Does quality of life improve for clients with autoimmune or neuromuscular disorders who received stem cell replacement?

ORIGINAL ARTICLE

Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis

Fangfang Ge1 & Hong Lin1 & Zhuyi Li1 & Ting Chang1

Received: 19 March 2018 /Accepted: 29 November 2018 /Published online: 10 December 2018 # Fondazione Società Italiana di Neurologia 2018

Abstract Background Autologous hematopoietic stem-cell transplantation (AHSCT) has been utilized as a treatment option for multiple sclerosis (MS) since 1995. However, this procedure has not been widely implemented in clinical practice owing to its mortality risk. Here, we conduct a meta-analysis to evaluate the long-term efficacy and safety of AHSCT in MS treatment, aiming to optimize the benefit/risk ratio of this therapeutic strategy. Methods We searched the PubMed Web site and clinicaltrials.gov databases. The efficacy endpoints were progression-free survival (PFS) and disease activity-free survival. The safety outcomes were transplant-related mortality (TRM) and overall deaths. Results Eighteen eligible studies with a total of 732 participants were enrolled. The PFS was 75% (95% CI, 0.69–0.81), and the estimate of disease activity-free survival was 61% with 48-month follow-up. Subgroups analysis showed that low- and intermediate-intensity regimens were associated with higher PFS 80%. Relapsing remitting MS (RRMS) benefited more from AHSCT than other MS subtypes with PFS 85%. Patients with Gd+ lesions at baseline MRI responded better to AHSCTwith PFS 77%. The estimate of TRM was 1.34% (95% CI, 0.39–2.30), and the overall mortality was 3.58%. TRM was significantly higher in high-intensity regimen studies (3.13%) and in older studies (1.93%) performed before 2006. Conclusions This meta-analysis provides evidences that AHSCT can induce long-term remissions for MS patients with a high degree of safety. We indicate low- and intermediate-intensity regimens and RRMS patients with the presence of Gd+ lesions at baseline MRI can obtain the optimal benefit/risk ratio from AHSCT.

Keywords Multiple sclerosis . Autologous hematopoietic stem-cell transplantation . Meta-analysis . Systematic review .

Progressive

Introduction

Multiple sclerosis (MS) is an immune-mediated and CNS de- myelinating disease affecting more than two million people

worldwide especially manifests in young adults. This disorder can give rise to permanent disability, impair quality of life, and shorten life expectancy. During the past two decades, disease- modifying treatments (DMTs) have become available and shown to reduce clinical relapse, suppress disease activity in patients with relapsing remitting MS (RRMS). However, DMTs showed little benefit in disability progression and could not effectively treat other subgroups of MS: progressive and treatment-refractory MS [1, 2]. Given B cells and humoral immunity play a key role in MS pathogenesis, recently B cell depletion strategy has been an option for MS treatment [3, 4]. Promising results from B cell depletion by three therapeutic monoclonal antibodies (rituximab, ocrelizumab, and ofatumumab) in clinical phase II and III trials have confirmed the efficacy and safety of such therapy in MS, including pro- gressive forms [5, 6]. However, outcome assessments in most

Fangfang Ge and Hong Lin contributed equally to this work.

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-018-3670-1) contains supplementary material, which is available to authorized users.

* Ting Chang [email protected]

1 Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China

Neurological Sciences (2019) 40:479–487 https://doi.org/10.1007/s10072-018-3670-1

studies are limited to a short follow-up and the long-term outcomes of B cell depletion are still uncertain.

Autologous hematopoietic stem-cell transplantation (AHSCT), traditionally used for the treatment of hematologi- cal tumors, has been utilized as a treatment option for severe autoimmune diseases (ADs) since 1995 [7, 8]. It has been shown that AHSCT can induce long-term remissions com- pared with conventional immunosuppressive therapy. The re- sults of retrospective analysis and prospective randomized phase II/III studies identified its feasibility, efficacy, and safety in the major ADs particularly for MS [9, 10]. A series of retrospective reports from the European Group for Blood and Marrow Transplantation (EBMT) [11–13], which owned largest cohort of MS patients underwent AHSCT, showed a progression-free survival at 3 and 5 years of 74% and 45%, respectively. Meanwhile, transplant-related mortality has dropped dramatically from 7.3% in 1995–2000 to 1.3% in 2001–2007, and further decreasing to 0.7% during 2008– 2016 and down to 0.2% in the past 5 years (2012–2016) over the years [14].

