Evidenze dal MIOT network

A. Pepe, MD, Ph.D.

U.O.C. MRI , Fondazione Toscana G. Monasterio, Pisa, Italy

alessia.pepe@ftgm.it

I Alessia Pepe HERE DECLARE

DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS

MIOT and E-MIOT were “no profit “ supported by Chiesi SPA,

Apopharma Inc. and Bayer.

28 September, 2018

Why MIOT in 2004 ???

No systematic

multiregional

databases

T2*

T2*

RGDr Spadola

LEDr RenniDr ColaciDr Cavalli

PADr Cuccia

Prof Maggio-Dr Pitrolo

SRDr Campisi

Dr Commendatore

RomaDr SorrentinoProf Smacchia

NAProf Boffa

Dr Filosa- Dr Spasiano

AG Dr GerardiDr Argento

KRDr Allò

CADr Spiga- Prof Moi

FIDr Casini

CTDr CarusoDr Rosso

Dr Giugno

MEDr Rigoli

Dr Roccamo

MODr Palazzi

CLDr Fiorenza

Dr Quota

FEProf Borgna

Dr Gamberini

PDDr Putti

ANDr Maddaloni

BRDr Quarta

FGDr Dello Iacono

Dr Roberti

MTDr

Ciancio

BODr Benni

Dr Facchini

RCDr D’Ascola

Dr Errigo

VRProf De Franceschi

Dr Armari

PGDr Caniglia

RODr Mattei

TNDr Scaccetti

PEDr Pulini

BADr Sardella

Prof Pietrapertosa

TPDr Carollo

TADr PelusoDr Sarli

CSDr Bisconte

OTDr Massa

PRDr Barone

PZDr Grippo

PCDr Carrà

SSDr CosmiDr Cirotto NU

Dr Bitti

SIDr Caini

ORDr Murgia

ARDr De Bari

Dr Paci

RADr Macchi

REDr Romano

VVDr Santamaria

PUDr Leopardi

MIOT/eMIOT network

66 centers

Open system !!!!!

11 MR centers

– HEART

– LIVER

– PANCREAS

Cause of death in thalassemia

( Borgna-Pignatti C et al. Haematologica 2005)

CAUSE OF DEATH IN THALASSEMIA MAJOR

All patients Patients born after 1970

% %

Heart Failure 60.2 50.8

Infection 6.8 14.8

Arrhythmia 6.8 6.6

Myocardial infarction 1.8

Cyrrhosis 4.1

Thrombosis 4.1 3.3

Malignancy 3.6 3.3

Diabetes 3.2 3.3

Accident 1.8 1.6

Renal Failure 1.4

HIV/AIDS 1.4 3.3

Iron overload cardiomyopathy:

how to do the diagnosis in 2004

Cardiac symptoms and signs

Lab Test (serum ferritin)

LIC

Ecocardiography

correlation with heart iron

correlation with heart iron

late

late

Cardiac biopsy Invasive and low sensitivity

Heterogeneity of iron

distribution in

haemochromatotic

myocardium

Jensen

MAGMA 2001

Olson

JACC 1987

Olson

JACC 1989

Buja

Am J Med 1971

Fitchett

Cardiov Res1980

Grugre NR

Mag Res Med 2006

House MJ

J Card Mag Res 2014Grugre NR

JMRI 2006

Mapping iron in human heart tissue

(House MJ J Card Mag Res 2014)

Heart T2* multislice technique

(International Patent PCT/IB2006/000880)

(Chu W et al JMRI 2012)

(Pepe A. et al. JMRI 2006)

(Ramazzotti A. et al. JMRI 2009)

CV = 9%

ICC=0.96

Primary Aim: validation

MIOT data base today

2006

2018

MIOT recognized as one of the biggest

thalassemia data base in the world

(Berdoukas and Wood Haematologica 2011)

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

19

25

60 64

10085

129118

190

159 153131

Source: Scopus 03/07/2018Papers: 65Sum of Times Cited : 1225H-index: 21

Pennell DG Circulation 2013

Frequency of cardiac iron overload in TM

Frequency (%)

CountrySample size,

N

Severe:

T2* < 10 ms

Mild to

moderate:

T2* 10-20 ms

Normal:

United Kindom 109 20 43 37

Hong Kong 180 26 24 50

Turkey 28 46 39 14

Australia 30 37 27 37

Oman 81 24 22 54

United States 141 13 21 66

Italy (Sardinia) 167 13 (< 8 ms) 52 ( 8-20 ms) 35

Italy (MIOT) 220 30% < 20 ms 66

Greece 159 68% 32

Worldwide survey 3445 20 22 58

Pennell DG Circulation 2013

Frequency of cardiomiopathy in TM

Geographic AreaPatients

N

LV dysfunction

N (%)

Tanner MA et al

J Cardiovasc Mag Res 2006Italy (Sardinia) 167 19 (11.4%)

Marsella M. et al.

