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

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1 C-LICNET NETWORK: POTENTIAL WORLDWIDE MRI NETWORK FOR THE MANAGEMENT OF THALASSEMIA SYNDROMES Prof. Aurelio Maggio Campus of Hematology Franco and Piera Cutino A.O. Riuniti Villa Sofia Cervello - Palermo

2 DEFINITION OF IRON LOAD 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 Britthenam GM, Blood 1997)

3 BENEFITS OF LIVER IRON CONTROL? LIC predicts total body storage iron in TM 1 Absence of pathology heterozygotes of HH where liver levels < 7 mg/g dry weight Liver pathology abnormal ALT if LIC > 17 mg/g dry weight 2 liver fibrosis progression if LIC > 16 mg/g dry weight 3 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 died 4 improvement of subclinical cardiac dysfunction with venesection alone post-bmt 5 1. Angelucci E, et al. N Engl J Med. 2000;343: Jensen PD, et al. Blood. 2003;101: Angelucci E, et al. Blood. 2002;100: Brittenham GM, et al. N Engl J Med. 1994;331: Mariotti E, et al. Br J Haematol. 1998;103: Buja LM, Roberts WC. Am J Med. 1971;51:209-21

4 LIVER IRON CONCENTRATION PREDICTS TOTAL BODY IRON STORES

5 PROGRESSION OF HEPATIC FIBROSIS IN IRON OVERLOADED EX-THALASSAEMIC PATIENTS

6 IRON-CHELATING THERAPY AND THE TREATMENT OF THALASSEMIA Olivieri NF and Brittenham GM. Blood 1997

7 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

8 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 Feb 20.

9 CONTRASTING RELATIONSHIP OF LIC TO FERRITIN IN TI AND TM Origa, Hamatologica 2007,

10 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.

11 RELATIONSHIP BETWEEN R2 AND NEEDLE BIOPSY LIC (DRY WEIGHT) St Pierre TG, et al. Blood. 2005;105:

12 LIC threshold 1 (mg Fe/g dry weight) SENSITIVITY AND SPECIFICITY OF R2-LIC MEASUREMENTS TO BIOPSY LIC Clinical relevance 1 Sensitivity 2 Specificity Upper 95% of normal 94% (86 97) 3.2 Suggested lower limit of optimal range for LICs for chelation therapy in transfusional iron overload 7.0 Suggested upper limit of optimal range for LICs for transfusional iron overload and threshold for increased risk of ironinduced complications 15.0 Threshold for greatly increased risk for cardiac disease and early death in patients with transfusional iron overload 94% (85 98) 89% (79 95) 85% (70 94) 1. Olivieri NF, Brittenham GM. Blood. 1997;89: St Pierre TG, et al. Blood. 2005;105: % (88 100) 100% (91 100) 96% (86 99) 92% (83 96)

13 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

14 LICNET LIVER IRON CUTINO NETWORK IL 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, Pediatrics and Radiological Centres and supported by Association Piera Cutino, for the non-invasive determination of Cardiac and Liver Iron Concentration in patients with hemoglobinopathy and other hematological disorders with secondary iron overloading.

15 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 TOTAL NUMBER OF TESTS PERFORMED R2 : 1202 CALTANISSETTA RAGUSA D.ssa Fiorino Dr.Rizzo-D.ssa Quota (Gela) Dr. V. Spadola Dr. C.Fidone Dr. G. Vaccaro Dr. V.Santoro Dr. D. Schembari Osp. S.Elia Osp. Civile Paternò Arezzo T2*: 389 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. Arcadi D.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 Gamberini D.ssa M.Fortini Dr. R. Righi Arcispedale S. Anna PADOVA D.ssa Putti D.ssa Giorgi Azienda Ospedaliera Universitaria di Padova

16 CONTEXT Analysis performed on a cross-sectional data set of 363 patients with hemoglobiopathies and other transfusion-dependent or iron loading anemias attending 16 Italian Centers participating in the LICNET initiative Data were retrieved for all patients who underwent a Liver R2 MRI exam between 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 the time of MRI assessment