Considering the limitation of retrospective reports, recent- ly, the results of phase II clinical trial (ASTIMS) have been published, comparing mitoxantrone (MTX) with AHSCT for the treatment of aggressive forms of MS [15]. This was the first multicenter, randomized trial to assess the effects of AHSCT vs conventional therapies for MS. The data of ASTIMS demonstrated AHSCT was significantly superior to MTX in reducing MRI activity and clinical relapse in severe cases of MS. However, this procedure has not been widely implemented in clinical practice and only been a rescue treat- ment when other therapy failed; the most important reasons were its mortality risk and uncertainty about optimal patients/ transplant regimen choice.

In this situation, we performed a systematic review and meta-analysis to evaluate the long-term efficacy and safety of AHSCT in MS treatment, with aim to select proper participants/methodology and optimize the benefit/risk ratio of this therapeutic strategy.

Methods

All analyses were based on previous published studies, and ethical approval and patient consent had been stated in all included studies.

Search strategy

We searched the PubMed Web site and clinicaltrials.gov databases (published until December 31, 2017) using the keywords Bmultiple sclerosis^ and Bautologous

hematopoietic stem-cell transplantation.^ The search was re- stricted to English language and published articles.

Study selection

Two authors screened the search results, excluded irrelevant publications based on the title and abstract, then obtained full- texts of potentially relevant articles. Eligible studies were se- lected according to the following criteria: (1) only uncon- trolled observational studies were included; (2) English lan- guage and published articles included; and (3) the efficacy outcome was progression-free survival reported. In addition, we excluded trials based on the following criteria: (1) case reports and studies that included fewer than ten patients; (2) published only as abstract. The other two neurologists inde- pendently extracted the following messages: numbers of en- rolled patients, age, length of follow-up, interval from diagno- sis to transplantation, types of MS, numbers of Gd+ at base- line MRI scan, Expanded Disability Status Scale (EDSS) score at baseline, conditioning regimen intensity, efficacy, and safety outcomes.

Efficacy and safety measures

In this systematic review and meta-analysis, the primary effi- cacy endpoint is progression-free survival, which is defined as the probability of being alive without confirmed disability progression (increase in EDSS > 1 if initial EDSS < 5.0 or > 0.5 if initial score > 5.5 after transplantation). The secondary efficacy endpoint is disease activity-free survival (no acute clinical relapse, no sustained progression of EDSS score, and no gadolinium-enhanced or new T2 lesions on MRI scan). The safety outcome is transplant-related mortality and overall mortality. Transplant-related mortality is defined as deaths within 100 days of AHSCT treatment.

Data synthesis and analysis

Data was entered into and analyzed using the Stata12. The efficacy outcome measures were pooled using the method of inverse variance, with random effects; the combined estimates were reported with 95% CIs. The I2 test was used to assess the presence of between-study heterogeneity. I2 with significance was set at P < 0.10 statistically. Fixed-effect model was used to assess low heterogeneity (P > 0.10), and random-effect model was used to assess high heterogeneity. Publication bias was assessed by visual examination of funnel plots. A strati- fied analysis was performed to explain the heterogeneity.

480 Neurol Sci (2019) 40:479–487

Results

Study characteristics

Eighteen RCTs were included in our meta-analysis with a total of 732 participants enrolled [16–33]. The search procedure is listed in Fig. 1. The mean onset age of all patients was ranged from 9 to 64 years. The mean MS duration ranged from 4 to 336 months, and the mean follow-up after AHSCT therapy ranged from 19 months to 6.7 years. Numbers of participants ranged from 14 to 145, detailed features are summarized in Table 1, and all trials reported progression-free survival assessed by EDSS scores, TRM, and overall mortality. According to EBMT classification, a combination of total body irradiation (TBI) plus anti-thymocyte globulin (ATG) (TBI/ATG) is considered a high-intensity conditioning regi- men, and intermediate-intensity regimen used mostly is the BEAM plus ATG (BEAM/ATG). BEAM is a combination of etoposide, melphalan, carmustine, and cytosine arabino- side. Four studies utilized a high-intensity regimen, and three trials analyzed the subgroup of Gd+ lesion at baseline MRI. There were 329 RRMS, 307 SPMS, 51 PPMS, and 44 pro- gressive relapsing MS (PRMS) patients.

