Bone Marrow Transplantation (2020) 55:283–306 https://doi.org/10.1038/s41409-019-0684-0 FEATURE 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) Basil Sharrack1,2 Riccardo Saccardi3 Tobias Alexander4 Manuela Badoglio 5 Joachim Burman 6 ● ● ● ● ● Dominique Farge 7,8,9,10 Raffaella Greco11 Helen Jessop12 Majid Kazmi13 Kirill Kirgizov14 Myriam Labopin5 ● ● ● ● ● ● Gianluigi Mancardi15 Roland Martin 16 John Moore17 Paolo A. Muraro 18 Montserrat Rovira19 ● ● ● ● ● Maria Pia Sormani20,21 John A. Snowden 12 for the 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) Received: 11 August 2019 / Accepted: 17 August 2019 / Published online: 26 September 2019 © Springer Nature Limited 2019. This article is published with open access Abstract These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials. Introduction data indicating that after 5 years only 25% of people are still working. As a result, MS has an economic impact dis- Multiple sclerosis (MS) proportionate to its prevalence related to the high cost of disease modifying therapies (DMTs), the direct and indirect MS is the most common chronic inflammatory demyeli- costs of relapses and associated costs of benefits and per- nating disease of the central nervous system (CNS) and the sonal care [3]. leading cause of non-traumatic neurological disability of MS is typically a biphasic disease. In the intial phase, young adults [1]. It affects ~2.3 million people worldwide the illness usually runs a relapsing remitting (RRMS) with a prevalence of 1 in 700 adults [2]. Following diag- course [4] characterised by repeated episodes of inflam- nosis, patients rapidly fall out of employment, with recent mation within the CNS, often accompanied by Gadolinium (Gd) enhancing lesions on magnetic resonance imaging (MRI) and characterised pathologically by inflammatory * John A. Snowden infiltrates rich in T and B cells and macrophages [1]. The john.snowden1@nhs.net ensuing secondary progressive MS (SPMS) phase is Extended author information available on the last page of the article characterised by slow accumulation of disability with a 284 B. Sharrack et al. progressive decline in inflammation, and increasing axonal disability consequent upon degenerative changes. In such and neuronal loss [5]. Other clinical variants include pri- settings aHSCT has been reported as a means of intensive mary progressive MS (PPMS) where patients experience immunomodulation [13, 18, 19, 21]. disability progression from disease onset [4], and aggres- sive (or malignant) MS where the illness runs a fulminant course with rapid accumulation of significant disability Activity of HSCT in ADs: the EBMT Registry [6]. The Expanded Disability Status Scale (EDSS) [7] is and the EBMT activity survey the most commonly used method of assessing disability progression in MS, whilst MRI is used to assess disease The activity of HSCT and cell therapy in Europe is activity and atrophy. reflected by two complementary but different database Inflammatory forms of MS respond to immunomodula- analyses; the EBMT Registry, for which full EBMT tion with DMTs that aim to achieve a state of No Evidence membership mandates reporting of detailed data, and the of Disease Activity (NEDA), reflected by absence of clinical broader EBMT activity survey, which captures annual relapses, disability progression and MRI disease activity [8]. HSCT activity, both from all EBMT members (full and In the majority of patients with RRMS, the illness can be associate) and other non-EBMT centres. Severe treatment- controlled by currently approved DMTs and various pro- resistant ADs, predominantly MS, have been treated with fessional guidelines are available with recommendations for both aHSCT and allogeneic HSCT (allo-HSCT) for over their sequential use based on baseline disease activity and two decades and are currently the fastest growing indi- response to treatment [9]. However, a significant proportion cation group for HSCT in the annual EBMT activity of patients continue to have clinical and/or MRI disease survey [21–23]. activity despite the use of DMTs [10]. Whilst more effica- The EBMT Registry is currently the largest database cious DMTs may lead in many but not in all patients to worldwide for HSCT with over half a million registrations, relatively high levels of disease control in the short term including over 3000 patients treated for autoimmune and reflected by NEDA, these agents are expensive and have inflammatory diseases. The current status of the EBMT significant risks including infusion-associated reactions, Registry in relation to MS and other immune-related neu- secondary autoimmunity and infections including pro- rological diseases is summarised in Table 1 and Figs. 1–3, gressive multifocal leukoencephalopathy (PML). Unfortu- alongside the increasing activity in other ADs. There have nately, the treatment options are very limited once the been various degrees of uptake by national neurological and neurodegenerative phase of SPMS is established [11]. HSCT communities across EBMT, but overall the growing Equally, PPMS is very challenging to treat although some evidence base is reflected by a progressive increase in patients with clinical and MR scan activity may respond to registrations, particularly in the last 5 years. Over time there immunomodulation [12]. has been a shift from SPMS to RRMS (Fig. 3). Paediatric There is increasing published evidence, including ran- patients (<18 years) undergoing aHSCT for MS are rare, domised controlled trials (RCTs), which convincingly with only 28 registrations to date. demonstrates robust clinical efficacy of autologous HSCT NRM, an unfamiliar concept to most neurologists, is (aHSCT) in patients with highly active MS, along with used interchangeably in these guidelines with the closely- improved safety with markedly reduced levels of non- related treatment-related mortality (TRM) parameter, and is relapse mortality (NRM) risk, which supports its incor- an important consideration for HSCT in immune-mediated poration into standard MS treatment algorithms [13–21]. neurological diseases, which may be severely disabling but only rarely immediately life-threatening. In MS, NRM (and Other neuroinflammatory diseases TRM) have significantly improved significantly in EBMT registry data [21], with recently reported levels of 0.2%, Autoimmunity and neuroinflammation may affect the CNS similar to levels derived from meta-analysis of published and peripheral nervous systems (PNS) in a range of diseases studies [16], and this may be attributed to greater experi- including chronic inflammatory demyelinating polyneuro- ence, patient selection, transplant technique and accredita- pathy (CIDP), neuromyelitis optica (NMO), myasthenia tion [13–21]. gravis (MG), stiff person syndrome (SPS) and autoimmune It is not possible to provide meaningful estimates of the encephalopathies [17]. There are also patients with systemic activity trends and NRM risks of aHSCT in the rarer autoimmune diseases (ADs), where there is a significant immune-mediated neurological diseases given small num- neuroinflammatory component managed in neurology bers, heterogeneity and varying degrees of disability and co- clinics. Whilst many patients respond well to standard morbidity. The published literature includes some outcomes treatment pathways, responses may be inadequate leading to and may be open to selection bias. These rare indications the development of significant and potentially permanent are the subject of ongoing EBMT registry-based analyses. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 285 Table 1 Summary of autologous HSCT for MS and other immune-mediated neurological diseases in the EBMT Registry, July 2019 N (%) Multiple sclerosis 1446 (92.9) Malignant/aggressive 37 (2.7) Progressive (primary or secondary) 617 (45.8) Relapsing remitting 693 (51.4) Missing (n = 99, 6.8%) Other neurological disease 105 (7.1) Chronic inflammatory demyelinating polyneuropathy 54 (3.5) Neuromyelitis optica 17 (1.1) Myasthenia gravis 9 (0.6) Encephalitis 5 (0.3) Stiff person syndrome 4 (0.3) Other neurological diseases 21 (1.3) 250 Multiple sclerosis Other neurological autoimmune disease Other AD 200 Auto-HSCT 150 100 50 0 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 Year Fig. 1 EBMT ADWP activity—autologous HSCT for MS, other immune-mediated neurological diseases and other autoimmune diseases by year, 1994–2018 (N = 2766) Likewise, the numbers of patients who have received allo- HSCT, which covers the main adult and paediatric ADs but HSCT for neurological ADs are low [21], even in a recent provides limited detail [27]. EBMT analysis of allo-HSCT [24]. The aim of these updated guidelines is to provide a more detailed and comprehensive review of the evidence, registry data and mechanisms of action and to provide specific EBMT guidelines and recommendations recommendations for patient selection, treatment proce- dures, follow-up and future development of HSCT in Multi-disciplinary guidelines across a wide range of ADs patients with MS and other immune-mediated neurological were published by the EBMT ADWP in 1997 and 2012 to diseases. As previously, the guideline authorship group cover general principles of patient selection, stem cell col- includes clinicians from relevant professional groups active lection, graft manipulation, conditioning regimens, sup- in the ADWP, including nursing, statistical and data man- portive care and follow-up [25, 26]. These included agement representation, all with experience in HSCT for guidelines for MS and other immune-mediated neurological neurological ADs. The principal target audience is trans- diseases, but, given the increase in evidence, updates are plant physicians, nurses and their teams as well as neurol- now warranted. The EBMT has recently published a broad ogists working with transplant teams, or considering referral update of all malignant and non-malignant indications for of patients. The guideline is not primarily targetted at 286 B. Sharrack et al. 400 Multiple sclerosis Other neurological autoimmune disease Other AD 300 Auto-HSCT 200 100 0 Ita Un Ge Kin Sw ny Sp Po Ne d Fr rlan Au Ru lia Cz B e Re Gr Ch e No Sw y Hu rlan Isr ary Lit Tu nia De Au