hematopoietic stem cell transplantation. Stem Cell Therapy for Autoimmune Disease. 2004:277-283. doi:10.1201/9780367813895-33
24. Rogojan C, Frederiksen JL. Hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Scand. 2009; 120(6):371-382. doi: 10.1111/j.1600-0404.2009.01168.x
25. Mohammadi R, Aryan A, Omrani MD, Ghaderian SMH, Fazeli Z. Autologous hematopoietic stem cell transplantation (AHSCT): An evolving treatment avenue in multiple sclerosis. Biologics. 2021;15:53-59. doi: 10.2147/BTT.S267277
26. Ismail A, Sharrack B, Saccardi R, Moore JJ, Snowden JA. Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation. Curr Opin Support Palliat Care. 2019;13(4): 394-401. doi: 10.1097/ SPC.0000000000000466
27. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008; 7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
28. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, Rykavicin OA, Ionova TI, Melnichenko VY, Fedorenko DA, Kulagin AD, Shamanski SV, Ivanov RA, Gorodokin G. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hema- tol. 2008; 36(8):922-928. doi: 10.1016/j.exphem.2008.03.001
29. Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kartashov AV, Kurbatova KA, Gorodokin GI, Novik AA. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012; 40(11):892-898. doi: 10.1016/j.exphem.2012.07.003
30. Chen B, Zhou M, Ouyang J, Zhou R, Xu J, Zhang Q, Yang Y, Xu Y, Shao X, Meng L, Wang J, Xu Y, Ni X, Zhang X. Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China. Neurol Sci. 2012; 33(4):881-886. doi: 10.1007/ s10072-011-0859-y
31. Saccardi R, Freedman MS, Sormani MP, Atkins H, Farge D, Griffith LM et al. European Blood and Marrow Transplantation Group; Center for International Blood and Marrow Research; HSCT in MS International Study Group. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult Scler. 2012; 18(6):825-834. doi: 10.1177/1352458512438454
32. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13(3):227-231. doi: 10.1002/ana.410130302
33. Common Toxicity Criteria. Version 2.0. Publish Date: April 30, 1999. https://ctep.cancer.gov/protocoldevelop- ment/electronic applications/docs/ctcv20 4-30-992.pdf.
34. Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E et al. Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation). Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002; 249(8): 1088-1097. doi: 10.1007/s00415-002- 0800-7
35. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984; 34(10):1368-1372. doi: 10.1212/wnl.34.10.1368
36. Hays RD, Sherbourne CD, Mazel RM. User's Manual for Medical Outcomes Study (MOS). Core measures of health- related quality of life. RAND Corporation, MR-162-RC. http://www.rand.org
37. Ionova T, Value of patient-reported outcomes in multiple sclerosis patients undergoing autologous hematopoietic stem cell transplantation. Proc. Int. Conf. "Stem cell transplantation for treatment of autoimmune diseases", Moscow, 2019. P. 44-45
38. Hobart J, Freeman J, Lamping D, Fitzpatrick R, Thompson A. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71(3):363-370. doi: 10.1136/jnnp.71.3.363
39. Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA, Jenkinson C, Peto V, Thompson AJ. Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. J Neurol Neurosurg Psychiatry. 2003; 74(6):710-714. doi: 10.1136/jnnp.74.6.710
1. Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin. 1995; 13(1):119-146. PMID: 7739500
2. Koch-Henriksen N, S0rensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010; 9(5):520-532. doi: 10.1016/S1474- 4422(10)70064-8
3. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2
4. Hafler DA. Multiple sclerosis. J Clin Invest. 2004; 113(6):788-794. doi: 10.1172/JCI21357
5. Visser, LA, Louapre, C, Uyl-de Groot CA, Redekop WK. Health-related quality of life of multiple sclerosis patients: a European multi-country study. Arch Public Health 79, 39 (2021). doi: 10.1186/s13690-021-00561-z
6. Lucchetta RC, Tonin FS, Borba HHL, Leonart LP, Ferreira VL, Bonetti AF, et al. Disease-modifying therapies for relapsing-remitting multiple sclerosis: A network meta-anal- ysis. CNS Drugs. 2018;32(9):813-826. doi: 10.1007/s40263- 018-0541-5
7. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72(2):152-158. doi: 10.1001/jamaneurol.2014.3537
8. Burt RK, Cohen B, Rose J, Petersen F, Oyama Y, Stefoski D et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005; 62(6):860-864. doi: 10.1001/archneur.62.6.860
9. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005
10. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
11. 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; 23(2):201-204. doi: 10.1177/1352458516645670
12. Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman 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;55(2):283-306. doi: 10.1038/s41409-019- 0684-0
13. Gavriilaki M, Sakellari I, Gavriilaki E, Kimiskidis VK, Anagnostopoulos A. Autologous hematopoietic cell transplantation in multiple sclerosis: Changing paradigms in the era of novel agents. Stem Cells Int. 2019; 2019:5840286. doi: 10.1155/2019/5840286
