Haematopoietic stem cell transplantation is the

Transcription

1 Haematopoietic stem cell transplants: principles and indications Haematopoietic stem cell transplantation is the most widely used cellular immunotherapy. The procedure involves the administration of haematopoietic stem cells to replace the recipient s haematopoietic system (Sureda et al, 2015). Haematopoietic stem cell transplantation is an established method for treating numerous malignant and certain benign conditions with the potential of cure. Haematopoietic stem cell transplantation is a multi-step procedure that includes the collection of haematopoietic stem cells, the treatment of the patient with a conditioning regimen followed by the infusion of haematopoietic stem cells and subsequent generation of a new haematopoietic and immune system (Figure 1, Table 1). This review provides an overview of the transplant procedure and reports on experience in autoimmune diseases. Overview of haematopoietic stem cell transplantation Autologous and allogeneic haematopoietic stem cell transplantation Two major forms of haematopoietic stem cell transplantation can be distinguished: 1. In autologous haematopoietic stem cell transplantation (Figure 1a) the stem cells are collected from the recipient him/herself and are reinfused at a later time. 2. In allogeneic haematopoietic stem cell transplantation (Figure 1b) the cells originate from a different person who can be related or unrelated to the patient (Sureda et al, 2015). The major benefit of autologous haematopoietic stem cell transplantation is achieved via the effects of the conditioning treatment. The infusion of haematopoietic stem cells allows the delivery of toxic therapies, which would result in prolonged myelosuppression and a higher risk of complications without haematopoietic stem cell rescue. In allogeneic transplant the donor immune system significantly contributes to the elimination of disease via the development of the graft vs leukaemia or tumour effect (Horowitz et al, 1990). The graft vs leukaemia effect can fully eradicate the underlying disease. Disease indications Haematopoietic stem cell transplantation can be beneficial for many conditions. The European Society for ABSTRACT Haematopoietic stem cell transplantation was proposed as a treatment strategy just over 60 years ago. Owing to great advances in the field, haematopoietic stem cell transplantation has become an established method for the treatment of many haemato-oncological, immunological and hereditary conditions with the potential of cure. The number of haematopoietic stem cell transplants performed worldwide reached one million by This review provides an overview of autologous and allogeneic haematopoietic stem cell transplantation including disease indications, the individual steps of the procedure and outcome, and highlights achievements in the treatment of autoimmune diseases. Although autoimmune conditions account for only 1% of indications for autologous haematopoietic stem cell transplant, this is increasingly used to treat high-risk autoimmune diseases. Haematopoietic stem cell transplantation can induce long-term remission by resetting the immune system via eradication of autoreactive immune cells and the generation of a de novo self-tolerant immune system. Data seem most encouraging in multiple sclerosis and systemic sclerosis and it is likely that the number of procedures performed to treat these conditions will rise in the future. Blood and Marrow Transplantation (EBMT) regularly updates recommendations on disease indications (Sureda et al, 2015). Haematopoietic stem cell transplantation for the treatment of specific conditions can be graded into one of four categories: standard of care (S), clinical option (CO), developmental (D) and generally not recommended (GNR). For indications in the S category, the results of transplantation are Dr Katalin Balassa, Clinical Research Fellow in Bone Marrow Transplantation, Oxford University Hospitals NHS Foundation Trust, Department of Clinical Haematology, Cancer and Haematology Centre, Churchill Hospital, Headington, Oxford OX3 7LE and NHS Blood and Transplant, Oxford Dr Robert Danby, Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Department of Clinical Haematology, Cancer and Haematology Centre, Churchill Hospital, Headington, Oxford and Anthony Nolan Research Institute, London Professor Vanderson Rocha, Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Department of Clinical Haematology, Cancer and Haematology Centre, Churchill Hospital, Headington, Oxford and NHS Blood and Transplant, Oxford Correspondence to: Dr K Balassa (katalin.balassa@ouh.nhs.uk) This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0, licenses/by-nc-nd/4.0/). British Journal of Hospital Medicine, January 2019, Vol 80, No 1 33

