the impact of mri in changing prognosis of thalassemia major. st. pierre - 15-16 sep... ·...

The impact of MRI in changing prognosisof ThalassemiaMajor

Tim St Pierre

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 (Tim St Pierre) HERE DECLARE

DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS

YES, -over the past two years – I do have a personal financial relationship with a commercial interest and control over educational content related to the products and/or services of the commercial interest(s).

*if yes please provide information below. - Resonance Health Ltd - FerriScan- …………………………………………....-NO, have no relevant personal financial relationship in the medical/health field.

DISCLOSURE OF PROMOTIONAL TALKS

NO, I have not presented any promotional talks for any pharmaceutical companies within the past 12 months

YES, I have presented promotional talks for one or more pharmaceutical companies within the past 12 months

*if yes please provide information below.- …………………………………………….- …………………………………………….

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 Tim St Pierre

How can a diagnostic test improve clinical outcome?

• Diagnostic test does not DO anything to a patient

• Impact of diagnostic test can result from • its influence on decision making regarding interventions

• its influence on patient adherence to treatment regimens

• Clinical decision making relies upon the predictive power of the test

What evidence do we have that MRI measurements of tissue iron have an impact on outcomes?

• What is the evidence that MRI measurements of tissue iron concentration are predictive of outcome?

• What is the evidence that clinical decisions are determined at least in part by MRI measurements?

• What is the evidence that patient adherence to treatment regimens is improved after MRI measurements?

• What is the evidence that clinical outcomes are improved when MRI measurements are used?

How can impact of a diagnostic test or monitoring tool be measured?

• Ideally measured in randomised study comparing outcomes for patients with and without the diagnostic test or monitoring tool

• Ethical problems arise for such studies if test is already perceived to be useful

• Retrospective or observational studies can give supporting evidence but are confounded by other factors

Predictive power of tissue iron measurements

LIC is a surrogate measure of total body iron stores (TBIS) in patients with thalassaemia major

There is a very strong correlation between LIC and total body iron stores in thalassaemia major patients

Angelucci et al (2000) N Eng J Med 343, 327

LIC and long-term prognosis

LIC(mg Fe/g dw)

13 year Cardiac Disease Free Survival

Number Patients Group

< 7 93.3% (SE 6.4) 15 (i)

7 – 15 71.4% (SE 17.1) 7 (ii)

> 15 50.0% (SE 15.8) 10 (iii)

Telfer et al (2000) BJH 110: 971-977

32 thalassaemia major patients followed for median period of 13.6 years after single biopsy LIC measurement

Iron in the heart indicates risk heart disease and heart failure within 12 months

Kirk P, et al. Circulation. 2009;120:1961-8.

T2* < 10 ms, relative risk 159, p < 0.001

T2* < 6 ms, relative risk 268, p < 0.001

Cardiac failure

Pro

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Follow-up time (days)

600 120 180 240 300 360

0.3

0.2

0.1

0

0.4

0.5

0.6< 6 ms

6–8 ms

8–10 ms

> 10 ms

Arrhythmia

600 120 180 240 300 360

0.15

0.10

0.05

0

0.20

0.25

0.30

< 10 ms

10–20 ms

> 20 ms

T2* < 20 ms, relative risk 4.6, p < 0.001

T2* < 6 ms, relative risk 8.65, p < 0.001

Follow-up time (days)

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Studies on the Impact of MRI Tissue Iron Measurements

Modell, et al. (2008) J Cardiovasc Magn Reson, 10: 42.

• 850 thalassemia major patients in UK

• Retrospective study

• Compare rates of death pre and post 1999

• Post 1999 data includes data up to 2003

• In 1999• Cardiac T2* was introduced

• UK Register information on continuing high mortality circulated to all collaborating doctors

Modell, et al. (2008) J Cardiovasc Magn Reson, 10: 42.

Number of deaths of patients with thalassaemia major in the UK by intervals

Modell, et al. (2008) J Cardiovasc Magn Reson, 10: 42.

Investigators identified possible factors for dramatic drop in deaths post 1999

• Introduction of cardiac T2* for identifying patients requiring intensified chelation therapy (considered the most relevant factor)

• Improved application of conventional methods for assessing cardiac function

• Communication of the need for vigilance of heart disease to treating doctors

• The referral of patients to expert centres for assessment

• The promotion of new developments to patients, nurses and doctors by the UK Thalassaemia Society

Modell, et al. (2008) J Cardiovasc Magn Reson, 10: 42.

Investigators concluded:-

Since 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload.

The most likely causes for this include

• the introduction of T2* CMR to identify myocardial siderosis

• appropriate intensification of iron chelation treatment,

• other improvements in clinical care.

Chouliaras, et al. (2011) JMRI, 34: 56.

• 804 thalassemia major patients

• Retrospective study (period 2003 to 2009)

• Most patients had access to DFO, DFP, or combination therapy during the period of study

• Note that DFX became available in 2006

• Numbers of cardiac deaths recorded for pre-MRI and post-MRI patients

• Risk of cardiac death per 1000 patient years calculated

Chouliaras, et al. (2011) JMRI, 34: 56.

P = 0.22

Chouliaras, et al. (2011) JMRI, 34: 56.

The investigators concluded:

MRI has become a vital component of ongoing management and seems to have a beneficial effect on cardiac mortality in thalassemia major.

Origa, et al. (2013) British J Haematol, 163: 400.

• 313 thalassaemia major patients

• Cardiac T2* measurements between 2002 – 2012

• 157 male & 156 female

• Mean age at first scan 26.7 ± 6.2 y

Origa, et al. (2013) British J Haematol, 163: 400.

