Agreement Between R2 and R2* Liver Iron Estimates Is Independent of the Type of Iron Removal Therapy: Results from the Twitch Trial

Abstract Introduction: TCD with Transfusions Changing toHydroxyurea (TWiTCH Clinical Trials.gov NCT01425307), an NHLBI-sponsored multicenter trial, compared transfusion pluschelation (Standard Arm) tohydroxyurea (HU) plus phlebotomy (Alternative Arm) in children with sickle cell disease at high risk for stroke. Alternative arm patients underwent serial phlebotomy (10mL/kg, maximum 500mL) every 4 weeks after reaching maximal tolerated dose (MTD) of HU and discontinuing transfusions. Changes in liver iron concentration (dLIC), measured as mg Fe per gram dry weight liver, by both MRI R2 (FerriScan) and R2* were key secondary outcome measures. R2 and R2* are two, different MRI techniques that exploit the magnetic properties of tissue iron to estimate iron concentration. We previously reported significant differences between the two approaches at the baselinetimepoint. The purpose of this investigation was to determine the limits of agreement between measurements ofdLIC over a period of one year by R2 and R2* methods in both arms of the study. Methods: MRI R2 and R2* data were collected prior to randomization, and after 1 year (midpoint) and 2 years of therapy (study exit). dLIC between baseline to midpoint and midpoint to study completion was calculated for both R2 and R2* LIC values. Since LIC measurement variability increases with iron burden, each dLIC pair (R2 and R2*) were normalized to the patients iron burden at the start of the observation interval. That is, dLIC from baseline to midpoint was normalized to baseline LIC, while dLIC from midpoint to study end was normalized to midpoint LIC. The geometric mean of LICR2 and LICR2* was used to represent the baseline and midpoint LIC. Bland Altman analysis was performed on measurements of the percent change of dLICR2 and dLICR2* to determine the limits of agreement between the two techniques. Results: R2 measurements were performed in 104 patients at baseline, 94 at midpoint and 99 at study end, while R2* measurements were performed in 101, 87, and 89 patients, respectively. However, missing data limited Bland Altman comparisons ofdLIC to 74 patients between baseline to midpoint and 69 patients from midpoint to study end. Figure 1 (left) plots the measureddLIC using R2 (vertical axis) against the measureddLIC change by R2* (horizontal axis) for the Standard Arm participants. Dots represent LIC change over the first year and open circles represent LIC changes over the second year. The dotted line represents perfect agreement. Figure 1 (right) demonstrates the corresponding relationship for the patients in the Alternative Arm. Although the alternative arm appears to have greater disagreement, this represents an artifactcause by the transient increases in LIC that occurred as patients bridged from standard to alternative therapy. Iron chelationwas stopped when patients began hydroxyureabut patients required an overlap period of transfusions for stroke prophylaxis. Figure 2 demonstrates the difference in dLIC measured by R2 and R2*, expressed as a percentage of starting LIC, plotted against the starting LIC value. The standard arm (open circles) and alternative arms (dots) completely overlap. 95% limits of agreement between the two measures ofdLIC were -45.7% to 63.7% (light lines). At LIC values > 8.3 mg/g,dLIC predicted by R2 was larger than predicted by R2*, while the converse was true for LIC values below 8.3 mg/g, similar to our published baseline findings for LIC measurements. Conclusions: LIC by R2 and R2* tracked one another closely over time in patients in both study arms. These data indicate that either technique can be used with confidence to monitor patients on iron removal therapy (chelation or phlebotomy), but that the techniques should not be interchanged. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Wood: Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Biomed Informatics: Consultancy; World Care Clinical: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; AMAG: Consultancy; AMAG: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Biomed Informatics: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy. St Pierre:Resonance Health: Consultancy, Equity Ownership. Piccone:Novartis: Other: Speaker. Hankins:Novartis: Research Funding. Rogers:Apopharma: Consultancy. Ware:Bayer Pharmaceuticals: Consultancy; Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

Download Full-text

Liver Iron Concentration By MRI In Chronically Transfused Children With Sickle Cell Anemia In The Twitch Trial

Blood ◽

10.1182/blood.v122.21.780.780 ◽

2013 ◽

Vol 122 (21) ◽

pp. 780-780

Author(s):

John C. Wood ◽

Zora R. Rogers ◽

Isaac Odame ◽

Janet Kwiatkowski ◽

Margaret Lee ◽

...

