C-LICNET NETWORK: POTENTIAL WORLDWIDE MRI NETWORK … - 0.2FINAL C-LICNET... · 2017-10-04 · SENSITIVITY AND SPECIFICITY OF R2-LIC MEASUREMENTS TO BIOPSY LIC LIC threshold1 (mg

“C-LICNET NETWORK: POTENTIAL WORLDWIDE MRI NETWORK FOR THE MANAGEMENT OF THALASSEMIA

SYNDROMES “

Prof. Aurelio MaggioCampus of Hematology Franco and Piera Cutino

A.O. “Riuniti Villa Sofia Cervello”- Palermo

● PERSISTENT SERUM FERRITIN LEVEL >1000 ng/ml or worst >2500 ng/ml without any other signs of inflammation .THESE STATEMENTS ARE BASED ON RETROSPECTIVE AND PROSPECTIVE SURVIVAL STUDIES (Borgna Pignatti et al. Haematologica 2004;Olivieri NF et al.NEJM 1994; Maggio et al. Blood Cells Mol Dis 2009)

● LIVER IRON CONCENTRATION > 3.2 mg/gr/ dried weightn >57,14 micro M/g / dried weight. THIS STATEMENT IS BASED ON HEREDITARY HEMOCHROMATOSIS CLINICAL STUDIES (Olivieri NF and BritthenamGM, Blood 1997)

DEFINITION OF IRON LOAD

BENEFITS OF LIVER IRON CONTROL ?

• LIC predicts total body storage iron in TM1

• Absence of pathology

– heterozygotes of HH where liver levels < 7 mg/g dry weight

• Liver pathology

– abnormal ALT if LIC > 17 mg/g dry weight2

– liver fibrosis progression if LIC > 16 mg/g dry weight3

• Cardiac pathology at high levels

– Increased LIC linked to risk of cardiac iron in unchelated patients 2,6

– LIC >15 mg/g dry weight association with cardiac death

• all of 15/53 TM patients who died4

• improvement of subclinical cardiac dysfunction with venesectionalone post-BMT5

1. Angelucci E, et al. N Engl J Med. 2000;343:327-31.2. Jensen PD, et al. Blood. 2003;101:91-6. 3. Angelucci E, et al. Blood. 2002;100:17-21.

4. Brittenham GM, et al. N Engl J Med. 1994;331:567-73. 5. Mariotti E, et al. Br J Haematol. 1998;103:916-21.6. Buja LM, Roberts WC. Am J Med. 1971;51:209-21

LIVER IRON CONCENTRATION PREDICTSTOTAL BODY IRON STORES

PROGRESSION OF HEPATIC FIBROSIS IN IRON OVERLOADED EX-THALASSAEMIC PATIENTS

IRON-CHELATING THERAPY AND THE TREATMENT OF THALASSEMIA

Olivieri NF and Brittenham GM. Blood 1997

WHY NOT JUST USE SERUM FERRITIN ?

•Advantages•Simple•Widely available• Serum ferritin broadly correlated with body iron (macrophages)• Validated as predictor of complications of iron overload in TM

•Disadvantages•Origin of serum ferritin differs above values of 4K•Raised by inflammation or tissue damage•Lowered by vitamin C deficiency•Relationship of ferritin to body iron varies in different diseases

•Low relative to LIC in Thalintermedia (hepatocellular> macrophages)•Higher and variable in SCD

SINGLE COMPLICATIONS ARE ASSOCIATED WITH HIGHER RISK FOR DEATH IN COMPARISON WITH SERUM FERRITIN

CONCENTRATION

Maggio A, Vitrano A, Capra M, et al.,Blood Cells Mol Dis. 2009 Feb 20.

CONTRASTING RELATIONSHIP OF LIC TO FERRITIN IN TI AND TM

Origa, Hamatologica 2007, 92 583

A review of the literature shows that, unlike FerriScan® R2--

‐MRI, liver T2* methods generate data that are scanner and

method specific and hence are not sufficiently standardised

to enable reliable liver iron concentration measurements

using calibration curves published from other centres.

St Pierre TG, et al. Blood. 2005;105:855-61.

