Christopher P. DentonProfessor of Experimental Rheumatology

Royal Free Hospital and UCL Medical School, London, UK

Is stem cell transplant a cure for scleroderma?

No ....

.... perhaps sometimes ....

Overview

Challenges in sclerodermaCurrent treatment with immunosuppressionObservational trials – UK, ESOS, deSScipher

Cyclophosphamide lung studies

Stem cell transplantProcedure

History

Evidence

PerspectivePotentially helpful in some patients

Case selection – “predicting the future”

Current strategies – UK and NHS pathway

Complications of systemic

sclerosis

Timing of the development of internal organ involvement in systemic sclerosis

Diffuse SSc Limited SSc

1995 – 2003 incident SSc cohort at RFH (n=677)

48.8%

16.9%

7.8%

14.4%

Disease duration (months)

n = 276 (40.8%)

Cum

ulat

ive

inci

denc

e (%

)

60

50

40

30

20

10

0

0 60 120 180

24.5%

22.9%

4.0%3.3%

n = 401 (59.2%)

Cum

ulat

ive

inci

denc

e (%

)

60

50

40

30

20

10

0

0 60 120 180Disease duration (months)

Nihtyanova, Denton et al Arthritis Rheumatol (on line, 2014)

SSc

Regular review

Screening for major complications: a cornerstone of global management

ECGEchocardiogramClinical examCardiac MRICardiac catheterisation

Heart involvementPulmonary function testsCXRHRCTClinical examLung biopsy(BAL)

Interstitial lung fibrosis

Clinical exam (BP)eGFRUrinalysis

Renal involvementPulmonary hypertension

ECGEchocardiogramPulmonary function testsClinical examRight heart cath.

dcSSc lcSSc

0 12 24 36 48 6050

60

70

80

90

10093%

91%P=0.534

Disease duration (months)

Surv

ival

(%)

Disease onset

1990 -1993 n=234

2000 -2003 n=286

0 12 24 36 48 60

50

60

70

80

90

100

84%

69%P=0.018

Nihtyanova et al, QJM 2010; 103:109-15

Improving survival in systemic sclerosis: a historical perspective

NSIP

Treatment of skin and lung fibrosis in scleroderma

Potential immunomodulatory strategies Methotrexate

CyclophosphamideAzathioprineMycophenolate mofetilStem cell transplant (autologous/allogeneic)Tacrolimus, rapamycinBiological agents (rituximab, abatacept,

basiliximab)Oral tolerance to type I collagenHyperimmune caprine serum (AIMSPRO®)

Early stage diffuse systemic sclerosis

0

10

20

30

40

50

0

10

20

30

40

50

BaselineYear1 Year2 Year3 BaselineYear1 Year2 Year3 BaselineYear1 Year2 Year3

BaselineYear1 Year2 Year3 BaselineYear1 Year2 Year3

Cyclo then MMF ATG then MMF MMF

No active therapy Other (MTX etc)mR

SS

Skin score over time, by treatment protocol

Skin score change in UK observational study of dcSSc

Herrick et al, J Rheum (2010); 37: 116-24.

Herrick et al, J Rheum (2010); 37: 116-24.

147 patients from 12 centres

– No difference between protocols– Intention to treat analysis– Deterioration usually led to intensified therapy

ESOS – EULAR-ODP funded– MTX, cyclophosphamide, MMF ~300 subjects

1Hoyles et al Arthritis Rheum 2006; 54:3962-70

Cyclophosphamide for lung fibrosis in SSc• Fibrosing alveolitis in scleroderma trial (FAST)1

monthly intravenous cyclophosphamide 600mg/m2 for 6 months followed by (po) azathioprine, or placebo in 45 patients

– Over 12 months improvement/stabilisation FVC in favour of active treatment (p=0.04, BMI corrected – uncorrected p=0.08)

– Magnitude of difference 5.5% (4.8% adjusted) – active arm improved (+2.5 % predicted) – placebo arm worsened (-3.0 % predicted)