14. 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 autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017; 74(4):459-469. doi: 10.1001/jaman- eurol.2016.5867
15. Miller AE, Chitnis T, Cohen BA, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis: recommendations of the National Multiple Sclerosis Society. JAMA Neurol. 2021;78 (2):241-246. doi:10.1001/jamaneu- rol.2020.4025
16. Tolf A, Fagius J, Carlson K, Akerfeldt T, Granberg T, Larsson EM, Burman J. Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurol Scand. 2019; 140(5):320-327. doi:10.1111/ane.13147
17. 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(5):845-854. doi: 10.1016Zj.bbmt2019.02.014
18. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015; 313(3):275-284. doi: 10.1001/ jama.2014.17986
19. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC et al. 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. 2019; 321(2):165-174. doi: 10.1001/jama.2018.18743
20. Zhukovsky C, Sandgren S, Silfverberg T, Einarsdottir S, Tolf A, Landtblom A-M, et al. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2020. doi: 10.1136/ jnnp-2020-323992
21. Bertolotto A, Martire S, Mirabile L, Capobianco M, De Gobbi M, Cilloni D. Autologous hematopoietic stem cell transplantation (AHSCT): standard of care for relapsing-remitting multiple sclerosis patients. Neurol Ther. 2020;9(2):197-203. doi:10.1007/s40120-020-00200-9
22. Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hi- epe F et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006; 54(12):3750- 3760. doi: 10.1002/art.22256
23. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hematopoietic stem cell transplantation. Stem Cell Therapy for Autoimmune Disease. 2004:277-283. doi:10.1201/9780367813895-33
24. Rogojan C, Frederiksen JL. Hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Scand. 2009; 120(6):371-382. doi: 10.1111/j.1600-0404.2009.01168.x
25. Mohammadi R, Aryan A, Omrani MD, Ghaderian SMH, Fazeli Z. Autologous hematopoietic stem cell transplantation (AHSCT): An evolving treatment avenue in multiple sclerosis. Biologics. 2021;15:53-59. doi: 10.2147/BTT.S267277
26. Ismail A, Sharrack B, Saccardi R, Moore JJ, Snowden JA. Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation. Curr Opin Support Palliat Care. 2019;13(4): 394-401. doi: 10.1097/ SPC.0000000000000466
27. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008; 7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
28. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, Rykavicin OA, Ionova TI, Melnichenko VY, Fedorenko DA, Kulagin AD, Shamanski SV, Ivanov RA, Gorodokin G. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hema- tol. 2008; 36(8):922-928. doi: 10.1016/j.exphem.2008.03.001
29. Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kartashov AV, Kurbatova KA, Gorodokin GI, Novik AA. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012; 40(11):892-898. doi: 10.1016/j.exphem.2012.07.003
30. Chen B, Zhou M, Ouyang J, Zhou R, Xu J, Zhang Q, Yang Y, Xu Y, Shao X, Meng L, Wang J, Xu Y, Ni X, Zhang X. Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China. Neurol Sci. 2012; 33(4):881-886. doi: 10.1007/ s10072-011-0859-y
31. Saccardi R, Freedman MS, Sormani MP, Atkins H, Farge D, Griffith LM et al. European Blood and Marrow Transplantation Group; Center for International Blood and Marrow Research; HSCT in MS International Study Group. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult Scler. 2012; 18(6):825-834. doi: 10.1177/1352458512438454
32. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13(3):227-231. doi: 10.1002/ana.410130302
33. Common Toxicity Criteria. Version 2.0. Publish Date: April 30, 1999. https://ctep.cancer.gov/protocoldevelop- ment/electronic applications/docs/ctcv20 4-30-992.pdf.
34. Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E et al. Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation). Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002; 249(8): 1088-1097. doi: 10.1007/s00415-002- 0800-7
35. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984; 34(10):1368-1372. doi: 10.1212/wnl.34.10.1368
36. Hays RD, Sherbourne CD, Mazel RM. User's Manual for Medical Outcomes Study (MOS). Core measures of health- related quality of life. RAND Corporation, MR-162-RC. http://www.rand.org
37. Ionova T, Value of patient-reported outcomes in multiple sclerosis patients undergoing autologous hematopoietic stem cell transplantation. Proc. Int. Conf. "Stem cell transplantation for treatment of autoimmune diseases", Moscow, 2019. P. 44-45
38. Hobart J, Freeman J, Lamping D, Fitzpatrick R, Thompson A. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71(3):363-370. doi: 10.1136/jnnp.71.3.363
39. Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA, Jenkinson C, Peto V, Thompson AJ. Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. J Neurol Neurosurg Psychiatry. 2003; 74(6):710-714. doi: 10.1136/jnnp.74.6.710