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Riccardo SaccardiCareggi University Hosp, Florence
More than 2000 procedures were reported to the Registries
Most of available data are derived from small series and registry analysis
Comparative trials in major diseases are ongoing
Still some skepticism/lack of interest among referring specialists
Transplant technology
Patients selection
Endpoints definitions
Quality of data
Biobanking
4
HSCT for ADs: EBMT Registry January 2013 *
*All transplants not yet registered for 2012
EBMT Geneva 2012
• Transplant procedures 1508• Patients 1468• Male/Female (%) 39/61• Centres /Countries 229/32• Overall Follow up 2.9y (<1-24)
Autograftsn=1397
Allograftsn=111
First 1382 85Second 15 22
Third 4Median age at 1st transplant 36y (3-76) 14y (<1-69)
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Number of HSCT: 1508- EBMT Registry January 2013 *
*All transplants not yet registered for 2012
Title of the presentation ‐ Author
MULTIPLE SCLEROSIS 524CONNECTIVE TISSUE D. 458SSc 304 SLE 104 PM-DM 20Sjogren 3Antiphosph. syndrome 3Other/Unknown 24ARTHRITIS 175Rheumatoid arthritis 89Juvenile chronic arthritis :
- Systemic JIA 52 - Other JIA 18- Polyarticular JIA 10
Psoriatic arthritis 3Other 4INFLAMMATORY BOWEL 117Crohn's disease 99 Ulcerative colitis 4 Other 11
HAEMATOLOGICAL83
ITP25
Evans’19
AIHA19
Other 19
VASCULITIS43
Wegener’s 10
Behcet’s 8Takayasu
2 Microscopic poly. nodosa
3 Classical poly. nodosa
1 Churg-Strauss
HSCT in ADsDisease distribution/year
Both the availability of innovative drugs and emerging data about the efficacy of HSCT have modulated its application across the last 15 years
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HSCT FOR ADs DISEASE BREAKDOWN <> 2005
EBMT Registry March 2013*
1994-2004 (n=575) 2005-2012 (n=662)
Transplant technology
Saccardi R, Gualandi F, Autoimmunity, 2008
p = 10-3
Nash R Blood 2008
TBI/CTX CD34+, n = 36( 8 † TRM, † 4 SSc)
Vonk M Ann Rheum Dis 2008SSc: Durable regression of Skin fibrosis at 7 yrs
Verrecchia F J Rheum 2007
HD CTX CD34+, n = 26( 1† TRM, † 3 SSc)
• Patients with SP MS have longer progression-free survival following HSCT with intermediate-intensity conditioning regimens than with high-intensity conditioning regimens.
• The evidence was insufficient to determine whether the treatment was effective in patients with other types of MS.
Reston JT et Al, MSJ 2011
HSCT for ADs: Megafile analysisDeterminants PFS
The European Group for Blood and Marrow Transplantation
3 yrs PFS % Univariate Multivariate
Age < 35Age > 35
56±346±3
p=0.001 p=0.004, HR 1.3795%CI (1.1-1.7)
Year TX < 2001Year > 2001
43±359±3
p<0.0001 p=0.0015, HR 1.4795%CI (1.16-1.86)
Nb AHSCT AD >13Nb AHSCT AD ≤13
53±348±3 P=0.45
CONDITIONING-Low-Intermediate-High-Not specified
46±457±346±649+4
p=0.011
DIAGNOSIS P < 0.00001 p = 0.0007Farge et Al,
Haematologica2010,95(2):284-92.
Very early patients as compared to the previously reported data
81% of cases ameliorated by at least 1 or more EDSS points
Toxicity modest but not negligible neutropenic fever (5), zoster (2), C. difficilis diarrhoea (1), Hemorragic
cystitis (1) (+ AT in Campath series) out of 21 pts
Frequent relapses (23%) Need for prospective comparative trials
Canadian MS-BMT Trial
H Atkins, personal communication
EBMT ADWP GUIDELINES 2011
The European Group for Blood and Marrow Transplantation
Snowden et Al,
BMT 2011
CONDITIONING REGIMENS•High intensity conditioning regimens (including irradiation at any dose), should be restricted to clinical trial setting (level III).
•Intermediate intensity conditioning regimens provide a balance between safety and efficacy, whilst facilitating data analysis and clinical trial planning (level II):
•Cyclophosphamide 200mg/kg with polyclonal or monoclonal anti-T cell serotherapy is recommended generally;
•For multiple sclerosis specifically BEAM + ATG (or other anti-T cell serotherapy) is recommended.