RELATIONSHIP BETWEEN R2 AND NEEDLE BIOPSY LIC (DRY WEIGHT)

SENSITIVITY AND SPECIFICITY OF R2-LIC MEASUREMENTS TO BIOPSY LIC

LIC

threshold1

(mg Fe/g dry weight)

Clinical relevance1 Sensitivity2 Specificity2

1.8 Upper 95% of normal 94%(86–97)

100%(88–100)

3.2 Suggested lower limit of optimal range

for LICs for chelation therapy in

transfusional iron overload

94%(85–98)

100%(91–100)

7.0 Suggested upper limit of optimal range

for LICs for transfusional iron overload

and threshold for increased risk of iron-

induced complications

89%(79–95)

96%(86–99)

15.0 Threshold for greatly increased risk for

cardiac disease and early death in

patients with transfusional iron overload

85%(70–94)

92%(83–96)

1. Olivieri NF, Brittenham GM. Blood. 1997;89:739-61. 2. St Pierre TG, et al. Blood. 2005;105:855-61.

FERRISCAN – CURRENT STATUS

• Centralised analysis of locally acquired data

• Ease of set-up using MRIs available in most hospitals

• Regulatory clearance by

– FDA (USA)

– CE Mark (Europe)

– Health Canada (Canada)

– TGA (Australia), MedSafe (New Zealand)

• 206 active sites across 25 countries

• > 8000 patient measurements

LICNET – LIVER IRON CUTINO NETWORKIL NETWORK NAZIONALE PROMOSSO DALL’ASSOCIAZIONE PIERA CUTINO ONLUS, DEDICATO ALLA

DIAGNOSTICA DEGLI ACCUMULI DI FERRO NEL FEGATO TRAMITE RISONANZA MAGNETICA NUCLEARE (R2)

What is CLIC-NET ?

It is a national network, involving Hematological , Pediatricsand Radiological Centres and supported by Association PieraCutino, for the non-invasive determination of Cardiac and LiverIron Concentration in patients with hemoglobinopathy andother hematological disorders with secondary iron overloading.

CARDIAC-LIVER ITALIAN CUTINO NETWORK (C-LICNET)

SUPPORTED BY FOUNDATION FRANCO AND PIERA CUTINO

CITY THALASSEMIA RESPONSIBLE

RADIOLOGY REFERENT

HOSPITAL

PALERMO D.ssa L.Pitrolo Dr. L.Tese’Dr. Gioia

AOOR“Villa-Sofia Cervello”

SIRACUSA D.ssa S.Campisi Dr. F. Butera Osp. “Umberto I”

CALTANISSETTA D.ssa FiorinoDr.Rizzo-D.ssa Quota (Gela)

Dr. G. VaccaroDr. V.Santoro

Osp.”S.Elia”

RAGUSA Dr. V. SpadolaDr. C.Fidone

Dr. D. Schembari Osp.”Civile Paternò Arezzo”

SCIACCA (AG) D.ssa C.Gerardi Dr. F.Barbiera Osp.“Giovanni Paolo II”

CATANIA D.ssa.R.Rosso Dr. Polizzi Osp.“V.Emanuele”

CALTAGIRONE (CT)

Dr. R. Giugno Dr. Bellissima Osp. “Gravina”

MESSINA D.Ssa L.C.Rigoli Dr. S. Mazziotti Policlinico Universitario “G.Martino”

REGGIO CALABRIA

D.ssa Oliva Dr. ArcadiD.Ssa Zappavigna

Osp ."Bianchi - Melacrino - Morelli"

COSENZA D.ssa Bisconte Dr. C. Zanolini Osp.“Annunziata”

BARI D.ssa G.Specchia Dr. A. Scardapane Policlinico di Bari -Università degli Studi di Bari “Aldo Moro”.

NAPOLI Dr. A.Filosa D.ssa. R. De Ritis Ospedale “Cardarelli”

FERRARA D.Ssa GamberiniD.ssa M.Fortini

Dr. R. Righi Arcispedale”S. Anna”

PADOVA D.ssa Putti D.ssa Giorgi Azienda Ospedaliera Universitaria di Padova

R2 : 1202

T2*: 389

TOTAL NUMBER OF TESTS PERFORMED

CONTEXT

Analysis performed on a cross-sectional data set of 363 patients withhemoglobiopathies and other transfusion-dependent or iron loadinganemias attending 16 Italian Centers participating in the LICNET initiative

Data were retrieved for all patients who underwent a Liver R2 MRI exambetween 2013 and 2015

Data used for current analyses include demographics (age, gender,diagnosis), laboratory values (serum ferritin level, liver function tests [ALT),and treatment (transfusion receipt and amount, iron chelator type) at thetime of MRI assessment

PECULIAR FINDINGS OF THE STUDY

•Large group with different hemoglobinopathies andhematological diseases with different transfusion status(Thalassemia Major, Thalassemia Intermedia, Sickle-Cell-Disease and Other Anemias)

•Liver Iron Concentration versus Serum Ferritincorrelations across different diseases and transfusionstatus

PATIENTS’ CHARACTERISTICS AND LABORATORY VALUES

Vitrano et al, Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET. Eur J Haematol. 2016 Oct;97(4):361-70

R2 MRI

R2 MRI of (A) b-TM and high LIC, (B) b-TM and low LIC, (C) b-TI and high LIC, (D) b-TI and low LIC, (E) SCD and high LIC, and (F) SCD and low LIC. The right-sided color panel reflects the R2 value in 1/s. LIC, liver iron concentration in mg Fe/g dry weight; TM, b-thalassemia major; TI, b-thalassemia intermedia; SCD, sickle cell disease.


