Автономная трансплантация стволовых клеток с помощью гематопоиетической гематомии для множественных склерозов в Соединенном Королевстве: A 20-year Ретроспективный анализ деятельности и гематологических результатов Британского общества трансплантации крови и мозга и клеточной терапии (BSBMTCT).

INTRODUCTION

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) and the main cause of disability in the working‐age population.
1
MS leads to a 7‐year reduction in life expectancy and a threefold increase in all‐cause mortality.
2
MS prevalence in the United Kingdom exceeds 150 000, with a global incidence of 3.6 cases per 100 000 person‐years.
3
,
4

MS presents as relapsing‐remitting MS (RRMS) in approximately 85% of cases, beginning in the third decade with a female to male ratio of 2.3:1,
4
or as primary progressive MS (PPMS) with typical onset in the fourth decade.
5
,
6
,
7
RRMS involves episodes of neurological symptoms (relapses) followed by recovery. PPMS is marked by accumulation of disability without distinct relapses. Over time, many RRMS patients transition to secondary progressive MS (SPMS), with steady progression of disability.

Evidence exists for autoimmune pathogenesis, with both T and B lymphocytes implicated through activation, cytokine production, CNS trafficking and consequent neuroinflammation.
8
,
9
Associations with EBV infection support a potential trigger for the aberrant immunity.
10
Early effective therapy is key to countering neurodegenerative processes and progressive disability that characterises SPMS. High‐efficacy disease‐modifying therapies (DMTs) for RRMS, including alemtuzumab (anti‐CD52),
11
ocrelizumab (anti‐CD20),
12
ofatumumab (anti‐CD20)
13
and natalizumab (anti‐ α4‐integrin),
14
reduce relapse frequency and associated disability and can be used first line in some patients.
15
They are not curative, require long‐term use, pose cumulative risks, high healthcare costs and ultimately disease progression independent of relapse activity (PIRA) occurs.
16
,
17

Autologous haematopoietic stem cell transplantation (AHSCT) is a one‐off therapy that achieves sustained disease remission in patients with MS (pwMS).
18
,
19
AHSCT enables immune reset by ablating pathogenic immune cells with reconstitution of a self‐tolerant immune system.
18
,
19
The extent of immune cell ablation depends on conditioning regimen intensity, which targets the lymphoid compartment alone or both lymphoid and myeloid compartments.
18
Moderate‐ and low‐intensity conditioning regimens are mostly used in the treatment of MS due to favourable tolerability and efficacy profiles.
20

AHSCT has proven superior to DMTs in achieving no evidence of disease activity (NEDA) (i.e. absence of relapses, MRI activity and disability progression).
21
,
22
,
23
Recent data from real‐world studies showed 40% of patients maintain NEDA 10 years post‐therapy.
24
Since AHSCT was first used for MS in the 1990s, the tolerability of the procedure has improved and mortality rates reduced from 7.3% to 0.2%.
20
However, safety concerns and lack of awareness still restrict AHSCT access.

AHSCT has been commissioned through the NHS for severe MS since 2013
25
; despite this, uptake in the UK remains low, with less than 0.3% of patients potentially eligible undergoing the procedure up to 2024. This is an underestimate as a percentage of patients travelled abroad to receive AHSCT due to a lack of perceived access.
26
The Mexico group published on 1700 patients having AHSCT for MS, and 18.8% were from the United Kingdom (319 patients) and similar numbers are likely to have travelled to Russia and other sites.
26
Since 2016, there has been a significant upturn in AHSCT activity for MS, driven by raised awareness, commissioning guidance and publication of several papers.
22
,
23
,
27
,
28

We report the UK‐wide experience of AHSCT for MS from 2002 to 2023, highlighting outcomes, toxicities, access factors and identifying factors associated with better tolerability and efficacy that can help improve clinical practice.

METHODS AND STATISTICAL ANALYSIS

Patient selection

We retrospectively collected data from patients treated with AHSCT at 14 participating centres between 2002 and 2023. Patients' eligibility for AHSCT was adjudicated on a case‐by‐case basis by a multidisciplinary team (MDT), including neurologists and haematologists, according to recognised principles
18
based on active disease, relapses or MRI activity, defined by new T2 and/or gadolinium enhancing lesions, despite DMT, or ‘aggressive’ disease if treatment naive, and fit for AHSCT. All patients signed informed consent to treatment and data collection in accordance with the Declaration of Helsinki. Patients on active clinical trials were not included.

All UK transplant centres reporting autologous AHSCT for MS activity to the BSBMTCT/EBMT databases during the study period were invited to participate. Supporting Information data were collected with an encrypted password‐protected Excel spreadsheet sent to each participating centre. Fully anonymised data returned from the centres were checked for consistency by the study team.

Treatment procedure

Stem cell mobilisation was predominantly cyclophosphamide (dose range: 2–4 g/m 2 ) followed by G‐CSF daily at a dose of 5–10 μm/kg daily starting 24 h post‐cyclophosphamide for 7–10 days. G‐CSF only mobilisation (10 μm/kg) was allowed for those failing cyclophosphamide‐based mobilisation.

