© 2019 Medis Medical Imaging Systems

Update on iron overload assessment with MRIEissa Agour, PhD Netherlands

Value of MRI for iron overload

MR analysis

Trace treatment response with MRI

CONTENTSOverview on iron overload

Iron overload monitoring

Summary

Clinical cases

© 2019 Medis Medical Imaging Systems

IRON OVERLOAD OVERVIEW

Common causes of iron overload and possible complications

Primary: • Hereditary haemochromatosis (HHC): HFE gene are associated with up to 90 percent of cases

Secondary: • Transfusional: Iron overload is common in patients on intermittent or regular blood transfusions

• Non-Transfusional: Chronic liver disease

Pituitary gland

Heart

Liver

Pancreas

Gonadal

Increased iron uptake can cause organs damage

Possible complications in iron overload

Cirrhosis/Liver Failure

Increased Iron uptake Non-transferrin-bound into plasmaProduction of Free hydoroxyl radicals Fibrosis

Heart FailureHealthy heart

Healthy Liver

It is important to monitor iron progress to prevent further complications

The importance of monitoring affected organs

For early detection of iron overload before advanced complications

Decide on dose for chelation and delivery modes.

Adjust transfusion plans

Monitor the response of the treatment.

Based on the result, you can update the treatment plans

Diagnosis

Treatment plan

Monitor response

© 2019 Medis Medical Imaging Systems

METHODS TO ASSESS IRON OVERLOAD

Methods to assess iron depositionBL

OO

D TE

ST- S

ERU

M F

ERRI

TIN

Easy Affordable cost Allows longitudinal follow-up

LIVE

R BI

OPS

YDirect measurement of iron Provides info in histology/pathology T2

* M

RI: L

IVER

& C

ARDI

AC

Direct measurement of iron Iron status Aassessment of liver and heart Allows longitudinal follow-up

Blood Test

Serum Ferritin

Brittenham et al. Am J Hematol. 1993;42:81, Origa R, et al. Haematologica. 2007;92:583-8., Taher A, et al. Haematologica. 2008;93:1584-5.

.

SERUM FERRITIN

Sickle cell anemiaThalassemia major

• Indirect measurement • Fluctuates in response to inflammation and abnormal liver function • Underestimates iron overload in thalassemia intermedia

Liver Biopsy

Liver Biopsy

Angelucci E, et al. N Engl J Med. 2000;343:327-331

LIVER BIOPSY

Liver iron concentrations correlate to the total body iron stores

Invasive and painful Sampling error Inadequate standardization between laboratories. Difficult to follow up

Liver

MRI and analysis

Angelucci E, et al. N Engl J Med. 2000;343:327-331

MRI

Liver

• Requires dedicated MRI sequence and analysis

T2*= 5.1ms

Today's challenges to assess iron overload with MRI

Blood test result is influenced by other factors Enhance patient outcome through disease progression Difficult to accurately assess and follow up liver iron status without invasive biopsies. Complicated image interpretation

Referring PhysicianRadiologist

Concerns about images quality to support decisions making

Concerns for Diagnosis accuracy

Lack of Standardization and reproducibility

13

Value of MRI:

✓ Evaluate the iron progression in liver and heart

✓ CMR can quantitatively assess myocardial iron load

✓ CMR can evaluate the heart function through the treatment period

T2 and T2* MRI for tissue iron assessment

• Signal intensity decreases by the paramagnetic effect of iron

• The time constant of decay for the relaxation time T2 is inversely proportional to the myocardial iron content.

• The more the iron content, the shorter are the T2 and T2*, the time constant of decay for spin echo and gradient echo-induced relaxation time, respectively

Decreasing Echo Time (TE)

Normal Mild Moderate Heavy

V Berdoukas

E Angelucci (mg/g)