KEY LABORATORY STUDIES (N=363)

Parameter Value

Serum ferritin in ng/ml, median (IQR) 803 (431-1498)

ALT in IU/l, mean (SD) 37.5 (28.8)

ANALYSIS I

EXPLORING LIC IN THE STUDY GROUP AND ITS ASSOCIATION WITH PATIENT

CHARACTERISTICS

LIC DISTRIBUTION ACCORDING TO AGE GROUP. LIC, LIVER IRON CONCENTRATION IN mg Fe/g DRY WEIGHT


LIC DISTRIBUTION ACCORDING TO UNDERLYING DISEASE


LIC DISTRIBUTION ACCORDING TO IRON CHELATOR


ANALYSIS II

EXPLORING ASSOCIATION BETWEEN LIC AND SERUM FERRITIN LEVELS

LIC VS SERUM FERRITIN

Pearson’s r = 0.729, p<0.001

LIC VS SERUM FERRITIN ACROSS DIAGNOSESThalassemia major (n=198) Thalassemia intermedia (n=94)

Sickle cell disease (n=56) Other anemias (n=26)

r = 0.754, p<0.001 r = 0.691, p<0.001

r = 0.761, p<0.001 r = 0.263, p = 0.205

LIC VS SERUM FERRITIN PER TRANSFUSION STATUS

Pearson’s r = 0.729, p<0.001

LIC = 0.005 X Serum ferritin + 0.405

Pearson’s r = 0.726, p<0.001

LIC = 0.006 X Serum ferritin + 1.533

For the same LIC, non-transfused patients show lower serum ferritin levels

Non-transfused

Transfused

WHAT SERUM FERRITIN LEVELS BEST PREDICT LIC OF 7 mg/g

• A serum ferritin of 900 ng/ml had the best predictive power (highest sum of sensitivity and specificity)

• Data stratified per transfusion showed a value of 600 ng/ml for non-transfused and 1200 ng/ml for transfused patients

WHAT SERUM FERRITIN LEVELS BEST PREDICT LIC OF 15 mg/g

• A serum ferritin of 1700 ng/ml had the best predictive power (highest sum of sensitivity and specificity)

• Data stratified per transfusion showed a value of 800 ng/ml for non-transfused and 2000 ng/ml for transfused patients

CORRELATIONS AND PREDICTABILITY BETWEEN SERUM FERRITIN AND LIVER IRON CONCENTRATION


ANALYSIS I

EXPLORING LIC IN THE STUDY GROUP AND ITS ASSOCIATION WITH PATIENT ALT

CORRELATION BETWEEN LIC AND ALT


ANALYSIS I

EXPLORING LIC IN THE STUDY GROUP AND ITS ASSOCIATION WITH PATIENT CARDIAC

MAGNETIC RESONANCE T2*

LICR2 vs CMRT2*values >1 year apart excluded (n=137)

Pearson’s r = -0.110, p=0.199

ANALYSIS II

EXTENDING OUR EVALUATION TO DETERMINE LONGITUDINAL CHANGES

OVERTIME IN A LARGE NUMBER OF PATIENTS WHO HAD AN ADDITIONAL MR,

DURING LICNET SURVEY, IN A REAL LIFE SETTING, AND USING DIFFERENT

CHELATION REGIMEN

This was a cross-sectional study attending 9 Italian centres.The underlying diagnosis were Thalassemia Major (TM),Thalassemia Intermedia (TI), Sickle Cell Disease (SCD),Myelodysplastic Syndrome (MDS) , Diamond-Blackfan Anemia(DBA). Regular transfused’ status was defined as receipt of ≥7

mL/kg/month of packed red blood cells. LIC comparisons overtime were made using t test and/or Wilcoxon test.Correlations between LIC, SF and ALT values were made usingSpearman’s correlation coefficient. All p-values are two sided

with the level of significance set at <0 .05. Descriptive analysisand blood requirement changes are reported on Table 1 and 2.LIC of 7–15 mg Fe/g dry weight (dw) and >15 mg Fe/g dwsuggested increased and greatly increased risk of morbidity,respectively.

METHOD

Table 1. Descriptive analysis of patients characteristics. DFO, deferoxmaine; DFP, deferiprone; DFX, deferasirox; HCV, hepatitis C virus.

