Role of T1 Mapping As a Complementary Tool to T2* for Cardiac Iron Overload Assessment

Abstract Introduction. Iron overload-related heart failure is the principal cause of death in transfused Thalassemia Major (TM) (Modell B, Cardiovasc Magn Reson 2008;10:42-48). Iron toxicity is dose dependent so a strategy of chelation therapy titration (Kirk P, Circ 2009;120:1961-1968) before the onset of left ventricle (LV) impairment changes outcomes (AlpenduradaF, Eur Heart J. 2010; 31:1648-54). The presence of iron in tissue detectably changes the magnetic properties of water, T1, T2 and T2*, as validated against tissue in animal and human models (Carpenter JP, Circ 2011;14:1519-28). T2*, the most used technique, is susceptible to non-iron influence (susceptibility artefact) and has low accuracy for high and low iron levels (Carpenter JP, J Cardiovasc Magn Reson. 2014;12:16-62). T1 mapping could complement T2* as it appears to have superior reproducibility and to detect mild iron missed by T2* (Abdel-Gadir A. J Cardiovasc Magn Reson. 2015;17(Suppl1):P312. Sado DM, J Magn Reson Imaging. 2015;41:1505-11), but studies to date have been small and not using state-of-the-art sequences. Methods. In a prospectively single centre study of 138 TM patients and 32 healthy volunteers (HV) (no known medical conditions, normal CMR scan), we compared T1 mapping (Modifier Lock Locker Inversion sequence - MOLLI - Siemens Works in progress 448B) to the gold-standard dark (DB) and bright (BB) blood T2*, acquired on an Avanto 1.5T (Siemens Healthcare, Erlangen, Germany). For both T2* sequences, a single 10mm mid-ventricular short axis slice was imaged at 8 echo-times (2.58ms to 18.19ms, increment 2.23ms), flip angle=20¡, FOV read/phase=400mm/56,3%. The same slice was used for T1 images (thickness 6mm, distance factor=67%, FOV read/phase=360/75%, TR=740, TE=1.13, with motion correction for the in-line map generation). Results and discussion.All participants provided informed consent. Table1 illustrates patients' and HV's details. T2* was defined normal under the cutpoint value of 20ms. T1 normal range, defined by the HV cohort was 918-1015ms (the 2.5-97.5 quantiles with CI 95%). For DBT2*<20ms, both BBT2* and T1 mapping were broadly indistinguishable from DBT2* (DBT2* vs BBT2* R2=0.95; DBT2* vs T1 R2=0.92; all p<0.001). All subjects with low DBT2* (n=24, 17.4%) had low T1; 52 patients had normal DBT2* but low T1 mapping, i.e. 38% patients were reclassified from normal to iron loaded by T1. The relationship between DBT2* and MOLLI was described by a log-log linear regression (R2=0.80, p<0.001). Upper panel of Fig1 shows T1 vs DBT2* correlation over a 20ms window as the window moves by 1ms at a time on X-axis (so at X-axis point 'n', the Y-value is the R2 of the correlation of DBT2* vs T1 over the range n-to-n+20ms). As shown by lower panel of Fig1, three domains can be observed: strong relationship in the T2*=0-20ms range (R2=0.92, p<0.001); good relationship in the 21-28ms range, where the curve depicts a plateau (R2=0.80-0.77, p<0.001) and no relationship above 28ms. Given the conservative approach used to set T2* normality as above 20ms (Carpenter JP, Circ 2011;14:1519-28), the evidence that T2* SD values increase even for borderline T2* mean values (~20ms) (Anderson LJ, Eur Heart J. 2001;22:2171-9), and that 39% of normal T2* subjects have a low T1, we support prior suggestions that T1 is detecting mild iron in most of the subjects with DBT2*=20-28ms, missed by T2* as the threshold has had to be set too low for sensitivity reasons (Sado DM, J Magn Reson Imaging. 2015;41:1505-11). T1 mapping is thus a useful complementary tool to T2* both for clinical and research purposes. The reported reproducibilities of T1 square for power calculations and would translate into 6.25 to 49 times more power in studies to detect iron change (Alam MH, J Cardiovasc Magn Reson. 2015;24:17-102). Colour maps make iron instantly visible and add a confirmation step. Whether mild iron missed by T2* is important is unclear. In our cohort, 24-months follow-up was available for 9 patients with normal DBT2* and low T1. Although no statistical consideration is possible due to the small number, in those patients an increase in LV end diastolic volume was observed (from 78±18ml to 84±15ml), suggesting possible cardiotoxicity of even mild amount of iron. Further work is needed, especially in frail cohorts like children starting chelation and around pregnancy. Table 1 Table 1. Figure 1 Figure 1. Disclosures Moon: gsk: Consultancy; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