Keyword(s):

Iron Overload ◽

Research Funding ◽

Iron Concentration ◽

Altman Analysis ◽

Liver Iron Concentration ◽

Limits Of Agreement ◽

Advisory Committees ◽

Liver Iron ◽

Markers Of Inflammation ◽

Tissue Iron

Abstract Introduction Chronic transfusion therapy represents the standard of care for sickle cell anemia (SCA) patients with abnormal transcranial Doppler (TCD) ultrasound or prior stroke. While effective, monthly transfusions produce iron overload and toxicity if not controlled with chelation therapies. Liver iron concentration (LIC) is a powerful surrogate for total body iron stores. Unfortunately, liver biopsy is not suited for longitudinal analysis because it is invasive, expensive, and prone to sampling variability. MRI transverse relaxation rates, R2 and R2*, are highly correlated with LIC and have mostly supplanted liver biopsy for iron quantification in clinical practice and clinical trials. Since R2 and R2* have different sensitivity to the size and scale of tissue iron distribution, we compared the agreement of LIC values predicted by R2 and R2* in children with SCA and transfusional iron overload from the prospective multicenter TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial (ClinicalTrials.gov; NCT01425307). Methods 133 patients underwent LIC assessment using both R2 and R2* techniques at 22 MRI sites. All sites used 1.5 Tesla magnets and torso phased array coils. Images for R2 measurements were collected on validated scanners and analyzed centrally according to the FerriScan” protocol (Resonance Health, Western Australia, see St Pierre, T.G., et al. Blood,105, 855-861, 2005). Images for R2* assessment were collected using multiple-echo gradient echo sequences (see Wood, J.C., et al. Blood,106, 1460-1465, 2005). Images were analyzed centrally at Children's Hospital Los Angeles, using an exponential-plus-constant fit to the signal decay. Bland-Altman analysis on log-transformed LIC values was used to test agreement between LICR2 and LICR2*; the residuals of this relationship were probed for association with transfusion/chelation history, markers of inflammation, and markers of hemolysis. Results Figure 1A illustrates the scattergram between LICR2* and LICR2. The variance of the disagreement between the two techniques increases with LIC, so log-transformation was performed prior to Bland Altman analysis. LICR2* was systematically higher than LICR2 below about 5 mg Fe/g dw and systematically lower above 5 mg Fe/g dw. Bland Altman comparison of the log-transformed data (Figure 1B) reveals a downward trend (r2 of 0.203, p<0.0001). After correcting for the trend, 95% limits of agreement were -0.42 to 0.42, translating to 95% limits of agreement of the ratio of the two LIC measurements of 0.66 to 1.52. After controlling for mean log LIC, differences in log LIC values were not associated with transfusion or chelation history, markers of inflammation, or markers of hemolysis. Discussion Systematic bias is present between LICR2 and LICR2* in a cohort of children with SCA and transfusional iron overload. Even after correcting these differences, LICR2 and LICR2* also demonstrate significant intrasubject variability, comparable to the error both techniques displayed with respect to biopsy, precluding use of these metrics interchangeably. This implies that LICR2 and LICR2* have potentially clinically significant deviations from true LIC. Rather than sampling or MRI measurement errors, which are consistently < 10% in multiple studies, these disparities likely reflect calibration bias introduced by intersubject differences in tissue iron distribution. Longitudinal LIC determination should lessen their impact, however, and the changes in LIC predicted by R2 and R2* will be compared using one and two year data from the TWiTCH trial. Disclosures: Wood: Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Kwiatkowski:Shire: Consultancy; Resonance Health: Research Funding. St. Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

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 ◽

10.1182/blood.v126.23.2155.2155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2155-2155 ◽

Cited By ~ 1

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.

Download Full-text

Advances in Biomagnetic Liver Susceptometry Allow the Measurement of Liver Iron Concentration with a Room Temperature Sensor

Blood ◽

10.1182/blood-2018-99-117355 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4890-4890

Author(s):

Ashutosh Lal ◽

William Avrin ◽

Viktoriia Kolotovska ◽

Lisa Calvelli ◽

Marcela Weyhmiller

Keyword(s):

