MRI-Guided Iron Assessment and Oral Chelator Use Improve Iron Status In Thalassemia Major Patients: a Six-Year Single Center Retrospective Cohort Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 563-563 ◽  
Author(s):  
Diana X Nichols-Vinueza ◽  
Matthew T White ◽  
Andrew J Powell ◽  
Puja Banka ◽  
Ellis J. Neufeld
Keyword(s):  
Side Effects ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Status ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Target Range ◽  
Single Center ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Background Patients (pts) with thalassemia major (TM) require regular red blood cell transfusions. Adequate iron chelation prevents morbidity and mortality due to transfusional iron overload, and must be guided by accurate assessment of tissue iron levels. Magnetic resonance imaging (MRI) can non-invasively measure liver iron content (LIC) and cardiac iron, and has almost entirely supplanted liver biopsy for LIC at our center. The therapeutic goal is to either (a) maintain iron status within a consensus target range, or (b) decrease the iron burden in pts above the target. Three chelators are FDA approved in the US: deferoxamine (DFO), deferasirox (DFX), and deferiprone (DFP), (approval years 1968, 2005 and 2011 respectively). The aim of this study was to evaluate our ability to improve iron status over time in the MRI and oral chelator era. Methods This IRB-approved, single-center, retrospective observational study covered the period from Jan 2005, when MRI iron assessments became standard at our center, to Dec 2012. The study population included all TM pts followed for chelation at our center who had >2 MRI studies during the study period. LIC was measured by calculating T2* and, starting April 2006, also by measuring T2 using the commercial Ferriscan® technique. Liver T2* was converted to LIC using a regression equation (Wood et al. Blood, 2005; 106:1460). Cardiac iron concentration was measured by calculating cT2*; in this abstract both T2* in msec and its reciprocal R2* (1000/cT2* in Hz, which varies proportionally to iron) are reported. The target for LIC was <7 mg/g dry wt (dw), (mean of T2* and Ferriscan LIC) and for cardiac iron, cR2*<50 Hz (i.e. cT2* >20 msec). Statistical analyses were performed in SAS. Results 42 pts (55% male) met the inclusion criteria and had a median age at first MRI of 17.5y (range 1.9-43). Over a mean follow-up period of 5.2±1.9 y, 190 MRIs were performed with median of 4.5 MRIs per pt, interquartile range 3-6. In 2005, DFO was the predominant chelator (70% vs 26% on research use of chelators, DFX; n=27); DFX predominated after its commercial launch. 29/40 (73%) were on DFX by 2009, but this proportion dropped to 23/36 (64%) by 2012. 13/42 pts (31%) remained within the target ranges for cardiac T2* and LIC throughout the study period. 29/42 pts (69%) had at least one cardiac T2* or LIC out of the target range in a total of 97 MRIs. 38/97 (40%) of these out-of-range MRIs prompted a change in chelation strategy: 61% dose change only, 34% change of monotherapy agent, and 5% change from monotherapy to combination. Two pts died of heart failure due to iron overload during the study period; both had taken DFP before their deaths, but for divergent duration (3 days vs 5 y). The median number of chelation changes was 1.4 per pt/y (IQR 0.9-1.9). 175/229 (76%) dosing changes were for iron status as assessed by MRI or ferritin; 7/229 (3%) were dose decreases for side effects, and 2% were due to weight change only. Change in chelators occurred 82 times during the study. 34% of chelator changes were due to low or high iron status by MRI or Ferritin. 11% of changes were for side effects to a prior chelator and 54% were for other reasons (commercial launch of DFX or clinical trials). From initial to final MRI, both LIC and T2* status of our pts improved significantly (figure). At the initial MRI, 16/41 (40%) of pts were in target range for both LIC and cR2*, 4/41 (10%) were in the highest (undesirable) range of LIC>15 mg/g dw, and/or cardiac T2* <10 msec. From first to last cardiac T2* assessment (n=38), 63% of pts started and ended within the target range, 13% improved from abnormal to target range, 24% remained out of the target range. The two pts who died were among the persistent abnormal cardiac T2* group. For LIC (n=42), 45% remained in the target range throughout, 33% started out of target range and ended within, 12% improved but not to the target, 7% worsened, and one outlier remained severe. Conclusions The introduction of routine MRI assessments of LIC and cardiac R2* (T2*), together with the introduction of oral chelators, has improved the fraction of TM pts with liver and cardiac iron within the target range at our center. Annual MRIs facilitate chelation changes when necessary. Legend: A: Cardiac iron status from first to last MRI for each subject. Reciprocal cR2* and cT2* are on left and right Y-axes. B: Liver iron status. P-values are by Wilcoxon signed-rank test. Disclosures: Neufeld: Shire: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Apopharma: Consultancy.