ark Ro a Si an ng rk hu ae ly ee lan str str ec ain lgi ite th ss ina rw ng nm m rm ed itz ey ce s ap e an a l um ubli c h ia a a i d e en a or ia e d p d gd om c Country Fig. 2 EBMT registry: overall national activity in autologous HSCT indicated for MS, other immune-mediated neurological diseases and other autoimmune diseases by country, 1994–2018 (N = 2766) 100% 80% 60% Auto-HSCT 40% Relapsing/remitting MS Aggressive/malignant MS Progressive MS 20% 0% 19 19 19 19 19 8 20 20 0 20 1 20 2 20 3 20 4 20 20 6 20 7 20 20 9 20 0 20 1 20 20 3 20 4 20 5 20 6 20 7 95 96 97 9 99 0 0 0 0 0 05 0 0 08 0 1 1 12 1 1 1 1 1 18 Year Fig. 3 EBMT registry: relative activity according to reported multiple sclerosis type: RR-MS versus progressive MS (SPMS/PPMS) versus aggressive/malignant MS patients, families and non-specialist health professional particular category is graded (levels I, II and III) based on carers, although it supplements recently published infor- consideration of health benefits, side effects and risks and mation from the EBMT [28]. Evidence was sourced from balanced against the non-HSCT options. Each recommen- PubMed searches of original observations and key reviews dation provides potential for auditing clinical practice. The and, where relevant, recent EBMT congress presentations, guideline also considers the resource implications and other with a view to updating the previous EBMT 2012 guide- issues relevant to implementation of HSCT in this area. lines [26]. As per other EBMT guidelines and recommen- Other than EBMT support there is no funding body sup- dations [26, 27], evidence for indications is systematically porting these guidelines, commercial or otherwise, and classified in four categories where HSCT should be con- conflicts within the authorship are disclosed. The EBMT sidered (S/CO/D/GNR—see Table 2 and related footnotes). ADWP plan future updates according to developments in Strength of the evidence supporting the assignment of a evidence base and clinical practice. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 287 Table 2 Summary of recommendations for HSCT and cellular therapy in multiple sclerosis and other immune-mediated neurological diseases Autologous HSCT MSD MUD MMAD Cellular Allo HSCT Allo HSCT Allo HSCT therapy Highly active relapsing remitting MS failing DMTs S/I D/III GNR/III GNR/III D/III Progressive MS with active inflammatory component CO/II D/III GNR/III GNR/III D/III Aggressivea (malignant) MS not previously treated with a full CO/II D/III GNR/III GNR/III D/III course of DMT Progressive MS without active inflammatory component GNR/III GNR/III GNR/III GNR/III D/III Paediatric MS CO/II GNR/III GNR/III GNR/III D/III CIPD CO/II GNR/III GNR/III GNR/III D/III NMO CO/II D/III D/III D/III D/III MG CO/II GNR/III GNR/III GNR/III D/III SPS CO/II GNR/III GNR/III GNR/III D/III Systemic ADs e.g. SLE, vasculitis, Behcet’s disease, Sjogren’s syndrome, CO/II GNR/III GNR/III GNR/III D/III refractory coeliac disease with neurological manifestations As updated by Duarte et al. [27], EBMT indications are classified in four categories, listed below, to describe the settings where these types of transplants ought to be performed. The strength of the evidence supporting the assignment of a particular category is graded in three levels: Grade I: 181 Evidence from at least one well-executed randomised trial Grade II: Evidence from at least one well-designed clinical trial without randomisation; cohort or case-controlled analytic studies (preferably from more than one centre); multiple time-series studies; or dramatic results from uncontrolled experiments Grade III: Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports from expert committees Standard of care (S): Indications categorised as S are reasonably well defined and results compare favourably (or are superior) to those of non- transplant treatment approaches. Obviously, defining an indication as the standard of care does not mean an HSCT is necessarily the optimal therapy for a given patient in all clinical circumstances. “Standard of care” transplants may be performed in a specialist centre with experience in HSCT and an appropriate infrastructure as defined by the JACIE guidelines Clinical option (CO): The CO category applies to indications for which the results of small patient cohorts show efficacy and acceptable toxicity of the HSCT procedure, but confirmatory randomised studies are missing, often as a result of low patient numbers. The broad range of available transplant techniques combined with the variation of patient factors such as age and co-morbidity makes interpretation of these data difficult. Our current interpretation of existing data for indications placed in this category supports that HSCT is a valuable option for individual patients after careful discussions of risks and benefits with the patient but that for groups of patients the value of HSCT needs further evaluation. Transplants for indications under this heading should be performed in a specialist centre with major experience in HSCT with an appropriate infrastructure as defined by JACIE guidelines Developmental (D): Indications have been classified as D when the experience is limited, and additional research is needed to define the role of HSCT. These transplants should be done within the framework of a clinical protocol, normally undertaken by transplant units with acknowledged expertise in the management of that particular disease or that type of HSCT. Protocols for D transplants will have been approved by local research ethics committees and must comply with current international standards. Rare indications where formal clinical trials are not possible should be performed within the framework of a structured registry analysis, ideally an EBMT non-interventional/observational study. Centres performing transplants under this category should meet JACIE standards Generally not recommended (GNR): The GNR category comprises a variety of clinical scenarios in which the use of HSCT cannot be recommended to provide a clinical benefit to the patient, including early disease stages when results of conventional treatment do not normally justify the additional risk of a HSCT, very advanced forms of a disease in which the chance of success is so small that does not justify the risks for patient and donor, and indications in which the transplant modality may not be adequate for the characteristics of the disease. A categorisation as GNR does not exclude that centres with particular expertise on a certain disease can investigate HSCT in these situations. Therefore, there is some overlap between GNR and D categories, and further research might be warranted within prospective clinical studies for some of these indications a Aggressive MS as per Menon et al. [6] Clinical evidence for aHSCT in MS and active MS, with long-term clinical and MRI remissions immune mediated neurological diseases observed in a majority of patients with acceptable safety. These include (1) a small phase II RCT that, despite some Multiple sclerosis (MS) methodological limitations, demonstrated the superiority of aHSCT with the ‘BEAM-ATG’ intermediate intensity Although the first patients to be treated with aHSCT for MS conditioning regimen in suppressing MRI activity and were in 1995 [29, 30], there is now growing evidence from clinical relapses compared with mitoxantrone [31]; (2) large registry studies and two prospective comparative trials single arm prospective studies demonstrating aHSCT with to support the efficacy of aHSCT in patients with highly cyclophosphamide-ATG (‘Cy-ATG’), ‘BEAM-ATG’, or 288 B. Sharrack et al. high-intensity (‘BuCy-ATG’) conditioning regimens considered for aHSCT, with treatment failure defined by the induced sustained clinical remissions and suppression of documented occurrence of at least two clinical relapses or MRI activity in patients with active MS [32–35]. one clinical relapse and the presence of MRI activity at an Similar outcomes were reflected in other large retro- independent time point in the previous 12 months spective series [15, 36–38]. Long-term outcomes have been [16, 18, 20, 41, 42]. analysed in a large cohort of patients treated before 2006, which included a mixture of RRMS, SPMS and PPMS [15]. ’Aggressive’ MS Systematic analyses of NEDA rates following aHSCT support durable clinical remission in a high proportion of About 4–14% of MS patients have ‘aggressive’ disease and patients with RRMS, suggesting that potential benefit could experience an accelerated (3–4 times faster) disease course exceed that seen after approved DMTs including those [6, 49]. Various terminologies have been used to describe considered to be highly efficacious [39, 40]. this ‘aggressive’ phenotype, including ‘malignant’, ‘fulmi- The evidence-base has been significantly boosted by the nant’ and ‘Marburg variant’. The ‘therapeutic window’ in a recent publication of interim results of the first large RCT patient with ‘aggressive’ MS is significantly shorter and, in phase III study, MIST, comparing aHSCT using a non- this relatively rare context, aHSCT is highly effective at myeloablative regimen (Cy-ATG) versus FDA approved inducing prolonged clinical remissions [50–52]. Thus, DMTs with no deaths or serious toxicity in the HSCT group deteriorating patients with ‘aggressive’ disease at risk of [41]. Moreover, 30 patients who were originally rando- irreversible disability should be rapidly considered for mised into the DMT arm were crossed over to the transplant aHSCT, even if a full course of DMT has not been com- arm after reaching the primary endpoint of the trial, with pleted to formally establish treatment failure [20, 26, 50]. significant fall in EDSS after receiving aHSCT [42]. The interim results of MIST provide evidence that aHSCT Progressive MS with active inflammatory component is safe and has superior efficacy compared with many cur- rently available DMTs, although, for historical reasons, MIST Registry studies and other cohort analyses have repeatedly did not include alemtuzumab, ocrelizumab or cladribine in the shown that aHSCT is more efficacious in patients with control arm. Therefore, there remains a need for comparative RRMS than SPMS or PPMS [13–16, 18, 20, 26, 27]. Even studies that randomise patients to aHSCT versus these agents so, several reports support the association of Gd- [43–45]. Even so, it would appear that aHSCT still offers enhancement with favourable outcomes [15, 16, 31, 53]. clear advantages with NEDA rates of 66–93% compared with More recent data from the siponimod trial [11] support a alemtuzumab, natalizumab or ocrelizumab. The area needs to role for ongoing inflammation in the chronic progressive be systematically resolved via prospective RCTs (see section phase of MS and aHSCT may therefore be justified at this Clinical trials of aHSCT in MS). stage provided that disease activity has been documented. In PPMS, registry-based studies have supported very Patient selection for aHSCT in MS limited benefit with aHSCT, if at all, and therefore recom- mendations have previously discouraged its use [26]. Undoubtedly aHSCT is more intensive and has greater However, some studies have suggested that immunomo- short-term toxicities than any DMT. It is used in MS pri- dulation may provide benefit [54, 55]. More recently, marily as an anti-inflammatory and immunomodulatory treatment with ocrelizumab has been associated with lower treatment, which makes the presence of significant clinical rate of clinical and MRI progression [12]. Given the poor and MRI evidence of an active inflammatory component, prognosis, the support from registry data [15, 16] and the along with fitness to tolerate it, a pre-requisite. Younger limited treatment options, very occasional patients with patients, shorter duration of disease, lower EDSS scores, high levels of persistent inflammatory activity with rapidly active inflammatory disease, and absence of other co- accumulating disability may be considered. Prospective morbidity have been associated with favourable outcomes studies are warranted to explore the potential of aHSCT [15, 16, 18–20, 27, 39, 40, 46–48]. Any decision to proceed in PPMS. must assess the balance of benefits and risks particularly in terms of reversibility or stabilisation of disability and other Paediatric MS neurological features. MS is a rare disease in children, but its consequences are Highly active relapsing remitting MS failing DMT particularly severe as disability may be life-long [56]. In a cohort of 21 patients under 18 years, aHSCT was well In line with MIST and other studies, patients with highly tolerated and associated with improvements of EDSS scores active RRMS failing at least one line of DMT may be in 81% of patients with progression free survival (PFS) of Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 289 100% at 3–5 years, hence potentially more efficacious (four received BEAM-based, and the remainder in children than in adults [17]. Given a greater potential cyclophosphamide-based protocols) of whom 90% for late effects, a reasonable approach is to try other improved, and 35% experienced further relapses [58–62]. less toxic treatments first, e.g. interferon or fingolimod [57], Recently, a large single centre experience was reported and reserve aHSCT for patients with breakthrough with high levels of response [63]. inflammation. Myasthenia gravis (MG) Recommendations MG, an immune-mediated disease targeting the neuromus- cular junction, has been treated with aHSCT, with ten ● aHSCT should be offered to patients with RRMS with patients described in the literature. Seven were treated at a high clinical and MRI inflammatory disease activity (at single centre with high-intensity conditioning regimens least 2 clinical relapses, or one clinical relapse with Gd- containing total body irradiation (TBI) or busulphan, with enhancing or new T2 MRI lesions at a separate time good tolerance and durable remission in all patients after a point, in the previous 12 months) despite the use of one median follow-up of 40 months [64]. Similar outcomes in or more lines of approved DMTs. Evidence best three further patients using cyclophosphamide-based con- supports treatment in patients who are able to ambulate ditioning were reported [65–67]. independently (EDSS 5.5 or less), who are younger than 45 years and have disease duration less than 10 years Stiff person syndrome (SPS) (level S/I). ● Patients with ‘aggressive’ MS, who develop severe SPS is a rare immune-mediated neurological disorder disability in the previous 12 months, are suitable characterised by muscle rigidity, spasms, brain stem candidates for aHSCT. Given the potential for irrever- hyperexcitability and high glutamic acid decarboxylase- sible disability, such patients may be considered even specific antibodies. aHSCT has successfully been used to before failing a full course of DMT (level CO/II). treat limited numbers of SPS patients [68, 69]. Most ● Patients with SPMS should be considered for aHSCT, patients respond to aHSCT, although responses are variable preferably in a prospective clinical trial, only when and may depend on the variant and duration of SPS. inflammatory activity is still evident (clinical relapses and Gd-enhancing or new T2 MRI lesions) with Neuromyelitis optica (NMO) documented disability progression in the previous 12 months (level CO/II). NMO is an inflammatory autoimmune disorder of the CNS, ● Patients with PPMS should be considered for aHSCT, characterised by pathogenic anti-aquaporin four antibodies preferably in a prospective clinical trial, only when (AQP-4Ab) and a generally worse prognosis than MS. The inflammatory activity is evident (Gd-enhancing and EBMT summarised 16 patients with refractory NMO trea- new T2 MRI lesions) with documented evident ted with aHSCT (treated mainly with the ‘BEAM-ATG’ disability progression in the previous 12 months (level regimen); three cases remained progression- and treatment- CO/II). free, whilst anti-AQP-4Ab antibodies persisted in 13 ● Paediatric patients with MS who have breakthrough patients who required further treatments for relapses or inflammatory disease with less toxic treatments may be disability progression [70]. Other data come from two case considered for aHSCT (level CO/II). reports and a Chinese study in 21 patients with so-called opticospinal MS [71–73]. A recent case report showed a sustained clinical, radiological and immunopathological aHSCT in other immune-mediated neurological NMO remission with rituximab treatment prior to aHSCT diseases [74]. Recent data from Northwestern University support favourable clinical outcomes of aHSCT with the Cy-ATG Chronic inflammatory demyelinating polyneuropathy regimen combined with rituximab, with clearance of anti- (CIDP) AQP-4Ab [75]. CIDP is an immune-mediated disease targeting Other immune-mediated neurological diseases peripheral nerves. To prevent disability, immunosup- pressive treatments should be initiated before irreversible Autoimmune encephalitis and other rare neurological axonal damage has occurred. There is limited experience diseases treated with aHSCT feature in the EBMT registry with aHSCT in CIDP with a total of 20 patients reported (see Table 2), but published reports are limited. 290 B. Sharrack et al. Systemic ADs with neurological manifestations HSCT and disease specialists. Experience is important as conditioning regimens used in aHSCT in ADs induce more In addition to autoimmune neurologic diseases, rheumatic profound immunosuppression than in haemato-oncological diseases with CNS or PNS involvement and insufficient indications due to ATG, with a higher incidence of acute response to conventional immunusuppressive or biologic reactions, viral reactivations and infections. In addition, therapies represent a growing indication for aHSCT. Where administration of DMTs before aHSCT may have an impact there is a significant or predominant neurological compo- on the graft characteristics and immune reconstitution and nent, they may be managed in neurology clinics. further studies are required. There is a need for an extended In a recently published study presenting the outcomes of competency and package of care for neurological patients, aHSCT in 30 patients with SLE, ten patients suffered from including specific pre-transplant work-up with attention to neuropsychiatric manifestations, responding to aHSCT with cardio-respiratory function, specific neurological supportive cyclophosphamide, rabbit ATG and rituximab [76]. Similar care measures, prolonged infective monitoring after the results are obtained in smaller case series, which are sum- procedure, consideration of physiotherapy/rehabilitation marised in a retrospective EBMT survey [77]. [26]. Centre experience and accreditation may improve Systemic vasculitis may have neurological manifestations. patient care and outcomes via implementation of specific Published literature on aHSCT for refractory BD with severe staff training, procedures and audit in the institutional CNS involvement includes two patients from a retrospective quality management system [21, 86]. data analysis from the EBMT registry [78] and smaller series Recommendations including one case undergoing first autologous followed by allogeneic HSCT [79]. All patients achieved complete ● aHSCT should be delivered in transplant units that remission, but one patient relapsed 2 years after HSCT. Data provide high quality care and are accredited by JACIE on Granulomatosis with Polyangiitis (formerly Wegener’s or equivalent organisations (level II). granulomatosis) with CNS involvement is limited to a single ● Units should be experienced with close collaboration case reported to the EBMT registry, which achieved a com- between HSCT and neurology specialists throughout the plete response following conditioning with Cy-ATG patient journey including medium- and long-term follow and CD34-selected aHSCT [80]. Sjogren’s syndrome, up (level II). polymyositis-dermatomyositis and refractory coeliac disease (RCD) with neuromuscular manifestations have also been treated with aHSCT with favourable responses reported Multidisciplinary teams (MDTs) and patient consent [61, 81–85]. Recommendations Any decision to proceed must assess the balance of benefits and risks particularly in terms of reversibility or stabilisation ● Patients with refractory CIDP, MG, NMO, SPS and of disability and other neurological