Patients went through standard pretransplant work‐up before admission for AHSCT. Conditioning was cyclophosphamide/ATG with cyclophosphamide 200 mg/kg based on ideal body weight and rabbit‐ATG (r‐ATG, Thymoglobulin, Sanofi) at either 6.0 mg/kg or 7.5 mg/kg or carmustine/etoposide/cytarabine/melphalan regimen plus an equivalent dose of rATG (BEAM‐ATG). Stem cell reinfusion was delivered with a minimum dose of 2.0 × 10 6 /kg CD34+ cells following a 24‐h wash‐out. Supportive care and monitoring (including platelet and packed red cell transfusions, antimicrobial prophylaxis, management of fever, dietetics and physiotherapy support) were provided as per centre protocols. All centres were accredited by JACIE (Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and European society for Blood and Marrow Transplantation (EBMT)).

Statistical analysis

Data were analysed in Stata 18 (StataCorp. 2023. Stata Statistical Software : Release 18 . College Station, TX: StataCorp LLC.) Survival and other time‐to‐events (e.g. time to EDSS progression) were calculated by Kaplan–Meier, and comparisons between groups were made by Cox regression. EDSS progression was calculated from serial EDSS assessments, and patients were deemed to be at risk for progression from +90 days post‐transplant. Interaction terms were used to assess the effects of viral reactivation (which took place before 90 days) and ATG dose on EDSS progression. Comparisons between viral reactivation rates were made by logistic regression. Results were reported as hazard ratio (HR) together with the 95% confidence interval (CI).

Outcomes

This analysis focuses on the safety and transplant‐related complications of AHSCT, with efficacy data restricted to progression‐free survival described below. More detailed analysis of neurological outcomes is the focus of another manuscript under consideration elsewhere.
29

Efficacy

Clinical effectiveness was assessed as progression‐free survival (PFS) in the entire cohort and by MS phenotype. Progression‐free survival was defined as the absence of disability progression—an increase in EDSS score by 0.5 points if the baseline extended disability status scale (EDSS) score was ≥6.0 and by 1 point if the baseline EDSS score was <6.0, confirmed 6 months after. Each event was adjudicated by a local neurologist based on examination and medical records review.

Safety

Significant adverse events during the in‐patient stay, first 100 days post AHSCT, and then, late effects beyond day 100 were all recorded. Specifically, we collected data on the incidence of fever >38.0°C occurring anytime during the AHSCT procedure; rATG reactions and significant fluid overload (defined by >5% weight gain +/− peripheral or central oedema and need for diuresis); moderate to severe (Grade ≥ 2) nausea and diarrhoea. Data on viral reactivations assessed by whole blood PCR monitoring for EBV and CMV DNA were also collected. Clinically significant CMV viraemia was defined as CMV DNA copies >1000/mL or >3 Log copies/mL on two consecutive readings and/or where antiviral treatment was required. EBV viral load >300 000 copies/mL (or 30 000 IU/mL using WHO standard PCR) or where treatment with anti‐CD20 therapy (rituximab) was required for EBV‐related symptoms was considered clinically significant for the purpose of this study.

Transplant‐related mortality (TRM) was defined as all deaths within 100 days of stem cell re‐infusion to include deaths occurring after commencing conditioning but prior to stem cell reinfusion. Specific late effect information was collected on the incidence of a secondary autoimmune disease and any new cancer diagnosis at any stage post AHSCT.

RESULTS

Three hundred and sixty‐four patients with MS (pwMS) were included in this analysis from 14 transplant centres. 210 (58%) were female, median age at transplant was 40 years (range: 18–66, IQR: 33–47). 209 (58%) had RRMS, 130 (36%) had progressive MS (47 PPMS; 83 SPMS) and 25 patients' subtype was not recorded (6%). Median EDSS at time of AHSCT was 6.0 (range: 0–9) and disease duration of 10 years (range: 4–34 years) (Table  1 ).