Liver and Cardiac Iron Measurements in Very Young Chronically Transfused Patients Show Dangerous Levels of Iron Loading

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1086-1086
Author(s):  
Vasilios Berdoukas ◽  
Mammen Puliyel ◽  
Adam Bush ◽  
Thomas Hofstra ◽  
Bhakti P. Mehta ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Iron Status ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Cardiac Iron ◽  
Total Body

Abstract Abstract 1086 Recurrent blood transfusion results in significant iron overload that can cause serious organ damage and death if not properly treated. Liver iron concentration (LIC) is the best indicator of total body iron status and can be measured non-invasively by magnetic resonance imaging (MRI). In the past, it was recommended that LIC assessments by liver biopsy begin after about 6 years of age (yo). MRI is also an excellent way to monitor iron cardiomyopathy, which remains a major cause of death in chronically transfused patients. To understand how rapidly iron overload develops, we reviewed the 1316 MRI iron studies we have performed since 2002 and summarized the LIC and cardiac R2* in a subset of 127 subjects who had their first MRI studies before 10 yo. Because of the known serious pitfalls in the assessment of total body iron by measurement of ferritin, LIC is measured by MRI in our center as standard of care in all patients on chronic transfusion soon after the start of iron chelation therapy. Most children less than 6 years of age require general anesthesia for this procedure. In some older children cooperation can be achieved by distraction techniques. Thirty three percent had sickle cell disease (SCD), 33% thalassemia major (TM), 11% Blackfan Diamond anemia (DBA), 3% congenital dyserythropoietic anemia (CDA), and 8.6% had other transfusion dependent anemias (OTRAN) and 11.4% had studies done not related to transfusion. This paper will focus on the 114 subjects whose MRI was done to evaluate transfusion related iron overload. The median age at first MRI was 6 years with 25% having their first study before 3.7and 10% before 2.1 yo. The median LIC was 9.8 mg/g dry weight (dw) and 10% of subjects had a first LIC > 22 mg/g dw. Only 2.5% had evidence of cardiac iron (T2* < 20ms). The median LICs (mg/g dw) were 8.9 for SCD, 11.8 for TM, 13 for DBA, 6.1 for CDA, and 8.7 OTRAN and were not statistically different. The minima ranged from 0.6 in OTRAN to 4.2 for CDA and the maxima ranged from 25 in CDA to 39.7 for SCD. There was significant iron loading even when we restricted the analysis to 27 subjects with a first MRI at < 3.5 yo; SCD (2.3 median (med), 2.8 maximum (max)), TM (14.6 med, 35 max), DBA (13 med, 15 max),CDA (6.6 med, 25 max) and OTRAN (5.8 med, 11 max). There were 4 subjects who had evidence of cardiac iron loading. Two had DBA with T2* of 18 ms and 16 ms at 2.5 and 3.7 years of age respectively. A third DBA subject had a T2* of 20 ms at only 4.6 yo. Two TM subjects had a T2* of 15 ms at 6.6 and 9.1 yo respectively. These data indicate that there is significant elevation in LIC by the age of 3.5 years with a median LIC of 11 mg/g dw and 25% of subjects having a LIC > 15 mg/g dw. These are very high levels of iron loading. Furthermore, 2.5% of subjects in this age already have evidence of cardiac iron loading. On the basis of such findings, direct measurement of liver iron by MRI is essential as soon as possible after the start of regular transfusions and cardiac iron should be measured early in high risk children with Diamond Blackfan anemia and thalassemia major. Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 618-618
Author(s):  
Janet L. Kwiatkowski ◽  
Mohsen Saleh Elalfy ◽  
Caroline Fradette ◽  
Mona Hamdy ◽  
Amal El-Beshlawy ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Concentration ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Upper Limit ◽  
Iron Load ◽  
The Difference

Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation. Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage. Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment. Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints. With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs. Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias. Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study. Disclosures Kwiatkowski: Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment. OffLabel Disclosure: Deferiprone is an oral iron chelator.

scholarly journals Association of Liver Iron Concentration Levels with Myocardial T2* Responses in Transfusion-Dependent Thalassemia Major Patients Treated with Deferasirox and Deferoxamine- Extension of Cordelia Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2155-2155 ◽  
Author(s):  
Dudley J Pennell ◽  
John B Porter ◽  
Antonio Piga ◽  
Jackie Han ◽  
Alexander Vorog ◽  
...  
Keyword(s):  
Research Funding ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Removal ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Time Points ◽  
Cardiac Iron ◽  
Time Point

Abstract Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC <7, 7 to <15 and ≥15 mg Fe/g dry weight (here after mg/g) both at baseline (BL) and specific visits, to assess the relation of absolute LIC and changes in LIC overtime, with mT2* and cardiac iron concentration (CIC), respectively. During the study, mT2* (ms), and LIC (mg/g) were measured every 6 mo at the same time point. CIC (mg/g) was analyzed as a post hoc parameter derived from mT2*. The change in mT2* was assessed as geometric mean (Gmean)±coefficient of variation (CV), ratio of the Gmean at specific time points divided by that at BL (Gmean at specific time point/Gmean BL) and both CIC and LIC as mean±SD, unless otherwise specified. Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC <7, 7 to <15, ≥15, respectively, during the extension study. The LIC levels for pts categorized by LIC <7, 7 to <15 and ≥15 improved from BL to Mo 24 as follows: 72% decrease (mean absolute change, -15.1±14.1), 66% decrease (-26.6±13.0), and 19% decrease (-10.2±15.7), respectively. For pts with BL LIC <7, 7 to <15, ≥15, mT2* improved from BL to Mo 24 as follows: 43% increase (14.0±18.1 to 21.6±31.1; mean abs change, 7.8±4.0), 50% increase (12.3±34.4 to 19.1±46.4; 8.0±6.0), and 30% increase (11.1±30.8 to 14.5±40.8; 4.1±5.0). The CIC values improved from BL to Mo 24 by 38% (1.8±0.4 to 1.1±0.5), 40% (2.3±0.9 to 1.4±0.7), and 23% (2.6±1.0 to 1.9±1.0), respectively. The mT2* responses for pts categorized according to visit specific LIC levels (LIC <7, 7 to <15, ≥15) from BL to Mo 12 were 22% increase (mean abs change, 3.7±4.3) in LIC <7, 21% increase (2.7±2.0) in LIC 7 to <15, and 7% increase (1.5±3.2) in LIC ≥15. From BL to Mo 24, mT2* increased by 51% (mean abs change, 7.8±5.3), 35% (4.1±2.5), and 11% (2.0±4.4), respectively. The CIC levels improved from BL to Mo 24 by 40% (mean abs change, -1.0±0.8) in LIC <7, 31% (-1.0±0.6) in LIC 7 to <15, and 6% (-0.1±0.8) in LIC ≥15. The change in mT2* (Gmean ratio) at Mo 6, 12, 18 and 24 are shown in the Figure A. The mT2* response was higher in pts who achieved a lower LIC category (LIC <7) at respective time points and this change in mT2* was more apparent at 18 and 24 mo of treatment with DFX. Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell: Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Pulmonary Hypertension Is Uncommon In Well-Transfused Thalassemia Major Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4273-4273
Author(s):  
Jon Detterich ◽  
Leila Noetzli ◽  
Susan Carson ◽  
Paul Harmatz ◽  
Thomas D. Coates ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Iron Overload ◽  