Blood ◽

10.1182/blood.v128.22.1288.1288 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1288-1288

Author(s):

Yesim Aydinok ◽

Metin Delebe ◽

Gunes Basol ◽

Selen Bayraktaroglu ◽

Nihal Karadas ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Thalassemia Major ◽

Average Dose ◽

Advisory Committees ◽

Baseline Characteristics ◽

Labile Iron ◽

The Impact

Abstract Background Ascorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment. Objectives Perform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity. Patients and Methods Enrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched). Results 22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year. At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1). In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS. A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2). Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo). Conclusions TM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. Table 1 Baseline characteristics of patients based on AA status Table 1. Baseline characteristics of patients based on AA status Table 2 Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Table 2. Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Disclosures Aydinok: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

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Frequency, Pattern, and Associations of Renal Iron Accumulation in Sickle Beta-Thalassemia

Blood ◽

10.1182/blood-2021-144592 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3086-3086

Author(s):

Alessia Pepe ◽

Luigi Barbuto ◽

Laura Pistoia ◽

Vincenzo Positano ◽

Francesco Massei ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Thalassemia Major ◽

Iron Deposition ◽

Beta Thalassemia ◽

Advisory Committees ◽

Frequency Pattern ◽

Iron Load ◽

Significant Difference ◽

Chronic Hemolysis

Abstract Background: Chronically transfused homozygous sickle cell disease (HbSS) patients were shown to have higher kidney iron deposition than thalassemia major patients, not associated to total body iron and mainly caused by chronic hemolysis. Kidney iron deposition has not been explored in sickle beta-thalassemia (Sβ-thal), resulting from the inheritance of both sickle cell and beta-thalssemia genes. Aim: This multi center study aimed to study frequency, pattern, and associations of renal iron accumulation in sickle beta-thalassemia. Methods: Thirty-three Sβ-thal patients (36.49±14.72 years; 13 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) network were considered. Moreover, 20 healthy subjects, 14 HbSS patients and 71 thalassemia major (TM) patients were included as comparison groups. Hepatic, cardiac, pancreatic, and renal iron overload was quantified by the gradient-echo T2* technique. In each kidney T2* was measured in anterior, posterolateral, and posteromedial parenchymal regions and the global T2* value was calculated as the average of the two kidneys T2* values. Results. Global renal T2* were significantly higher in healthy subjects versus both Sβ-thal patients (49.68±10.09 ms vs 43.19±8.07 ms; P=0.013) and HbSS patients (49.68±10.09 ms vs 26.21±17.07 ms; P<0.0001). Sβ-thal patients showed comparable age, sex, frequency of regular transfusion, hematochemical parameters, and hepatic, cardiac and pancreatic iron load than HbSS patients, but they had a significant lower frequency of renal iron overload (global renal T2*<31 ms) (9.1% vs 57.1%; P=0.001). Regularly transfused patients (16 Sβ-thal and 10 HbSS) were compared with TM patients, homogeneous for age and sex, but TM started regular transfusions significantly earlier and they were more frequently chelated. No significant difference was detected in terms of hepatic and cardiac iron levels, but TM patients had significantly lower pancreas T2* values than both the other two groups and significantly higher global renal T2* values than HbSS patients (42.87±9.43 ms vs 24.39±15.74 ms; P=0.001). In Sβ-thal patients no significant difference was detected between T2* values in left and right kidneys, and global renal T2* values were not associated to age, gender, splenectomy, and they were comparable between regularly transfused and non transfused patients. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (Figure 1). Conclusion. Renal iron deposition is not common in Sβ-thal patients, with a prevalence significantly lower compared to that of HbSS patients, but with a similar underlying mechanism due to the chronic hemolysis. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

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What Predicts Adrenal Insufficiency in Patients with Thalassemia Major?