METHOD

Table 2. Blood requirement changes. DFO, deferoxmaine; DFP, deferiprone; DFX, deferasirox; hb, hemoglobin.

METHOD

Patients’ characteristics

Overall 130 patients were evaluated, with a median (range) age years of 35 (range: 6–78) and including 60 (46.2%) men. The underlying diagnosis were regularly transfused TM (n=86, 66.2%), TI (n=33, 25.4%), SCD (n=6, 4.6%), MDS (n=3, 2.3%), DBA (n=2, 1,5%). Overall HCV PCR-RNA positive, patients were n 16 (12.3 %). Patients’ characteristics for all patients, in respective subgroups of

considered chelation regimens, are summarized on Table 1.

Blood requirement changesOverall median change (range) in pre-transfusion Hb (range), g/dl 0.0 (-1.5; -1.8) (p=0.5) and median change in blood requirement (range), g/dL 2.0 (-636.8; -124.9) (p=0.172) were not statistically significant different over time. Table 2 reports the median change (range) in pre-transfusion Hb (range) and median change in blood requirement (range) .

RESULTS

Table 3. Changes in iron measures. DFO, deferoxmaine; DFP, deferiprone; DFX, deferasirox; LIC, liver iron concentration; dw, dry weight; SF, serum ferritin.

RESULTS

Changes in iron and other laboratory measuresLIC changes across underlying diseases The median duration (range) between MRI1 and MRI2 days was 483 (184-1076). Median change in LIC (range), mg Fe/g dw was stable across DFP (p= 0.54), DFX (p= 0.51), DFO+DFP (p= 0.51) regimens, while decreased significantly during DFO chelation treatment (p=0.002) (Tab. 3). Fig. 1 shows changes in LIC determinations, during the period of the study.

SF level changes across underlying diseasesMedian change in SF level (range), ng/ml was stable (p=0.566,Table 3) across underlying diseases in DFP (p=0.068), DFX (p=0.721), DFO+DFP (0.333), other combination (p=0.237) (Table 3), while decreased significantly ( p= 0.003) during DFO treatment (Table 3).

Changes in laboratory measuresMedian change of serum creatinine (SCr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), across all chelation treatments over time did not show any statistically significant difference ( data not show

RESULTS

RESULTS

Figure 1. Change in LIC (liver iron concentration in mg Fe/g dry weight) categories between MRI1 and MRI2. DFO, deferoxmaine; DFP, deferiprone; DFX, deferasirox.

CONCLUSIONS

Overall patients, across all chelation regimens, showed a statistically significantdifference in variation of LIC between MRI1 versus MRI2 (p=0.011, Table 3). Overallvariation of LIC, during a period of 483 (184-1076) days, was -0.8 (-29.0-33.0) mg Fe/gdw. There was not statistically significant difference in pre-trasfusion Hb (p=0.5) and inblood requirement (0.172) . Overall 7.7% of patients, across different chelationregimens and during a period of 483 (184-1076) days, moved from high risk group (LIC >15 mg Fe/g dw ) to intermediate risk group ( LIC 7-15 mg Fe/g dw ) withstabilization of iron overloading in patients in low risk group at baseline . All chelationregimens were able to move LIC from high risk group ( LIC >15 mg Fe/g dw ) tointermediate risk group ( LIC 7-15 mg Fe/g dw ) . In the other combination group, thepatients moved from the intermediate risk group (LIC 7-15 mg Fe/g dw ) to the lowrisk group ( LIC <7 mg Fe/g dw) . However, the limit of this study is that it does notallow any comparisons among different chelation regimens. Indeed, being a cross-sectional study with different sample size and baseline LIC values among differentcohorts of chelation regimens during real-life, this does not lead to reach effectivenessconclusions about single chelation regimens.

• Serum ferritin alone Is not a reliable tool in non-transfused patients

• Non-transfused patients show lower serum ferritin levels for predicting both 7mg/g/dw and 15mg/g/dw. This issue is relevant for management of chelation treatment in this cohort of patients

• Measurement of LIC gives valuable information about management of chelation treatment In transfused and non transfused patients

• Therefore,spreading of LIC determination is the most relevant future challenge for reducing mortality in Thalassemia Intermedia and to improve further survival in Thalassemia Major

CONCLUSIONS

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C-LICNET NETWORK: POTENTIAL WORLDWIDE MRI NETWORK … - 0.2FINAL C-LICNET... · 2017-10-04 · SENSITIVITY AND SPECIFICITY OF R2-LIC MEASUREMENTS TO BIOPSY LIC LIC threshold1 (mg