Efficacy endpoints assessment

In the pooled cohort of 708 patients with a median follow-up of 48 months after transplantation, the pooled estimate of PFS

was 75% (95% CI, 0.69–0.81; I2 = 74.7%, P < 0.0001), sug- gesting substantial heterogeneity among studies (Fig. 2). The difference in onset age, MS subtypes, intensity of condition- ing regimens, and baseline MR characteristics among studies can contribute to the heterogeneity of consequence. Therefore, we analyzed the associations of subgroups with PFS separate- ly for this outcome (Fig. 3). Onset age appeared to have no significant association with PFS, and there was slight differ- ence between under 40 years and beyond 40 years with PFS 53% (95% CI, 0.29–0.78) vs 51% (95% CI, 0.30–0.72). However, other factors were significantly associated with PFS. Low- and intermediate-intensity regimen resulted in higher PFS than do high-intensity regimen 80% (95% CI, 0.75–0.85) vs 58% (95% CI, 0.40–0.75). RRMS patients benefited more from AHSCT than other MS subtypes with PFS 85% (95% CI, 0.77–0.92). Patients with Gd+ lesions at baseline MRI responded better to AHSCT than Gd− patients with PFS 77% (95% CI, 0.61–0.94) vs 47% (95% CI, 0.33– 0.62). The pooled proportion of patients who were disease activity-free survival was 61% (95% CI, 0.53–0.69; I2 = 49%, P = 0.056) at a median follow-up of 48 months (Fig. A1).

Mortality

In the pooled cohort of 731 transplanted patients, 9 transplant- related deaths occurred. As show in Fig. 4, the estimate of TRM was 1.34% (95% CI, 0.39–2.30, I2 = 37%, P = 0.058).

Fig. 1 Flowchart of included/ excluded studies

Neurol Sci (2019) 40:479–487 481

Ta b le 1

C h ar ac te ri st ic s o f st u d ie s in cl u d ed

in th e m et a- an al y si s

A ut h o rs

S am

p le si ze ,

n A g e (y ea rs ), m ed ia n

(r an g e)

R eg im

en in te n si ty

M S d u ra ti o n , m ed ia n

(r an g e)

T y p es

o f M S

M R I

ac ti v e

M R I

in ac ti v e

E D S S , m ed ia n

(r an g e)

F o ll o w -u p , m ed ia n

(r an g e)

F as sa s et al .[ 2 2 ]

2 4

4 0 (2 2 – 5 4 )

In te rm

ed ia te

1 0 .5 (2 – 2 8 ) y ea rs

1 3 S P. 3 P R .8 P P

6 1 8

6 .0 (4 .5 – 8 .0 )

4 0 (2 1– 5 1 ) m o n th s

B u rt et al .[ 3 3 ]

2 1

N A (2 1 – 5 2 )

H ig h

N A (9

m on th s– 1 5 ye ar s)

1 4 S P. 6 P R .1 R R

9 1 2

7 .0 (3 .0 – 8 .5 )

N A (1 – 5)

y ea rs

N as h et al .[ 2 6 ]

2 6

4 1 (2 7 – 6 0 )

H ig h

8 4 (1 0 – 2 7 7 ) m o n th s

8 P P. 1 7 S P. 1 R R

N A

N A

7 .0 (5 .0 – 8 .0 )

2 4 (3 – 3 6 ) m o n th s

S ai z et al .[ 2 9 ]

1 4

3 0 (2 2 – 4 5 )

In te rm

ed ia te

8 .0 (1 – 1 9 ) y ea rs

5 R R .9 S P

5 9

6 .0 (4 .5 – 6 .5 )

3 y ea rs

S ac ca rd i et al .[ 2 8 ]

1 9

3 6 (2 6 – 52 )

In te rm

ed ia te

12 (4 – 1 9 ) y ea rs

1 5 S P. 4 R R .

N A

N A

6 .6 (5 .5 – 8 .0 )

3 6 (1 2– 7 2 )

N i X S et al .[ 2 7 ]

2 1

3 7 (1 5 – 58 )

In te rm

ed ia te

46 (6 – 1 4 4 ) m o n th s

1 6 S P. 2 P P. 2 P R .