TABLE 1 Demographics and transplant. Factor Level Patients Type of MS Unless o/w stated
N (unless o/w stated) % (unless o/w stated) Secondary progressive Primary progressive Relapsing remitting Total 364 83 47 209 Patient sex Male 154 42% 38 46% 34 72% 70 33% Female 210 58% 45 54% 13 28% 139 67% Age at transplant Median Range Median Range Median Range Median Range 40 year 19–66 year 43 year 25–62 year 47 year 31–64 year 38 year 19–66 year Mean/SD IQR Mean/SD IQR Mean/SD IQR Mean/SD IQR
40 year
9.4 year
33–47 year
44 year
7.9 year
38–49 year
46 year
8 year
39–50 year
38 year
9.4 year
31–45 year By decade <30 53 15% 5 6% 0 42 20% 30–39 123 34% 21 25% 12 26% 76 36% 40–49 127 35% 38 46% 22 47% 63 30% 50–59 56 15% 18 22% 11 23% 27 13% 60+ 5 1% 1 1% 2 4% 1 0.5% Length of MS at SCTAHSCT (since 1st symptoms) Median Range Median Range Median Range Median Range 10 year 4 month to 34 year 12 year 3–29 year 7 year 1–31 year 9 year 4 month to 34 year Mean/SD IQR Mean/SD IQR Mean/SD IQR Mean/SD IQR 10 year/6 year 6–14 year 13 year/5 year 9–17 year 8 year/5 year 4–11 year 10 year/6 year 5–13 year Age at symptom onset Median Range Median Range Median Range Median Range 29 year 9–56 year 30 9–51 37 19–55 27 9–56 Mean/SD IQR Mean/SD IQR Mean/SD IQR Mean/SD IQR 30 year/9 year 23–36 30/8 25–35 37/8 32–42 28/9 21–34 Year of transplant 2002–2012 13 4% 5 6% 0 8 4% 2013–2015 29 8% 8 10% 0 21 10% 2016–2023 322 88% 70 84% 47 100% 180 86% Baseline EDSS
Median range
Mean
Median Range Median Range Median Range Median Range 6 0–9 6.125 0–8 6 2–7 5.5 1.5–9 Mean/SD IQR Mean/SD IQR Mean/SD IQR Mean/SD IQR 5.2/1.6 4–6.5 6.0/1.0 6–6.5 5.5/1.3 4.5–6.5 4.9/1.7 3.5–6 0–4.5 100 31% 5 6% 14 30% 81 41% >4.5 223 69% 73 94% 33 70% 117 59% Not reported 41 5 0 11 Different grouping 0–3.0 46 14% 1 1% 3 6% 42 21% 3.5–5.5 92 28% 13 17% 15 32% 64 32% >5.5 185 57% 64 82% 29 62% 92 46% Prior treatment Naïve to prior DMT 32 11% 5 7% 17 68% 10 5% Unknown prior DMT 70 8 22 15 Conditioning Cyclo/ATG/Methyl pred 227 62% 71 89% 41 87% 115 55% Cyclo/ATG 125 34% 6 8% 6 13% 88 42% BEAM/ATG 9 3% 3 4% 0 6 3%
Not reported
3 3 0 0 Dose of ATG ≤6 mg/kg 141 39% 23 28% 8 17% 96 46% >6 mg/kg 219 61% 58 72% 39 83% 111 54% No ATG/not reported 4 2 0 2 Abbreviations: AHSCT, autologous haematopoietic stem cell transplantation; ATG, anti‐thymocyte globulin; BEAM, bis‐chloro‐ethyl‐nitrosourea (BCNU), cytosine arabinoside, etoposide, melphalan; Cyclo—cyclophosphamide; DMT, disease modifying therapy; EDSS, Expanded Disability Status Scale; IQR, interquartile range; MS, multiple sclerosis; N , number; SD, standard deviation.

Demographics and transplant.

40 year

9.4 year

44 year

7.9 year

46 year

8 year

38 year

9.4 year

Median range

Mean

Abbreviations: AHSCT, autologous haematopoietic stem cell transplantation; ATG, anti‐thymocyte globulin; BEAM, bis‐chloro‐ethyl‐nitrosourea (BCNU), cytosine arabinoside, etoposide, melphalan; Cyclo—cyclophosphamide; DMT, disease modifying therapy; EDSS, Expanded Disability Status Scale; IQR, interquartile range; MS, multiple sclerosis; N , number; SD, standard deviation.

Figure  1A,B shows geographical location of the most active centres and the patients undergoing AHSCT. Activity was centred around London and Sheffield, which historically have been the most active UK centres for AHSCT in autoimmune diseases. Many patients travelled a significant distance to undergo AHSCT, including 15 from the Republic of Ireland (Figure  1 ). Assuming uniform incidence of MS across England and Wales (regional incidence data are not available), and using postcode origin of patients, we derived incidence rate of AHSCT/million population (Table  2 ). This confirmed inequity of access with some regions undertaking markedly less activity compared to the regions around London and Sheffield.

(A) Map showing approximate locations of home addresses of patients receiving autologous stem cell transplantation in the (A) United Kingdom (B) England only.

TABLE 2 Regions of addresses of PWMS and centres where they were treated. Regional team/country of home address Transplant centre: regional team Region population (2021/2022 Census) Transplants per 1 000 000 people London Midlands NE & Yorks NW SE SW Scotland Private Total London 83 0 2 0 0 0 0 0 85 8 799 728 9.66 Midlands 27 1 17 0 0 0 0 0 45 10 830 811 4.15 NE & Yorkshire 7 0 31 0 0 0 0 0 38 8 441 200 4.50 NW 7 0 5 6 0 0 0 0 18 7 103 985 2.53 SE 72 0 1 0 3 0 0 0 76 8 977 685 8.47 SW 12 0 4 0 0 7 0 0 23 5 707 515 4.03 East 24 0 2 0 0 0 0 0 26 6 629 125 3.92 England total 232 1 62 6 3 7 0 0 311 56 490 049 5.51 Scotland 0 0 0 0 0 0 1 0 1 5 436 600 0.18 Wales 0 0 0 0 0 0 0 0 0 3 107 500 0 Northern Ireland 0 0 0 0 0 0 0 0 0 1 903 175 0 UK NHS total 232 1 62 6 3 7 1 0 312 66 937 324 4.66 Republic of Ireland 15 0 0 0 0 0 0 0 15 5 149 139
a

2.91 Unknown
b

7 1 5 1 0 0 0 22 36 ‐ ‐ Total UK + Ireland 254 2 67 7 3 7 1 22 363 72 086 463 5.04 Abbreviations: NE, North East; NHS, National Health Service; SE, South East; SW, South West; UK, United Kingdom.
a
2022 census.
b
Most of the ‘unknowns’ will likely be private patients.