Research Funding ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Cell Disease ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Abstract 4273 Introduction: Pulmonary hypertension is a common and serious cardiovascular complication in patients with thalassemia intermedia and sickle cell disease. Circulating platelet and erythrocyte fragments, as well as cell-free hemoglobin from intravascular hemolysis, may contribute to nitric oxide depletion, intimal proliferation, and pulmonary vascular remodeling. Splenectomy has been also been associated with pulmonary hypertension in some studies. Ineffective erythropoiesis, via release of PLGF and elevation of other proinflammitory cytokines, has also been associated with pulmonary hypertension. However, the risk for pulmonary hypertension in thalassemia major patients remains controversial, with prevalence estimates ranging from 10%-60%. We report echocardiography results from 80 thalassemia major patients enrolled in the Early Detection of Iron Cardiomyopathy Trial (EDICT) at Children's Hospital Los Angeles. Methods: Patients were enrolled from August 2004 until May 2009 in a combined cross-sectional and observational trial probing for early predictors of cardiac dysfunction. Patient visits were scheduled within one week of transfusion. All patients underwent echocardiography and cardiac MRI analysis within 4 months of each other; most were performed during the same clinical visit (median time between scans one day). Comprehensive assessments of pulmonary artery pressure (tricuspid and pulmonary regurgitation velocities), systolic function, and diastolic function were performed using two dimensional imaging, M-mode, and routine and tissue Doppler. All images were collected by experienced echocardiography technicians and analyzed by the principal investigator. Three to five beat averages were used to improve measurement stability. Tricuspid regurgitation (TR) jet was only reported if a full envelope was recognized; at our institution, the upper limit of normal for TR jet is 2.7 m/s. Results: Patient demographics are summarized in Table 1. Patients were gender-balanced and well distributed between 11 and 47 years of age. Patients who had been splenectomized (N=34) tended to be older. Iron overload was severe, with a mean liver iron concentration of 12.4 ± 14.2 mg/g dry weight. Roughly half of the patients had detectable cardiac iron and 9% had overt left ventricular dysfunction (LVEF < 56%). TR jet was detectable in 62/80 patients. Only one patient exhibited pulmonary artery hypertension (TR jet 2.9 m/s), however this patient also had severe cardiac iron overload and overt left ventricular systolic and diastolic dysfunction (LVEF 42.7%, E/E' 10). Two patients had TR jets of 2.6 ms and three had TR jets of 2.5 m/s. Pulmonary insufficiency jets were normal in all patients. TR velocity did not correlate with age, cardiac index, cardiac iron or liver iron, but demonstrated a weak (r=0.29, p=0.02) association with left ventricular diastolic dysfunction (E/E′). Discussion: The EDICT patient cohort suggests a low risk for pulmonary hypertension in well-transfused thalassemia major patients. The single elevated TR jet was explained by iron cardiomyopathy and normalized (2.2 m/s) after two years of aggressive chelation therapy. TR velocities at the upper limits of normal (2.5-2.7 m/s) were observed in five patients; these have been associated with poor outcomes in some sickle cell disease cohorts, but not in thalassemia major. Long-term surveillance remains critical as pulmonary hypertension risk may increase with age. Disclosures: Harmatz: Novartis: Research Funding. Coates:Novartis: Research Funding, Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

