The MIOT network: an Italian model for management of … - Palermo sep 2017.pdf · 2017. 10. 4. · 2016 2016 MIOT recognized as one of the biggest thalassemia data base in the world

A. Pepe, MD, Ph.D.

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

Pisa, Italy

[email protected]

The MIOT network:

an Italian model for

management of

Thalassemia

Syndromes

Following the Policy of the National Regulation 3.3 , page 17, on CME

disclosures, dated 5 November 2009, and on behalf of the Provider , -

Collage S.p.A.- n. 309

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.

I understand that continuing education accreditation guidelines prohibit me

from accepting any reimbursement (financial, gifts or in-kind exchange) for

this presentation from any source other than the accredited CME provider (

Collage S.p.A.)

15-16 September, 2017

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

Myocardial Iron Overload in Thalassemia

MIOT- network

• > 1000 availabilty MR scans/yr

• Standard acquisition and post-processing

• Central web based data-base

70 centers

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

Myocardial Iron Overload in Thalassemia

MIOT- network

A. Meloni, A. Ramazzotti, V. Positano, C. Salvatori, M. Mangione, P. Marcheschi, B. Favilli, D. De Marchi, S.

Prato, A. Pepe, G. Sallustio, M. Centra, M.F. Santarelli, M. Lombardi, L. Landini

International J Medical Informatics 2009

Mean dist = 387 km

Only Pisa

mean dist = 951 km

MIOT data base

2006

Dec, 2016

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%)

C- Borgna-Pignatti, A. Meloni, G. Guerrini, L. Gulino, Aldo Filosa, Giovan B. Ruffo, T.

Casini, E. Chiodi, M. Lombardi, A. Pepe

Br J Haem 2014

Myocardial iron pattern in pediatric TM patients

Clinical significances

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

Myocardial fibrosis in TM pediatric pts

detected in 12 (15.8%) of the 76 patients that completed the MRI

protocol.

The youngest patient with fibrosis had 13 yrs of age NO

contrast medium < 12 yrs

Casale M, Meloni A, Filosa A, Cuccia L, Caruso V, Palazzi G, MD; Gamberini MR, Pitrolo L, Putti MC, Domenico Giuseppe

D’Ascola DG, Casini T, Quarta A, Maggio A, Neri MG, Positano V, Salvatori C, Toia P, Valeri G Midiri M, Pepe ACirculation Cardiovasc Imag 2015

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

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 by MIOT:

monotherapy

Prospective comparisons inter-treatment in pts with

basal T2* in the mid-ventricular septum≥ 8 and ≤ 20 ms

Combined

MIOT

JCMR 2013

(n = 17)

DFO

MIOT

(n = 16)

Combined

Tanner

Circulation 2007

(n = 28)

DFO

Tanner

(n = 30)

Basal Heart T2* (ms) 12.6 13.7 11.7 12.4

Post Heart T2* (ms) 17.1 17.0 17.7 15.7

Diff Heart T2* (ms) +4.46 +3.3 +6.0 +3.3

DFP Dose (mg/kg/d) 74 75

DFP Frequencies (days/week) 6.8 7

DFO Dose (mg/kg/d) 40.9 41.6 34.9 43.4

DFO Frequencies (days/week) 3.4 5.5 5 5

DFO global dose (mg/kg/week) 139 174

DFP global dose (mg/kg/week) 503 525

DFO global dose (mg/kg/week) *Compliance

131 159

DFP global dose (mg/kg/week)

*Compliance474 433

A. Pepe, A. Meloni, G. Rossi, L. Cuccia, G.D. D’Ascola, M. Santodirocco, P. Cianciulli,V. Caruso, M.A. Romeo, A. Filosa,

L. Pitrolo, M.C. Putti, A. Peluso, S. Campisi, M. Missere, M. Midiri, L. Gulino,V. Positano, M. Lombardi, P. Ricchi

J Cardiovasc Mag Res 2013

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

2006-

2016

2016

MIOT recognized as one of the biggest

thalassemia data base in the world

(Berdoukas and Wood Haematologica 2011)

MIOT today

Source: Scopus 31/12/2016

Papers: 52

Sum of Times Cited : 952

H-index: 18

Diabetes and thalassemia major

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

Br J Haematology 2013

♥ Prevention of glucose disorder metabolism,

particularly in young patients

♥ To intensify the chelation therapy in patients

in whom excess pancreatic iron is found

or when patients develop glucose metabolism

disorders

♥ Improvement is possible (Farmaki et al BJH,

2006)!

Why measure

Pancreatic Iron Concentration?

Pancreas T2*

G. Restaino, A. Meloni,V. Positano, M. Missere, G. Rossi, L. Calandriello, P. Keilberg, O.

Mattioni, A. Maggio, M. Lombardi, G. Sallustio, A. Pepe

MRM 2011

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

Why an accurate pancreatic

monitoring of iron loading?

(Pepe A. et al ASH 2014)

eMIOT

Multicenter,

sperimental,

controlled,

5 years,

“no-profit”,

Data collectionData sharing and storing

• 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

• Filomena Santarelli, PhD: sequences development

• Luigi Landini, Prof.: engineering skills coordinator

• Paolo Marcheschi, MSc: development and management website

• Giuseppe Rossi, MSc: bio-statistician

• Daniele De Marchi, RT: radiologic technologist

• Petra Keilberg, RT: radiologic technologist

• Claudia Santarlasci: secretary

CL

AU

DIA

MA

UR

IZIO

GIU

SE

PP

EA

NT

ON

EL

LA

LA

UR

A

AL

ES

SIA

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