Regions of addresses of PWMS and centres where they were treated.

Abbreviations: NE, North East; NHS, National Health Service; SE, South East; SW, South West; UK, United Kingdom.

2022 census.

Most of the ‘unknowns’ will likely be private patients.

98% (352/361) of patients received a cyclophosphamide/rATG conditioned AHSCT and 2% (9/361) received BEAM/ATG. 61% (219/360) of patients received an rATG dose of 7.5 mg/kg or more (Table  1 ). All patients engrafted post stem cell reinfusion. Median time to neutrophil engraftment was 11 days (range: 10–13 days).

Safety outcomes

Early complications occurred in 97% (253/261), where data were available. Most reported were: fluid overload (>2% body weight gain) in almost all patients (218/221; 99%), clinically significant fluid retention/weight gain in 161/307 patients (52%) and high‐grade fever during conditioning in 86% (225/261 patients) (Table  3 ).

TABLE 3 Transplant outcomes. Outcome Level Patients % (unless o/w stated) Type of MS Unless o/w stated
N
Secondary progressive Primary progressive Relapsing remitting Total 364 83 47 209 Median Range Median Range Median Range Median Range Follow up 3 year 9 month 1 month to 11 year 9 month 4 year 3 month 1 month to 11 year 9 month 4 year 1 month 1 month to 7 year 1 month 3 year 7 month 1 month to 11 year 9 month Status at follow up Alive 357 83 45 202 Dead (TRM) 4 0 1 3 Dead (MS) 2 0 0 2 Late death (non‐MS) 1 0 1 0 Neutrophil engraftment Yes 361 99% 83 100% 46 100% 207 99% No 3
a

1% 1
a

2
a

1% Median days 11 11 11.5 11 IQR 10–12 10–13 10–13 10–12 Overall survival 100D 99% 97–100% 100% ‐ 96% 84–99% 99% 95–100% 1 year 99% 97–100% 100% ‐ 96% 84–99% 99% 95–100% 5 year 98% 95%–99% 100% ‐ 96% 84–99% 97% 92–99% 10 year 94% 87–97% 100% ‐ ‐ ‐ 91% 76–97% OS 5 year by baseline EDSS 0–4.5 100% ‐ 100% ‐ 100% ‐ 100% ‐ >4.5 96% 91–99% 100% ‐ 94% 78–98% 95% 85–98% OS by continuous EDSS
p ‐value
p  = 0.032 HR = 1.86 ‐ ‐
p  = 0.320 HR = 5.31
p  = 0.038 HR = 1.73 Evaluable for EDSS progression
N  = 271
N  = 271
N  = 64
N  = 39
N  = 168 EDSS progression free survival 1 year 91% 86–94% 87% 75–93% 81% 64–91% 94% 89–97% 2 year 83% 78–86% 77% 63–86% 78% 61–88% 87% 80–92% 3 year 74% 68–80% 68% 53–79% 61% 42–76% 80% 72–86% 4 year 68% 61–74% 63% 47–75% 46% 26–64% 75% 66–82% 5 year 62% 55–69% 59% 43–72% 46% 26–64% 68% 57–76%
p ‐value and HR for difference v. RR
p  = 0.047 HR = 1.69
p  = 0.014 HR = 2.07 Reference Evaluable for EDSS progression 2013–2023
N  = 262
N  = 262
N  = 60
N  = 39
N  = 163 EDSS progression free survival (AHSCT between 2013 and 2023) 1 year 91% 87–94% 88% 76–94% 81% 64–91% 95% 90–97% 2 year 84% 79–88% 79% 65–88% 78% 61–88% 87% 81–92% 3 year 74% 68–80% 69% 54–80% 61% 42–76% 80% 72–86% 4 year 68% 61–75% 63% 47–76% 46% 26–64% 76% 67–82% 5 year 64% 56–71% 59% 41–73% 46% 26–64% 70% 60–78%
p value for difference v. RR
p  = 0.039 HR = 1.78
p  = 0.010 HR = 2.17 Reference Transplant related mortality 100D 1% 1–3% 0% 4% 1–16% 2% 0–5% 1 year 1% 0–3% 0% 4% 1–16% 2% 0–5% Any EBV reactivation No 72 23% 20 27% 10 23% 42 22% Yes 235 76% 53 72% 33 75% 149 77% Primary infection 4 1% 0 1 2% 3 2% Not available 53 ‐ ‐ ‐ ‐ EBV by ATG dose ATG dose ≤ 6.0 33/112 29% 8/18 44% 4/8 50% 21/86 24% ATG dose ≥ 7.5 39/199 20% 12/55 22% 6/36 17% 21/108 19%
p ‐value 0.051 0.075 0.064 0.483 Any CMV reactivation No 241 78% 63 89% 26 60% 152 79% Yes 66 21% 8 11% 17 40% 41 21% Not available 57 ‐ ‐ ‐ ‐ CMV by ATG dose ATG dose ≤ 6.0 9/110 8% 0/18 0% 1/7 14% 8/85 9% ATG dose ≥ 7.5 57/197 29% 8/53 17% 16/36 44% 33/108 31%
p ‐value
p ‐0.0005
p ‐0.100
p ‐0.215
p ‐0.0005 Complications (where data available) Fever during priming Yes 50 20% 16 21% 7 16% 27 21% No 199 80% 60 79% 37 84% 102 79% Unknown 12 0 1 11 Fever during conditioning Yes 225 86% 65 85% 37 80% 123 88% No 36 14% 11 14% 9 20% 16 12% Unknown 0 0 0 0 Fever post conditioning Yes 188 73% 58 77% 31 72% 99 71% No 70 27% 17 23% 12 28% 41 29% unknown 3 1 1 1 Grade 2+ Nausea/vomiting Yes 134 52% 35/75 47% 21/45 47% 78/138 57% No 124 48% Unknown 3 Grade 2+ diarrhoea Infective 14 5% 3 4% 4 9% 7 5% Not infective 81 63% 51 68% 31 69% 81 59% None 163 31% 21 28% 10 22% 50 36% Fluid overload/weight gain No 146 48% 24 33% 15 37% 107 55% Yes 161 52% 48 67% 26 63% 87 45% Abbreviations: AHSCT, autologous haematopoietic stem cell transplant; ATG, anti‐thymocyte globulin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; EDSS, Expanded Disability Status Scale; HR, hazard ratio; MS, multiple sclerosis; N , number; OS, overall survival.
a
Three patients died before neutrophil recovery.