Association Between Cardiac Iron Clereance and Hepatic Siderosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4833-4833
Author(s):  
Alessia Pepe ◽  
Laura Pistoia ◽  
Domenico D'Ascola ◽  
Maria Rita Gamberini ◽  
Francesco Gagliardotto ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Hepatic Iron ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Follow Up Study ◽  
Hepatic Iron Overload

Abstract Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months. Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values. Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO). Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1). Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001). Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values. In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2). Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes. In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

scholarly journals MRI Evaluation of Liver and Cardiac Iron Overload Impact on Hematopoietic Stem Cell Transplantation with β-Thalassemia Major

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5738-5738
Author(s):  
Libai Chen ◽  
Yuelin He ◽  
Jianyun Wen ◽  
Wenjing Yang ◽  
Xuan Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Iron Overload ◽  
Hematopoietic Stem Cell ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Hematopoietic Stem ◽  
Cardiac Iron

OBJECTIVE: To assess the effects of liver and cardiac iron overload detected by magnetic resonance imaging (MRI) T2* on hematopoietic stem cell transplantation in children with β-thalassemia major. METHODS:Summary of 380 cases of β-thalassemia major patients more than 5 years old in Nanfang hospital, southern medical university from 2012 to 2019.Iron concentrations in the liver and heart were calculated based on MRI T2* test results of liver and heart. Age, serum ferritin, left ventricular ejection fraction (LVEF), and liver function were compared to evaluate the effect of iron overload on organ function in patients with β-thalassemia major before transplantation.168 patients underwent allogeneic hematopoietic stem cell transplantation, 48 were HLA-mismatched transplantation, and 120 were HLA-identical allogeneic hematopoietic stem cell transplantation.To analysis the influence between implantation rate, hematopoietic reconstruction time, mortality, and common complications after transplantation such as graft-versus-host disease, hepatic venous obstruction, infection, immune hemolysis, and pancytopenia and liver and cardiac iron overload detected by magnetic resonance imaging (MRI) T2*. RESULTS:Myocardial iron overload occurred in 73 cases (19.2%), including 29 cases of cardiac T2*15~20 ms (mild), 23 cases of 10~14 ms (moderate), and 21 cases of <10 ms (severe).There were 305 cases (80.2%) with liver iron overload, including 98 cases with 2.7~6.3 ms (mild), 166 cases with 1.4~2.7 ms (moderate), and 41 cases with <1.4 ms (severe).LVEF decreased in 5 cases (1.6%).Liver iron was positively correlated with serum ferritin (r=0.523, P=0.001), cardiac iron concentration was positively correlated with serum ferritin (r=0.33, P=0.1), age was positively correlated with cardiac iron concentration (r=0.4, P=0.14), and age was negatively correlated with left ventricular ejection fraction (r=-0.36, P=0.001).After transplantation, liver iron concentration was positively correlated with hemoglobin implantation time (r=0.49, P=0.043), heart iron concentration was positively correlated with mortality (r=0.39, P=0.012), serum ferritin was negatively correlated with implantation rate (r=-0.26, P=0.012), and serum ferritin was positively correlated with infection incidence correlation (r=0.441, P=0.034).There were no statistically significant differences in liver, heart MRI T2*, liver iron concentration and heart iron concentration between the two groups before and after transplantation. CONCLUSION:Magnetic resonance imaging (T2*) is an effective and non-invasive method to detect the iron overload in the heart and liver caused by blood transfusion in β-thalassemia patients. Iron overload can have adverse effects on hematopoietic stem cell transplantation,and effective iron removal before transplantation can improve the success rate of transplantation.Quantitative assessment of iron overload in the liver and heart by MRI can be used as a necessary examination before transplantation. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
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.

scholarly journals Correlation between Changes in Cardiac Iron and Hepatic Iron in Pediatric Patients with Thalassemia Major

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2241-2241
Author(s):  
Alessia Pepe ◽  
Antonella Meloni ◽  
Aldo Filosa ◽  
Laura Pistoia ◽  
Tommaso Casini ◽  
...  
Keyword(s):  
Iron Overload ◽  
Statistical Significance ◽  
Iron Concentration ◽  
Good Control ◽  
Thalassemia Major ◽  
Hepatic Iron ◽  
Myocardial Iron ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Mri Study

Introduction. A prospective magnetic resonance imaging (MRI) study demonstrated a good control of myocardial iron overload (MIO) in terms of prevention and treatment in children with thalassemia major (TM). The aim of the present study was to evaluate if changes in MIO were related to baseline hepatic iron or changes in hepatic iron overload (HIO). Methods. We considered 68 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) project with less than 18 years at the first MRI scan and who performed a follow-up (FU) study at 18±3 months. Myocardial and hepatic iron burdens were quantified by the T2* technique. The value of 20 ms was used as conservative normal value for the global T2* value. Liver T2* values were converted into liver iron concentration (LIC) values. A LIC<3 mg/g/dw indicated significant no HIO, between 3 and 7 mg/g/dw mild HIO, between 7 and 15 mg/g/dw moderate HIO, and ≥15 mg/g/dw severe HIO. Results. Thirty-six patients were females and mean age at the time of the baseline MRI was 13.74±3.09 years. Baseline global heart T2* values were 29.72±11.21 ms and 16 (23.5%) patients showed significant baseline MIO. The percentage changes in global heart T2* values per month in the whole patient population were 0.66±1.70 and they resulted significantly higher in the 16 patients with significant baseline MIO versus the patients with no baseline MIO (1.99±2.53% vs 0.25±1.09% ms; P=0.002). Percentage changes in global heart T2* values per month were not influenced by initial MRI LIC values (R=0.048; P=0.695) (Figure 1A) and were comparable among the 4 groups of patients identified on the basis of baseline MRI LIC values (14 no HIO: 0.29±1.12% vs 21 mild HIO: 0.75±1.56% vs 15 moderate HIO: 0.82±2.03% vs 18 severe HIO: 0.71±2.00%; P=0.876). Percentage changes in global heart T2* values per month were not associated to final MRI LIC values (R=-0.134; P=0.277) (Figure 1B). The correlation between % changes in global heart T2* and MRI LIC values did not reach the statistical significance (R=-0.244; P=0.067) (Figure 1C). In patients with baseline MIO no correlation was found between % changes in global heart T2* values per month and initial MRI LIC values (R=-0.325; P=0.219) or % changes in MRI LIC values per month (R=-0.353; P=0.180). Conclusion. In pediatric TM patients changes in cardiac iron are not correlated to baseline MRI LIC values and changes in hepatic iron. So, our data seem not supporting the hypothesis for which it is necessary to clean the liver before removing iron from the heart. Figure 1 Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Myocardial iron overload