features. Decision- systemic AD with neurological manifestations may be making requires critical multidisciplinary input from neu- considered for aHSCT (level CO/II). rology and haematology specialities and may also involve other core members, such as nursing and professions allied to medicine (PAMs). Informed consent should be obtained for all phases of aHSCT procedure the transplant procedure, A frank discussion about potential risks, including TRM risk, transient worsening General principles of function and other early and late transplant-related toxicities is an essential part of the consent process. The Centre experience and accreditation discussion should also include the risk-benefit of alter- native treatments, including DMTs. Patients with child- aHSCT is an intensive procedure with a level of immediate bearing potential should be counselled appropriately as transplant-related risks and other toxicities. Registry studies temporary or permanent ovarian/testicular failure and support a positive impact of JACIE accreditation [86] on infertility following aHSCT are known risks [87, 88]. PFS, whilst the centre experience in ADs resulted in a Fertility preservation strategies should be discussed. All statistically significant improvement of TRM/NRM, PFS patients should be invited to provide separate consent for and overall survival [15, 21]. Such improvement is likely submission of their anonymised/pseudonymised personal related to progressively improved patient selection, a dedi- data to the EBMT, or equivalent, registry in accordance cated pattern of care and the full integration between the with relevant data protection and other regulations. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 291 Transplant technique successful mobilisation. ‘Wash-out’ periods, commonly used in neurological practice for switching between A variety of transplant techniques have been used, both in DMTs, aim to reduce the risks of PML and other infec- mobilisation and conditioning (Table 3). In accordance with tions [89]. There is no consensus to support duration of previous EBMT guidelines [21, 26], two ‘intermediate- wash-out periods. The following ‘wash-outs’ are exam- intensity’ conditioning regimens have been used most ples; at least 6 weeks for dimethyl fumarate, fingolimod commonly in MS: BEAM-ATG and cyclophosphamide and natalizumab, and 6 months for alemtuzumab, ocreli- 200 mg/kg + ATG (Fig. 4). Data on transplant technique for zumab and cladribine given the more profound lympho- aHSCT in other immune-mediated neurological disorders penia and risk of infection. Accelerated elimination outside MS is limited and heterogeneous. should be considered in patients on teriflunomide (https://www.aubagiohcp.com/content/pdf/drug_elimina Pre-transplant ‘wash-out’ tion_guide.pdf). No wash-out is necessary for interferon and glatiramer acetate. There have been no reports of Prior to mobilisation, DMTs and other immunomodula- PML following aHSCT in current EBMT registry data, tory drugs should be discontinued as early as possible, but CSF JCV-PCR should be done on patients transi- which may help minimise risks and inhibitory effects on tioning from natalizumab if they have high JCV antibody Table 3 Categorisation of conditioning regimens used for autologous HSCT, with examples used in MS and other immune-mediated neurological diseases [20, 21, 26] Intensity Examples of conditioning regimens High Total body irradiation (TBI), cyclophosphamide and ATG Busulfan, cyclophosphamide and ATG (BuCyATG) Intermediate (myeloablative) Carmustine (BiCNU) 300 mg/m2, etoposide 800 mg/m2, cytarabine arabinoside 800 mg/m2 and melphalan 140 mg/m2 (BEAM, with total doses of chemotherapy provided) and ATG (‘BEAM-ATG’) Intermediate (lymphoablative/non- Cyclophosphamide 200 mg/Kg and rabbit ATG (Cy-ATG) myeloablative) Low Chemotherapy onlya regimens e.g. single agent cyclophosphamide 100 mg/kg for mobilisation and repeated 100 mg/kg for conditioning (without rituximab) [96, 97] Please note doses are examples and the authors do not take responsibility for drug and doses administered, which lies with individual authorised prescribers in HSCT units. Doses and types of ATG vary between published regimens a Addition of serotherapy (i.e. antibody therapy) to chemotherapy renders the regimen ‘intermediate-intensity’) 120 100 BEAM+ATG Cyclophosphamide +ATG 80 Auto-HSCT 60 40 20 0 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 Year Fig. 4 Trends in transplant conditioning used for autologous HSCT in Multiple Sclerosis: BEAM-ATG versus Cy-ATG (EBMT Registry 1995–2018) 292 B. Sharrack et al. Index. Steroid pulses may be used to reduce the risk of [21, 26]. Higher intensity regimens, such as the ‘BuCy- relapses during the wash-out period. ATG’ regimen, are efficacious but have been associated with potentially serious side effects, including veno- Peripheral blood stem cell [PBSC] mobilisation and occlusive disease [34]. TBI, with its greater short and leukapheresis long-term risks, including infections, secondary malig- nancies, NRM and EDSS progression possibly due to Most patients treated for AD have received priming doses radiation neurotoxicity, is now rarely used, if at all, and was of cyclophosphamide of 2–4.5 g/m2 with uromixetan reported as ineffective in advanced MS [94]. Regimens of a (Mesna) and/or cautious hyperhydration followed by G- lower intensity such as cyclophosphamide 120 mg/kg with CSF 5–10 μg/kg prior to leukapheresis [26, 29–38, 41]. ATG seem to be associated with an increased rate of relapse Administration of G-CSF alone may induce disease flare, [95]. There is experience in Mexico of a low-intensity but its combined administration with ‘priming’ che- regimen where cyclophosphamide at 100 mg/kg has been motherapy usually prevents flares, reduces T-cell numbers used prior to re-infusion with unfrozen PBSC, with and in the graft and improves PBSC yields [90]. There are no without post-transplant rituximab. However, long-term data in terms of efficacy, but cyclophosphamide at a dose of outcome data are limited [96, 97]. 2 g/m2 is likely to be safer than higher doses but potentially Since the publication of the EBMT 2012 guidelines [26], less effective in terms of both mobilisation potential and there has been an increase in the use of Cy-ATG regimen in disease control. The procedure can usually be carried out as MS whilst BEAM-ATG usage has also been maintained an outpatient regimen, but in disabled patients hospital (Fig. 4). At present, there is no comparative data as to the admission may be considered. The need for repeat harvest relative efficacy and safety of these two most commonly appears to be rare, with little data to support the need for used intermediate-intensity conditioning regimens. There- off-licence use of plerixafor. fore, EBMT guidelines advocate using either of these two In line with EBMT recommendations, the minimum dose regimens for MS. The question of relative safety and of CD34+ cells for re-infusion is 2.0 × 106/kg, although efficacy between these two intermediate treatment regimens other generic recommendations have proposed 4−5 × 106/ may be resolved through an ongoing EBMT registry kg as the optimal dose [91, 92]. Considering that MS and analysis. neurological disorders are non-malignant indications, it With respect to T-cell depleting serotherapy, the majority would be pragmatic to aim for 5 × 106/kg as an optimal of MS patients have been treated with rabbit ATG (rATG) target before freezing, with 2.0 × 106/kg as a minimum from various sources (Thymoglobulin/Sanofi-Genzyme and safety threshold. Doses higher than 8 × 106/kg are unlikely Grafalon/Neovii). Despite potential immunomodulatory to improve the rate of engraftment and have a theoretical advantages in non-transplant settings [98], the use of horse- risk of increased T cell contamination of the graft. ATG (hATG) has been limited compared with rATG and Neurological patients undergoing mobilisation are at risk associated with a greater level of toxicity in one early study of febrile neutropenia during mobilisation, and, if fever running from 2001–2006 [99]. However, in a more recent occurs, there may be a related transient worsening of neu- study the safety of a specific type of hATG (ATGAM, rological function, referred to as the Uhthoff phenomenon Pfizer) was assured with outcomes comparable to recent [93]. Oral antibiotic prophylaxis should be considered with data using rATG [100]. The choice of type and dose of a rapid pathway for hospital readmission and treatment of rATG depend on availability and centre preference, but fever including use of steroids. Where disability precludes in the published literature has been most commonly poly- rapid readmission, patients can be hospitalised for the clonal rATG of Thymoglobulin type given in dose range of mobilisation phase. 5–7.5 mg/kg. Higher serum levels and type of ATG have been linked with infection and other outcomes in allogeneic Conditioning regimens HSCT [101–103] and non-transplant aplastic anaemia [104] settings, but this has not been systematically investigated in Previous EBMT ADWP recommendations recommended relation to aHSCT for ADs. Other forms of serotherapy, the use of ‘intermediate intensity’ regimens namely cyclo- such as alemtuzumab, have been used, although data sug- phosphamide 200 mg/kg with T-cell depleting serotherapy gest a higher rate of complications including secondary (most commonly ATG) as a generic regimen across ADs, autoimmunity [33]. Given the heterogeneity of types of and, for MS, ‘BEAM-ATG’, was specifically recommended ATG and other serotherapy, further evaluation of their use (Table 3) [26]. The use of ‘high-intensity’ regimens in conditioning regimens is urgently warranted. including TBI or busulfan was not recommended on Although HSCT units are likely to be experienced in grounds of short and long-term toxicity, whilst the ‘low- the administration of ATG, it requires special attention intensity’ regimens were considered to be less efficacious given the potential for severe allergic-type reactions. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 293 These risks can be minimised with pre-medication con- infection, but also a risk of retaining cyclophosphamide sisting of antihistamines, paracetamol and steroids along metabolite, acrolein, which may cause haemorrhagic with consideration of graduated dosing regimens and cystitis. All patients should be assessed for residual slow infusion rates. Varying doses of methylprednisolone volume with ultrasound and, if necessary, a urinary (up to 1000mg [41]) have been used as pre-medication, catheter should be in situ for the period of cyclo- but a minimum of methylprednisolone 2 mg/kg intrave- sphophamide administration. This should be accompanied nously is recommended with a sufficient time interval by uromixetan (Mesna) as per departmental standard (e.g. 30–60 min) before the start of the ATG infusion. As operating procedures. Patients with long-term indwelling there is ongoing risk of ATG-related fever and other catheters should be managed appropriately, with vigilance reactions after the infusion a tapering dose of oral or for the higher level of infection risk. intravenous steroid is often used routinely, with break- Occurrence of fever may affect the physical and mental through febrile or other episodes treated with additional state of the patient, and increase nursing needs to a greater pulses of intravenous methylprednisolone (e.g. 250 mg) degree in MS than in most other febrile transplant patients. whilst ensuring that infection is fully covered. Causes include ATG reactions, sepsis, urinary infections and viral reactivations. Fever of any type may temporarily com- CD34+ selection and other graft manipulation promise neurological function, referred to as the Uhthoff phenomenon [93], and sustained fever during the transplant The question of graft manipulation is unclear and is period have been reported to affect long term efficacy [33]. confounded with inevitable but unquantifiable degree of Fever should be pro-actively managed appropriate to the in vivo depletion of T cells and other immune effector clinical picture to induce rapid defervescence. cells when ATG is included in the conditioning regimen. Vitamin D may have an impact on health and immune In MS, both unmanipulated and manipulated autologous responses in MS and HSCT, and, given that patients are grafts have been used. CD34+ selection has featured in hospitalised during HSCT, routine supplementation should some clinical trials, including in combination with the be considered [106]. higher intensity BuCy-ATG regimen. Whether this con- Assessment and planning for rehabilitation should be tributes to the reported benefits and toxicity is unclear. An performed prior to the transplant, for both the inevitable EBMT retrospective analysis failed to show benefit of deconditioning effect of the aHSCT procedure and specific to graft manipulation in MS [105], and use in most other neurological function of the patient. This area is currently the ADs [26]. Moreover, CD34+ selection may be associated subject of a detailed EBMT ADWP review and guidance. with excess infection and the selection procedure adds Recommendations significantly to the costs and logistics of aHSCT. In the absence of firm evidence of benefit, the recommendation ● All patients should be discussed within a MDT is that CD34+ selection or other graft manipulation is not (level III). used outside a clinical trial setting in MS and other neu- ● Informed written consent, including discussions regard- rological diseases. ing alternative therapeutic options, should be obtained in accordance with national and local regulatory and legal Supportive care, nursing and rehabilitation aspects requirements (level III). ● Cyclophosphamide 2 g/m2 and G-CSF 5–10 μg/kg are Most patients have nursing and supportive care (including recommended for mobilisation as they are likely to be transfusion) requirements common to patients undergoing sufficient for successful mobilisation, prevent flare and aHSCT for other indications. The main difference in be potentially safer than higher doses (level II). patients is the degree of baseline disability. In addition, the ● For leukapheresis, an optimal target CD34+ cell dose is administration of conditioning chemotherapy and ATG with 5 × 106/kg before freezing, with 2 × 106/kg as a mini- high-dose steroids and hyperhydration in most regimens mum safety threshold (level II). requires close inpatient observations, including fluid and ● For conditioning, the use of ‘intermediate-intensity’ electrolyte balance. Twice-daily weighing is recommended. regimens namely cyclophosphamide 200 mg/kg + ATG As some neurology patients are prone to seizures, some or ‘BEAM-ATG’ is recommended (level II). units incorporate prophylaxis against seizures during con- ● The use of ‘high-intensity’ regimens, including TBI or ditioning. The risk of potential physical and psychological busulfan, should be restricted to study protocols in side effects of high-dose steroids should be highlighted to highly selected patients (level II). both patients and nursing staff. ● De-escalated regimens may be less efficacious, but the Urinary bladder dysfunction is common in MS, and balance of benefits and risks of such regimens should be residual volumes of urine represent not only a risk of established with clinical trials (level II). 294 B. Sharrack et al. ● In the absence of high quality data in other immune- recommended on a 3-monthly basis in the first year and then mediated neurological diseases, aHSCT technique should annually in order to guide infection prophylaxis and detect reflect the practice in MS depending on the experience of paraproteinaemia [110]. the transplant unit i.e. use of the EBMT recommended Transient alopecia and amenorrhoea are common adverse ‘generic’ regimen of cyclophosphamide 200 mg/kg + effects, but menstrual function may recover especially in ATG or BEAM-ATG (choice depending on the experi- younger patients (<30 years of age) [88]. Haemorrhagic ence of the transplant unit) with the addition of B-cell complications (e.g. gastrointestinal bleeding, hemorrhagic depleting monoclonal antibodies (such as rituximab) when cystitis) have been reported. the disease origin includes a relevant antibody-mediated component (level II). Late effects/long-term complications ● In the absence of firm evidence of benefit, CD34 + selection or other graft manipulation should not be used International guidelines and recommendations cover outside a clinical trial setting (level II). screening and management of ‘late effects’ following ● Teams should be trained and competent with manage- HSCT [107, 111]. Late effects following aHSCT may ment of complications of the transplant regimen used in result from the transplant regimen and altered post- MS and other immune-mediated neurological diseases, transplant immune reconstitution, but may also be driven including administration of and reactions to ATG and by pre-treatment of the underlying neurological disease. prevention and prompt management of fever in this Since 2012 ‘late effects’ follow-up has been highlighted in context (level III). the EBMT ADWP guidelines [26], but limited data is ● Given the deconditioning effect of the aHSCT procedure available on the frequency and nature of late effects fol- combined with neurological disability highlight rehabi- lowing aHSCT above what would be expected in the litation requirements should be assessed before and general population, and also what would be expected in the during the transplant admission and in place at the time MS population treated with DMTs [44, 112]. Impact on of discharge (level III). gonadal function and fertility should have been covered counselling related to the informed consent process, but should be revisited in routine follow-up of late effects [87, 88]. Other recognised late effects include secondary Early and late post-transplant follow up autoimmunity (up to 10%) either de novo or within the spectrum of the original AD [41, 113–115], endocrino- aHSCT may be associated with both early and late com- pathy [33, 41] and late cancers [15, 35]. Concurrent AD is plications or late effects [26, 107]. not infrequent and an appropriate screening (e.g. thyroid function) at baseline is mandatory. Although data are Post-discharge monitoring and early post-transplant limited, the risk of PML appears low, with no current complications reports post-aHSCT, including in over 1400 patients trea- ted for MS in the EBMT registry despite the frequent use of The use of aHSCT in neurological disorders has key differ- DMTs prior to transplantation (Table 1). Late effects are ences compared to other common indications, notably related the subject of ongoing EBMT retrospective studies, but in to the neurological condition themselves and degree of the meantime, it is important that systematic screening is immunosuppression [108]. Post-discharge monitoring is pre- undertaken in accordance with current recommendations dominantly focused on infection in the first months after for late effects [26, 107]. aHSCT with prophylaxis as per centre protocols akin to allo- HSCT recommended. Generally oral prophylaxis should Post-transplant vaccinations cover fungal infections (with an azole) for 3 months and herpes virus (with aciclovir) and pneumocystis infection for a Vaccination post-HSCT is a balance between reducing the minimum of 6 months post-aHSCT, with many units risk of infection but comes with a theoretical risk of trig- extending to 12 months. Viral reactivation is important so gering immune events, which is a concern in the setting of PCR-based EBV/CMV monitoring is mandated during first ADs [116, 117]. Vaccination practice varies [118], but in 100 days. CMV re-activation occurs at a greater rate and cases general, only vaccinations with live attenuated viruses are of CMV infection have been reported. EBV reactivation considered to pose a higher risk of inducing a relapse of usually resolves spontaneously, but may need treatment with MS, and these are generally avoided in routine post- rituximab and may be associated with neurological events and transplant vaccination schedules. However, there is no de-novo paraproteinemia [109]. Immune monitoring of T- and clear-cut data to support the reactivation of MS or other B-cell subsets and immunoglobulin levels/electropheresis is ADs following