Magnetic Field ◽

Iron Overload ◽

Research Funding ◽

Room Temperature ◽

Low Cost ◽

Iron Concentration ◽

Liver Iron Concentration ◽

Limits Of Agreement ◽

Liver Iron ◽

Sensing System

Abstract Introduction: Iron overload is frequently observed in diverse states ranging from thalassemia, sickle cell disease, hereditary hemochromatosis, transfusion-dependent anemias, cancer chemotherapy and chronic liver disease. Management of iron overload depends on the ability to quantify and monitor the patient's iron stores with precision. Organ iron measurement by relaxometry-based MRI techniques has become the current standard. MRI is expensive and has the added limitations of multiple existing methods and reduced dynamic range with 3 Tesla scanners. Liver iron measurements by magnetic susceptometers using superconductive quantum interference device (SQUID) technology are expensive and have limited availability. In this study an improved low-cost device, the room-temperature susceptometer (RTS, Insight Magnetics, San Diego, CA), was tested against the Model 5700 Ferritometer ® 3-Channel SQUID BioSusceptometer System (Tristan Technologies, Inc. San Diego, CA). Both systems quantify liver iron concentration (LIC) using bulk magnetic susceptibility. Where the SQUID uses an ultra-stable sensing system immersed in liquid helium, the RTS cancels the temperature and magnetic-field fluctuations inherent in an apparatus that works at room temperature. The RTS uses three main techniques to sense the very weak magnetic field produced by liver iron: (a) oscillatory magnetic fields that can be detected with high sensitivity using coils of ordinary copper wire, (b) field-producing and field-sensing coils to cancel the signal due to the applied magnetic field, and (c) movement of the sensing unit periodically toward and away from the patient so as to distinguish the patient's magnetic field response from the interfering signal caused by temperature fluctuations in the sensing system. Methods: This study compared measurements of LIC from RTS to those by the SQUID. The RTS in this study was modified from an earlier model to make the baseline reading more stable, and to increase the accuracy of the water reference measurement to which the patient's magnetic response is compared. The magnetic-field source and sensing coils were enlarged to increase the signal of the liver compared with that of the overlying tissue. LIC was measured once on the SQUID and once on the RTS at a single visit. Using ultrasound imaging, optimum liver measurement position was determined and marked with an x-y-positioning and z-distance sensing Locator Loop (Positronic Systemtechnik GmbH, Germany). The locator loop remained attached to the patient for measurements with both devices to preserve measurement location. LIC calculation was corrected for the susceptibility and geometry of the overlying tissue. Measurement results from SQUID and RTS were analyzed independently by two investigators. Results: Thirteen adults (10 with transfusion-dependent thalassemia and 3 controls) with body mass index (BMI) <25 were enrolled. All measurements were completed at a single visit with no failures. LIC values (µg/g wet-liver weight), ranged from -33 to 6493 with SQUID, and -305 to 7237 with RTS. In the three controls, the LIC was -33, 144 and 427 µg/g with SQUID, and -305, 451 and 230 µg/g with RTS. The overall correlation between the two methods was excellent, yielding an r2 = 0.976 and slope = 1.037 ± 0.068 (p<0.001, Fig 1). Bland-Altman analysis of percent-difference versus the average of the two methods showed bias -2.72 (95% limits of agreement -149.1 to 143.6) for all subjects, which improved to 1.94 (95% limits of agreement -41.1 to 45.3) when the average values below 350 µg/g (n=4) were excluded (Fig 2). The percent difference between the two methods was influenced by the subject's BMI (p=0.050 for all subjects; p=0.031 after excluding average LIC <350 µg/g), with the least difference observed in the BMI range of 20-23 Kg/m2. Conclusion: This study shows that, with the recent improvements in the RTS technology, LIC measurements now closely align with those using SQUID. The remaining difference between the two methods likely results from the models used to compensate for the overlying tissue. Further comparison of RTS to SQUID and MRI-based methods in diverse iron overload states is warranted in a larger study. This work may ultimately make low-cost noninvasive measurement of iron overload accessible to the large number of patients in the US, and to resource-limited countries around the world. Disclosures Lal: Bluebird Bio: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Novartis: Research Funding; Celgene Corporation: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding. Avrin:Insight Magnetics: Employment, Other: Proprietor of company developing the study device, Patents & Royalties: Own rights to patents on the study device. Weyhmiller:Insight Magnetics: Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood-2019-122062 ◽

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.