Blood ◽

10.1182/blood.v118.21.5299.5299 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5299-5299

Author(s):

Karen E Huang ◽

Steven D Mittelman ◽

Thomas D. Coates ◽

Mitchell Geffner ◽

John C Wood

Keyword(s):

Iron Overload ◽

Adrenal Insufficiency ◽

Board Of Directors ◽

Cortisol Level ◽

Research Funding ◽

Thalassemia Major ◽

Stimulation Test ◽

Glucagon Stimulation Test ◽

Advisory Committees ◽

Research Contract

Abstract Abstract 5299 Background: Thalassemia is one of the most common genetic blood disorders worldwide. With recent improvements in medical therapy, patients with transfusion-dependent thalassemia, i.e., thalassemia major, are living longer. As a result, there is a greater need to address endocrine complications related to chronic iron overload. Adrenal insufficiency (AI), in particular, is important to identify because therapies are available and can be life-saving. Objectives: The objectives of this study are to determine the prevalence of AI in our population of subjects with thalassemia major; to identify risk factors that predict AI in these individuals; and to localize the origin of the AI within the hypothalamic-pituitary-adrenal (HPA) axis. Methods: This is a prospective study of individuals with thalassemia major with an enrollment goal of 30 subjects. All subjects enrolled were initially tested for AI using a glucagon stimulation test. Those found to have AI (stimulated cortisol <18 mcg/dL) subsequently underwent an ovine corticotrophin-releasing hormone (oCRH) stimulation test for confirmatory purposes and to define the physiological basis for the AI. Results: Eleven subjects (8 - 29 years old, 6 female) have been enrolled to date. In our population of patients with TM, the prevalence of AI was 55%. There was no correlation between age, number of years transfused, or ferritin levels and AI. All male patients failed the glucagon stimulation test, whereas 5 of 6 females passed the glucagon stimulation test, p = 0.0024. There was no correlation between 8 AM ACTH levels and 8 AM cortisol levels. There was a significant correlation (p = 0.025) between 8 AM cortisol level and peak cortisol level following glucagon stimulation testing. Of the six subjects with AI, two subjects subsequently failed the oCRH stimulation test (peak cortisol < 21.9 mcg/dL). In these two subjects, peak oCRH ACTH levels were elevated, 144 and 164 pg/mL, respectively, suggesting primary adrenal insufficiency. Conclusions: We conclude that 8 AM cortisol level is a good predictor of adrenal insufficiency in our population, and can potentially be used as a simple screening test for AI with a strong negative predictive value. There appears to be a male predominance of AI in our population. This may indicate a protective role of female sex in this population. Two subjects had classic primary AI with robust ACTH levels in the face of inadequate cortisol production following oCRH testing. Four subjects (all males) who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol response to oCRH, indicating a possible hypothalamic origin to their AI. This dysfunction is likely independent of iron overload and warrants further investigation. Alternatively, these subjects may have impaired sympathetic nervous system function leading to hypoglycemic unawareness. Both outcomes are novel to the field and of medical significance. Disclosures: Geffner: Daiichi- Sankyo: Steering Committee for Clinical Trial; Eli Lilly, Inc.: Research Contract; Endo Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Data Safety Monitoring Board and Research Contract; Novo Nordisk: Research Funding; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prospective Changes of Pancreatic Iron in Thalassemia Major

Blood ◽

10.1182/blood-2021-144590 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3084-3084

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Crocetta Argento ◽

Luciana Rigoli ◽

Monica Benni ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Serum Ferritin ◽