Highly intense treatments do not seem to provide benefits over intermediate/low Irregular distribution of conditioning regimens and graft manipulation across the diagnosis Is low (Cyc±ATG) enough? Recent data with more intense regimens missing
Clinical monitoring Viral reactivations in the short/intermediate term
Nursing
Skin ulcers in SSc
Ulcers dressing scheme
Cover
Secondary dressing
Main dressing
Topical application
2° cleansing
disinfect
1 ° cleansingIRRIGATION ONLY
15 MIN/LESION
SIMPLE MEDICATION
COMPLEX MEDICATION
Degree of disability at baseline
(MS 5,7 days vs SS 0 days of complete dependance)
Hypersensibility to hyperthermia (infections/ATG)
High rate of diarrhoea
(4,5 gg with ≥3 evacuations a day)
Bladder Catheterization (average 15,7 days)
Motory rehabilitation
Emotional support to keep a realistic expectation of HSCT outcome with the patient and his/her family.
Biol Blood Marrow Transplant, 2012
Diagnosis n (%)
MS 160 (47)
SSC 97 (29)
SLE 27 (8)
Diabetes mellitus 22 (7)
Rheumatoid arthritis 10 (3)
Autoimmune cytopenia 7 (2)
Myasthenia gravis 3 (1)
Other* 13 (4)
Total 339Mortality was higher in patients from centers that performed ≤15 autologous HCTs for AID
The European Group for Blood and Marrow Transplantation
% TRM
Univariate Multivariate
Age>35Age<35
4±16±1
p=0.45
Year TX<2001Year TX ≥ 2001
5±14±1
p=0.53
Nb AHSCT AD >13Nb AHSCT AD ≤13
3±17±1
p=0.004 p=0.003, HR 0.3295%CI (0.16-0.69)
COND INTENSITY-Low-Intermediate-High-Not specified
4±13±15±26+1
p=0.51
DIAGNOSIS P < 0.0001 P=0.03
HSCT for ADs: Megafile analysisd100 TRM: 5±1%
Farge et Al, Haematologica2010,95(2):284-92.
Transplant technology
Patients selection
Endpoints definitions
Quality of data
Biobanking
Identification of early poor‐prognosis factors Definition of determinants of clinical response to HSCT Close interaction with referring specialists
Analysis of Registry database
Identification of Transplant‐related risk factors Risk/benefit analysis
Definition of highly active RRMSConsensus definition:
• ≥ 1 severe relapse/s (∆EDSS ≥ 1) and Functional Systems Scale (FSS) change of ≥ 2 in motor, cerebellar or brain stem deficit (or documented changes in neurological examination consistent with these magnitudes) and/or incomplete recovery from clinically significant relapses;
And
• ≥ 1 gadolinium-positive (Gd+) lesion of diameter ≥ 3 mm oraccumulation of ≥ 0.3 T2 lesions/month in two consecutive MRIs 6–12 months apart.
Saccardi et al., MSJ 18: 825 (2012)
Sospedra & Martin, Annu. Rev.Immunol. 2005
•Affects CNS in young adults (20-40 years)•Autoimmune inflammation, T and B cell-mediated •Relapsing vs. progressive forms/stages•Immuno-modulatory treatments incompletely effective
Multiple Sclerosis
Mult Scler J, 2012
n 74
Age 35.7 (16–53)
Baseline EDSS 6.3 (3.5–9)
Mobilization CTX + G‐CSF
Conditioning Reg BEAM/ATG
Follow‐up (months) 48.3 (0.8‐126)
p=0.009
Variable HR (95% CI) P-valueCIBMTR vs. EBMT 1.1 (0.81-1.5) 0.50Age 1.02 (1.0-1.04) 0.02Fem vs. Male 0.92 (0.67-1.25) 0.60Disease duration 1.0 (0.99-1.05) 0.26Conditioning IntensityInt vs. lowHigh vs. low
0.77 (0.51-1-17)0.88 (0.54-1.47)
0.44
ATG 1.27 (0.83-1.95) 0.27Other regimens vs. BEAM 1.08 (0.72-1.64) 0.70Progressive vs. Relapsing 1.72 (1.15-2.57) 0.01Chemoembolization 1.02 (0.58-1.82) 0.94>2 vs. 1-2 lines of therapy 1.46 (1.06-2.00) 0.022001-2006 vs. 1995-2000 1.18 (0.85-1.64) 0.34
Muraro et Al, EBMT 2013
Txz13_58.ppt
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Months0 962412 36 48 60 72 84
Progressive Forms
Relapsing Forms
PFS @ 5 years (P=0.008)Relapsing: 65% (95% CI, 51-76%)
Progressive: 42% (95% CI, 35-49%)
Disease* N HR (95% CI) P-value
Relapsing 63 1.00 -
Progressive 218 1.63 (1.06-2.5) 0.02
* Multivariate analysis Muraro et Al, EBMT 2013
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Year 1 Year 2 Year 3 Year 4
%
RelapsingProgressiveOverallP=0.007
P<0.001
P=0.04
P=0.03
Muraro et Al, EBMT 2013
At admission (‐8) At discharge (+15)