Transplant outcomes.

Abbreviations: AHSCT, autologous haematopoietic stem cell transplant; ATG, anti‐thymocyte globulin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; EDSS, Expanded Disability Status Scale; HR, hazard ratio; MS, multiple sclerosis; N , number; OS, overall survival.

Three patients died before neutrophil recovery.

There were 5/364 deaths (1.4%) within 100 days of stem cell reinfusion predominantly due to toxicity of the conditioning regimen with acute decompensation leading to cardio‐respiratory failure or dysrhythmia, with two patients dying pre‐stem cell reinfusion. Two of the subjects had PPMS and three reported having RRMS. The median EDSS was 6.5 for this group and the median disease duration was 8 years from diagnosis (range: 5–17 years) and 9 years from first symptoms (range: 6–31 years). The three patients reported as RRMS had a median EDSS score of 6.5 with a median disease duration from first symptoms of 9 years (range: 7–18 years) suggesting they were more likely established secondary progressive MS or transitioning at the time of AHSCT (Table  4 ).

TABLE 4 Mortality. Age at transplant (years) 43 58 41 51 30 Gender M F F F F Significant medical history Mild emphysema Hypothyroidism, hypertension Nil Asthma (fatty liver, hypercholesterolaemia) Asthma Disease type PPMS PPMS RRMS RRMS RRMS Disease duration (years from diagnosis) 5 17 9 8 5 Disease duration (years from onset of symptoms) 6 31 9 18 7 DMT pre transplant None None Natalizumab, interferon, dimethylfumarate
Copaxone and
natalizumab
Alemtuzumab and interferon EDSS prior to transplant 6.5 6.5 6.5 6.5 6.0 ATG dose (mg/kg) planned/received 7.5/7.5 7.5/5 7.5/7.5 6/6 7.5/7.5 Fluid overload with clinical signs Yes Yes Yes Yes Yes Timing of death Conditioning 23 days after AHSCT 4 days after AHSCT Conditioning 54 days after AHSCT Cause of death Cardiac arrest and pulmonary oedema
ARDS
Chest infection/sepsis
Cardiac arrest, post‐traumatic subarachnoid haemorrhage
Cardiac arrest
Dyselectrolytaemia
Sepsis, PLTD Abbreviations: AHSCT, autologous haematopoietic stem cell transplantation; ARDS, acute respiratory distress syndrome; ATG, anti‐thymocyte globulin; DMT, disease‐modifying therapy; EDSS, Expanded Disability Status Scale; F, female; M, male; PTLD, post‐transplant lymphoproliferative disorder.

Mortality.

Copaxone and

natalizumab

ARDS

Chest infection/sepsis

Cardiac arrest

Dyselectrolytaemia

Abbreviations: AHSCT, autologous haematopoietic stem cell transplantation; ARDS, acute respiratory distress syndrome; ATG, anti‐thymocyte globulin; DMT, disease‐modifying therapy; EDSS, Expanded Disability Status Scale; F, female; M, male; PTLD, post‐transplant lymphoproliferative disorder.

Late deaths beyond day +100

Three further deaths occurred beyond 1 year after transplant due to MS progression in one, and one died of COVID beyond 1 year post AHSCT. The third patient was lost to follow up, with the cause of death unknown. EDSS at the time of AHSCT was 6, 6.5 and 7.5, reflecting significantly advanced disease.