2018 ◽  
pp. 364-374
Author(s):  
John P Carpenter ◽  
John C Wood ◽  
Dudley J Pennell
Keyword(s):  
Heart Failure ◽  
Iron Overload ◽  
Iron Concentration ◽  
Left Ventricular ◽  
Breath Hold ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Single Breath ◽  
Developing Heart ◽  
Cost Efficient

The heart is the target lethal organ in thalassaemia major. Cardiovascular magnetic resonance (CMR) measures iron using the magnetic relaxation time T2*. This allows comparison with the left ventricular function and conventional iron measurements such as liver iron and serum ferritin. The single breath-hold cardiac-gated CMR acquisition takes only 15 seconds, making it cost-efficient and relevant to developing countries. Myocardial T2* of <20 ms (increased iron) correlates with reduced left ventricular ejection fraction, but poor correlation exists with ferritin and liver iron, indicating poor capability to assess future risk. Myocardial T2* of <10 ms is present in >90% of thalassaemia patients developing heart failure, and approximately 50% of patients with T2* of <6 ms will develop heart failure within 1 year without intensified treatment. The technique is validated and calibrated against human heart iron concentration. The treatment for iron overload is iron chelation, and three major trials have been performed for the heart. The first trial showed deferiprone was superior to deferoxamine in removing cardiac iron. The second trial showed a combination therapy of deferiprone with deferoxamine was more effective than deferoxamine monotherapy. The third trial showed that deferasirox was non-inferior to deferoxamine in removing cardiac iron. Each drug in suitable doses can be used to remove cardiac iron, but their use depends on clinical circumstances. Other combination regimes are also being evaluated. Use of T2*, intensification of chelation treatment, and use of deferiprone are associated with reduced mortality (a reduction in deaths by 71% has been shown in the United Kingdom). The use of T2* and iron chelators in the heart has been summarized in recent American Heart Association guidelines.

scholarly journals Longitudinal analysis of heart and liver iron in thalassemia major

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2973-2978 ◽  
Author(s):  
Leila J. Noetzli ◽  
Susan M. Carson ◽  
Anne S. Nord ◽  
Thomas D. Coates ◽  
John C. Wood
Keyword(s):  
Longitudinal Analysis ◽  
Time Lag ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Accumulation ◽  
Liver Iron ◽  
Cross Sectional ◽  
Cardiac Iron ◽  
Cardiac Iron Overload ◽  
Magnetic Resonance Imaging Mri

Abstract High hepatic iron concentration (HIC) is associated with cardiac iron overload. However, simultaneous measurements of heart and liver iron often demonstrate no significant linear association. We postulated that slower rates of cardiac iron accumulation and clearance could reconcile these differences. To test this hypothesis, we examined the longitudinal evolution of cardiac and liver iron in 38 thalassemia major patients, using previously validated magnetic resonance imaging (MRI) techniques. On cross-sectional evaluation, cardiac iron was uncorrelated with liver iron, similar to previous studies. However, relative changes in heart and liver iron were compared with one another using a metric representing the temporal delay between them. Cardiac iron significantly lagged liver iron changes in almost half of the patients, implying a functional but delayed association. The degree of time lag correlated with initial HIC (r = 0.47, P < .003) and initial cardiac R2* (r = 0.57, P < .001), but not with patient age. Thus, longitudinal analysis confirms a lag in the loading and unloading of cardiac iron with respect to liver iron, and partially explains the weak cross-sectional association between these parameters. These data reconcile several prior studies and provide both mechanical and clinical insight into cardiac iron accumulation.

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