Haematologica 2011Italy (MIOT) 776 147 (19%)

Clinical significances for different pattern

Meloni A, Restaino G, Borsellino Z, Caruso V, Spasiano A, Valeri G, Zuccarelli A, Toia P, Salvatori C,

Positano V Midiri M, Pepe A

Int J Card 2014

812 TM pts

Chelation therapy and compliance

70% of the patients changed

chelation therapy (type and/or

dose-frequencies)

Meloni A, Positano V, Ruffo GB, Spasiano A, D'Ascola DG, Peluso A, Keilberg P, Restaino G, Valeri G, Renne S,

Midiri M, Pepe A.

European Heart Journal - Cardiovascular Imaging 2015

87.793.7

MIO iron pattern in the MIOT network

in thalassemia major

Myocardial T2* and risk of cardiac complications

At 24 months follow up 527 TM pts

Heart failure or death 4

Arrhythmias 13

Pulm. Hypertension 1

Others 3

Cardiac events 21

At 24 months follow up 652 TM pts

Death 4

Heart failure 80

Arrhythmias 98

Cardiac events 182

Kirk P et al. Circulation 2009Pepe A. et al Eur Heart J Cardiovasc Imag 2017

Homogeneous HR = 5.56; P = 0.016

Myocardial T2* and cardiac function

(Anderson LJ et al. Eur Heart J 2001)

(Marsella M et al Haematologica 2011)

A. Pepe, V. Positano, M. Capra, A. Maggio, C. Lo Pinto, A. Spasiano, G. Forni, G. Derchi, B.

Favilli, G. Rossi, E. Cracolici, M. Midiri, M. Lombardi

Heart 2009

• LGE: 24% (28/115) pts

• Location of DE aspecific and no endo-

epicardial: 93% (26/28) pts

• LGE followed coronary distribution: 2 pts

Late Gadolinium Enhancement

in thalassemia major

Myocardial fibrosis by LGE in thalassemia major

HCV-RNA + DM +DM +

HCV RNA +

OR P OR P OR P

Myocardial fibrosis

(LGE)0.98 0.946 0.86 0.864 2.69 0.007

HCV infection Myocardial fibrosis

myocarditis

DM

A. Pepe, A. Meloni, G. Rossi, V. Caruso, L. Cuccia, A. Spasiano, C. Gerardi, A. Zuccarelli, D. D’Ascola, S. Grimaldi, M.

Santodirocco, S. Campisi,11 M.E. Lai, B. Piraino, E. Chiodi, C. Ascioti, L. Gulino, V. Positano, M. Lombardi, M.R. Gamberini

Br J Haematology 2013

Why a multiparametric CMR approach?

Pepe A, Meloni A, Rossi G, Midiri M, Missere M, Valeri G, Sorrentino F, D’Ascola GD, Spasiano A, Filosa A, Cuccia L,

Dello Iacono N, Forni G, MD11; Vincenzo Caruso V, Maggio A, Pitrolo L, Peluso A, De Marchi D, Positano V., Wood JC

Eur Heat J Card Imag 2017

(Wood JC et al Haematologia 2008)

Onset of cardiac iron loading in pediatric TM patients

35 pts < 10 yrs

Borgna Pignatti C et al Br J Haem 2014

First CMR for cardiac T2* should be performed as soon as the child can

cooperate without sedation

Pennell DJ et al Circulation 2013

A. Pepe, A. Meloni, M. Capra, P. Cianciulli, L. Prossomariti, C. Malaventura, M.C.Putti, A.Lippi, M. A. Romeo, M.G. Bisconte,