FAST primary outcome: FVC

p=0.08

2.44

2.46

2.48

2.50

2.52

2.54

2.56

2.58

2.60

2.62

2.64

baseline 3 months 6 months 9 months 12months

Months since baseline

Abs

olut

e FV

C (m

ean

at e

ach

time

poin

t)

ACTIVE PLACEBO

Oral cyclophosphamide in SSc-PF: the Scleroderma Lung Study (SLS-I)

24 month follow-up data suggest maximum treatment effect on FVC at 18 months then benefit diminishes but improved dyspnoea score remains

cyclophosphamide

1Tashkin et al NEJM 20062Tashkin et al Am J Respir Crit Care Med 2007

• Scleroderma lung study1 (SLS) oral cyclophosphamide (1-2 mg/kg/d) or placebo over 12 months in 158 patients.

• 1° endpoint FVC (change in % predicted) adjusted for baseline severity

2.5% placebo-subtracted difference in favour of cyclophosphamide (p<0.03)

• 2° endpoint %TLC, dyspnoea score, HAQDI, Skin score all p<0.05 in favour of cyclophosphamide

Haemopoetic stem cell transplanation (HSCT) for diffuse cutaneous SSc

• Intensive immunosuppression may lead to long term improvement in outcome for dcSSc

• HSCT allows high dose cyclophosphamide with rapid recovery from myelosuppression

• Prospective controlled trials underway: ASTIS in Europe and SCOT trial in USA. ASSIST results published.

– Compare immunosuppression plus ASCT with monthly cyclophosphamide with time-to-event analysis

– Compatible protocols. SCOT uses TBI (with shielding of lungs and kidneys)

What is an autologous stem cell transplant?

Mobilisation4-6g cyclophosphamide

Conditioning8-16g cyclophosphamide

Change in skin score.

Binks M et al. Ann Rheum Dis 2001;60:577-584

©2001 by BMJ Publishing Group Ltd and European League Against Rheumatism

High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes.

McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, Mayes MD, McDonagh KT, Nelson JL, Gooley TA, Holmberg LA, Chen CS, Wener MH, Ryan K, Sunderhaus J, Russell K, Rambharose J, Storb R, Furst DE. Blood. 2002;100:1602-10.

Skin score

DLco

HAQ-DISevere dcSSc (n=19)

Phase I/II study

Treatment related mortality in major ASCT studies

First author Number of transplants

TRM (%) Study designComments citation

Binks 41 17 Open observational

TRM 10.5% with ASTIS eligible cases

ARD 2001

Farge 57 9 Open observational

Included some cases in Binks et al

ARD 2004

Nash 34 23 Open observational

3 TRM beyond 100 days

Blood 2007

Burt 19 0 Prospective randomised

Highly selected cases

Lancet 2011

van Laar 79 10 Prospective randomised

Full dataset awaited

A&R [abstr] 2012

Burt 90 6 Open observational

Intensive cardiac screening

Lancet 2013

Figure 3 1-year follow-up for patients receiving haemopoetic stem-cell transplantations, monthly cyclophosphamide, or transplantation after failure of cyclophosphamide HSCT=haemopoietic stem-cell transplantation. FVC=forced vital capacity. DLCO=diffusing ...

Richard K Burt , Sanjiv J Shah , Karin Dill , Thomas Grant , Mihai Gheorghiade , James Schroeder , Robert Craig ,...

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

The Lancet, Volume 378, Issue 9790, 2011, 498 - 506

http://dx.doi.org/10.1016/S0140-6736(11)60982-3

ASTIS outcome dataReported at EULAR and ACR meeting 2012

156 subjects – HSCT [n=79] or iv cyclophosphamide (x12) [n=77]

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

Favourable outcomes in mRSS, SHAQ and VC

Worsening of renal function

Van Laar J, Farge D, Tyndall A et al ACR presentation (2012), manuscript submitted.