Download Full-text

Liver Iron Concentration Estimates by R2* Are More Robust Than by Ferriscan During Rapid Changes in Iron Burden

Blood ◽

10.1182/blood.v118.21.5296.5296 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5296-5296

Author(s):

John C Wood ◽

Amber Jones ◽

Hugh Y Rienhoff ◽

Ellis J. Neufeld

Keyword(s):

Liver Biopsy ◽

Research Funding ◽

Iron Concentration ◽

Drug Consumption ◽

Dose Titration ◽

Outcome Variable ◽

Gradient Echo ◽

Liver Iron ◽

Body Iron ◽

Tissue Iron

Abstract Abstract 5296 Introduction: MRI assessment of LIC concentration is increasing utilized as the primary outcome variable of clinical trials for iron chelation. The MRI parameters R2 and R2* can both be used for this purpose but have slightly different sensitivities to the scale and distribution of tissue iron deposits. As a result, these techniques may provide significantly disparate results in any given patient and may diverge following abrupt changes in chelation therapy. It is not practical, nor ethical, to use liver biopsy to validate R2 and R2* LIC measures on a short time scale. Thus, we used calculations of chelator molar efficiency to determine whether predicted changes in LIC were consistent with the known iron balance assessed by transfusional burden and drug consumption. Methods: The Phase II trial of FBS701, a novel oral iron chelator, measured LIC by both R2 and R2* at screening, 12 weeks, and 24 weeks of therapy; nine thalassemia centers participated in 7 countries. 51 individuals completed 24 weeks of treatment. Liver R2 was collected and analyzed using a FDA-approved protocol and a commercial vendor (Ferriscan Resonance Health, Australia). Liver R2* was measured using gradient echo sequences with minimum echo times ranging from 1.0–1.2 ms. All gradient echo images were transferred to a central core laboratory for R2* calculation using a three component decay model (exponential + offset). Only patients with LIC values between 3 and 30 mg/g by Ferriscan LIC were allowed to participate. Transfusional iron burden was calculated from transfusional volumes documented for six months prior to entering the study and corrected for hematocrit. Change in total body iron was calculated using the Angelucci equation. Chelator efficiency was calculated using the net change in body iron concentration by drug consumption, calculated on a molar basis, to yield a unit-less number; drug concentration was divided by two to account for the chelator-iron stoichiometry. Observed changes in LIC were judged to be erroneous if they produced an estimated chelator efficiency greater than one or less than zero. We also assume that the efficiency between 0–12 weeks and 12–24 weeks should be comparable; the variance between these two values was used as an independent metric of Ferriscan, robustness for LIC measurement. Results: Figure 1 demonstrates the calculated chelator efficiency from 12–24 weeks versus 0–12 weeks, using LIC values calculated by Ferriscan(open circles) and by R2* (solid dots). The solid line indicates the line of identity and the inset box represents the physiologically possible range. 19/95 Ferriscan LIC measurements were physiologically impossible compared with 5/95 R2* LIC measurements (p=0.004 by Fischer's exact test). Ferriscan 12–24 week efficiency measurements were uncorrelated with Ferriscan 0–12 week measurements and generally strayed a greater distance from the line of identity, with a three-fold larger mean-squared error (0.375 versus 0.126) than for efficiencies calculated using R2*. Discussion: Both R2 and R2* are biopsy-validated, clinically accepted tools for noninvasive LIC estimation and can be used to track liver iron on a long-term basis. However, the ability of these techniques to accurately track short-term changes (below 1 year) has never been studied; such changes may be important for rapid dose-titration. In this study, Ferriscan LIC estimates were inconsistent with measured iron-balance, producing many nonphysiologic estimates of chelator efficiency and poor consistency between observations at three-month intervals. It is not known whether this represents an intrinsic property of R2 measurements, caused by undue sensitivity to microscopic iron particle distribution, or a limitation specific to the Ferriscan processing. However, given the previously published success of the Ferriscan technique with respect to liver biopsy when assessed on longer time-scales, we believe that these data represent a disequilibrium phenomenon, i.e., that R2 measurements are transiently inaccurate following an abrupt chelation change. Longer-term studies will be necessary to test this hypothesis. Nonetheless, caution should be used in trying to interpret Ferriscan results at intervals of six months or less. R2* LIC measurements are intrinsically less sensitive to changes in tissue iron distribution and more accurate reflections of iron balance at shorter time intervals. Disclosures: Wood: Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:Ferrokin BioSciences: Employment. Rienhoff:Ferrokin BioSciences: Employment, Equity Ownership. Neufeld:Ferrokin BioSciences: Research Funding; Novartis: Research Funding.