Late effects

Following AHSCT, 5/315 (1.6%) patients were diagnosed with new malignancies; skin cancers ( n  = 2 at 14 months post‐transplant and at unknown date), T‐acute lymphoblastic leukaemia (T‐ALL) ( n  = 1 at 4 years post‐transplant), prostate cancer ( n  = 1 at 5 years post‐transplant) and breast cancer ( n  = 1 at 2 years post‐transplant). 24/305 (7.9%) patients developed secondary autoimmune disease predominantly thyroid disease ( n  = 21), immune thrombocytopenia ( n  = 2) and coeliac disease ( n  = 1).

Viral reactivations

CMV reactivation (>10 copies/mL DNA) was detected in 66/307 cases (21%) and data were not available in 56 cases (15%). Clinically significant CMV reactivation (defined above) occurred in 47/66 cases (15% of patients where we had data), but no CMV disease was observed. CMV reactivation was more commonly associated with a higher rATG dose >6.0 mg/kg (29% vs. 8%. p  = 0.0005; Table  3 ).

EBV serological status prior to AHSCT was positive in all cases apart from one indeterminate and one seronegative patient. EBV reactivation (defined by viraemia >10 DNA copies/mL consecutively), as previously described
30
was demonstrated in 76% of the total group, although four cases (1.1%) were incorrectly described as primary infection (despite serological evidence of EBV pre‐AHSCT). In 53 cases (14.5%), EBV monitoring was not performed. Rates of EBV reactivation were not significantly increased with rATG doses >6.0 mg/kg (24% vs. 71%. p  = 0.051; Table  3 ).

Very high levels of EBV reactivation are associated with adverse outcomes.
30
Of the 307 patients for whom we had EBV monitoring data, 235 EBV reactivation cases occurred with 15 (6%) requiring treatment with rituximab. Rituximab was not used in patients treated in Sheffield and other centres outside London, where a lower total rATG dose of 6.0 mg/kg was deployed, no adverse sequelae of EBV reactivation were reported at these sites. Following adoption of pre‐emptive rituximab after 2019 by the Pan‐London group at a threshold of 500 000 copies/mL (50 000 IU/mL), no cases of clinically significant EBV disease were seen.

Efficacy outcomes

Progression‐free survival was 62% (95% CI: 55%–69%) for the overall group at 5 years and significantly higher in RRMS patients compared with PPMS (HR 2.07) and SPMS (HR 1.69) patients ( p ‐0.04). Similar outcomes were noted in patients transplanted pre‐ and post‐2013 (Table  3 ). Even in the PPMS group, 46% had no EDSS progression 5 years post AHSCT (Table  2 , Figure  2 ). The PFS differences beyond 90 days AHSCT were strikingly better in patients with ATG dose ≤6.0 mg/kg versus higher doses (HR = 2.52, p ‐0.0005; Figure  S1 ), mainly noted in RRMS patient groups (Table  5 ). The PFS was also significantly lower in patients with significant EBV viral reactivation (above 300 000 cp/mL, 30 000 IU/mL) as well as CMV reactivations (Table  5 , Figures  S2 and S3 ).

Kaplan–Meier curves of progression‐free survival by subtype. [Colour figure can be viewed at wileyonlinelibrary.com ]