2 hmed /12/20 9:57 page 34 #2 i i Figure 1. The process of haematopoietic stem cell transplantation. a. Autologous. b. Allogeneic. Donor choice In autologous haematopoietic stem cell transplantation the stem cells are collected from the patient. However, in allogeneic transplantation a suitable donor must be selected. Recipient donor human leukocyte antigen (HLA) matching is among the strongest determinants of the outcome in allogeneic haematopoietic stem cell transplantation (Petersdorf, 2013). For matching HLA-A, -B, -C, -DR, -DQ and -DP genes are taken into account. Other factors such as donor age, gender and 34 recipient donor cytomegalovirus matching are considered during donor selection (Juric et al, 2016). In about 30% of patients, a HLA-matched related donor is available and is the preferred donor of choice (Gragert et al, 2014). For patients lacking a suitable HLA-matched related donor, transplantation from a matched unrelated donor is the standard option. Despite millions of voluntary adult unrelated donors it can be challenging to find a well HLA-matched donor for patients from ethnic minorities (Gragert et al, 2014). Alternatively haematopoietic stem cells from umbilical cord blood or haplotype-matched (haploidentical) related donors can be used (Passweg et al, 2017). Haplotype matching means that only one of the two HLA haplotypes is matched between the recipient and the donor. This is possible for almost all individuals, given that one s parents, children and half of the siblings are haplotype matches for an individual. Stem cell source and collection of stem cells Haematopoietic stem cells used for transplantation can come from three sources: bone marrow, peripheral blood or umbilical cord blood (Sureda et al, 2015). Bone marrow harvest was the first established method for stem cell collection, performed in the operating theatre under general anaesthesia from the posterior iliac crest (Miller et al, 2008). The establishment of effective and safe peripheral blood haematopoietic stem cell mobilization techniques and donor convenience caused a shift towards the use of peripheral blood haematopoietic stem cells in the 1990s (Miller et al, 2008). For mobilization in patients, various regimens are available that consist of chemotherapeutic agents and granulocyte-colony stimulating factor (G-CSF) (Mohty et al, 2014). In autologous haematopoietic stem cell transplants the haematopoietic stem cells collected from the patient are frozen, thawed and reinfused later when the patient is prepared by the conditioning treatment (Figure 1a). In allogeneic donors, haematopoietic stem cell superior to other modalities. For CO indications, haematopoietic stem cell transplantation is effective, but because of the low number of patients, evidence-based comparisons are difficult to make. There is only limited experience with D indications, so haematopoietic stem cell transplantation for these indications is encouraged within the scope of a clinical trial. For GNR indications haematopoietic stem cell transplantation is not justified. According to the EBMT survey published in 2017, in the EBMT-reporting countries transplants were performed in patients in 2015 of which 59% were autologous and 41% allogeneic (Passweg et al, 2017). Almost 99% of autologous haematopoietic stem cell transplants were performed for malignancies, of which 90% were for plasma cell diseases (multiple myeloma and others, 52%) or lymphoma (38%). Autoimmune diseases accounted for 1% of indications for autologous haematopoietic stem cell transplant. Of allogeneic haematopoietic stem cell transplants, 88% were delivered for haematological malignancies: 39% for acute myeloid leukaemia, 16% for acute lymphoid leukaemia and 33% for others. Among benign conditions bone marrow failure was the most common indication (5%) followed by primary immune deficiency (3%) and thalassaemia or sickle cell disease (3%). Overall 0.1% of allogeneic haematopoietic stem cell transplants were performed for autoimmune diseases. British Journal of Hospital Medicine, January 2019, Vol 80, No 1