Download Full-text

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Blood ◽

10.1182/blood.v122.21.1016.1016 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1016-1016 ◽

Cited By ~ 2

Author(s):

John Porter ◽

Ali T Taher ◽

Yesim Aydinok ◽

Maria D Cappellini ◽

Antonis Kattamis ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Iron Removal ◽

Advisory Committees ◽

Liver Iron ◽

Cardiac Iron ◽

Significant Difference ◽

Liver Iron Overload ◽

The Impact

Abstract Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al., 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC <7, 7–≤15 and >15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p-values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (LIC >15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p=0.0016) and 46% (7.3 ±7.3 ms, p<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those with LIC >15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC <7, LIC 7-≤15 and LIC >15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase (p <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher:Novartis Pharma: Honoraria, Research Funding. Aydinok:Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini:Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali:Novartis Pharma: Employment. Martin:Novartis Pharma: Employment. Pennell:Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria.

Download Full-text

Combination of Tmprss6-ASO and the Iron Chelator Deferiprone Improves Erythropoiesis and Reduces Iron Overload in a Mouse Model of Beta-Thalassemia

Blood ◽

10.1182/blood.v124.21.4024.4024 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4024-4024

Author(s):

Carla Casu ◽

Mariam Aghajan ◽

Rea Oikonomidau ◽

Shuling Guo ◽

Brett P. Monia ◽

...

Keyword(s):

Iron Content ◽

Research Funding ◽

Serum Iron ◽

Iron Absorption ◽

Iron Concentration ◽

Iron Chelation ◽

Iron Chelator ◽

Liver Iron ◽

Hepcidin Expression ◽

Liver Iron Content

Abstract Patients affected by non-transfusion dependent thalassemia (NTDT) do not require chronic blood transfusion for survival. However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis (IE), the hallmark of disease, leads to a variety of serious clinical morbidities. In NTDT the master regulator of iron homeostasis, hepcidin, is chronically repressed. Consequently, patients absorb abnormally high levels of iron, which eventually requires iron chelation to prevent the clinical sequelaes associated with iron overload. It has been shown that in mice affected by NTDT (Hbbth3/+), a second-generation antisense oligonucleotide (Tmprss6-ASO) can reduce expression of transmembrane serine protease Tmprss6, the major suppressor of hepcidin expression. This leads to reduction of hemichrome formation in erythroid cells, amelioration of IE and splenomegaly, and increased hemoglobin levels (Guo et al, JCI, 2013). Now we propose the use of Tmprss6-ASO in combination with iron chelators for the treatment of NTDT using Hbbth3/+ mice as a preclinical model. Our hypothesis is that use of chelators will benefit from the positive effect of Tmprss6-ASO on erythropoiesis and iron absorption, further ameliorating organ iron content. To this end, Hbbth3/+ animals were treated with Tmprss6-ASO at 100 mg/kg/week for 6 weeks with or without the iron chelator deferiprone (DFP) at a dose of 1.25 mg/ml. Additional animals were treated with DFP alone. We fed the animals with a commercial or physiological diet, containing 200 or 35 ppm of iron, respectively. We did not observe major differences in the treated animals fed the commercial or physiological iron diet and, for this reason, the data were combined for simplicity. Administration of DFP alone was successful in decreasing organ iron content. Compared to untreated Hbbth3/+ animals, we observed a reduction of 30% and 33% in the liver and spleen, respectively, and no change in the kidney. However, erythropoiesis was not improved (looking at IE, splenomegaly, RBC production and total Hb levels). This was associated with increased serum iron levels (+25%). In Tmprss6-ASO treated Hbbth3/+ animals, we observed an improvement in liver iron content (36% reduction), amelioration of IE, and increased RBC and Hb synthesis (~2 g/dL). Compared to treatment with Tmprss6-ASO alone, combination of DFP with Tmprss6-ASO achieved the same level of suppression of Tmprss6 in the liver (~90%) and reduction of serum iron parameters. This was associated with improvement of IE, decreased reticulocyte counts and splenomegaly, and increased RBC and Hb synthesis (~2 g/dL). While we observed that both Tmprss6-ASO and DFP separately reduced liver iron content to the same extent (~30-36%), combination treatment further reduced iron concentrations in the liver and kidney (69% and 19%, respectively), with no changes in the spleen. Additional analyses are in progress to evaluate the amount of hepcidin in serum as well as expression of erythroferrone, the erythroid regulator of hepcidin. Our first conclusion is that administration of an iron chelator alone is not sufficient to improve erythropoiesis despite that organ iron content is reduced. We speculate that when iron is removed from the liver, hepcidin expression becomes more susceptible to the suppressive effect of IE rather than the enhancing effect of reduced liver organ iron concentration. In addition, the combined effect of iron mobilized from organs and unchanged (or even augmented) iron absorption leads to increased serum iron concentration. As we have shown previously, amelioration of IE in this model requires decreased erythroid iron intake and hemichrome formation. