Transplantation in Autoimmune Disease He Huang, M.D., Ph.D. Bone - - PowerPoint PPT Presentation

Transplantation in Autoimmune Disease

He Huang, M.D., Ph.D. Bone Marrow transplantation Center The First Affiliated Hospital Zhejiang University School of Medicine China

Contents

• Rationale for HSCT
• Auto-HSCT for autoimmune disease
• Allo-HSCT for autoimmune disease

Autoimmune Disease (ADs)

• Organ specific

– Type 1 diabetes mellitus – Multiple sclerosis (MS)

• Systemic diseases

– Systemic lupus erythematosus (SLE) – Rheumatoid arthritis (RA) – Systemic sclerosis (SSc)

Severe Autoimmune Disease

• May result in severe intractable health states
• shorten lives considerably
• cause significant disability

Pathogenesis of ADs

• Parallels the lymphoproliferative disorders
• Lymphoproliferative disorders

– failure of cell cycle regulation and subsequent clonal expansion of a transformed precursor

• Autoimmune conditions

– failure to inhibit polyclonal expansion and activation upon exposure to self-antigens

Pathogenesis of ADs

• Genetic susceptibility
• The failure of the checkpoints available to

prevent autoimmunity following exposure to environmental challenges

Therapy for Autoimmune Disease

• Replacement therapies for organ specific

disease

• For systemic diseases

– Glucocorticoids – Immunosuppressive agents – Biologics

• Could not be cured
• Can carry their own burden of side effects

Haematopoietic stem cell transplantation in ADs

• A ‘one-off’ intensive treatment
• Can induce prolonged remissions, stabilization

and potentially cure

• Initially in animal models starting three

decades ago

• Initially in the first clinical studies from 1995

HSCT in Ads: experimental models

• the curative potential of autologous bone

marrow transplantation was discovered in rats with induced Arthritis and induced EAE

DW Van Berkkum et al, BMT 2003

Rationale for HSCT

• Transformed hematopoietic precursors beget

transformed progeny

• precursors in patients with autoimmune

disease beget progeny with a new repertoire

• f characteristics
• ‘resetting’ or ‘rebooting’ the immune system

Rationale for HSCT

• The types of protocol used in transplantation have

been both myeloablative and lymphoablative.

• Patients suffer from a genetic predisposition that

leads to regulatory escape and subsequent self- reactivity.

• transplanted patients will develop a new repertoire.

HSCT: Resetting

• S. Abrahamsson et al. autoimmumty 2008

Auto-HSCT: Just Immune Suppression?

• A profound lymphopenia in the first year after

transplantation.

– B cells, natural killer (NK) cells, and CD81 T cells display a rapid and complete reconstitution to pretransplantation levels – the recovery of CD41 T cells has consistently been

• bserved to be delayed, and often incomplete
• Is Auto-HSCT Just Immune Suppression?

Auto-HSCT: Just Immune Suppression?

• CD4+ T cells recover after a 2-year follow-up in

young adults treated for MS and RA.

– Quantitative recovery of lymphocytes was not correlated to inflammatory activity or disease relapse

• Immune deficit is an insufficient explanation

for a prolonged absence of autoimmune disease activity after autologous HCT

Muraro et al, J Exp Med. 2005 Snowden JA et al, J Rheumatol. 2004

Auto-HSCT: Immune Resetting

• regeneration of a new, naïve T cell repertoire

emerging from the thymus.

Muraro et al, J Exp Med. 2005

Auto-HSCT: Immune Resetting

• A detailed analysis of T cell receptor showed

the regeneration of a different and more diverse TCR posttransplant.

Muraro et al, J Exp Med. 2005

Auto-HSCT: Immune Resetting

• Regeneration of naïve T cell also can be seen

in SLE.

Alexander T et al, Blood. 2009

Auto-HSCT: Immune Resetting

• forkhead transcription factor 3 (FoxP3)

– Expressed by CD4+CD25+ cell – suppressors of immune responses

Low expression in SLE patients normal expression after HSCT

Alexander T et al, Blood. 2009

Contents

• Rationale for HSCT
• Auto-HSCT for autoimmune disease
• Allo-HSCT for autoimmune disease
• Economic costs

Auto-HSCT for ADs

SaccArdi R et al. autoimmunity,2008

Auto-HSCT for ADs: EBMT

Data courtesy of EBMT: update to Jan 2010

• EBMT Registry
• Patients 1122 Male/Female % 37/63
• Centres/Countries 198/ 30
• Transplant Procedure 1152
• Median Follow Up 2.8 Years
• Autograft 1074 First 1064 Second 10
• Allograft 77 First 57 Second 15 Third 3

Auto-HSCT for ADs: EBMT

• distribution for diagnosis
• Multiple Sclerosis 417
• Connective Tissue Disease 355
• Arthritis 172
• Inflammatory Bowel 40
• Hematological 68
• Vasculitis 34
• Other 55

Data courtesy of EBMT: update to Jan 2010

Auto-HSCT for ADs: EBMT

• number of HSCT per year

Data courtesy of EBMT: update to Jan 2010

Auto-HSCT for ADs: EBMT

• Transplants by year 1996-2009

Data courtesy of EBMT: update to Jan 2010

Auto-HSCT for ADs: TRM

• TRM for 1995–2000 was 7.3%;
• TRM for 2001–2007 was 1.3%.