3 collection via apheresis procedure happens 5 6 days after G-CSF injections (Miller et al, 2008). Many allogeneic transplant centres use fresh haematopoietic stem cells, so the collection from the donor and conditioning of the patient happen simultaneously (Figure 1b). Using fresh cells gives a higher number of viable cells as a proportion of cells are destroyed during freezing and thawing. Conditioning intensity For successful engraftment of donor haematopoietic stem cells the host immune system must be eradicated and suppressed (Thomas et al, 1975). The pre-transplant conditioning regimen, of chemotherapy and/or radiotherapy, aims to eliminate the host immunity so preparing the bone marrow for the new cells. Besides immunoablation, conditioning may also have a beneficial activity against the underlying disease (Bacigalupo et al, 2009). There are three categories of conditioning regimens: myeloablative (high intensity), reduced intensity (intermediate intensity) and non-myeloablative (low intensity) conditioning based on the myelosuppressive effect (the duration and degree of cytopenia induced) and stem cell support requirement. Myeloablative conditioning results in prolonged, usually irreversible pancytopenia and fatal consequences unless restoration of haematopoiesis occurs following the infusion of haematopoietic stem cells (Bacigalupo et al, 2009). Myeloablative conditioning maximizes disease control and has a lower risk of relapse at the price of higher toxicity (Scott et al, 2017). Only patients below 55 years of age and without significant comorbidities assessed by comorbidity tools, such as the hematopoietic cell transplantation comorbidity index, are eligible for the myeloablative conditioning approach (Sorror et al, 2005; Sorror, 2013). The recognition that the success of allogeneic haematopoietic stem cell transplantation in malignancies heavily relies on the post-transplant graft vs leukaemia effect and not only the anti-tumour activity delivered by myeloablative conditioning led to the development of less intense conditioning regimens. The reduced intensity and non-myeloablative conditioning approaches opened the prospect of haematopoietic stem cell transplantation for older patients and patients with comorbidities and are now widely used for both malignant and non-malignant indications. Non-myeloablative conditioning is the least toxic form of conditioning treatment causing only minimal cytopenia, but it is sufficiently immunosuppressive and immunoablative to make engraftment viable. Reduced intensity conditioning causes a level of toxicity between those of myeloablative and non-myeloablative conditioning (Bacigalupo et al, 2009). Conditioning regimens show great variations with regards to combination, timing and dosing of the agents (Bacigalupo et al, 2009; Nakamura and Forman, 2014). Table 1. Haematopoietic stem cell transplantation terminology Priming or mobilization Stem cell harvest Conditioning treatment D0 Neutrophil engraftment Platelet engraftment Graft vs host disease prophylaxis Graft vs host disease Acute graft vs host disease Chronic graft vs host disease Graft failure or rejection Treatment given before peripheral blood stem cell collection to release stem cells from the patient s or donor s bone marrow into the peripheral blood Collection of stem cells either from patient s or donor s bone marrow (via aspiration) or peripheral blood (via apheresis) Preparative regimen consisting of chemotherapy or chemotherapy and radiotherapy given to the patient before infusion of stem cells to destroy the patient s own lymphohaematopoietic system and prepare the bone marrow for the arrival of the new stem cells Day of infusion of stem cells. Days after D0 are counted as D+1, D+2 etc The first day of three consecutive days when the absolute neutrophil count is 500 cells/µl ( /litre) or greater. The median time to engraftment is usually around 2 weeks after infusion of stem cells The first day of three consecutive days when the unsupported platelet count is /litre or greater Immunosuppressive treatment given following allogeneic haematopoietic stem cell transplantation to prevent graft vs host disease and graft rejection. It usually includes calcineurin inhibitors, ciclosporin or tacrolimus Major complication of allogeneic haematopoietic stem cell transplantation as a consequence of immunological attack on recipient targets delivered primarily by alloreactive T lymphocytes Acute inflammatory condition, presenting as skin rash, nausea, vomiting, diarrhoea and cholestatic