Having a stem cell transplant for scleroderma a patient and doctor perspective

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1 Having a stem cell transplant for scleroderma a patient and doctor perspective Professor Chris Denton, On behalf of an excellent team across UCLPartners Royal Free Hospital and University College London, UK

2 Overview of management of systemic sclerosis SYSTEMIC SCLEROSIS lcssc dcssc Overlap SSc Therapy: Vascular Therapy: Vascular Immunosuppressive Manage according to severity and activity of overlap features arthritis, myositis, lupus Identification and treatment of severe organ-based complications Therapy of major Organ-based complications Management of common morbidity Raynaud s, upper GI, anorectal disease, erectile dysfunction, calcinosis, telangiectasia Denton et al, Rheumatology 2016;55:

3 Autologous haemopoetic stem cell transplanation (HSCT) for diffuse cutaneous SSc Intensive immunosuppression may lead to long term improvement in outcome for dcssc ASCT allows high dose cyclophosphamide with rapid recovery from myelosuppression Registry data supportive but highlighted treatment related mortality Prospective controlled trials: ASSIST (n=19) Lancet 2011 ASTIS in Europe (n=156) JAMA, 2014) SCOT trial in USA (n=75) ACR, 2016 Results now reported and all three studies favour ASCT for long term survival

4 Autologous haemopoietic stem cell transplantation Mobilisation 4-6g cyclophosphamide Conditioning 8-16g cyclophosphamide

5 Treatment related mortality in HSCT studies First author Number of transplants Binks Open observational Farge 57 9 Open observational Nash Open observational TRM (%) Study design Comments citation TRM 10.5% with ASTIS eligible cases Included some cases in Binks et al 3 TRM beyond 100 days ARD 2001 ARD 2004 Blood 2007 Burt 19 0 Prospective randomised Highly selected cases Lancet 2011 van Laar Prospective randomised Burt 90 6 Open observational Selected cases JAMA 2014 Intensive cardiac screening Lancet 2013 Sullivan 36 3 Prospective randomised Selected cases with insurance approval ACR 2016

6 ASTIS outcome data Reported at EULAR and ACR meeting subjects HSCT [n=79] or iv cyclophosphamide (x12) [n=77] Overall survival (y) 18 events (death or organ failure) HSCT and 24 in control arm EFS was significantly better in HSCT group at 84 months (p=0.002) 10% treatment related mortality (TRM, n=8) in HSCT group, no TRM in control arm HSCT Favourable outcomes in mrss, SHAQ and VC Worsening of renal function Clinical variable Transplant (n=67) Control (n=64) P value mrss 19.7 (10.2) 8.7 (12.1) SHAQ 0.57 (1.14) 0.2 (0.78) 0.03 VC (% predicted) 4.5 (13.4) 2.2 (13.7) JAMA. 2014;311: Control GFR (ml/min) 11.9 (28.6)* 0.95 (22.9) 0.02 *2 cases of irreversible renal failure excluded Van Laar J, Farge D, Tyndall A et al JAMA. 2014;311:

7 Agreed pathway for UK patients to be evaluated for autologous stem cell transplantation

8 Stem cell transplantation for severe scleroderma a patient perspective Sarah

9 An evolving connective tissue disease

10 MRSS An immunological switch to severe scleroderma 50 Treatment 45 Vascular Immunosuppression HSCT Sildenafil Iloprost bosentan MMF Raynaud s phenomenon MCTD dcssc pregnancy Time 2017

11 Discussion about HSCT

12 HSCT the process short version

13 HSCT the process Directors cut

14 HSCT the benefits

15 MRSS An immunological switch to severe scleroderma 50 Treatment 45 Vascular Immunosuppression HSCT Sildenafil Iloprost bosentan MMF Raynaud s phenomenon MCTD dcssc pregnancy Time 2017

16 HSCT a final balanced view of outcome

17 Concept of targeted therapy in systemic sclerosis Pathway Process Organ Varga, J., Denton, C., et al. (2015) Systemic sclerosis Nat. Rev. Dis. Primers doi: /nrdp

18 Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (fasscinate): a phase 2, randomised, controlled trial. Skin MRSS change over 48 weeks Lung FVC change cumulative distribution plot Hypothesis that IL6 may be an important driver in a 24 weeks 24 weeks subgroup of diffuse SSc is supported (Khan, Ong et al, 2012) p=0.009 Blocking IL6 signalling with TCZ appears to improve skin 19% disease and reduce the risk of lung function decline (de 3% Lauretis et al, 2013) Safety was acceptable but more infections seen in TCZ patients 48 weeks Phase III pivotal trial underway (FocuSSced) p= Weighted values for THBS1 and MS4A4A mrna expression 23% 10% Khanna D, Denton CP et al. Lancet. 2016, 387:

19 Linda diffuse cutaneous SSc refractory to standard immunosuppressant therapy

20 Conclusions Standard immunosuppression is helpful in many cases of diffuse systemic sclerosis Some patients benefit from high intensity immunosuppression and stem cell transplant (rescue) Stem cell transplant is a major procedure with substantial risk and mortality New trials of well tolerated targeted treatments are looking promising potential for a licensed treatment for diffuse scleroderma?

21 Many thanks to. Our patients especially Sarah and Linda The Scleroderma team at Royal Free Research Funders Colleagues in many institutions and organisations UKSSG colleagues International collaborators EUSTAR, WSF, SCTC and FESCA Arthritis Research Campaign (UK), Raynaud s and Scleroderma Association (UK), Wellcome Trust (UK), Nuffield Foundation (UK), Scleroderma Society (UK), Rosetrees Trust, Scleroderma Research Foundation (USA), MRC, EULAR, Royal Free Charity