Data courtesy of EBMT

Auto-HSCT for ADs: EBMT

• Overall Survival

Farge et al, Haematogica, 2010.

Auto-HSCT for ADs: EBMT

• D100 TRM

Farge et al, Haematogica, 2010.

Auto-HSCT for ADs: EBMT

• PFS

Farge et al, Haematogica, 2010.

Auto-HSCT for ADs: EBMT

• PFS

Farge et al, Haematogica, 2010.

Auto-HSCT for ADs: Stem Cells Harvest

• mobilisition

– Cyclophosphamide (1.5–4.0 g/m2 total dose over 1–2 days) – Followed by daily granulocyte colony-stimulating factor (G-CSF; 5–12 μg/kg/day) until harvest – Can also be mobilised with G-CSF alone, but flare

• f the disease with occurrence of neurological

symptoms has been reported

• Stem cells dose: 3×10⁶ CD34+ cells/kg bodyweight

Auto-HSCT for ADs: conditioning regimen

• usually done within 30–60 days of stem-cell

collection

– BEAM – Carmustine + CTX – TBI+CTX – BuCy or Bu alone – fludarabine + CTX

• in-vivo T-cell depletion: ATG or monoclonal

antibodies

Auto-HSCT for MS

• After a follow-up period of 3 years, a median
• f 60–70% of treated cases did not progress.

– assessed by expanded disability status scale (EDSS) scores

• Some patients improved, but in most cases,

the EDSS score remained stable

Auto-HSCT for MS

• the number of stable patients was reduced

with time

– Barcelona group: PFS 85% for 3 years – 62.5% for 6 years – Italian prospective trial: PFS 84% for 3 years – 58% for 8.5 years

Auto-HSCT for MS: Conditioning Regimen

• A EBMT retrospective multicenter study
• 20 centers, 85 patients

R Saccardi et al, Multiple Sclerosis 2006

Auto-HSCT for MS: Conditioning Regimen

• Confirmed-Progression-free Survival + 95% CI

– BEAM 79±13 – Cyclophosphamide 90±19 – Radiation or Busulphan based 51±35 – P=0.21

• High-intensity regimens do not result in a

better neurological outcome

R Saccardi et al, Multiple Sclerosis 2006

Auto-HSCT for MS: Age

• Another EBMT retrospective multicenter study
• 169 patients
• Median age: 34 y, range from 15 to 58 y.
• Median disease duration: 6.7 y. range from

0.2-28.5 y.

Mancardi GL et al, Lancet Neurol 2008

Auto-HSCT for MS: Age

• patients younger than 40 years of age had a significantly

better outcome, independently of disease duration

Mancardi GL et al, Lancet Neurol 2008

Auto-HSCT for MS: Quality of Life

• The collaborative Italian BMT study group

addressed the effect of AHSCT on the patients’ quality of life

• life-54 questionnaire
• 19 patients
• median follow-up of 36 months (range, 12 to

72 months)

R Saccardi et al, blood 2005

Auto-HSCT for MS: Quality of Life

treatment was followed by significant improvements in the physical and mental health composite scores

R Saccardi et al, blood 2005

Auto-HSCT for MS: Quality of Life

• Another retrospective study
• SF-36 questionnaire
• Total SF-36 score raise from 52.2 to 78.9

RK Burt et al, Lancet Neurol 2009

Auto-HSCT for MS: Ongoing Clinical Trails

L Griffth et al, BBMT in press

Auto-HSCT for SLE

• A single-arm trial
• 50 patients with SLE refractory to standard

immunosuppressive therapies

• Either organ- or lifethreatening visceral

involvement

• Peripheral blood stem cells
• Conditioning Regimen: CTX + ATG

RK Burt et al, JAMA 2010

Auto-HSCT for SLE

RK Burt et al, JAMA 2010

Auto-HSCT for SLE

• The level of ANA

RK Burt et al, JAMA 2010

Auto-HSCT for SLE

• The SLE Disease Activity Index

RK Burt et al, JAMA 2010

Auto-HSCT for SLE: heart failure

• Cyclophosphamide-based HSCT protocols is

the risk of cardiotoxicity

• A retrospective analysis of the Chicago group
• A subgroup of 6 patients with cardiac

dysfunction

• Conditioning Regimen: CTX + ATG/alemtuzumab

Y Loh et al, BMT 2007

Auto-HSCT for Type 1 Diabetes Mellitus

• Transplantation for MS and SLE

– patients are the most severe cases and generally have not responded to usual therapies. – significant mortality rates

• Type 1 diabetes mellitus

– Well controlled by insulin – Is HSCT necessary?