hyperbilirubinaemia, usually within the first 100 days of transplant. Its severity directly correlates with prognosis Typically presents months after allogeneic haematopoietic stem cell transplantation and resembles autoimmune conditions with autoimmune and fibrotic features. Any organ can be targeted and its development can significantly affect quality of life and long-term prognosis Rare complication of haematopoietic stem cell transplantation with no engraftment (primary graft failure) or rejection following engraftment (secondary graft failure) Complications and outcome Although the outcomes of haematopoietic stem cell transplantation show improvement over time, the procedure is associated with significant transplant-related morbidity, mortality and long-term health issues (Arnaout et al, 2014). In autologous haematopoietic stem cell transplantation, patients are most vulnerable during the neutropenic period and the risk of infections declines significantly after neutrophil engraftment. In experienced centres autologous haematopoietic stem cell transplantation-related mortality is rare (approximately <1%). British Journal of Hospital Medicine, January 2019, Vol 80, No 1 35

4 Immunoablative therapy followed by autologous haematopoietic stem cell transplantation has been in the forefront of multiple sclerosis research for the last two decades. In allogeneic haematopoietic stem cell transplantation, patients require prolonged immunosuppression for the prevention and treatment of graft vs host disease and rejection. Consequently the risk of infections is increased for many months until immune reconstitution develops (Sahin et al, 2016). Acute graft vs host disease is the most important allogeneic transplant-specific complication, accounting for significant mortality, whereas chronic graft vs host disease can cause long-term morbidity, disability and poor quality of life (Table 1) (Ferrara et al, 2009). Allogeneic haematopoietic stem cell transplantrelated mortality can be as high as over 30% at 1 year post-transplant (Juric et al, 2016). Organ dysfunctions (cardiac, pulmonary, endocrine and musculoskeletal), infertility and secondary cancers are significantly more prevalent among allogeneic haematopoietic stem cell transplantation survivors than the general population (Savani et al, 2011). Transplantation for autoimmune diseases Basic concepts Disease-modifying treatments significantly improved patient outcomes in autoimmune diseases (Snowden et al, 2012). However, a proportion of patients are refractory to conventional therapies and definite cure or long-term remission is rare (Snowden et al, 2012). Autologous haematopoietic stem cell transplantation has been used for the management of autoimmune diseases since the 1990s (Snowden et al, 2017). The rationale is that the conditioning treatment followed by infusion of haematopoietic stem cells can reset the immune system by eradicating autoreactive immune cells and allowing the generation of a de novo self-tolerant immune system (Arruda et al, 2016; Swart et al, 2017). EBMT published a summary of haematopoietic stem cell transplantation activity for autoimmune diseases in 2017, including transplants between 1994 and 2015 (Snowden et al, 2017). During this period, 1951 first autologous haematopoietic stem cell transplants and 105 allogeneic haematopoietic stem cell transplants were performed. Allogeneic haematopoietic stem cell transplant activity did not increase and it was performed almost exclusively in paediatric cases. Autologous haematopoietic stem cell transplant activity increased gradually and outcomes varied across the different diseases. Two diseases accounted for two thirds of autologous haematopoietic stem cell transplants: over 800 were delivered for multiple sclerosis and over 400 for systemic sclerosis. Activity for these two indications continued to rise over the years. For Crohn s disease, activity increased until 2011 and declined since then. For systemic lupus erythematosus and inflammatory arthritis the number of autologous haematopoietic stem cell transplants has gradually decreased. Based on clinical data, EBMT recommends autologous haematopoietic stem cell transplantation as CO indication for various autoimmune diseases. Allogeneic haematopoietic stem cell transplantation remains a D or GNR indication for all conditions except for cytopenias where it is graded as CO (Snowden et al, 2012; Sureda et al, 2015). For mobilization of stem cells in autoimmune diseases