Iron Concentration ◽

Pancreatic Head ◽

Thalassemia Major ◽

Common Finding ◽

Inverse Association ◽

Advisory Committees ◽

Baseline Serum

Abstract Introduction. Pancreatic iron deposition is a common finding in thalassemia major, being detected in more than one third of patients undergoing their first T2* Magnetic Resonance Imaging scan (MRI) for this purpose. However, no longitudinal studies on pancreatic iron are available in literature. Aim: The aim of this multicenter study was to evaluate the changes in pancreatic iron overload in TM patients enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) Network who performed a baseline and a follow-up (FU) MRI scan at 18 months. Methods. We considered 416 TM patients (37.77±10.46 years; 220 females) consecutively enrolled. Iron overload was quantified by the T2* technique. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. Results. Pancreatic iron overload (global pancreas T2*<26 ms) was detected in 367 (88.2%) patients. Of them, only 14 (3.8%) improved at the FU. Out of the 49 (11.8%) patients without baseline pancreatic iron overload, 15 (30.6%) showed pancreatic iron overload at the FU MRI. A significant inverse association was detected between % change in global pancreas T2*and baseline global pancreas T2* values (R=-0.369; P<0.0001). Patients with baseline pancreatic iron overload showed significantly higher % changes in global pancreas T2* values (see Figure). Changes (%) in global pancreas T2* were not associated with baseline serum ferritin levels or MRI liver iron concentration (LIC) values but were inversely correlated with % changes in serum ferritin levels (R=-0.199; P<0.0001) and % changes in MRI LIC values (R=-0.255; P<0.0001). A significant positive association was found between % changes in global pancreas and global heart T2* values (R=0.133; P=0.007). At baseline MRI, 169 patients showed an alteration of glucidic metabolism: 32 had impaired fasting glucose, 65 impaired glucose tolerance, and 72 diabetes mellitus. These patients showed significantly higher % changes in global pancreas T2* than patients with a normal glucidic metabolism (33.06±79.48% vs 11.93±59.47%; P=0.003). Conclusions. Our data showed that it is difficult to remove the iron from the pancreas and higher improvements were detected in more heavily loaded patients, with alterations of glucidic metabolism. The reduction in pancreatic iron was paralleled by a decrease in hepatic and cardiac iron. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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A Multicenter, Randomized, Open-Label Trial Evaluating Deferasirox Compared with Deferoxamine for the Removal of Cardiac Iron in Patients with β-Thalassemia Major and Iron Overload (CORDELIA).

Blood ◽

10.1182/blood.v120.21.2124.2124 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2124-2124 ◽

Cited By ~ 2

Author(s):

Dudley J Pennell ◽

John B Porter ◽

Antonio Piga ◽

Yongrong Lai ◽

Amal El-Beshlawy ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Lower Limit ◽