17 PECULIAR FINDINGS OF THE STUDY Large group with different hemoglobinopathies and hematological diseases with different transfusion status (Thalassemia Major, Thalassemia Intermedia, Sickle-Cell- Disease and Other Anemias) Liver Iron Concentration versus Serum Ferritin correlations across different diseases and transfusion status

18 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 Oct;97(4):361-70

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

20 KEY LABORATORY STUDIES (N=363) Parameter Value Serum ferritin in ng/ml, median (IQR) 803 ( ) ALT in IU/l, mean (SD) 37.5 (28.8)

21 ANALYSIS I EXPLORING LIC IN THE STUDY GROUP AND ITS ASSOCIATION WITH PATIENT CHARACTERISTICS

22 LIC DISTRIBUTION ACCORDING TO AGE GROUP. LIC, LIVER IRON CONCENTRATION IN mg Fe/g DRY WEIGHT Vitrano et al, Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET. Eur J Haematol Oct;97(4):361-70

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

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

25 ANALYSIS II EXPLORING ASSOCIATION BETWEEN LIC AND SERUM FERRITIN LEVELS

26 Pearson s r = 0.729, p<0.001 LIC VS SERUM FERRITIN

27 LIC VS SERUM FERRITIN ACROSS DIAGNOSES Thalassemia major (n=198) Thalassemia intermedia (n=94) r = 0.754, p<0.001 r = 0.691, p<0.001 Sickle cell disease (n=56) Other anemias (n=26) r = 0.761, p<0.001 r = 0.263, p = 0.205

28 LIC VS SERUM FERRITIN PER TRANSFUSION STATUS For the same LIC, non-transfused patients show lower serum ferritin levels Non-transfused Pearson s r = 0.726, p<0.001 LIC = X Serum ferritin Transfused Pearson s r = 0.729, p<0.001 LIC = X Serum ferritin

29 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

30 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

31 CORRELATIONS AND PREDICTABILITY BETWEEN SERUM FERRITIN AND LIVER IRON CONCENTRATION Vitrano et al, Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET. Eur J Haematol Oct;97(4):361-70

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

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

34 ANALYSIS I EXPLORING LIC IN THE STUDY GROUP AND ITS ASSOCIATION WITH PATIENT CARDIAC MAGNETIC RESONANCE T2*

35 Pearson s r = , p=0.199 LICR2 vs CMRT2* values >1 year apart excluded (n=137)

36 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

37 METHOD 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 over time were made using t test and/or Wilcoxon test. Correlations between LIC, SF and ALT values were made using Spearman s correlation coefficient. All p-values are two sided with the level of significance set at <0.05. Descriptive analysis and 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 dw suggested increased and greatly increased risk of morbidity, respectively.

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

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

40 RESULTS 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 changes Overall 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; ) (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).

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

42 RESULTS Changes in iron and other laboratory measures LIC changes across underlying diseases The median duration (range) between MRI1 and MRI2 days was 483 ( ). 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 diseases Median 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 measures Median 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

43 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.

44 CONCLUSIONS Overall patients, across all chelation regimens, showed a statistically significant difference in variation of LIC between MRI1 versus MRI2 (p=0.011, Table 3). Overall variation of LIC, during a period of 483 ( ) days, was -0.8 ( ) mg Fe/g dw. There was not statistically significant difference in pre-trasfusion Hb (p=0.5) and in blood requirement (0.172). Overall 7.7% of patients, across different chelation regimens and during a period of 483 ( ) days, moved from high risk group ( LIC >15 mg Fe/g dw ) to intermediate risk group ( LIC 7-15 mg Fe/g dw ) with stabilization of iron overloading in patients in low risk group at baseline. All chelation regimens were able to move LIC from high risk group ( LIC >15 mg Fe/g dw ) to intermediate risk group ( LIC 7-15 mg Fe/g dw ). In the other combination group, the patients moved from the intermediate risk group (LIC 7-15 mg Fe/g dw ) to the low risk group ( LIC <7 mg Fe/g dw). However, the limit of this study is that it does not allow any comparisons among different chelation regimens. Indeed, being a crosssectional study with different sample size and baseline LIC values among different cohorts of chelation regimens during real-life, this does not lead to reach effectiveness conclusions about single chelation regimens.

45 CONCLUSIONS 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