protocols often contain chemotherapy (such as cyclophosphamide or BEAM [BCNU, etoposide, cytarabine, melphalan]), as G-CSF on its own could induce a flare of the underlying disease (Snowden et al, 2012). Most centres apply the non-myeloablative or the reduced intensity conditioning approach. Higher intensity conditioning can halt disease activity for a prolonged period at the price of increased toxicity. Multiple sclerosis Multiple sclerosis is an autoimmune disease of the CNS typically manifesting in young adulthood. There is enormous demand for alternative treatment modalities given that multiple sclerosis is the commonest cause of non-traumatic neurological disability in young adults (Massey et al, 2018). The disease typically starts with a relapsing-remitting course, followed by secondary progressive disease after a variable length of onset (typically years) leading to gradual neurological deterioration and disability (Massey et al, 2018). Although disease-modifying treatments introduced in the 1990s resulted in improved long-term outcomes, conventional therapies are ineffective to prevent progressive decline (Sormani et al, 2017). Immunoablative therapy followed by autologous haematopoietic stem cell transplantation has been in the forefront of multiple sclerosis research for the last two decades (Sormani et al, 2017). According to EBMT, multiple sclerosis has been the top indication among all autoimmune conditions (Snowden et al, 2017). Several non-controlled, single-arm studies confirmed the feasibility of the approach, but there are only two randomized controlled trials with available data. The Autologous Haematopoietic Stem Cell Transplantation trial in MS (ASTIMS) assessed the efficacy of autologous haematopoietic stem cell transplantation vs mitoxantrone on disease activity measured by magnetic resonance imaging (Mancardi et al, 2015). Autologous haematopoietic stem cell transplantation reduced the number of new T2 lesions counted over 4 years compared with mitoxantrone. Autologous haematopoietic stem cell transplantation also lowered the annualised relapse rate. The Hematopoietic Stem Cell Therapy for Patients with Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy (MIST trial, NCT ) has been 36 British Journal of Hospital Medicine, January 2019, Vol 80, No 1

5 still recruiting, including a UK arm. The preliminary results of the study presented at the EBMT 2018 congress showed very encouraging results from autologous haematopoietic stem cell transplantation in the treatment of relapsing-remitting multiple sclerosis. To date the largest non-randomized controlled trial report is the joint EBMT-CIBMTR study summarizing autologous haematopoietic stem cell transplantation of 281 patients between 1995 and 2006 (Muraro et al, 2017). The study included 57% of transplants for multiple sclerosis registered with EBMT or CIBMTR during the study period. The 5-year probability of progression-free and overall survival was 46% and 93% respectively. The results are remarkable considering that the majority of patients suffered from progressive disease. Younger age, relapsing-remitting multiple sclerosis, fewer prior therapies and lower level of disability were associated with better outcome. Other studies suggest that autologous haematopoietic stem cell transplantation is feasible and effective, achieving good progression-free survival rates (up to 91% at 5 years) especially in relapsingremitting multiple sclerosis (Burman et al, 2018). Non-myeloablative (cyclophosphamide-based) or reduced intensity conditioning (BEAM-based) regimens were used, but consensus is lacking on the best conditioning intensity and modality. Transplant-related mortality has reduced significantly over time and, according to a meta-analysis, only one death has occurred in 349 patients treated post-2005 (0.3%) (Sormani et al, 2017). Increasing evidence supports that immunoablation followed by autologous haematopoietic stem cell transplantation can induce durable remissions in multiple sclerosis and might be superior to conventional therapies. Where autologous haematopoietic stem cell transplantation fits in the treatment algorithm is yet to be defined, but it might be a second line treatment option for patients with relapsing-remitting multiple sclerosis (Freedman and Atkins, 2016). Studies suggest that younger patients with highly active relapsing-remitting multiple sclerosis without severe disability could achieve best response rates, but selected patients