Research Funding ◽

Thalassemia Major ◽

Iron Removal ◽

Efficacy And Safety ◽

Advisory Committees ◽

Cardiac Iron ◽

Randomized Controlled

Abstract Abstract 2124 Background: Without effective iron chelation therapy (ICT), patients with transfusional iron overload are at risk of excess iron-related cardiac complications. Cardiac iron accumulation can be measured using T2* magnetic resonance (normal >20 ms, high risk <10 ms). There are few randomized controlled trials assessing ICT for cardiac iron removal. CORDELIA is a Phase II, multinational, randomized comparison of efficacy and safety of 1-yr treatment with deferasirox or deferoxamine (DFO). Primary objective was non-inferiority of deferasirox vs DFO for cardiac iron removal after 1 yr. Methods: Patients with β-thalassemia major, cardiac T2* 6–20 ms, no clinical symptoms of cardiac dysfunction, aged ≥10 yrs, history of ≥50 transfusions, left ventricular ejection fraction (LVEF) ≥56% and liver iron concentration (LIC) ≥3 mg Fe/g dry weight (dw) were recruited. Patients were randomized to an intensified DFO regimen with a target dose of 50–60 mg/kg/d sc for 8–12 hrs, 5–7 d/wk, or deferasirox with a target daily oral dose of 40 mg/kg/d. Dose adjustment recommendations were based on continuous assessment of efficacy and safety markers. Efficacy was assessed in the per-protocol analysis population. Primary efficacy endpoint was change after 1-yr treatment (using last available value ≥150 d after randomization) in cardiac T2* expressed as the ratio of geometric means (Gmean) at end of study (EOS) over baseline (BL) for deferasirox divided by the ratio of Gmeans for DFO. Non-inferiority was pre-defined if the lower limit of the 2-sided repeated 95% confidence interval (CI) for ratio of Gmeans was >0.9. Results: From 925 screened patients, 197 patients (mean age 19.8 ± 6.4 yrs) were randomized. Mean time since start of transfusions was 19.3 and 18.4 yrs in deferasirox and DFO patients, respectively. All patients had received previous ICT. At BL, Gmean cardiac T2* was 11.4 ms; mean ± SD LIC was 29.8 ± 17.5 mg Fe/g dw in deferasirox patients and 30.3 ± 17.9 mg Fe/g dw in DFO patients; median (range) serum ferritin level was 5062 (613–15331) and 4684 (677–13342) ng/mL, respectively. 160 (81.2%) patients completed 1 yr. Mean actual dose of deferasirox was 36.7 ± 4.2 mg/kg/d and DFO was 41.5 ± 8.7 mg/kg/d for 7 d/wk. Overall, Gmean cardiac T2* increased by 12% with deferasirox and 7% with DFO after 1 yr (Fig A). The Gmean ratio between the two arms was 1.0557 (95% CI 0.9981, 1.1331). Lower limit of the 95% CI was >0.9, demonstrating non-inferiority of deferasirox vs DFO, with a trend towards superiority (P=0.0567). Trends toward increases were observed in patients with severe or mild/moderate cardiac iron (Fig B, C). In patients with BL LIC <7 mg Fe/g dw, increase in cardiac T2* was 30% for deferasirox (n=11) and 10% for DFO (n=8), for BL LIC 7–<15 mg Fe/g dw increase was 19% (n=14) for deferasirox and 13% (n=14) for DFO, and in patients with BL LIC ≥15 mg Fe/g dw increase was 9% (n=66) and 5% (n=59), respectively. LVEF was stable with deferasirox (BL 66.9 ± 5.61%; EOS 66.3 ± 5.8%) and DFO (BL 66.4 ± 5.2%; EOS 66.4 ± 5.8%). LIC absolute change from BL was –8.9 ± 11.4 (95% CI –11.5, –6.4) mg Fe/g dw for deferasirox and –12.7 ± 11.4 (–15.3, –10.1) mg Fe/g dw for DFO. Overall adverse event (AE) rates were 67.7% in deferasirox patients and 75.8% in DFO patients. In deferasirox patients, most common AEs were diarrhea (12.5%), proteinuria (11.5%) and influenza (10.4%). Most common AEs in DFO patients were proteinuria (8.8%), upper respiratory tract infection (8.8%) and influenza (6.6%). Serious AEs occurred in 10.7% patients overall (10.4% deferasirox; 11.0% DFO), with many related to the underlying disease. 3 deferasirox patients and 1 DFO patient had 2 consecutive serum creatinine increases >33% above BL and >upper limit of normal (ULN). Overall, 14.6% of deferasirox patients and 3.3% of DFO patients had ALT levels >5xULN and >2xBL. One death (arrhythmia) in the deferasirox arm was considered unrelated to study drug. One death (meningitis) in a DFO patient was suspected to be related to DFO. Discussion: CORDELIA, the first randomized controlled trial comparing deferasirox with DFO for cardiac iron removal, met its primary endpoint in demonstrating non-inferiority of deferasirox vs DFO, with a trend for superiority. There was a trend toward more pronounced improvements in cardiac T2* with deferasirox vs DFO in patients with BL LIC <15 mg Fe/g dw. The frequency of AEs was similar between treatment groups and the deferasirox safety profile was comparable to previous reports. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CVIS: Equity Ownership. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Piga:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lawniczek:Novartis: Employment. Habr:Novartis: Employment. Weisskopf:Novartis: Employment. Zhang:Novartis: Employment. Aydinok:Ferrokin: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Changes in CMR Parameters and Prediction of Cardiac Complications in Thalassemia Major: Fibrosis Tells Us More Than Iron

Blood ◽

10.1182/blood-2021-144584 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2014-2014

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Pietro Giuliano ◽

Nicola Giunta ◽

Rosamaria Rosso ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Myocardial Fibrosis ◽