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

↓GFR (ml/min) 11.9 (28.6)* 0.95 (22.9) 0.02 *2 cases of irreversible renal failure excluded

Case selection for ASCT is critical to outcome

Nihtyanova et al, ACR oral presentation 2012

Time to death

Sur

viva

l

95%89%

72%

91%

75%

57%

94%85%

69%

Patients who fulfilled inclusion criteria

Patients who fulfilled inclusion and exclusion criteria

Patients excluded due to severe organ disease

86 80 68 51 Numbers at risk65 61 54 41 Numbers at risk21 19 14 10

398 incident SSc cases with disease onset between 1995 and 1999

• 86 fulfilled ASTIS inclusion

• 21 excluded due to severe organ disease

• 65 fulfilled eligibility criteria

Exclusion criteriaSevere heart, lung or kidney diseaseMalignancy

Inclusion criteriaDiffuse scleroderma with either:

Up to 4 years with skin score at least 15/51 and evidence of significant or worsening heart, lung, kidney disease (PH excluded by Echo)

Up to 2 years with severe skin (at least 20/51) and blood tests suggesting poor outcome (ESR, Hb)

Current statusASTIS trial – soon to be fully publishedOn going treatment programmes

Agreement from UKSSG and EBMT that this should be availableNHS policy being developedPoor prognosis cases

No major heart, lung or renal disease

Failed to respond to 6 months of cyclophosiphamide therapy

2 or 3 centres in UK – London, Sheffield,...

Links to Pulmonary hypertension centres

Strong support at Royal Free and UCL

Overall survival

Time to death

Sur

viva

l

94%85%

69%

ASTIS eligible cases with standard treatment 5 and 10 year survival

in the whole dcSSc cohort

5yr 10yr

86% 72%

86 80 68 51 Numbers at risk65 61 54 41 Numbers at risk21 19 14 10

Nihtyanova et al, ACR oral presentation 2012

ASTISASCT n=67, 16 (18 events) deaths at 33 months = 24% (27%)Control n=64, 24 deaths at 27 months = 37%

Event free survival• Time to death or development of irreversible end stage organ failure

Time to death

Surv

ival

65 61 52 40 Numbers at risk

95%87%

72%66%

Nihtyanova et al, ACR oral presentation 2012

ASTISASCT n=67, 16 (18 events) deaths at 33 months = 24% (27%)Control n=64, 24 deaths at 27 months = 37%

The challenge of severe diffuse systemic sclerosis

2013 RFH clinical database

Died after 5 years SSc – cardiac disease, lung fibrosisTreatment: cyclophosphamideMMFRituximabImmunoglobulinICD

Died after 5 years SSc –renal crisis/gut failure/cardiac diseaseTreatment: MTXcyclophosphamideMMFImmunoglobulinTPNHaemodialysis

16 year follow upAlive – paid employment minimal hospital inputTreatment: MMFCyclophosphamideAutologous stem cell transplant

6 year follow upAlive – workingRenal crisis – no dialysisTreatment: MMF

15 year follow upAlive – severe pain not workingTreated: MMF

Predicting poor outcome in early dcSScEarly diffuse SSc

< 2 years from the first symptom

randomly divided into derivation (n=260) and validation (n=187) cohorts

2 year mortality

Four independent predictors (assigned integer values) comprised the model:

age at first visit (-1, 0, 1),

skin thickness progression rate (0, 1),

gastrointestinal tract severity (0, 1, 2)

anaemia (0, 2).

Derivation and external validation of a prognostic modelComparison of risk class specific 2 year mortality in derivation and validation cohortsRisk class (sum of points)

Pittsburgh derivation cohort (n=252)

Pittsburgh validation cohort(n=126)

p-value Royal Free external validation cohort (n=110)

p-value

Low (≤1)Moderate (1-2)High (≥3)

N6310881

Deceased (%)1.614.849.4

N285048

Deceased (%)0.016.016.6

0.500.850.0002

N336116

Deceased (%)3.08.212.5

0.640.210.006

Domsic R , Nihtyanova S, et al Arthritis Rheumatol. 2014 [Epub ahead of print]

PF incidence in different risk groups in derivation and validation cohorts

Risk score1995-1999 cohort

(n=398)2000-2003 cohort

(n=279)

N PF (%) N PF (%)

<0 96 1 47 20 43 10 39 131 71 20 62 132 58 33 45 313 43 45 35 524 36 61 27 685+ 52 72 24 82

Long term prediction of the development of clinically significant lung fibrosis in SSc

42% of dcSSc and 22% of lcSSc developed csPF (p<0.001).