TMO Firenze+ 4 years
SSC PATIENT selection : EKG, cardiac echo with TAPSE, 24h Holter, MRI ,right heart catheter with fluid challenge = > update the EBMT guidelines
Saccardi R et al
Transplant technology
Patients selection
Endpoints definitions
Quality of data
Biobanking
In AD, the definitions of the end point of interest, especially of relapse and progression, need validation. They may be biologically and clinically distinct They are usually assessed through an activity score The definition of drug‐free remission is not universally accepted
A long‐term FU is usually required for a clinical assessment of efficacy
Concept of improvement
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J F M A M J L A S O N D J F M A M J L A S O N D J F M A M J L A S O N D J F M A M J L A S O N D J F M A M J L A S O N D J F M A M J L A S O N D J F M A M J
Mobilization CD34Cy 4g/m2 + G-CSF
HSCTBEAM + ATG
(*) MRI performed from 2003 to 2005 were all Gd-
Disease onset: Dec 1993
Last clinical relaspe: Jan 2001
Rebif44
Azatioprina
Mitoxantrone
2002 2003 2004 2005 2006 2007 2008
Patient (M) 36 years (at HSCT)
Patients Selection (1)Secondary Progressive
TMO Firenze
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0
J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N J M M Jl S N
Patients 129Male/Female 65/64
Corticosteroid
Rebif44
Azatioprina
Mitoxantrone
Mobilization CD34Cy 4g/m2 + G‐CSF
HSCTBEAM + ATG
Patient (F) 21 years (at HSCT)
* * *
(*) MRI performed in 2006 and 2007 were all Gd+despite immunosuppressive treatment
Patients Selection (1)
Clinical Relapse
Relapsing Remitting
Autoimmune Thyroiditis
TMO Firenze
Transplant technology
Patients selection
Endpoints definitions
Quality of data
Biobanking
Develop disease‐specific data forms Create an interdisciplinary group of transplantersand disease specialists Establish a data set to assess the disease status at baseline and at follow‐up
Hematological data can be collected with “conventional” forms through the Tx center
Disease‐specific data through the referring specialist
Muraro et Al, EBMT 2013
Characteristics N=281 (%)EBMT 170 (60) CIBMTR 111 (40)Centers (EBMT/CIBMTR) 25 (17/8)Age, median (range) 37 (15-65)Age<40y 171 (61)Female 164 (58)Follow up yrs median (range) 6.6 (0.2-16)
Muraro et Al, EBMT 2013
Transplant technology
Patients selection
Endpoints definitions
Quality of data
Biobanking
The immune “resetting” hypothesis in HSCT
Original data on mechanistic issues were generated by single center trials with a defined program of biobanking
Clinical data are available/acquirable for most patients reported to the Registries but biological samples are usually missing
General guidelines about basic characterization and storage of biosamplesare needed
CONCLUSIONSHSCT for the treatment of Autoimmune Diseases
• HSCT is capable to induce a major clinical response, free of immunosuppressive treatment, in most of patients diagnosed with a severe autoimmune diseases, refractory to approved therapies.
• Duration of the response is extremely variable, diagnosis being the major determinants of such variability. Clinical relapses show a better response to conventional treatment.
• The transplant activity should be in line with published guidelines and performed within institutional trials, approved by the competent authorities.
• It is an interdisciplinary medical activity across all the phases of the process
The European Group for Blood and Marrow Transplantation
HSCT FOR SEVERE ADs
• Paris– D. Farge– M. Badoglio– M. Labopin
• Genova– GL Mancardi– A Uccelli– MP Sormani
• Newcastle– J Van Laar
• Sheffield– J Snowden
• Prague– T Kozac– E Havradova
• Zurich– R Martin
• Barcelona– M Rovira– A Saiz
• Firenze– M Di Gioia– I Donnini
• Basel– A Gratwohl– A Tyndall
• Nottingham– C Hawkey
• London– P Muraro– M Kasmi
• Thessaloniki– A Fassas
• CIBMTR– M Pasquini– S Pavletic
• NIH– L Griffith
The European Group for Blood and Marrow Transplantation