Thalassemia Major ◽

Cardiac Complications ◽

Myocardial Iron ◽

Advisory Committees ◽

Risk Class ◽

Cox Regression Analysis

Abstract Introduction. Cardiovascular magnetic Resonance (CMR) has dramatically changed the clinical practice and improved the prognosis in thalassemia major (TM). This is the first study evaluating the predictive value of changes in CMR parameters (myocardial iron, function, and fibrosis) for cardiac complications in TM. Methods. We followed prospectively 709 TM patients (374 females; 29.77±8.53 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who performed a baseline and a 1 st follow up CMR scan after 18 months. Myocardial iron overload (MIO) was measured by multislice multiecho T2* technique and atrial dimensions and biventricular function by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Risk classes were defined based on the 4 patterns of MIO from worst to normal. For patients with baseline MIO (at least one segmental T2*<20 ms), improvement was defined as a transition to a better risk class, stabilization as no change in risk class, and worsening as a transition to a worse risk class. For patients without baseline MIO, the worsening was the transition to a worse risk class. The percentage change was used for continuous variables. For biventricular ejection fractions, improvement was a %change>10%, stabilization a %change between -10% and 10%, and worsening a %change<-10%. For biventricular volumes, LV mass index, and atrial areas, improvement was a % change<-10%, stabilization a % change between -10% and 10%, and worsening a % change>10%. Myocardial fibrosis was considered absent if not detected in any of the two CMRs and present if detected in at least one examination . Results. During a mean follow-up of 89.4±33.3 months, cardiac events were recorded in 50 (7.1%) patients: 24 (48%) episodes of heart failure, 24 (48%) arrhythmias (23 supraventricular and 1 hypokinetic), and 2 (4.0%) pulmonary hypertension. Mean time from the 1 st follow up CMR to the development of a cardiac complication was 75.31±35.35 months. In the univariate Cox regression analysis, cardiac iron cleareance and myocardial fibrosis were identified as univariate prognosticators (Table 1). In the multivariate analysis only myocardial fibrosis remained an independent predictor factor. Conclusion. The presence of myocardial fibrosis at the baseline CMR or developed within 18 months emerges as the strongest long-term predictor for cardiac complications in TM. Our data demonstrate the importance in using the contrast medium for CMR scans in thalassemia patients. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

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Deferasirox (Exjade®) ≥30 Mg/Kg/Day Is Effective in Reducing Iron Burden in Thalassemia Major Patients Previously Chelated with Monotherapy or Combination Therapy.

Blood ◽

10.1182/blood.v114.22.4058.4058 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4058-4058

Author(s):

Ali Taher ◽

Mohsen Saleh Elalfy ◽

Amal El-Beshlawy ◽

Dunhua Zhou ◽

Lee Lee Chan ◽

...

Keyword(s):