1 M al ig n an t

8 1 3

7 .5 (5 .0 – 9 .5 )

4 2 (6 – 6 5 ) m o n th s

H am

er sc h la k

et al .[ 2 3 ]

4 1

4 2 (2 7 – 5 3 )

In te rm

ed ia te

8 .0 (2 – 2 2 ) y ea rs

4 P P. 3 3 S P. 4 R R

8 2 7

6 .0 (4 .0 – 7 .0 )

3 y ea rs

Ju an

X u et al .[ 3 1]

3 6

3 5 (2 0 – 5 1 )

In te rm

ed ia te

7 2 .3 9 (7 – 3 3 6 ) m o n th s

3 6 S P

N A

N A

6 .5 8 (4 .5 – 9 .0 )

4 8. 9 2 (1 0 – 9 1 ) m o n th s

K ra su lo v a’ et al .[ 2 4 ]

2 6

3 3 (1 9 – 4 4 )

In te rm

ed ia te

7 .0 (2 – 1 9 ) y ea rs

11 R R 1 5 S P

N A

N A

6 .0 (2 .5 – 7 .5 )

6 6 (1 1 – 1 3 2 ) m o n th s

B in g C h en

et al .[ 3 2 ]

2 5

3 7 .3 (1 5 – 64 )

In te rm

ed ia te

48 (7 – 1 4 7 ) m o n th s

1 9 S P. 1 P P. 2 P R .3 R R

1 4

11 8 .0 (3 .0 – 9 .5 )

5 9. 6 (4 .5 – 11 1 ) m o n th s

B o w en

et al .[ 1 9 ]

2 6

4 1 (2 7 – 6 0 )

H ig h

8 4 (1 0 – 2 7 7 ) m o n th s

1 7 S P. 8 P P. 1 R R

7 1 6

7 .0 (5 .0 – 8 .0 )

4 8 (3 – 7 2 ) m o n th s

M an ca rd i et al .[ 2 5 ]

7 4

3 5 .7 (1 6 – 53 )

In te rm

ed ia te

11 .2 (1 – 2 8 ) y ea rs

4 1 S P. 3 3 R R

3 2

1 3

6 .5 (3 .5 – 9 .0 )

4 8. 3 (0 .8 – 1 2 6 ) m o n th s

B u rm

an et al .[ 2 1]

4 8

3 1 (9 – 52 )

In te rm

ed ia te

75 (4 – 3 0 0 ) m o n th s

4 0 R R .5 S P. 2 P P. 1 P R

3 2

1 6

6 .0 (1 .0 – 8 .5 )

4 7. 4 (1 2 – 1 0 8 ) m o n th s

B u rt et al .[ 1 8 ]

1 4 5

3 7 (1 8 – 6 0 )

L ow

6 1 (9 – 2 6 4 ) m o n th s

11 8 R R .2 7 P R

8 4

6 1

4 .0 (3 .0 – 5 .5 )

5 y ea rs

S h ev ch en k o

et al .[ 3 0 ]

9 9

3 4 .6 (1 8 – 5 4 )

In te rm

ed ia te

5 .0 (0 .5 – 2 4 ) y ea rs

4 3 R R .3 5 S P. 1 8 P P. 3P

R 4 0

5 9

3 .5 (1 .5 – 8 .5 )

4 8. 9 m o n th s

A tk in s et al .[ 2 0 ]

2 4

3 4 (2 4 – 4 5 )

H ig h

5 .8 (1 .3 – 11 .2 ) y ea rs

1 2 R R .1 2 S P

N A

N A

5 .0 (3 .0 – 6. 0)

6. 7 (3 .9 – 1 2 .7 ) y ea rs

N as h et al .[ 1 7 ]

2 5

3 7 (3 1 – 4 2 )

In te rm

ed ia te

4 .9 (2 .5 – 7 .3 ) y ea rs

2 5 R R

N A

N A

4 .5 (4 – 5 .0 )

6 2 (1 2 – 7 2 ) m o n th s

C as an o v a[ 1 6 ]

3 8

3 6 .7 (9 .1 )

In te rm

ed ia te

9 .5 (7 .6 ) y ea rs

2 2 R R .1 0 S P

2 0

1 8

5 .3 (1 .2 )

8 .4 (2 – 1 6 ) y ea rs

E D SS

E x p an d ed

D is ab il it y S ta tu s S ca le , N A n o t av ai la b le , R R re la p si n g re m it ti n g , SP

se co n da ry

p ro g re ss iv e, P P p ri m ar y p ro gr es si v e, P R p ro gr es si v e re la p si n g , m al ig na nt

m al ig n an t m u lt ip le sc le ro si s,

M R I ac tiv e n o . o f p at ie n ts w it h g ad o li n iu m -e n h an ce d le si o n s o n b as el in e M R I, M R I in ac tiv e n o . o f p at ie n ts w it h o u t g ad o li ni u m -e n h an ce d le si o n s o n b as el in e M R I