A. Filosa, V. Caruso, A. Quarta, L. Pitrolo, M. Missere, M. Midiri, G. Rossi, V. Positano, M. Lombardi, A. Maggio

Haematologica 2011

EBM on chelation therapy in MIOT:

monotherapy by cross-sectional view

A. Pepe, A. Meloni, L. Pistoia, L. Cuccia, M.R. Gamberini, R. Lisi, G.D. D’Ascola, R. Rosso, M. Allò, A. Spasiano, G.

Restaino, R. Righi, M. Mangione,1 V. Positano, P. Ricchi

Br J Haemat 2018 (in press)

EBM on chelation therapy in MIOT:

monotherapy by prospective survey

One-year model all treatments equal effect

on cardiac morbidity and mortality

Drug costs

(€)

Administration

costs (€)

Monitoring

costs (€)

Total

costs (€)

QALYs

Ferriprox® (5,109) (0) (271) (5,380) (0.840)

Exjade® (34,164) (0) (334) (34,498) (0.840)

Desferal® (11,885) (2,600) (170) (14,656) (0.712)

Pepe A, Rossi G, Bentley A, Putti MC, Frizziero L, D'Ascola DG, Cuccia L, Spasiano A, Filosa A, Caruso V, Hanif A, Meloni A

Clin Drug Investigation 2017

New start….

Multicentric

experimental

five-year

Pancreas T2* and Heart

R=0.330, P<0.0001

A. Meloni, G. Restaino, M. Missere, D. De Marchi, V. Positano, G. Valeri, D.G. D’ascola,

A. Peluso, M.C. Putti,7 M. Lendini, M.G. Neri, M. Midiri, G. Sallustio, A. Pepe

Am J Haem 2015

Primary aim: validation for pancreatic T2*

A. Meloni A, D. De Marchi, L. Pistoia, E. Grassedonio, G. Peritore, P. Preziosi, G. Restaino, R. Righi, A.

Riva, S. Renne, N. Schicchi, A. Vallone, A. Peluso, C. Gerardi, V. Positano, A. Pepe

Eur Rad 2018 (in press)

• Alessia Pepe, MD, PhD: chief project and scientific coordinator

• Antonella Meloni, PhD: post-processing and tools management

• Laura Pistoia, PhD: ethics consultant and data base management

• Maurizio Mangione, MSc: website development and management

• Andrea Olivi, MSc: website development and management

• Filomena Santarelli, PhD: sequences development

• Luigi Landini, Prof.: engineering skills coordinator

• Paolo Marcheschi, MSc: development and management website

• Stefano, Salvadori MSc: bio-statistician

• Daniele De Marchi, RT: radiologic technologist

• Petra Keilberg, RT: radiologic technologist

• Claudia Santarlasci: secretary

CL

AU

DIA

MA

UR

IZIO

LA

UR

A

AL

ES

SIA

AN

TO

NE

LL

A

RGDr Spadola

LEDr RenniDr ColaciDr Cavalli

PADr Cuccia

Prof Maggio-Dr Pitrolo

SRDr Campisi

Dr Commendatore

RomaDr SorrentinoProf Smacchia

NAProf Boffa

Dr Filosa- Dr Spasiano

AG Dr GerardiDr Argento

KRDr Allò

CADr Spiga- Prof Moi

FIDr Casini

CTDr CarusoDr Rosso

Dr Giugno

MEDr Rigoli

Dr Roccamo

MODr Palazzi

CLDr Fiorenza

Dr Quota

FEProf Borgna

Dr Gamberini

PDDr Putti

ANDr Maddaloni

BRDr Quarta

FGDr Dello Iacono

Dr Roberti

MTDr

Ciancio

BODr Benni

Dr Facchini

RCDr D’Ascola

Dr Errigo

VRProf De Franceschi

Dr Armari

PGDr Caniglia

RODr Mattei

TNDr Scaccetti

PEDr Pulini

BADr Sardella

Prof Pietrapertosa

TPDr Carollo

TADr PelusoDr Sarli

CSDr Bisconte

OTDr Massa

PRDr Barone

PZDr Grippo

PCDr Carrà

SSDr CosmiDr Cirotto NU

Dr Bitti

SIDr Caini

ORDr Murgia

ARDr De Bari

Dr Paci

RADr Macchi

REDr Romano

VVDr Santamaria

PUDr Leopardi

Thanks

!!!

PIDr Massei