Combination Therapy ◽

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Concentration ◽

Thalassemia Major ◽

Advisory Committees ◽

Liver Iron ◽

Transfusion Requirements

Abstract Abstract 4058 Poster Board III-993 Background Despite the availability of effective chelators, many patients (pts) with β-thalassemia major (TM) present with high iron burden and serum ferritin (SF) >2500 ng/mL, demonstrated to be associated with significant negative outcomes including cardiac disease and organ failure. In the large, prospective EPIC trial including 854 TM pts who received prior chelation therapy, median baseline SF was 3139 ng/mL despite 10.8 yrs of therapy; hence the therapeutic goal was to reduce iron burden. Previous studies have shown that in TM pts with high transfusional iron, ≥30 mg/kg/day deferasirox (Exjade®) doses significantly reduce SF, while 20 mg/kg/day doses maintained SF levels. The objective of this analysis was to assess whether a mean actual deferasirox dose ≥30 mg/kg/day is effective in reducing SF in iron-overloaded pts with TM irrespective of prior chelation therapies. Methods Pts with TM (≥2 yrs) and transfusional iron overload as defined by SF levels ≥1000 ng/mL or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight were enrolled. Initial deferasirox dosing (10–30 mg/kg/day) was dependent on transfusion requirements and adjusted according to the protocol by 5–10 mg/kg/day (range 0–40 mg/kg/day) every 3 months based on SF trends and safety markers. Pts previously chelated with monotherapy deferoxamine (Desferal®; DFO) or deferiprone (Ferriprox®; DFP) or a combination of both and who received a mean actual deferasirox dose ≥30 mg/kg/day over 1 yr were included. The primary efficacy endpoint was the change in SF at 1 yr from baseline (BL). Results Overall, 129 TM pts (15%) who were previously chelated with DFO and/or DFP were treated with a mean actual deferasirox dose of ≥30 mg/kg/day during the 1 yr EPIC trial; 83 pts received prior DFO or DFP monotherapy and 46 received a combination of both. Mean age was 19.5±8.2 vs 23.0±7.2 yrs in prior monotherapy and prior combination therapy pts, respectively. A mean of 167 mL/kg vs 191 mL/kg was transfused in the yr prior to study entry and the mean duration of prior chelation therapy was 11.7±7.7 yrs vs 14.5±7.9 yrs, respectively. During the study, mean transfusional iron intake was similar in both groups (0.36±0.2 and 0.34±0.1 mg/kg/day, respectively). In prior monotherapy pts (mean dose 33.9±2.2 mg/kg/day), median SF decreased from 4885 ng/mL at BL to 4282 ng/mL after 1 yr (Figure) resulting in a decrease from BL of 1024 ng/mL (P<0.0001) based on last-observation-carried-forward (LOCF) analysis. In prior combination therapy pts (mean dose 34.1±3.9 mg/kg/day), median SF decreased from 5921 ng/mL at BL to 4327 ng/mL (Figure) resulting in a decrease from BL of 886 ng/mL (P=0.0078; LOCF). In patients with labile plasma iron (LPI) at BL, 1.3±2.1 and 1.7±3.1 μmol/L in the prior monotherapy and combination therapy groups, respectively after 1 yr was reduced to 1.1±2.6 and 1.4±2.7 μmol/L (LOCF). Overall, five pts (3.9%) discontinued therapy. Reasons for withdrawal were adverse events (AEs; cardiac failure), abnormal laboratory values (increased transaminases), consent withdrawal, lost to follow-up and protocol violation (all n=1). The most common investigator-assessed drug-related AEs were rash (n=14, 10.9%) and diarrhea (n=12, 9.3%). One pt (0.8%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits and one pt (0.8%) had increased alanine aminotransferase >10xULN on two consecutive visits; levels were already elevated. Conclusions This heavily transfused subgroup of TM pts, who had received prior chelation therapy with DFO and/or DFP for an average >10 yrs, continued to have high SF levels >4500 ng/mL. Monotherapy with ≥30 mg/kg/day deferasirox for 1 yr led to significant and clinically relevant reductions in SF in these pts irrespective of previous chelation therapies and was well tolerated. Longer-term studies are required to assess whether continued deferasirox could reduce SF <2500 ng/mL to minimize serious complications of iron overload. Disclosures: Taher: Novartis: Honoraria, Research Funding. Chan:Novartis: Honoraria, Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Sutcharitcharan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽

10.1182/blood-2019-130237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3542-3542 ◽

Cited By ~ 1

Author(s):

Natalia Scaramellini ◽

Carola Arighi ◽

Alessia Marcon ◽

Dario Consonni ◽

Elena Cassinerio ◽

...

Keyword(s):

Clinical Practice ◽

Liver Function ◽

Iron Overload ◽

Board Of Directors ◽

Chelation Therapy ◽

Iron Chelation ◽

Published Data ◽

Iron Chelation Therapy ◽

Iron Intake ◽

Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p<0.001) and for SF<500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT> 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value < 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Association between Native Myocardial T1 Mapping and Cardiac Function and Macroscopic Fibrosis in Thalassemia Major

Blood ◽

10.1182/blood-2020-134585 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-27

Author(s):

Alessia Pepe ◽

Nicola Martini ◽

Antonio De Luca ◽

Vincenzo Positano ◽

Laura Pistoia ◽

...

Keyword(s):