TABLE 5 Progression‐free survival for patients transplanted 2013 onwards. Unless otherwise specified All patients Type of MS Secondary progressive Primary progressive Relapsing remitting
N
% 3 year PFS 95% CI
N
% 3 year PFS 95% CI
N
% 3 year PFS 95% CI
N
% 3 year PFS 95% CI PFS from D90 Total 259 75% 68–80% 59 70% 55–82% 39 61% 42–76% 161 80% 72–86% PFS from D90 by Baseline EDSS ≤3.0 (reference) 35 89% 68–96% 0 ‐ ‐ 3 33% 1–77% 32 96% 73–99% 3.5–5.5 78 69% 55–79% 11 30% 4–62% 14 65% 31–85% 53 77% 61–87%
p  = 0.307 HR = 1.61 Reference
p  = 0.113 HR = 0.31
p  = 0.288 HR = 2.02 ≥6.0 146 75% 66–81% 48 79% 61–86% 22 64% 39–81% 76 75% 63–84%
p  = 0.196 HR = 1.75
p  = 0.040 HR = 0.32
p  = 0.075 HR = 0.29
p  = 0.067 HR = 3.07 Continuous EDSS 262
p  = 0.481 HR = 1.06
p  = 0.006 HR = 0.32
p  = 0.498 HR = 0.88
p  = 0.286 HR = 1.12 PFS from D90 by ATG dose ≤6.0 mg/kg 103 84% 75–90% 15 64% 30–85% 6 60% 13–88% 83 88% 78–94% ≥7.5 mg/kg 156 68% 58–75% 45 72% 54–84% 33 61% 40–76% 78 68% 54–79%
p  = 0.0005 HR = 2.52
p  = 0.916 HR = 1.06
p  = 0.621 HR = 0.73
p  = 0.001 HR = 3.31 EBV reactivation Non‐significant or none 209 81% 45 76% 28 72% 136 84% Significant EBV 50 19% 14 24% 11 28% 25 16% PFS from D90 by EBV reactivation Non‐significant or none 209 77% 70–83% 45 66% 48–79% 28 55% 32–73% 136 85% 77–91% Significant EBV 50 65% 49–77% 14 83% 45–95% 11 72% 35–90% 25 51% 29–70%
p  = 0.035 HR = 1.75
p  = 0.501 HR = 0.68
p  = 0.53 HR = 0.69
p  = 0.0005 HR = 3.68 PFS from D90 by EBV and ATG dose Non‐significant EBV & ATG ≤6.0 99 85% 76–91% 14 64% 30–85% 6 60% 13–88% 79 90% 81–85% Reference Non‐significant EBV & ATG ≥ 7.5 110 67% 55–77% 31 67% 44–82% 22 52% 26–73% 57 75% 57–87%
p  = 0.001 HR = 2.60
p  = 0.720 HR = 1.24
p  = 0.216 HR = 0.82
p  = 0.010 HR = 2.87 Significant EBV & ATG ≤ 6.0 4 50% 6–84% 0 ‐ ‐ 0 ‐ ‐ 4 50% 6–84%
p  = 0.139 HR = 3.01
p  = 0.066 HR = 4.10 Significant EBV & ATG ≥ 7.5 46 66% 50–79% 14 83% 45–95% 11 72% 35–90% 21 52% 28–72%
p  = 0.001 HR = 2.88
p  = 0.739 HR = 0.79
p  = 0.498 HR = 0.60
p  = 0.0005 HR = 6.15 CMV reactivation None or < 1000 and untreated 223 86% 52 88% 27 69% 144 89% >1000 or treated 36 14% 7 12% 12 31% 17 11% PFS by CMV reactivation None or < 1000 and untreated 223 76% 69–82% 52 70% 54–82% 27 62% 37–79% 144 81% 73–87% >1000 or treated 36 66% 46–79% 7 75% 13–96% 12 49% 19–73% 17 35% 2–76%
p  = 0.042 HR = 1.81
p  = 0.928 HR = 0.93
p  = 0.976 HR = 0.98
p  = 0.023 HR = 2.61 PFS by CMV reactivation and ATG dose
No CMV or <1000
ATG ≤ 6.0
100 83% 74–90% 14 64% 30–85% 6 60% 13–88% 80 88% 78–93% Reference
No CMV or < 1000
ATG ≥ 7.5
123 69% 58–78% 38 72% 52–84% 21 60% 31–80% 64 70% 53–82%
p  = 0.005 HR = 2.21
p  = 0.899 HR = 1.08
p  = 0.608 HR = 0.70
p  = 0.009 HR = 2.65
CMV > 1000 or treated
ATG ≤ 6.0
3 100% ‐ 0 0 3 100 ‐
CMV > 1000 or treated
ATG ≥ 7.5
33 62% 41–77% 7 75% 13–96% 12 58% 27–80% 14 62% 31–82%
p  = 0.001 HR = 3.20
p  = 0.987 HR = 0.99
p  = 0.699 HR = 0.76
p  = 0.0005 HR = 5.77 Abbreviations: AHSCT, autologous haematopoietic stem cell transplant; ATG, anti‐thymocyte globulin; CMV, cytomegalovirus; D, days; EBV, Epstein–Barr virus; EDSS, Expanded Disability Status Scale; HR, hazard ratio; MS, multiple sclerosis; N , number; PFS, progression‐free survival.

Progression‐free survival for patients transplanted 2013 onwards.

No CMV or <1000

ATG ≤ 6.0

No CMV or < 1000

ATG ≥ 7.5

CMV > 1000 or treated

ATG ≤ 6.0

CMV > 1000 or treated

ATG ≥ 7.5

Abbreviations: AHSCT, autologous haematopoietic stem cell transplant; ATG, anti‐thymocyte globulin; CMV, cytomegalovirus; D, days; EBV, Epstein–Barr virus; EDSS, Expanded Disability Status Scale; HR, hazard ratio; MS, multiple sclerosis; N , number; PFS, progression‐free survival.

DISCUSSION

This is the largest report on AHSCT for pwMS from the United Kingdom, where activity has steadily increased apart from a temporary drop‐off in activity in 2021–2022 due to the COVID‐19 pandemic. Most activity occurred post‐2016 in line with the increasing evidence base and funding support through 2013 NHSE Commissioning Policy.
25
The United Kingdom has been a leader in Europe for AHSCT for pwMS, yet the UK map shows activity concentrated around two major metropolitan centres, London and Sheffield, with large areas reporting little AHSCT activity for MS. There is a referral pathway for patients from the Republic of Ireland; however, the rest of the UK‐devolved nations, in particular Scotland and Northern Ireland, have shown no activity. NHS Wales commissioners have recently agreed a pathway, but this still means patients travelling to Sheffield. There is a need for the provision of expertise across the United Kingdom to drive equitable geographical access and meet increasing patient demands, supported by health economic analysis.
31
The STAR‐MS study,
32
which recently completed recruitment at 13 UK centres, may help through establishing multidisciplinary networks of support.
33

Our UK cohort is distinct in including 36% progressive MS patients historically excluded from randomised studies of AHSCT. Many patients had advanced disability at time of AHSCT (median EDSS 6.0) along with median failure of at least one high efficacy DMT. Prognosis for this ‘difficult to treat’ MS group is poor with rapid progression of disability. In this ‘real‐world’ cohort, 62% of patients remain free of progression at 5 years post‐AHSCT. Higher disability at time of AHSCT and primary progressive MS were associated with worse PFS.