with progressive multiple sclerosis might be eligible for the treatment (Atkins and Freedman, 2017). It is likely that autologous haematopoietic stem cell transplantation will be incorporated more in the management of multiple sclerosis in the future. Systemic sclerosis Systemic sclerosis is characterized by progressive fibrosis of skin and internal organs, and vasculopathy as a result of autoreactive immune activation, inflammation and increased fibroblast activity (Host et al, 2017). Systemic sclerosis has a poor prognosis, with mortality rates of 5 10% per year (Host et al, 2017). Monthly cyclophosphamide can offer short-term benefits, but none of the current therapies significantly modify the disease course (Sullivan et al, 2018). Autologous haematopoietic stem cell transplantation has been the first modality to result in improvement of lung function in patients with systemic sclerosis. Autologous haematopoietic stem cell transplantation has been increasingly used in systemic sclerosis. Three randomized controlled trials using the approach reported results in the last decade. The American Scleroderma Stem Cell versus Immune Suppression trial (ASSIST) compared outcome of non-myeloablative conditioning (cyclophosphamide + total body irradiation + antithymocyte globulin) autologous haematopoietic stem cell transplantation with monthly cyclophosphamide (Burt et al, 2011). All ten patients treated with autologous haematopoietic stem cell transplantation improved and improvements in skin score and lung function persisted during 2-year follow-up. On the other hand, eight of nine patients in the control group progressed within 12 months. Autologous haematopoietic stem cell transplantation has been the first modality to result in improvement of lung function in patients with systemic sclerosis, suggesting that interstitial lung disease might be at least partially reversed. In the Autologous Stem Cell Transplantation International Scleroderma trial (ASTIS) a total of 156 patients were randomly assigned to undergo non-myeloablative conditioning autologous haematopoietic stem cell transplantation or receive monthly cyclophosphamide (van Laar et al, 2014). Although in the first year there were more events including deaths (transplant-related mortality 10%) in the autologous haematopoietic stem cell transplantation arm, the transplant approach resulted in significantly better long-term event-free and overall survival. The survival benefit was striking in patients who had never smoked. The Scleroderma: Cyclophosphamide or Transplantation trial (SCOT) compared myeloablative conditioning (cyclophosphamide + total body irradiation + antithymocyte globulin) autologous haematopoietic stem cell transplantation with immunosuppression therapy (12 monthly infusions of cyclophosphamide) (Sullivan et al, 2018). Autologous haematopoietic stem cell transplantation resulted in significantly better event-free (74% vs 47%) and overall survival (86% vs 51%) at 72 months. Despite the high intensity of the conditioning regimen and previous concerns about use of total body irradiation in patients with systemic sclerosis, transplantrelated mortality was 0% in the first year post-transplant. Several other retrospective and prospective noncontrolled studies assessed the success of autologous haematopoietic stem cell transplantation in systemic sclerosis (Host et al, 2017). All studies showed an improvement in skin scores and some in other organ involvement as well. On the other hand, transplantrelated mortality was higher (0 23%) in patients with British Journal of Hospital Medicine, January 2019, Vol 80, No 1 37

6 KEY POINTS Haematopoietic stem cell transplantation is a multi-step procedure that includes collection of stem cells, treatment of the patient with a conditioning regimen and infusion of stem cells, generating a new haematopoietic and immune system. Haematopoietic stem cell transplantation is a curative treatment for many haemato-oncological, immunological and hereditary conditions. There are two major forms of haematopoietic stem cell transplantation: autologous and allogeneic. Autologous haematopoietic stem cell transplantation can induce durable remission and cure in several diseases with low transplant-related mortality. Allogeneic haematopoietic stem cell transplantation is a curative treatment for many otherwise incurable conditions, but the risks of morbidity and mortality are high. In autoimmune diseases, haematopoietic stem cell transplantation