Change in chelator much more likely for patients with low cardiac T2*

Origa, et al. (2013) British J Haematol, 163: 400.

Frequencies of cardiac T2* values for patients who did and did not develop arrhythmia or cardiac failure within one year of scan

Origa, et al. (2013) British J Haematol, 163: 400.

The investigators concluded:-

• Abnormal cardiac T2* values determined changes in treatment in most subjects.

• Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias.

• 327 transfusion dependent thalassemia patients

• Followed in period 2002 – 2011

• Mean follow-up 8.0 years (4.4 – 9.0 years)

• DFX > DFO > Combination therapy

• MRI iron measurements increased >5 fold

• 80% increase in number patients receiving LIC measurements

Kwiatkowski, et al. (2012) Blood, 119: 2746.

• Median LIC dropped• 10.7 => 5.1 mg Fe/g dw

• P < 0.001

• Median Cardiac T2* increased• 23.55 => 34.50 ms

• P = 0.23

• Fraction of patients with ftn>2500 ng/mL or LIC > 15 mg Fe/g dw or cardiac T2* < 10 ms• 33% => 26%

Kwiatkowski, et al. (2012) Blood, 119: 2746.

• Investigators concluded• Increasing use of magnetic resonance imaging and oral

chelation in thalassemia management has likelycontributed to improved iron burden

Kwiatkowski, et al. (2012) Blood, 119: 2746.

Evidence of Clinical Decision Making Based on MRI Tissue Iron

Measurements

• Retrospective study (period 2002 to 2008)

• 40 transfusion dependent patients

• Followed for 1.0 to 6.1 years (median 3.4 years)

• Liver R2-MRI measurement at baseline

• Median number of LIC measurements 5 (range 2-9)

Brown, et al. (2012) Internal Medicine Journal, 42: 990.

Brown, et al. (2012) Internal Medicine Journal, 42: 990.

Documented clinical decision making based on LIC

Improvements in iron burden observed

Brown, et al. (2012) Internal Medicine Journal, 42: 990.

Geometric mean LIC decreased

6.8 => 4.8 mg Fe/g dw

(p < 0.008)

LIC >15 mg/g

15 mg/g > LIC > 7 mg/g

LIC < 7 mg/g

• Investigators concluded• The data are consistent with previous observations that

introduction of non-invasive monitoring of LIC can contribute to a decreased body iron burden through improved clinical decision making and improved feedback to patients and hence improved adherence to chelation therapy.

Brown, et al. (2012) Internal Medicine Journal, 42: 990.

• 84 SCD patients - chronic transfusion

• Followed from 2006 to 2013

• After introduction of FerriScan R2-MRI in 2006• Proportion of patients obtaining LIC measurements

jumps from 21% to 81%

• Median LIC drops from first R2-MRI to last R2-MRI• 13.2 mg Fe/g dw => 7.9 mg Fe/g dw (p = 0.027)

• Deferasirox also became available in 2006

Stanley, et al. (2016) Pediatric Blood & Cancer, 63: 1414.

Clinical decisions made following liver iron concentration (LIC) assessment by R2-MRI. Documented decisions were specifically included in provider clinician notes within 6 months of the study.

Documented clinical decision making based on LIC

Stanley, et al. (2016) Pediatric Blood & Cancer, 63: 1414.

• The investigators concluded

• Increased availability of iron assessment through R2-MRI and of oral chelation paralleled improved management of iron overload in our population with SCD

• Routine liver R2-MRI should be performed in individuals with SCD who receive chronic red cell transfusions

Nichols‐Vinueza, et al. (2014) Am J Hematol, 89: 684.

• Single center retrospective study

• Study period 2005 – 2012

• LIC by MRI (FerriScan and T2*) and cardiac T2* measurements

• 42 patients (55% male) with at least 2 MRI visits

• Median age at first MRI 17.5 y

• Mean follow-up period 5.2 ± 1.9y

• Median number of MR scan per patient 4.5

• From baseline to last MRI• 63% of patients remained within target ranges for LIC

and cardiac R2*

• 13% improved from high values into the target range

• Median LIC decreased• 7.3 => 4.5 mg Fe/g dw

• P = 0.0004

• Median cardiac R2* decreased• 33.4 => 28.3 Hz

• p = 0.01

Nichols‐Vinueza, et al. (2014) Am J Hematol, 89: 684.

• DFO usage decreased from 70% to 10% in 2009

• DFX usage increased• 26% at baseline

• 73% by 2009

Nichols‐Vinueza, et al. (2014) Am J Hematol, 89: 684.

The investigators concluded:-

Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care.

Nichols‐Vinueza, et al. (2014) Am J Hematol, 89: 684.

Summary• Cardiac T2* has been shown to be predictive of cardiac

arrhythmia and failure within 12 months

• Liver iron concentration has been shown to be a surrogate measure for total body iron stores and predictive of long term (years) outcomes

• Studies have shown that both liver and heart iron assessments by MRI have led to clinical decision making on interventions

• Associations between the advent of implementation of tissue iron MRI measurements and improvements in body iron burdens have been observed

Summary

• No single study has been able to “prove” that MRI tissue iron measurement has an impact on prognosis for thalassaemia major

• Randomised trials required for proof would be unethical

• Taken together, multiple studies assessing the impact of MRI tissue iron measurements strongly suggest that they lead to improved iron burden through• Influencing clinical decision making on iron chelation

• Improved feedback to patients to encourage adherence

Thank your for your attention

Tim St PierreThe University of Western Australia

Tim.StPierre@uwa.edu.au