aHSCT and therefore CIBMTR-EBMT, Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 295 IDSA and ECIL recommendations should be followed with in order to guide infection prophylaxis and detect a case-by-case discussion with patients [107, 117, 119]. paraproteinaemia (level II). Measurements of specific antibody titres may be helpful in ● Centres should ensure systems are in place to provide deciding whether to vaccinate or not [117]. A standard-of- long-term follow-up. Annual simultaneous follow-up care post-transplant routine vaccination programme may be consultation of the neurology and HSCT specialists is based on IDSA and ECIL guidelines as follows: pneumo- recommended. If patients are discharged from the coccal conjugate vaccine at 3, 4 and 5 months, followed by transplant centre for medium- and long-term follow-up conjugate HIB, DTP and inactivated polio vaccine at 6, 7 under the referring neurologist, annual follow-up should and 8 months and pneumococcal polysaccharide vaccine at be a standard of care and the contact details should be 1 year. Later patients who are not on immunosuppressive made available to transplant centre data managers and/or therapy (e.g. for relapse) should have serology for measles the registry (level III). and varicella tested at 24 months and those who are nega- ● Patients who develop recurrence of disease activity after tive should be immunised with two doses of MMR and aHSCT should be managed on an individual case basis. varicella vaccine at least 4 weeks apart as per routine In general, assessment of risk:benefit, including cumu- practice. Patients should also have an annual Influenza lative toxicities of new and re-introduced DMTs should vaccine. a consideration (level III). Neurological follow-up and management of disease activity post-transplant Mechanisms of action The disease course after aHSCT should be monitored by aHSCT is performed with the premise to reconstitute, and regular neurological follow-up, with clinical assessments, ideally re-condition, the immune system towards a self- imaging and immune markers in blood or cerebrospinal fluid tolerant state by depleting the autoreactive immunologic (CSF) appropriate to the disease. In MS, NEDA can be memory with high-dose chemotherapy followed by a pro- assessed based on the clinical assessment and Gd enhanced found regeneration of a renewed and diverse immune sys- MRI of brain and/or spine, which is required at regular tem, i.e. ‘immune reset’ [120–123]. intervals post-transplant (at 6 months post-transplant and In MS, a range of mechanistic studies post-transplant have yearly afterwards). Ongoing rehabilitation and other symp- shown that the T-cell repertoire, particularly of CD4+ T cells, tomatic care should be provided as appropriate. Currently, may be almost completely renewed, its diversity increased there is no consensus about the management of patients who and that new thymic output of T cells is achieved following develop disease activity after aHSCT, including re-introduced aHSCT [124]. The analysis of TCR repertoires by deep DMTs and second aHSCT. sequencing confirms that aHSCT induces the regeneration of Recommendations circulating T-cell clones, more profoundly in the CD4+ T helper cell compartment [125]. Early post-transplant T-cell ● Post-discharge monitoring should be primarily focused repertoire diversity is associated with complete clinical on prophylaxis and management of infection in the first responses during the 5-year follow-up [35, 125]. 3–6 months after aHSCT. Antibiotic prophylaxis should Other studies examined proinflammatory T-cell effector be given as per centre protocols, but generally oral responses specifically, including Th17 cell frequency, the prophylaxis should cover fungal infections (with an mRNA expression of their master regulator ROR[gamma]t azole) for 3 months and herpes virus (with aciclovir) and and the production of the inflammatory cytokine IL-17A all pneumocystis infection for a minimum of 6–12 months decreased post-HSCT [126]. Several additional immune post-HSCT (level III). mechanisms that may contribute to the efficacy of ● PCR-based CMV monitoring is recommended during aHSCT in MS have include depletion of peripheral blood first 100 days post-HSCT and re-activations should be mucosal-associated invariant T (MAIT) cells, decrease of treated according to institutional protocols, similar to MS-associated inflammatory micro RNAs (miR-155, miR- allogeneic HSCT practice (level III). 142-3p, miR-16), along with increased immune T and NK ● PCR-based EBV monitoring is recommended during regulatory cells and increased expression of immune first 100 days post-HSCT and reactivations managed checkpoint receptors and regulatory molecules such as PD- with imaging and LDH, with rituximab considered on an 1, CTLA-4, GITR and TGF-b1 [127]. individual basis (level III). Other neuroinflammatory diseases have not been studied ● Immune monitoring of T- and B-cell subsets and to any significant extent in the context of immune recon- immunoglobulin levels/electropheresis is recommended stitution and further research is warranted. The collection of on a 3-monthly basis in the first year and then annually cellular, serum, plasma and CSF samples at baseline, during 296 B. Sharrack et al. the immunosuppression-free remission and at relapse/pro- the potential to neuroprotect and foster remyelination gression for mechanistic and pathogenetic studies in endogenous neurogenesis and differentiation in neural cells accordance with regulatory requirements for tissue banking [132]. Since 2007, over 15 small studies exploring the and ADWP guidelines is recommended [110]. feasibility and safety of MSC transplantation in multiple Recommendations sclerosis have been published [133]. These studies involved differing patient populations, cell products and routes of ● Systems for biobanking should be developed alongside administration. All were underpowered for drawing con- clinical trials, routine treatments and registry data in clusions on efficacy but reported an overall favourable order to support mechanistic and pathogenetic studies in safety profile. The results of two more similar studies MS and neuroinflammatory diseases (level III). (ACTiMuS, SIAMMS-II) are awaited and a larger rando- mised, double blind, cross-over phase I/II clinical trial (MESEMS) is ongoing [134–136]. Haematopoietic stem Developmental indications: allogeneic HSCT cells genetically manipulated to induce self-tolerance and cell therapy in immune-mediated against myelin epitopes have also been explored [137], neurological diseases which may have potential at improving long term remis- sions following aHSCT. Non-HSCT cell therapies for ADs Allogeneic HSCT should be considered a developmental indication as there limited evidence to support administration outside a clinical Allogeneic HSCT represents an attractive option for patients trial. Generally, there is a need to safeguard vulnerable with refractory ADs, offering the advantage of complete patients against unjustified hope whilst promoting further eradication of autoreactive cells combined with the regen- clinical trials and basic research [28]. Centres should be eration of a healthy immune system tolerant to autoantigens. accredited according to appropriate JACIE standards relat- However, because of its significantly higher level of NRM ing to immune effector cell (IEC) therapies [86]. risk, allo-HSCT has rarely been used in the treatment of ADs Recommendations [21, 24, 26, 128]. Only anecdotal data are available to date for allo-HSCT in neuroinflammatory ADs, notably severe NMO, ● Routine treatment with MSC and other cell therapy is where sustained clinical benefit with resolution of detectable not recommended as there is insufficient evidence as to anti-AQP-4Ab has been reported [129]. safety and efficacy in both the inflammatory and Major changes have occurred in the field of allo-HSCT progressive phases of MS (level III). [130, 131] including targetted reduced-intensity condition- ● Patients with MS and other immune-mediated neurolo- ing and post-transplant tolerising regimens, improved gical disorders should only be treated with MSCs in patient and donor selection and better supportive care open clinical trials. Centres should be accredited according to up the use of alloHSCT in ADs. Further clinical studies appropriate JACIE standards relating to immune effector with these modern approaches are warranted. cell therapies (level III). Recommendations ● Centres performing allogeneic HSCT should have Future development of HSCT in MS and appropriate experience and JACIE accreditation or neuroinflammatory diseases equivalent (level II). ● Allogeneic HSCT for immune-mediated neurological Data reporting to the EBMT Registry diseases is developmental and ideally should be performed in a prospective clinical study (level III). Data reporting to the EBMT Registry (and equivalent ● In the absence of data, conditioning regimens and other international registries) has been fundamental to building allogeneic HSCT technique should reflect the practice in the knowledge base of HSCT in AD and providing the basis other non-malignant diseases (level III). for prospective studies [21, 26]. A major upgrade of the EBMT Registry across all indications is centred around a mandatory core dataset maximising capture of essential data Mesenchymal Stromal Cells (MSC) and other defining the patient, procedure, disease, risks and donor experimental cellular therapies (if relevant), key time points and events required for risk stratification and benchmarking of outcomes. Alongside the A range of pre-clinical data and early phase trials provide core dataset, a modular system is available for defined support for mesenchymal stromal cells derived from auto- projects attempting to address strategic research questions logous and allogeneic sources as immunomodulators with generated by the EBMT scientific council, working parties Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 297 or other working groups. Modules can be used for retro- Given the growing evidence that an early therapy spective data or prospective non-interventional studies. In escalation in aggressive forms may prevent both the addition, developments should facilitate the incorporation development of severe disability and the shift towards the of non-HSCT treatments with the potential for direct data progressive phase through the permanent abrogation of reporting from neurologists and other disease specialists. inflammatory activity in the CNS, a reliable assessment of All of these aspects are especially relevant for HSCT in MS treatment response must include both clinical and radi- and other immune-related neurological diseases diseases ological metrics, as combined in ‘NEDA’ status [8]. Rate of where the timelines for development of clinical manifesta- NEDA in a set of patients at a given time from the treatment tions, particularly evolution of disability, are often long, and start and/or time to maintain a NEDA status are currently evaluation of late effects may take many years. considered the most reliable assessment of treatment effi- Transplant centre data managers are generally less cacy in MS and should be considered in any HSCT trial familiar with ADs, and many patients are seen in depart- [39, 40]. Improvement in EDSS is an endpoint that has been ments outside the transplant centre. Complete data regis- increasingly used for aggressive therapies in MS and should tration has proven more challenging for ADs than standard be included among the endpoints to assess aHSCT, taking haematological and oncological indications for HSCT. Data into account not only the magnitude of improvement levels managers should be adequately trained and supervised by but also its durability. relevant HSCT and neurological specialists and ideally In addition, validated health-related quality-of-life and neurological data reporting should be integrated by the neuropsychological instruments are important and easily referring neurologist and their teams. If aHSCT is to be achievable endpoints. Brain volume loss, optical coherence integrated into neurological care pathways, it is vital that tomography (OCT), corneal confocal microscopy and PET efficacy and safety are monitored as robustly as possible via imaging may increasingly provide more sophisticated means HSCT centres or collaborating neurologists over the long- of quantifying efficacy in the clinical trial setting. Alongside term. Aligning clinical databases with biobanked samples efficacy, there is the question of the risks of late effects of will allow greater understanding of mechanisms of action aHSCT compared with modern DMTs, several of which may and improved risk stratification of patients. have been administered to patients prior to transplant. Recommendations RCTs are the best means to establish the safety and efficacy of aHSCT versus alternative ‘standard of care’. ● Data relating to HSCT in MS and other neuroinflamma- Although this approach may be feasible for aHSCT in MS, tory diseases should be routinely reported to EBMT or there will always be the challenge of ‘standard of care’ equivalent registry (level III). evolving as new DMTs emerge, especially if recruitment is ● Data managers should be adequately trained and slow. This was an issue in the MIST trial, where alemtu- supervised by relevant HSCT and neurological specia- zumab became a standard of care in the years taken to lists (level III). complete recruitment for the trial [41, 138] and now ocre- ● Systems for biobanking should be developed alongside lizumab and cladribine currently provide similar competi- clinical trials and registry data (level III). tion for ongoing studies. In the rarer immune-mediated neurological disease indications RCTs are unlikely to be feasible, and other clinical trial designs may be more Statistical considerations for clinical studies appropriate and ongoing retrospective studies and pro- spective non-interventional studies based around the EBMT Statistical approaches commonly used in other areas of registry (which is generally limited to patients receiving HSCT practice are less easily applied to prospective clinical HSCT, making comparison with standard of care difficult) trials and retrospective studies in MS, where it is important along with other neurologically based registries, such as to define appropriate target endpoints to assess the response MSBase, may provide meaningful clinical data via pro- to administered treatments, whether they are HSCT or other spective cohort studies and case-control studies. The potent treatments. Fortunately, overall survival (OS) is high recognition of potential bias and adjustment for all potential and all-cause mortality (including NRM) is rare following prognostic factors is essential in any non-randomised setting aHSCT. However, concepts of NRM, PFS and OS are in order to accommodate inevitable confounding factors and commonly used in HSCT but are unusual to neurologists. selection bias in choosing aHSCT over another treatment. Moreover, relapses independent of disease progression do Recommendations not always represent a treatment failure. Progression of disability can be related to an advanced stage of the disease ● Where feasible, HSCT for MS and other immune- at HSCT and should not be considered as a treatment failure mediated neurological diseases should be offered in a if not associated with recurrence of neuroinflammation. clinical trial (level III). 298 B. Sharrack et al. ● In any study of MS and other immune-mediated Clinical trials of aHSCT in MS neurological diseases, well-defined and validated para- meters should be used to define response, progression While it is now clear that clinical and MRI activity in and remission. For MS, the NEDA status is appropriate patients with highly active RRMS may be suppressed with for this purpose and feasibly collected alongside other the use of aHSCT in a sustained manner, there remains a transplant data in the EBMT Registry (level III). need for comparative studies that randomise patients to ● Magnitude and durability of EDSS improvement should aHSCT versus other high-efficacy therapies, particularly the be included as an endpoint for evaluating aHSCT in MS more recently introduced alemtuzumab, ocrelizumab and (level III). cladribine, where there are highly relevant research ques- ● Prospective non-interventional studies provide an alter- tions regarding relative reported rates of NEDA, albeit native and pragmatic means of increasing clinical across prospective trials in RR-MS with varying eligibility knowledge, while eliminating bias associated with criteria, as summarised in Table 4. Current clinical trials, retrospective studies (level III). designed with a view to answer these and other questions, ● Although prospective studies are preferred, significant are summarised in Table 5. challenges should be recognised in their application to Another question is to whether aHSCT may offer benefit HSCT especially in the rare immune-mediated neurolo- for the progressive forms of MS, which may continue to gical diseases. When clinical trials are not available then have elements of ongoing and resistant neuroinflammation. patient data should be sent to EBMT (or equivalent) In the last two decades, a large number of patients with registry (level III). progressive disease have been treated with aHSCT and there Table 4 Mechanism of action and the relative rates of NEDA in prospective trials of high efficacy DMTs and autologous HSCT in RRMS Therapeutic Mechanism of action Rate of NEDA Ref Alemtuzumab Anti-CD52 monoclonal antibody 39–32% at 2 years [44, 138, 142] Ocrelizumab Anti-CD20 monoclonal antibody 48% at 96 weeks [143] Cladribine Synthetic deoxyadenosine analogue 47% at 96 weeks [144] Autologous HSCT with intermediate- Immune ablation and reconstitution Cy-ATG 93.3%, median follow up [33] intensity conditioning (with unmanipulated graft) 2 years BEAM-ATG (with CD34+ selected graft) 69.2% (EFS), median follow [35] up 5 years The trials differ in eligibility criteria and design, including prior DMT treatment and disease activity at study entry. The reader is referred to the original publications for more detailed comparison Table 5 Currently active clinical trials of autologous HSCT in MS Trial/identifier Description Centres/countries RAM-MS NCT03477500 Phase III RCT of autologous HSCT (Cy-ATG) versus alemtuzumab (later extended to Scandanavia, ocrelizumab and cladribine) Netherlands STAR-MS Phase III RCT of autologous HSCT (Cy-ATG) versus alemtuzumab or ocrelizumab UK BEAT-MS Phase III RCT of autologous HSCT (BEAM-ATG) versus standard of care US predominantly (NIH-led) MOST NCT03342638 Phase III RCT of autologous HSCT regimen (Cy-ATG versus Cy-ATG + intravenous Northwestern immunoglobulin) University, US COAST Phase II RCT of autologous HSCT (Cy-ATG) versus ocrelizumab or alemtuzumab Germany NET-MS (Italian Phase II RCTof autologous HSCT (BEAM-ATG) versus best available DMT Italy collaborative) Swiss aHSCT Open study of autologous hematopoietic stem cell transplantation in patients with RRMS University Hospital Registry Study and progressive forms of MS (5 year duration) Zurich, Switzerland Mexican open label study Outpatient Hematopoietic Grafting in Patients With Multiple Sclerosis Employing Clinica Ruiz, NCT02674217 Autologous Non-cryopreserved Peripheral Blood Stem Cells: A Feasibility Study Puebla, Mexico Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis. . . 