can improve outcomes for patients who are refractory to conventional treatment. Results are especially encouraging in multiple sclerosis and systemic sclerosis. support the potential of autologous haematopoietic stem cell transplantation to induce improvement or remission in resistant Crohn s disease (Brierley et al, 2018; Snowden et al, 2018). Conclusions Haematopoietic stem cell transplantation has enabled cure of thousands of patients with incurable diseases. Outcomes are improving, but significant risks still remain. Accumulating data support the feasibility and efficacy of haematopoietic stem cell transplantation in immune-mediated conditions, especially in multiple sclerosis and systemic sclerosis. An integral challenge for physicians is the identification of autoimmune disease patients at highest risk of progression at a stage when changes are still reversible and patients are fit for the procedure. The risks of early mortality and complications must be weighed against the long-term benefits. BJHM systemic sclerosis than in other autoimmune conditions. Pre-existing internal organ compromise likely contributed to high transplant-related mortality putting patients at increased risk of cardiovascular and other complications. Recommendations have been proposed for safer donor selection and pre-transplant assessment of eligibility, with particular regard to cardiopulmonary status (Farge et al, 2017). Based on available clinical data the European League against Rheumatism 2017 guidelines suggest that autologous haematopoietic stem cell transplantation should be considered in selected patients with rapidly progressive systemic sclerosis at risk of organ failure (Kowal-Bielecka and Fransen, 2017). However, because of the risk of early complications and mortality careful patient selection is warranted. Crohn s disease Despite great advances achieved by biological treatments in Crohn s disease, some patients have treatment-resistant disease and need alternative therapies (Snowden et al, 2018). The Autologous Stem Cell Transplantation in Crohn s Disease (ASTIC) trial was the first randomized controlled trial in Crohn s disease and compared early vs deferred autologous haematopoietic stem cell transplantation in patients with resistant Crohn s disease (Hawkey et al, 2015). All patients underwent stem cell mobilization before 1:1 randomization to autologous haematopoietic stem cell transplantation or standard of care. Only two patients in the autologous haematopoietic stem cell transplantation arm (9%) and one in the control arm (5%) achieved sustained disease remission, but 61% vs 23% were able to wean off treatment suggesting the clinical benefit of autologous haematopoietic stem cell transplantation. The study was discontinued prematurely as a result of an early death in the autologous haematopoietic stem cell transplantation arm. Data from single-arm cohorts and case reports The work of Dr K Balassa and Professor V Rocha was supported by NHS Blood and Transplant (NHSBT). The authors wish to thank Graham Cooper (Oxford Medical Illustration) for his help with the preparation of Figure 1. Conflict of interest: none. Arnaout K, Patel N, Jain M, El-Amm J, Amro F, Tabbara IA. Complications of allogeneic hematopoietic stem cell transplantation. Cancer Invest Aug (7): Arruda LCM, Clave E, Moins-Teisserenc H, Douay C, Farge D, Toubert A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr Res Transl Med Apr. 64(2): Atkins HL, Freedman MS. Five Questions Answered: A of Autologous Hematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis. Neurotherapeutics Oct. 14(4): Bacigalupo A, Ballen K, Rizzo D et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant Dec. 15(12): /j.bbmt Brierley CK, Castilla-Llorente C, Labopin M et al. Autologous Haematopoietic Stem Cell Transplantation for Crohn s Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation. J Crohn s Colitis Aug. 12(9): Burman J, Tolf A, Hägglund H, Askmark H. Autologous haematopoietic stem cell transplantation for neurological diseases. J Neurol Neurosurg Psychiatry Feb. 89(2): Burt RK, Shah SJ, Dill K et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet Aug. 378(9790): Farge D, Burt RK, Oliveira M-C et al. Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transplant Nov. 52(11): British Journal of Hospital Medicine, January 2019, Vol 80, No 1