3 – 6.6

3 – 6.9

6.6 – 16

7 – 14

>16.1

>14

T2* (ms) > 6.3 2.8 - 6.3 1.4 - 2.7 < 1.4

T2*= 5.1ms

V Berdoukas et al JCMR 2009 2. E Angelucci et al NEJM 2000

Liver

Normal Mild Heavy

T2* (ms) > 20.0 10.0 – 20.0 <10.0

R2* (s-1) <50 50-100 >100

T2*= 5.7ms

Carpenter et al. JCMR 2009, v 11, P224 Carpenter et al. Circulation 2011

Heart

MRI to assess cardiac function after iron overload

cardiac functionIn addition to iron overload quantification, CMR imaging can assess:

• LVEF, LV-End-systolic & LV-E-diastolic volumes

• Left ventricular mass

• Myocardial ischemia

• Myocardial viability

Myocardial viability

Kirk P, et al. Circulation. 2009;120

Left ventricular ejection fraction (LVEF)

T2* value versus arrhythmia and heart failure

Kirk et al. Circulation. 2009 Nov 17;120(20):1961-8 Marsella et al. Haematologica April 2011 96: 515-52

Lower T2* values are associated with increased risk of heart failure

Lower T2* values are associated with increased risk of arrhythmia

Prop

ortio

n of

pat

ient

s with

arr

hyth

mia

Prop

ortio

n of

pat

ient

s with

hea

rt fa

ilure

Lower cardiac T2* value is associated with heart dysfunction and arrhythmias

Maria Marsella et al. Haematologica 2011;96:515-520

Heart dysfunction Arrhythmias

■ Cardiac T2* can predict cardiac complications and heart failure (e.g. in Thalassemia Major)

■ 98% of patients who developed heart failure had T2* <10 ms.

Kirk P, et al. Circulation. 2009;120

THERAPY - IRON CHELATION TREATMENT

Therapy of iron overload states is important to prevent or reverse cardiac dysfunction

Deferoxamine, deferiprone, and deferasirox are the 3 iron-chelating drugs approved by the United States for management of chronic secondary iron overload.

Comparison of combined Deferiprone and Deferoxamine therapy vs. Deferiprone or Deferoxamine monotherapy

Pepe A. et al. J Cardiovasc Magn Reson. 2013 Jan 16;15:1

Combined DFP +DFO is more efficient for liver iron clearance

Liver Heart

But NOT for the heart-without effect on heart function, after 18 months.

Combined chelation therapy with subcutaneous Deferoxamine and oral Deferiprone reduces myocardial iron and improves cardiac function.

ESVI: LV end-systolic volume index

Myocardial and Liver T2* improved over 12 months

Improvement in LVEF and ESVI over 12 months.

Reduced iron after 3 years of therapy

Reduction in Cardiac Iron

Enhanced T2* value after 3 years of EXJADE therapy

EXJADE JADENU® (deferasirox)

Reduction in Liver iron concentration

CLINICAL CASES

22 YEAR OLD MALE, THALASSEMIA MAJOR

2015 Received 1 packed cell every 15 days • Oral Deferoxamine. • EF: 60% • T2*: 9.4 ms

1.5 years later • Chelation changed to IV Deferoxamine • EF increased to 63% • T2*: 10.5 ms.

Courtesy of Dr. Zahra Hoodbhoy and Dr. Babar Hasan, Department of Paediatrics and Child Health, Aga Khan University

15 YEAR OLD MALE, THALASSEMIA MAJOR, NYHA CLASS 1

28

2016 Received 1 packed cell every 15 days • On daily oral defesirox • EF: 63% • T2*: 6.2 ms

2 years later • EF increased to 65% • T2*: 10.1 ms.

Courtesy of Dr. Zahra Hoodbhoy and Dr. Babar Hasan, Department of Paediatrics and Child Health, Aga Khan University

Summary

• Therapy of iron overload states is important to prevent or reverse cardiac dysfunction

• The aim of the treatment is to prevent possible organs damage

• MRI is a useful tool to monitor treatment and response

• MRI can measure iron overload using T2* MRI and assess cardiac function using cine MRI

• Dedicated post-processing tool is needed to analyse T2* MR images and cine MR images

• A reduction in LVEF correlates with the myocardial iron content measured by T2* relaxation time

• Patients with a T2* relaxation time of less than 10 ms are at high risk for developing congestive heart failure and

need chelation therapy

• Iron management future is to be able to provide personalized chelation plan for different damaged organ