This paper identifies specific issues during AHSCT for MS, including poor tolerability of conditioning in those with advanced MS related to impaired cardio‐respiratory reserve not picked up on routine transplant work‐up tests. Other factors to be considered in patients with MS are the increased risk of seizures, poor mobility and falls risks, poor tolerance of rATG fever and incomplete bladder voiding. Overall TRM by day +100 was 1.4% with all patients affected having advanced levels of disability. TRM occurred very early in the transplant course, mainly starting during conditioning before the aplastic phase and potentially related to reduced cardio‐respiratory reserve in patients with advanced MS compounded by conditioning regimens (such as cyclophosphamide‐ATG) that induce significant fluid retention and direct cardiotoxicity which may result in rapid clinical deterioration. It is vital to judiciously monitor fluid balance (once/twice a day), exercise careful diuretic therapy and pay close attention to electrolyte levels, alongside careful management of fever. In addition to traditional infection management, consideration should be given to administration of high doses of methylprednisolone (250–500 mg iv given stat) for any fever persisting beyond 1 h. MS patients are also at higher risk of seizures and maintaining good electrolyte levels is vital. Mobility and bladder infections highlight the need to consider pre‐emptive catheterisation for patients with incomplete bladder emptying to reduce infection risk and facilitate fluid management.
34
Falls risk, particularly during the thrombocytopenic phase of AHSCT, requires a multidisciplinary approach involving the nursing team, physiotherapists and occupational therapists, with careful assessment of patients baseline functional status and support to aid recovery following AHSCT. Patients should be treated within rooms which make allowance for reduced mobility, poor balance and deconditioning due to treatment.
34
,
35

Viral reactivation, particularly EBV, remains a significant issue and routine monitoring is mandatory for the first 100 days. EBV is intrinsically linked with the development of MS, as reflected by the high seroprevalence of EBV in the MS population compared with the general population (Table  1 ). We previously reported that uncontrolled EBV reactivation resulted in clinically significant sequelae for patients.
30
This study reveals an interaction of reduced PFS and increased morbidity associated with an increased risk of viral reactivations, fluid overload, rATG dose and advanced EDSS (Table  5 ). Based on this, the Pan‐London group recently adjusted the EDSS threshold for ASHCT eligibility to 6.0 or less. They also recommended a reduction in the rATG dose to 6.0 mg/kg total to mitigate against the increased risk of viral reactivations (Table  3 ). The previous EBV reactivation treatment threshold of 500 000 cp/mL (50 000 IU/mL) has also been reduced by the Pan‐London group in light of the findings in this paper of adverse outcomes with reactivation above 300 000 cp/mL (30 000 IU/mL). A recent survey of transplant centres across Europe showed that 36.9% of centres used doses of 7.5 mg/kg or more of r‐ATG and it remained unclear if higher ATG doses conferred better disease control.
36
This report, for the first time, confirms no benefit and potential risks of higher ATG doses (>6.0 mg/kg). Therefore, it seems reasonable to cap the rATG dose to 6.0 mg/kg.

Our report highlights the importance of knowledge and learning exchange. Recognition of MS specific issues during AHSCT led to the harmonisation of MS‐specific AHSCT protocols across the United Kingdom alongside the development of a Pan‐London MDT. The UK experience has contributed to the recent recommendations for AHSCT in MS and related disorders produced by ECTRIMS and EBMT.
34
,
37

Study limitations include the retrospective study design and lack of comparator DMT arm preventing direct comparative safety and effectiveness analysis. Understanding the intensity of the immune ablation is also vital as not all transplants are of equal intensity. The recently published paper from the team in Mexico highlighted ‘the Mexican Method’ for AHSCT in 1700 patients, but the follow‐up was more restricted than in our series where more robust neurological follow‐up was performed. Comparison between the two protocols is therefore not possible in terms of safety and outcome.
38

In conclusion, AHSCT remains a very effective one‐off therapy for treatment of patients with severe MS. Careful patient selection by a multidisciplinary team is important to optimise risk/benefit and data collection is vital for meaningful ‘real‐world’ outcome analysis. Ongoing randomised prospective trials comparing efficacy of AHSCT versus high‐efficacy disease‐modifying therapy in RRMS, including STAR‐MS
33
in the United Kingdom, expand the experience and capacity and will provide strong evidence on the position of AHSCT in the treatment for pwMS.

CONFLICT OF INTEREST STATEMENT

Paolo A. Muraro has received fees from consulting to Cellerys, unrelated to this study; John A. Snowden declares advisory boards for Vertex, Jazz, Medac and BMS, not related to this study.

Supporting information

Figure S1.

Figure S2.

Figure S3.