Auto-HSCT for Type 1 Diabetes Mellitus

• A prospective phase 1/2 study from Brazil

– 23 patients, aged 12 to 35 years. – diagnosis of type 1 DM by measurement of serum levels of anti–glutamic acid decarboxylase antibodies – Mobilization: CTX + G-CSF – Conditioning Regimen: CTX + ATG

Couri et al, JAMA 2009

Auto-HSCT for Type 1 Diabetes Mellitus

• 7- to 58-month follow-up (mean, 29.8 months;

median, 30 months)

– 20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free. – 12 patients maintained this status for a mean 31 months (range, 14-52 months) – 8 patients relapsed and resumed insulin use at low dose (0.1-0.3 IU/kg).

Couri et al, JAMA 2009

Auto-HSCT for Type 1 Diabetes Mellitus

• C-peptide

levels after HSCT

Couri et al, JAMA 2009

Auto-HSCT for Type 1 Diabetes Mellitus

• 2 patients developed bilateral nosocomial

pneumonia

• 3 patients developed late endocrine dysfunction
• 9 patients developed oligospermia
• no mortality

Couri et al, JAMA 2009

Auto-HSCT for RA

• A report from the EBMT and ABMTR
• 15 centers, 76 patients
• median age 42 yrs, 74% female, 86%

rheumatoid factor positive

• Significant functional impairment was present

– median Health Assessment Questionnaire (HAQ) score of 1.4 (range 1.1-2.0) – Steinbrocker score mean 2.39 (SD 0.58)

Snowden JA et al, J Rheumatol. 2004

Auto-HSCT for RA

• Conditioning Regimen:

– CTX – CTX + ATG – BuCy – CTX + TBI

• mostly through CD34+ selection

Snowden JA et al, J Rheumatol. 2004

Auto-HSCT for RA

• Responses were measured using the American

College of Rheumatology (ACR) criteria

– 67% achieved at least ACR 50% response at some point following transplant. – a significant reduction in the level of disability measured by the HAQ (p < 0.005).

• Most patients restarted DMARD within 6 months

for persistent or recurrent disease activity, which provided disease control in about half the cases

Snowden JA et al, J Rheumatol. 2004

Auto-HSCT for RA

• Response was significantly related to

– seronegative RA – number of previous DMARD – presence of HLA-DR4 – removal of lymphocytes from the graft – not to duration of disease

Snowden JA et al, J Rheumatol. 2004

Contents

• Rationale for HSCT
• Auto-HSCT for autoimmune disease
• Allo-HSCT for autoimmune disease

Is GVA effect exist?

• GVA effect= graft-versus-autoimmunity effect
• Demonstrated by a case of refractory evans’

syndrome treated with allogeneic SCT followed by DLI.

AM Marmont et al, BMT 2003

Allo-HSCT for RA

• High recurrence rate of RA
• Allo-HSCT may improve outcomes
• The morbidity of myeloablation followed by

allo-HSCT precludes its use as an RA therapy

• Only a handful of selected individual cases
• RK. Burt et al, ARTHRITIS & RHEUMATISM 2004

Allo-HSCT for RA

• A case report: a 52-year woman

– treatment-refractory RA – a poor prognosis (24 swollen and 38 involved joints).

• Conditioning Regimen :Fludarabine + cyclophosphamide +

CAMPATH

• donor : the patient’s HLA-matched, rheumatoid factor–

negative sister

• RK. Burt et al, ARTHRITIS & RHEUMATISM 2004

Allo-HSCT for RA

• RK. Burt et al, ARTHRITIS & RHEUMATISM 2004

Allo-HSCT for RA

• RK. Burt et al, ARTHRITIS & RHEUMATISM 2004

Allo-HSCT for SLE

• A case report: a 43-year chinese woman
• A vascular necrosis of the hip joint, lupus

nephritis, bed-bound

• HLA-matched sibling donor
• Pre-transplantation: anti-SSA+, anti-ANA+,

anti-U1RNP+, C3 1.23 g/l, C4 0.1 g/l and ESR 110 mm/h

Q Lu et al, BMT 2006

Allo-HSCT for SLE

• Conditioning regimen: BuCy + ATG
• GVHD prophylaxis: CsA and MMF
• CD34+ dose at 4.5*10E6/kg
• hematological recovery was prompt
• grade III acute GVHD with skin rash and

diarrhe

• no recurrence of SLE 26 months after

transplantation

Q Lu et al, BMT 2006

Conclusion

• Severe Autoimmune may result in severe

intractable health states

• haematopoietic stem cell transplantation

‘resetting’ the immune system

• Phase I/II data for auto-HSCT in autoimmune

have been published by a number of groups.

• The efficacy of HSCT varies in different

autoimmune diseases

• Allo-HSCT has only a few selected individual cases