482 Neurol Sci (2019) 40:479–487

TRM was significantly higher in high-intensity regimen stud- ies (3.13%, 95% CI, 1.18–5.08) when compared with low- and intermediate-intensity regimen (0.97%, 95% CI, − 0.05– 1.98) and in older studies performed before 2006 (1.93%, 95% CI, 0.13–3.72) (Fig. 5). A total of 27 patients died during the follow-up, with the pooled estimate of overall mortality

was 3.58% (95% CI, 2.30–4.86, I2 = 64.7%, P = 0.000) (Fig. A2). The leading cause of overall mortality was infection (14cases) and pneumonia (6 cases). Of these 25 cases, six cases were associated with disease progression. The major cause of non-treatment-related deaths was disease progression.

Fig. 3 Forest plot for progression-free survival in stud- ies with different subgroups

Fig. 2 Forest plot for progression-free survival in each study and pooled estimates

Neurol Sci (2019) 40:479–487 483

Discussion

AHSCT, as a one-time treatment option for MS patients, has attracted eyeballs of neurologists recently. Compared with DMTs and B cell depletion treatments, AHSCT induced long-term sustained remissions for MS patients. However, this procedure is not uniform across studies referring to recruit- ment of patients with MS subtypes and the selection of inten- sity regimen, which could lead to the heterogeneity of conse- quence. Owing to the mortality risk and the lack of large

randomized controlled trial, the application of AHSCT in clin- ical practice is still limited. Therefore, this meta-analysis will provide more useful evidences about the long-term efficacy outcomes of AHSCT including demographic/disease-related and treatment-related variables as well as safety, with aim to optimize benefit/risk ratio of this procedure.

In this analysis, we chose to use progression-free survival as main efficacy endpoint. Seventy-five percent of patients remained free from EDSS score deterioration after AHSCT with a median follow-up of 48 months; the efficacy outcome

Fig. 4 Forest plot for transplant- related mortality in each study and pooled estimates

Fig. 5 Forest plot for transplant- related mortality in studies with different subgroups

484 Neurol Sci (2019) 40:479–487

was the same as those reported in previous and contemporary meta-analysis [34, 35]. In the present meta-analysis, 63% of patients had no new MRI lesions, no clinical relapse, and no EDSS progression post-AHSCT at 48 months, which sug- gested that AHSCT could induce sustained remissions for MS. Given substantial heterogeneity among studies in prima- ry efficacy endpoint (I2 = 74.7%, P < 0.0001), we analyzed the associations of different subgroups including onset age, MS subtypes, intensity of conditioning regimens, and baseline MR characteristics with PFS separately.

Different subtypes of MS were included in our analysis. The proportion of RRMS was 40%, and PFS was estimated to be 85% (95% CI, 0.77–0.92); by contrast, the PFS was estimated to be 52% in progressive MS (60%) after AHSCT treatment, indicating that RRMS respond better to AHSCT than other MS subtypes. This outcome was consistent with recent evidence of good efficacy in RRMS [36]. Other origi- nal studies proved the best candidates for transplantation seem to be patients with RRMS through long-term follow-up [16–18]. A possible explanation for this finding was RRMS patients had lower EDSS score prior to transplantation and were in the early stage of disorder. Muraro et al.’s report found lower baseline EDSS scores were the factors associated with better outcomes.

Progressive forms of MS are classified as aggressive forms that can lead rapidly to a high burden of disability and, at times, even to death in a short period of time. Currently avail- able DMTs proven to be effective for RRMS have little or no efficacy in progressive multiple sclerosis. Thus, effective treatments for progressive forms of MS remain a challenge in MS management. Although the pathogenic mechanism un- derlying progression is incompletely understood, axonal inju- ry is a major contributor to irreversible disability [37]. Accordingly, AHSCT, acting on the immune system, likely has little benefit in progressive MS [16, 18]. These findings suggests that other therapeutic approaches, such as neuropro- tective strategies, will be necessary in treatment of progressive multiple sclerosis. AHSCT should not be used as a rescue treatment after failure of all available treatments and the ideal candidate for AHSCT should be refined.