7 Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet May. 373(9674): /S (09) Freedman M, Atkins HL. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS YES. Mult Scler J Sep. 22(10): Gragert L, Eapen M, Williams E et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med Jul (4): NEJMsa Hawkey CJ, Allez M, Clark MM et al. Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease. JAMA Dec (23): Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood Feb 1. 75(3): Host L, Nikpour M, Calderone A, Cannell P, Roddy J. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol Sep Oct. 106(Suppl 4): Juric MK, Ghimire S, Ogonek J et al. Milestones of Hematopoietic Stem Cell Transplantation From First Human Studies to Current Developments. Front Immunol Nov 09. 7: Kowal-Bielecka O, Fransen J et al. EUSTAR Coauthors. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis Aug. 76(8): Mancardi GL, Sormani MP, Gualandi F et al. ASTIMS Haemato-Neurological Collaborative Group, On behalf of the Autoimmune Disease Working Party (ADWP) of the European Group for Blood and Marrow Transplantation (EBMT); ASTIMS Haemato-Neurological Collaborative Group On behalf of the Autoimmune Disease Working Party ADWP of the European Group for Blood and Marrow Transplantation EBMT. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A phase II trial. Neurology Mar (10): Massey JC, Sutton IJ, Ma DDF, JJ Moore. Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant. Front Immunol Mar 12. 9: Miller JP, Perry EH, Price TH et al. Recovery and safety profiles of marrow and PBSC donors: experience of the National Marrow Donor Program. Biol Blood Marrow Transplant Sep. 14(Suppl 9): Mohty M, Hübel K, Kröger N et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant Jul. 49(7): Muraro PA, Pasquini M, Atkins HL et al. Multiple Sclerosis Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol Apr (4): Nakamura R, Forman SJ. Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: considerations for evidence-based GVHD prophylaxis. Expert Rev Hematol Jun. 7(3): Passweg JR, Baldomero H, Bader P et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant Jun. 52(6): https: //doi.org/ /bmt Petersdorf EW. Genetics of graft-versus-host disease: the major histocompatibility complex. Blood Rev Jan. 27(1): Sahin U, Toprak SK, Atilla PA, Atilla E, Demirer T. An overview of infectious complications after allogeneic hematopoietic stem cell transplantation. J Infect Chemother Aug. 22(8): Savani BN, Griffith ML, Jagasia S, Lee SJ. How I treat late effects in adults after allogeneic stem cell transplantation. Blood Mar (11): Scott BL, Pasquini MC, Logan BR et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol Apr (11): Snowden JA, Saccardi R, Allez M et al. EBMT Autoimmune Disease Working Party (ADWP); Paediatric Diseases Working Party (PDWP). Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant Jun. 47(6): Snowden JA, Badoglio M, Labopin M et al. European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP); EBMT Paediatric Working Party (PWP); Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT); EBMT (JACIE). Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Advances Dec 26. 1(27): bloodadvances Snowden JA, Panés J, Alexander T et al. European Crohn s and Colitis Organisation (ECCO); European Society for Blood and Marrow Transplantation (EBMT); Autoimmune Diseases Working Party (ADWP); Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE). Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in Severe Crohn s Disease: A on Behalf of ECCO and EBMT. J Crohn s Colitis Mar (4): Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, Mancardi GL. Autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurology May (22): Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood Apr (15): Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood Oct (8): Sullivan KM, Goldmuntz EA, Keyes-Elstein L et al. SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med (1): Sureda A, Bader P, Cesaro S et al. Indications for allo- and auto-sct for haematological diseases, solid tumours and immune disorders: current practice in Europe, Bone Marrow Transplant Aug. 50(8): Swart JF, Delemarre EM, van Wijk F, Boelens JJ, Kuball J, van Laar JM, Wulffraat NM. Haematopoietic stem cell transplantation for autoimmune diseases. Nat Rev Rheumatol Apr. 13(4): Thomas ED, Storb R, Clift RA et al. Bone-Marrow Transplantation. N Engl J Med Apr (16): /NEJM van Laar JM, Farge D, Sont JK et al. EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA Jun (24): British Journal of Hospital Medicine, January 2019, Vol 80, No 1 39