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
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: 1906-10
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
Autologous haemopoietic stem cell transplantation Mobilisation 4-6g cyclophosphamide Conditioning 8-16g cyclophosphamide
Treatment related mortality in HSCT studies First author Number of transplants Binks 41 17 Open observational Farge 57 9 Open observational Nash 34 23 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 79 10 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
ASTIS outcome data Reported at EULAR and ACR meeting 2012 156 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) 0.001 SHAQ 0.57 (1.14) 0.2 (0.78) 0.03 VC (% predicted) 4.5 (13.4) 2.2 (13.7) 0.005 JAMA. 2014;311:2490-2498 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;311:2490-2498.
Agreed pathway for UK patients to be evaluated for autologous stem cell transplantation
Stem cell transplantation for severe scleroderma a patient perspective Sarah
An evolving connective tissue disease
MRSS An immunological switch to severe scleroderma 50 Treatment 45 Vascular Immunosuppression HSCT 40 35 Sildenafil Iloprost bosentan MMF 30 25 Raynaud s phenomenon MCTD dcssc 20 15 10 5 pregnancy 0 1992 1996 2000 2004 2008 2015 2016 Time 2017
Discussion about HSCT
HSCT the process short version
HSCT the process Directors cut
HSCT the benefits
MRSS An immunological switch to severe scleroderma 50 Treatment 45 Vascular Immunosuppression HSCT 40 35 Sildenafil Iloprost bosentan MMF 30 25 Raynaud s phenomenon MCTD dcssc 20 15 10 5 pregnancy 0 1992 1996 2000 2004 2008 2015 2016 Time 2017
HSCT a final balanced view of outcome
Concept of targeted therapy in systemic sclerosis Pathway Process Organ Varga, J., Denton, C., et al. (2015) Systemic sclerosis Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.2
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=0.0373 Weighted values for THBS1 and MS4A4A mrna expression 23% 10% Khanna D, Denton CP et al. Lancet. 2016, 387:2630-40
Linda diffuse cutaneous SSc refractory to standard immunosuppressant therapy
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?
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