A. Pepe, MD, Ph.D.
U.O.C. MRI , Fondazione Toscana G. Monasterio,
Pisa, Italy
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