Riccardo Saccardi Careggi University Hosp, Florence€¦ · Riccardo Saccardi Careggi University...

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)

5

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

7

HSCT FOR ADs DISEASE BREAKDOWN <> 2005

EBMT Registry March 2013*

1994-2004 (n=575) 2005-2012 (n=662)


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


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


% 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.


Patients selection


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

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Prob

abili

ty,

%

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

0

5

10

15

20

25

30

35

Year 1 Year 2 Year 3 Year 4

%

RelapsingProgressiveOverallP=0.007

P<0.001

P=0.04

P=0.03


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


Patients selection


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

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

6.5

7

7.5

8

8.5

9

9.5

10

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


Patients selection


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

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)



Patients selection


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


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


Riccardo Saccardi Careggi University Hosp, Florence€¦ · Riccardo Saccardi Careggi University...

Documents

Transcript of Riccardo Saccardi Careggi University Hosp, Florence€¦ · Riccardo Saccardi Careggi University...