The variables that predicted csPF development within 10 years

dcSSc, greater age at onset, lower FVC and DLCO, anti-topoisomerase I antibody (ATA)

anti-centromere antibody was protective.

Nihtyanova, Denton et al Arthritis Rheumatol (in press, 2014)

Targeting pathogenic processes in SSc: emerging concepts

Denton, C. P. & Ong, V. H. (2013) Targeted therapies for systemic sclerosisNat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.46

Agent Population Primary endpoint Intervention in active arm Design Phase and status

Sildenafil SSc with ischaemic DUs

Time to healing of ischaemic DUs

20 mg three times per day Double-blind RCT Phase III, recruiting

Autologous SCT;

dcSSc Event-free survival at 48 and 54 months

Autologous SCT and high-dose immunosuppression

RCT Phase II, ongoing

Allogeneic SCT dcSSc Event-free survival at 2 years

Allogeneic SCT and high-dose immunosuppression

Open label Phase I/II, ongoing

Ambrisentan dcSSc mRSS at 12 months 5–10 mg daily Open label Phase II

NAC dcSSc mRSS NAC vs Iloprost RCT Phase II/III, recruiting

Pomalidomide dcSSc and progressive lung fibrosis

Change in mRSS and FVC at week 52

1 mg daily over 52 weeks Double-blind RCT Phase II, recruiting

Rilanocept (IL-1 inhibitor) dcSSc 4 gene biomarker of skin disease and mRSS

320 mg day 0 and 160 mg weekly for 5 weeks, subcutaenously

Double-blind RCT Phase I/II, recruiting

Tadalafil (PDE5 inhibitor) SSc and lung fibrosis

Change in FVC over 6 months

20 mg alternate days over 5 months

Double-blind RCT Phase III, recruiting

Fresolimumab (GC1008)

dcSSc TGFb-regulated gene expression in skin

1 and 5mg/kg intravenously Open label Phase I, recruiting

Rituximab SSc–PAH Change in PVR over 24 weeks

2 infusions, 1000 mg. each, 14 days apart

Double-blind RCT Phase II, recruiting

Macitentan SSc and DUs Reduction of new DUs at 16 weeks

3 mg or 10 mg daily Double-blind RCT Phase III, recruiting

MMF; cyclophosphamide SSc and lung fibrosis.

FVC over 24 months MMF for 2 years or oral cyclophosphamide for 12 months

RCT Phase II, recruiting

Tocilizumab dcSSc mRSS at 6 months 162 mg once per week. subcutaneously

Double-blind RCT Phase II, recruiting

Rituximab dcSSc Death or major organ involvement at 28 weeks

1,000 mg on days 1 and 15 and at week 26

RCT Phase II, ongoing

Current registered clinical trials in systemic sclerosis

Denton, C. P. & Ong, V. H. (2013) Targeted therapies for systemic sclerosisNat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.46

Conclusions• Systemic sclerosis (SSc) outcome is improving

– Systematic investigation is important– Immunosuppression is helpful – Some patients do well with current treatment– Non-lethal complications should be a priority

• Stem cell transplant is feasible but not a cure– Long term outcome may be better than standard treatment in some cases– 1 in 10 patients may die directly from the treatment

• Choosing suitable patients is critical – as in all transplant programmes

• Less toxic and more targeted treatments for SSc are being sought.

Many thanks to ….• Our patients• The “Scleroderma team” at Royal Free• Research Funders• Colleagues in many institutions and organisations• UKSSG colleagues – especially Jaap van Laar• International collaborators – EUSTAR 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