In our analysis, the treatment response was most notable in the group of patients with low- and intermediate-intensity reg- imens than do high-intensity schemes with PFS 80% (95% CI, 0.75–0.85) vs 58% (95% CI, 0.40–0.75). The similar out- comes were observed in previous meta-analysis. Reston et al. reported 79.4% PFS in patients receiving intermediate- intensity conditioning regimens, while 44.6% PFS in patients receiving high-intensity regimens [35]. Since higher treatment intensity was associated with higher mortality risk, recently, BEAM, as an intermediate-intensity conditioning regimen, has been most frequently used. BEAM showed better out- come and less toxicity when compared with the high- intensity regimens [11, 30, 38]. We also demonstrated TRM

was significantly associated with regimen intensity: studies using high-intensity schemes had a TRM of 3.13% (95% CI, 1.18–5.08), while those using low- and intermediate-intensity regimens had a TRM of 0.97% (95% CI, − 0.05–1.98). These results in favor of low- and intermediate-intensity condition- ing regimen are the best choice.

In subgroup analysis, we found patients with Gd+ lesions prior to AHSCT were associated with a favorable outcome when compared to patients with Gd− lesions (PFS 77% vs 47%). The similar conclusions were drawn from previous published reports [21, 35]. Three trials analyzed the effects of Gd+ lesions at baseline MRI scan on PFS [19, 21, 25], and they found that the treatment response was most notable in the group of patients with the presence of Gd+ lesions at baseline. This phenomenon can be explained that patients with Gd+ lesions are more likely to have an inflammatory disease. This information might suggest the optimal therapeu- tic window for this procedure was in the inflammatory stages of MS.

The main problems of AHSCT are the safety issues, and TRM is the main concern that has limited the use of this procedure. With better selection of patients and decreased use of high-intensity conditioning regimen, TRM has dropped over the years [14]. In our meta-analysis, the estimate of TRM (1.34%) was the same as previous reports. A marked reduc- tion of TRM was closely related to the recruitment of RRMS patients and to use of low- and intermediate-intensity condi- tioning regimens. In view of previous studies, we found that no TRM occurred in those studies which enrolled RRMS pa- tients, suggesting MS subtype may be an important factor associated with higher deaths. In the latest meta-analysis, Maria Pia Sormani et al. also reported higher baseline EDSS scores and a lower proportion of patients with RRMS were significantly associated with a higher TRM [34]. Now, at least in north of Europe, the low-intensity protocol of 200 mg of cyclophosphamide for kg is the most utilized type of condi- tioning regimen, and Burt and colleagues reported 0% of TRM in their cohort of MS patients who received AHSCT with use of low-intensity conditioning therapy [18]. We ob- served 0.97% TRM in low and intermediate conditioning reg- imens from our subgroup analysis compared with higher TRM (3.13%) in high-intensity conditioning therapy. In com- bination, these data indicate that AHSCT is safe as a therapy option in MS treatment if RRMS patients with lower EDSS scores were enrolled and low- and intermediate-intensity con- ditioning regimens were used. Meanwhile, we analyzed the overall mortality (3.31%) and found disease progression and high-intensity conditioning regimen were the main cause.

Our meta-analysis is limited in many aspects. Firstly, only published data were included, which might cause potential publication bias. Secondly, this analysis lacked randomized control trials due to the published evidence mainly consisted of case series and retrospective database studies. Thirdly, the

Neurol Sci (2019) 40:479–487 485

differences in AHSCT procedure, characteristics of MS pa- tients, and the duration of follow-up across studies could lead to potential heterogeneity. Subgroup data were not always available in the included trials, and different subgroup analy- ses were affected by many factors. Finally, it is well known that EDSS has a number of shortcomings as a measurement of disability. It is difficult to compare EDSS progression in dif- ferent studies due to its poor reproducibility and low inter- rater agreement.

This meta-analysis provides evidences that AHSCT can induce long-term remissions for MS patients with a high de- gree of safety. We indicate low- and intermediate-intensity regimens and RRMS patients with the presence of Gd+ le- sions at baseline MRI can obtain the optimal benefit/risk ratio from AHSCT.

Author contributions C.T and G.F.F performed the study selection, data extraction, statistical analysis, and drafted the manuscript. All authors participated in study design, revised the protocol, contributed to interpre- tation of the results, critically revised the manuscript for important intel- lectual content, and read and approved the final version of this manuscript.

Funding information This work is financially supported by the National Natural Science Foundation of China (grant 81671233).

Compliance with ethical standards

Conflicts of interest The authors declare that they have no conflict of interest.

Publisher’s Note Springer Nature remains neutral with regard to jurisdic- tional claims in published maps and institutional affiliations.

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