299 is some evidence for reduced relapse rates and clinical the safe delivery of aHSCT with long-term clinical and MRI stabilisation, but it is difficult to interpret these studies due remissions observed in a majority of patients (S/I). In pro- to the lack of control groups [15, 16, 20, 31, 38, 47]. Further gressive MS and other neuroinflammatory indications data RCTs are required to assess the therapeutic benefit of are heterogeneous (CO/II) and aHSCT should be delivered aHSCT in SPMS and PPMS with evidence of significant on a clinical trial, if available. The evidence for allogeneic inflammation. HSCT is developmental (D/III). There is a need for clinical trials across all settings. Public health system delivery of HSCT in MS and Close co-operation between HSCT and neurological immune-mediated neurological diseases specialists in MS and neuroinflammation is critical. In addition to EBMT and national societies, the support of At a public health level, economic evaluation is a central national and international MS and neurological societies is consideration in delivering aHSCT for MS and neuroin- also essential to achieve education, and ultimately accep- flammatry diseases. MS results in a large burden on both the tance and implementation of this one-off intensive health and social care systems as well as the wider exche- approach to MS and other immune-related neurological quer. The costs incurred range from direct costs related to diseases. Patient groups, such as the EBMT Patient treatment with DMTs, but also reduces long-term quality of Advocacy Committee and national MS and other patient life and leads to unemployment, progressive disability and associations are also important. Centres of specialisation eventually dependency, high rates of unemployment with and experience will be required to support others in substantial impact on the affected individual and their carers bringing HSCT appropriately into neurological clinical with reduced quality of life and on the health care service. practice alongside modern DMTs. Standardisation of Compared with ongoing repeated treatments with modern practice will assist the support that experienced units can DMTs, aHSCT is a ‘one-off’ treatment, for which, ther- provide to less experienced units. At a public health level, apeutic benefits last for many years in appropriately selected health economic evaluations will be necessary to support patients. Favourable cost-effectiveness ratio in MS patients decision making and optimise equitable access to showing a sustained response to HSCT over some DMTs evidence-based treatments in publically-funded and pri- has been reported [139–141]. However, for accurate and up- vate healthcare systems [21, 28]. to-date evaluations, health economic evaluation should be combined with prospective clinical trials. There is great Acknowledgements We acknowledge EBMT centres, their data managers and patients for contributing registry data. We thank Daniele variability in funding for aHSCT in MS and other ADs Swain for support with referencing. across EBMT countries, and further evaluations are needed to provide equitable access according to clinical benefit as The EBMT JACIE Committee included: John Snowden (Chair), close to patients’ homes as feasible. Riccardo Saccardi, Eoin McGrath, Franco Bambi, Fermín Sanchez- Recommendations Guijo, Nina Worel. The EBMT Autoimmune Diseases Working Party (ADWP) included: John Snowden (Chair), Tobias Alex- ander (Secretary), Manuela Badoglio (Study Coordinator), Myriam ● Health economic evaluations are central to informing the Labopin (Statistician) and actively participating clinicians; Mario effective delivery of HSCT for MS and other neurolo- Abinun, Renate Arnold, Charlotte Brierley, Joachim Burman, Cristina gical disorders across various health services (level III). Castilla-Llorente, Nichola Cooper, Thomas Daikeler, Nicoletta del Papa, Dominique Farge, Jurgen Finke, Raffaella Greco, Hans Hag- ● Engagement with public health authorities and other glund, Joerg Henes, Falk Hiepe, Helen Jessop, David Kiely, Majid payers is essential across health services, enabling Kazmi, Kirill Kirgizov, Gianluigi Mancardi, Zora Marjanovic, Roland treatment and coordination of early- and long-term Martin, Thierry Martin, David Ma, John Moore, Paul Miller, Paolo follow up as close to patients’ homes as feasible Muraro, Maria-Carolina Oliveira, Alexey Polushin, Francesco Onida, Belinda Simoes, Mathieu Puyade, Igor Resnick, Montserrat Rovira, (level III). Riccardo Saccardi, Muhammad Saif, Ioanna Sakellari, Basil Sharrack, Emilian Snarski, Hans Ulrich Scherer, Claudia Sossa, Jeska de Vries- Bouwstra, Nico Wulffraat, Eleanora Zaccara. Conclusions 22 Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 23Haematology Department, Careggi We have reviewed the evidence for aHSCT for a range of University Hospital, Florence, Italy; 24EBMT Executive Office, immune-mediated neurological diseases which may respond Barcelona, Spain; 25Ospedale Pediatrico, Azienda Ospedaliero to aHSCT when other standard treatments have failed, or Universitaria Meyer (A.O.U. Meyer), Florence, Italy; 26IBSAL, are deemed likely to fail because of poor-prognostic fea- Hospital Universitario de Salamanca, Salamanca, Spain; 27Blood Group Serology and Transfusion Medicine, Medical University of tures. The evidence for effectiveness is highest in highly Vienna, Vienna, Austria; 28Department of Haematology, active RRMS where there is growing evidence from large Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 29 registry studies and a prospective phase III RCT supporting Klinik fur Rheumatologie und Klinische Immunologie, 300 B. Sharrack et al. Charite-Universitatsmedizin, Berlin, Germany; 30Great North Chil- Compliance with ethical standards dren’s Hospital, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 31Department of Haematology, Oncology Competing interests JAS declares speaker fees at educational events and Tumor Immunology, Charité Universitätsmedizin Berlin, supported by Sanofi, Janssen, Jazz, Mallinckrodt and Gilead, is a Berlin, Germany; 32Department of Haematology, Oxford University member of a trial IDMC for Kiadis Pharma and Chairs NHS England Hospitals NHS Foundation Trust, Oxford, UK; 33Unité de transplan- Clinical Reference Group (CRG) for Blood and Marrow Transplan- tation des cellules souches, Département d’Hématologie Gustave tation. RM has received personal remuneration for advisory functions Roussy, Villejuif, France; 34Department of Haematology, Hammer- and presentations by Merck, Teva, Sanofi, Novartis, Roche, Biogen, smith Hospital, Imperial College Health Care NHS Trust, Cell Protect and Neuway Pharma. He is a co-founder and co-owner of London, UK; 35University and University Hospital of Basel, Depart- Cellerys. PAM reports personal fees and non-financial support from ment of Rheumatology, Basel, Switzerland; 36Osp. G. Pini, Depart- Bayer, Biogen, Merck and Novartis, unrelated to the manuscript. ment of Rheumatology, Milan, Italy; 37Unité de Médecine Interne: PAM, BS and JS are grateful for support from the UK NIHR EME and Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Hôpital St- Biomedical Research Centre funding schemes. The other authors Louis, AP-HP, Paris, France; 38Centre de Référence des Maladies declare no competing interests. Auto-Immunes Systémiques Rares d’Ile-de-France, Filière FAI2R, Paris, France; 39EA 3518, Université Denis Diderot, Paris, France; 40 Publisher’s note Springer Nature remains neutral with regard to Department of Medicine-Hematology and Oncology, University of jurisdictional claims in published maps and institutional affiliations. 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Affiliations Basil Sharrack1,2 Riccardo Saccardi3 Tobias Alexander4 Manuela Badoglio 5 Joachim Burman 6 ● ● ● ● ● Dominique Farge 7,8,9,10 Raffaella Greco11 Helen Jessop12 Majid Kazmi13 Kirill Kirgizov14 Myriam Labopin5 ● ● ● ● ● ● Gianluigi Mancardi15 Roland Martin 16 John Moore17 Paolo A. Muraro 18 Montserrat Rovira19 ● ● ● ● ● Maria Pia Sormani20,21 John A. Snowden 12 for the 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) John Snowden22 Riccardo Saccardi23 Eoin McGrath24 ● ● ● ● Franco Bambi25 Fermín Sanchez-Guijo26 Nina Worel27 John Snowden28 Tobias Alexander29 ● ● ● ● ● Manuela Badolglio5 Mario Abinun30 Renate Arnold31 Charlotte Brierley32 Joachim Burman6 ● ● ● ● ● Cristina Castilla-Llorente33 Nichola Cooper34 Thomas Daikeler35 Nicoletta del Papa36 ● ● ● ● Dominique Farge10,37,38,39 Jurgen Finke40 Raffaella Greco41 Hans Hagglund42 Joerg Henes43 Falk Hiepe44 ● ● ● ● ● ● Helen Jessop45 David Kiely46 Myriam Labopin5 Majid Kazmi47 Kirill Kirgizov48 Gianluigi Mancardi15 ● ● ● ● ● ● Zora Marjanovic49 Roland Martin50 Thierry Martin51 David Ma52 John Moore53 Paul Miller54 Paolo Muraro55 ● ● ● ● ● ● ● Maria-Carolina Oliveira56 Alexey Polushin57 Francesco Onida58 Belinda Simoes59 Mathieu Puyade60 ● ● ● ● ● Igor Resnick61 Montserrat Rovira62 Riccardo Saccardi3 Muhammad Saif63 Ioanna Sakellari64 Basil Sharrack1,2 ● ● ● ● ● ● Emilian Snarski65 Hans Ulrich Scherer66 Claudia Sossa67 Jeska de Vries-Bouwstra66 Nico Wulffraat68 ● ● ● ● ● Eleanora Zaccara69 1 Department of Neurology, Sheffield Teaching Hospitals NHS 4 Klinik fur Rheumatologie und Klinische Immunologie, Charite- Foundation Trust, Sheffield, UK Universitatsmedizin, Berlin, Germany 2 NIHR Neurosciences Biomedical Research Centre, University of 5 EBMT Paris study office, Department of Haematology, Saint Sheffield, Sheffield, UK Antoine Hospital, INSERM UMR 938, Sorbonne University, 3 Paris, France Cell Therapy and Transfusion Medicine Unit, Careggi University Hospital, Firenze, Italy 306 B. Sharrack et al. 6 14 Department of Neuroscience, Uppsala University, N.N. Blokhin National Medical Center of Oncology, Institute of Uppsala, Sweden Pediatric Oncology and Hematology, Moscow, Russia 7 15 Unité de Médecine Interne, Maladies Auto-immunes et Pathologie Department of Neuroscience, University of Genova and Clinical Vasculaire (UF 04), Hôpital St-Louis, AP-HP, Paris, France Scientific Institutes Maugeri, Genoa, Italy 8 16 Centre de Référence des Maladies Auto-Immunes Systémiques Neuroimmunology and MS Research, Neurology Clinic, Rares d’Ile-de-France, Filière, FAI2R Paris, France University Hospital, Zurich, Switzerland 9 17 EA 3518, Université Denis Diderot, Paris, France Haematology Department, St. Vincent’s Health Network, 10 Darlinghurst, NSW, Australia Department of Internal Medicine, McGill University, 18 Montreal, QC, Canada Department of Brain Sciences, Imperial College London, 11 London, UK Hematology and Bone Marrow Transplantation Unit, Istituto di 19 Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific BMT Unit, Department of Hematology, IDIBAPS, Hospital Institute, Milan, Italy Clinic, Institut Josep Carreras, Barcelona, Spain 12 20 Department of Haematology, Sheffield Teaching Hospitals NHS Department of Health Sciences (DISSAL), University of Genoa, Foundation Trust, Sheffield, UK Genoa, Italy 13 21 Kings Health Partners, Department of Haematology, Guys IRCCS Ospedale Policlinico San Martino, Genoa, Italy Hospital, London, UK