Iron Overload ◽

Myocardial Fibrosis ◽

T1 Mapping ◽

Thalassemia Major ◽

Left Ventricular ◽

Lv Function ◽

Myocardial Iron ◽

Native T1 ◽

Molli Sequence ◽

Lv Volume

Background.Cardiovascular magnetic resonance (CMR) is the only available technique for the non-invasive quantification of MIO. The native T1 mapping has recently been proposed as an alternative to the universally adopted T2* technique, due to the higher sensitivity for detection of changes associated with mild or early iron overload. Objective.To study the association between T1 values and left ventricular (LV) function in thalassemia major (TM) and to evaluate for the first time if T1 measurements quantifying MIO are influenced by macroscopic myocardial fibrosis. Methods.146 TM patients (87 females, 38.7±11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent CMR. Native T1 values were obtained by Modified Look-Locker Inversion recovery (MOLLI) sequence in all 16 myocardial segments and the global value was the mean. LV function parameters were quantified by cine images. Late gadolinium enhancement (LGE) technique was used to detect macroscopic myocardial fibrosis. Results.No correlation was detected between global heart T1 values and LV volume indexes, LV mass index, or LV ejection fraction. Foourteen (9.6%) patients had an abnormal LV motion (13 hypokinesia and 1 dyskinesia) and they showed significantly lower global heart T1 values than patients without LV motion abnormalities (883.8±139.7 ms vs 959.0±91.3 ms; P=0.049). LGE images were acquired in 88 patients (60.3%) and macroscopic myocardial fibrosis was detected in 36 patients (40.9%). The 72.2% of patients had two or more foci of fibrosis. Patients with macroscopic myocardial fibrosis had significantly lower global heart T1 values (921.3±100.3 ms vs 974.5±72.7 ms; P=0.027) (Figure 1A). Data about the LGE was present for 1408 segments (88 patients x 16 segments) and 105 (7.5%) were positive. Segments with LGE had significantly lower T1 values than segments LGE-negative (905.6±110.6 ms vs 956.9±103.8 ms; P<0.0001) (Figure 1B). Conclusion.No correlation between T1 values and LV function parameters was detected, probably because the majority of the patients had normal or mild abnormal LV parameters. TM patients with macroscopic myocardial fibrosis showed significantly lower T1 values suggesting that T1 measurements for quantifying MIO are not influenced by macroscopic myocardial fibrosis and an association between myocardial iron and macroscopic fibrosis, previously detected only in pediatric TM patients. Figure Disclosures Pepe: Chiesi Farmaceutici S.p.A.:Other: no profit support and speakers' honoraria;Bayer:Other: no profit support;ApoPharma Inc.:Other: no profit support.Pistoia:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

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Native T1 Values and Cardiac Involvement in Patients with Thalassemia Major

Blood ◽

10.1182/blood-2020-134578 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Alessia Pepe ◽

Nicola Martini ◽

Antonio De Luca ◽

Vincenzo Positano ◽

Laura Pistoia ◽

...

Keyword(s):

Iron Overload ◽

T1 Mapping ◽

Thalassemia Major ◽

Clinical Impact ◽

Cardiac Complications ◽

Myocardial Iron ◽

Native T1 ◽

Molli Sequence ◽

History Of ◽

Myocardial T1

Background.The T2* cardiovascular magnetic resonance (CMR) is the gold standard for the non invasive detection of myocardial iron overload (MIO). The native myocardial T1 mapping has been proposed as a complementary tool, thanks to its higher sensitivity in presence of small amounts of iron, but no data are available in literature about its clinical impact. Objective:To explore the clinical impact of T1 mapping for detecting cardiac complications in thalassemia major (TM). Methods.We considered 146 TM patients (87 females, 38.7±11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Three parallel short-axis slices of the left ventricle (LV) were acquired with the Modified Look-Locker Inversion recovery (MOLLI) sequence. The native T1 values in all 16 myocardial segments were obtained and the global value was the mean. Results.Twenty-one patients had an history of cardiac complications: 11 heart failure, 8 arrhythmias (7 supraventricular and 1 ventricular), and 2 pulmonary hyperthension. Patients with cardiac complications had significantly lower global heart T1 values (879.3±121.9 ms vs 963.2±98.5 ms; P<0.0001) (Figure) but comparable T2* values (33.32±11.66 ms vs 37.17±9.15 ms; P=0.116). Cardiac complications were more frequent in the group of patients with reduced global heart T1 value (<928 ms for males and <989 ms for females) compared to the group with normal global heart T1 value (71.4% vs 39.5%; P=0.009). Odds ratio (OR) for cardiac complications was 3.8 (95%CI=1.3-10.9) for patients with reduced global heart T1 value versus patients with normal global heart T1 value. Conclusion:We found out a significant association between decreased native global heart T1 values and a history of cardiac complications, suggesting that an early detection of myocardial iron burden by native T1 can support the clinicians in modifing chelation therapy earlier. Figure Disclosures Pepe: ApoPharma Inc.:Other: no profit support;Bayer:Other: no profit support;Chiesi Farmaceutici S.p.A.:Other: no profit support and speakers' honoraria.Pistoia:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

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