John Snowden

Professor, BSc (Hons), MBChB. MD. FRCP. FRCPath, Consultant Hematologist & Director of Blood and Marrow Transplantation,
Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield. UK

John Snowden graduated from the University of Leeds in 1989 and trained in Internal Medicine and Haematology in the UK, New Zealand and Australia. In 2002, he was appointed as Consultant Haematologist & Director of Blood and Marrow Transplantation (BMT) in Sheffield Teaching Hospitals NHS Foundation Trust.

Professor Snowden is the elected Chair of the EBMT Autoimmune Disease Working Party (ADWP) and also the Chair of JACIE, the organisation which oversees the accreditation of BMT and cell therapy programmes internationally. In the UK he is President Elect of the British Society for BMT (BSBMT), Clinical Lead for NHS England Commissioning for BMT, and Chair of the Intercollegiate Committee on Haematology to the Royal College of Physicians and Royal College of Pathologists. He has published over 250 clinical and scientific articles, reviews and book chapters, and led on key national and international clinical guidelines (h-index 40). He holds honorary professorships in Sheffield and University College London.

The EBMT Experience of HSCT for Autoimmune Diseases:

PAST - PRESENT - FUTURE

The concept of using HSCT in autoimmune disorders originated in basic science and serendipitous clinical cases several decades ago. Over the last 20 years, HSCT has been progressively used as a specific treatment for patients with severe treatment resistant autoimmune disorders. In the vast majority of patients autologous HSCT has been performed, although occasionally allogeneic HSCT has been used, particularly in pediatrics.

The EBMT Autoimmune Diseases Working Party (ADWP) has been central to the evolution of this therapy in Europe and has maintained a database, which now contains over 3000 procedures for a wide variety of autoimmune diseases. In addition, the EBMT ADWP has produced guidelines and recommendations for clinical and research practice. Autoimmune and inflammatory diseases are now the fastest growing indication for E1SCT across Europe.

A wide range of autoimmune diseases have been treated. This talk will cover the evolution of the evidence base and guidelines and discuss the mechanistic studies of immune reconstition running alongside the clinical studies and will focus on autologous E1SCT in the main indications in neurology, rheumatology and gastroenterology; multiple sclerosis (MS), systemic sclerosis (SSc) and Crohn's disease (CD).

In MS over 1400 patients have been registered in the EBMT database. In addition to MS, a range of rarer inflammatory neurological diseases have been treated with E1SCT.

In SSc over 600 patients have been registered in the EBMT database and there are now 3 RCTs supporting survival benefits of autologous E1SCT over non-transplant treatment in SSc. Elowever, autologous E1SCT is a relatively high-risk procedure in SSc and selection of patients requires special consideration. EBMT guidelines have been produced for cardiopulmonary screening of SSc patients for E1SCT. In addition to SSc, a range of rarer inflammatory rheumatological diseases, such as SLE, JIA, inflammatory arthritis and vasculitis, have been treated with HSCT and the talk will cover the current literature and future developments.

Over 200 patients with inflammatory bowel disease have been registered in the EBMT database, predominantly treated for Crohn's disease. The EBMT ADWP has recently published joint review with the European Crohn's and Colitis Organisation (ECCO) and a retrospective analysis of transplanted Crohn's disease cases. Clinical trials are ongoing.

Across a number of autoimmune diseases, scientific studies have provided some support for a 're-booting' of the immune system by HSCT. Although allogeneic HSCT is essentially a means of replacing an aberrant immune system, long-term responses to autologous HSCT may be explained in some diseases by 're-setting' of the immune system through thymic reprocessing, T- cell repertoire changes and increased T-regulatory cell activity. Further research will be facilitated by the recent EBMT ADWP and associated publications for biobanking and immune reconstitution studies.

Compared with modem biological therapies in autoimmune diseases, there may be also health economic benefits from a single one-off HSCT procedure. Even so, treatment with HSCT is intensive with a range of toxicities and risks, which, despite being routine to haematologists, are less familiar to disease specialists. The field mandates close collaboration between haematologists and relevant disease specialists in patient selection, clinical management and follow up.

The EBMT has endeavored to promote good collaborative practice in this evolving field through a series of evidence-based guidelines and recommendations underpinned with quality assurance via JACIE accreditation. Relevant outputs are included in the reference list below.

1. Alexander T, Bondanza A, Muraro PA, Greco R, Saccardi R, Daikeler T, Kazmi M, Hawkey C, Simoes BP, Leblanc K, Fibbe WE, Moore J, Snarski E, Martin T, Hiepe F, Velardi A, Toubert A, Snowden JA, Farge D. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplantation 2015; 50:173-80

2. Alexander T, Farge D, Badoglio M, Lindsay JO, Muraro PA, Snowden JA; Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic stem cell therapy for autoimmune diseases - Clinical experience and mechanisms. Journal of Autoimmunity 2018 Aug; 92:35-46. doi: 10.1016/j.jaut.2018.06.002. Epub 2018 Jun 20.

3. Brierley CK, Castilla-Llorente C, Labopin M, Badoglio M, Rovira M, Ricart E, Dierickx D, Vermeire S, Hasselblatt P, Finke J, Onida F, Cassinotti A, Satsangi J, Kazmi M, Lopez-

Sanroman A, Schmidt C, Farge D, Travis SPL, Hawkey CJ, Snowden JA; European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP). 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 Crohns Colitis. 2018 May 18. doi: 10.1093/ecco-jcc/jjy069.

4. Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, Corbacioglu S, Dreger P, Dufour C, Gennery AR, Kuball J, Lankester AC, Lanza F, Montoto S, Nagler A, Peffault de Latour R, Snowden JA, Styczynski J, Yakoub-Agha I, Kroger N, Mohty M; European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019 Apr 5.

5. Farge D, Burt RK, Oliviera M-C, Mousseaux E, Rovira M, Marjanovic Z, Scherer HU, de Vries-Bouwstra J, Martin T, Saccardi R, Shah SJ, Lee DC, Denton C, Alexander T, Kiely DG, Snowden JA. Cardiopulmonary assessment of patients with systemic sclerosis for haematopoietic stem cell transplantation (HSCT): recommendations from the European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and collaborating partners. Bone Marrow Transplantation 2017; Nov; 52(11):1495-1503.

6. Greco R, Labopin M, Badoglio M, Veys P, Furtado Silva JM, Abinun M, Gualandi F, BornhauserM, Ciceri F, Saccardi R, Lankester A, Alexander T, Gennery AR, Bader P, Farge D, Snowden JA. Allogeneic HSCT for Autoimmune Diseases: A Retrospective Study From the EBMT ADWP, IEWP, and PDWP Working Parties. Front Immunol. 2019 Jul 4; 10:1570. doi: 10.3389/fimmu.2019.01570. eCollection 2019.

7. Jessop H, Farge D, Saccardi R, Alexander T, Rovira M, Sharrack B, Greco R, Wulffraat N, Moore J, Kazmi M, Badoglio M, Adams G, Verhoeven B, Murray J, Snowden JA. General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Bone Marrow Transplantation. 2019 Jan 31. doi: 10.1038/s41409-019- 0430-7

8. Kelsey PJ, Oliveira MC, Badoglio M, Sharrack B, Farge D, Snowden JA. Haematopoietic stem cell transplantation in autoimmune diseases: From basic science to clinical practice. Curr Res Transl Med, 2016;64:71-82

9. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, Dufour C, Kroger N,

Kuball J, Lankester A, Montoto S, Nagler A, Snowden JA, Styczynski J, Mohty M; European Society for Blood and Marrow Transplantation (EBMT). Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018 Mar 14.

10. Pockley AG, Lindsay JO, Foulds GA, Rutella S, Gribben JG, Alexander T, Snowden JA. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn's Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD-Low Intensity Therapy Evaluation Study Investigators. Front Immunol. 2018 Apr 4; 9:646.

11.Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D, Greco R, Jessop H, Kazmi M, Kirgizov K, Labopin M, Mancardi G, Martin R, Moore J, Muraro PA, Rovira M, Sormani MP, Snowden JA. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2019 in press.

12.Snowden JA, Badoglio M, Alexander T. The rise of autologous HCT for autoimmune diseases: what's behind it and what does it mean for the future of treatment? An update on behalf of the EBMT Autoimmune Diseases Working Party. Expert Rev Clin Immunol. 2019 Aug 15.

13.Snowden JA. Re-booting autoimmunity with autologous HSCT. Blood 2016;127:8-10

14.Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Maijanovic Z, Burman J, Moore J, Rovira M, Wulffraat NM, Kazmi M, Greco R, Snarski E, Kozak T, Kirgizov K, Alexander T, Bader P, Saccardi R, Farge D; 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 Adv. 2017 Dec 20;l(27):2742-2755.

15.Snowden JA, McGrath E, Duarte RF, Saccardi R, Orchard K, Worel N, Kuball J, Chabannon C, Mohty M. JACIE accreditation for blood and marrow transplantation: past, present and future directions of an international model for healthcare quality improvement.

16.Bone Marrow Transplantation 2017; Oct;52(10): 1367-1371

17.Snowden JA, Hawkey C, Hind D, Swaby L, Mellor K, Emsley R, Mandefield L, Lee E, Badoglio M, Polge E, Labopin M, Gribben J, Pockley AG, Foulds GA, Lobo A, Travis S, Parkes M, Satsangi J, Papaioannou D, Lindsay JO; Autologous Stem Cell Transplantation In Refractory CD - Low Intensity Therapy Evaluation Study Investigators; European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP). Autologous stem cell transplantation in refractory Crohn's disease - low intensity therapy evaluation (ASTIClite): study protocols for a multicentre, randomised controlled trial and observational follow up study. BMC Gastroenterol. 2019 May 31; 19(1):82.

18.Snowden JA, Panes J, Alexander T, Allez M, Ardizzone S, Dierickx D, Finke J, Hasselblatt P, Hawkey C, Kazmi M, Lindsay JO, Onida F, Salas A, Saccardi R, Vermeire S, Rovira M, Ricart E; 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 Review on Behalf of ECCO and EBMT. J Crohns Colitis. 2018 Mar28;12(4):476- 488.

19.Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, Denton C, Hawkey CJ, van Laar JM, Labopin M, Mancardi G, Martin R, Moore JJ, Passweg J, Peters C, Rabusin M, Rovira M, Farge D on behalf of the EBMT Autoimmune Disease (ADWP) and Paediatric Diseases (PDWP) Working Parties. Haematopoietic stem cell transplantation (HSCT) in severe auto-immune diseases (ADs): updated guidelines of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation 2012; 47:770-90.

20.Snowden JA, Sharrack B, Akil M, Kiely DG, Lobo A, Kazmi M, Muraro PA, Lindsay JO. Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases - a guide for the generalist. Clinical Medicine (London) 2018 Aug;18(4):329-334.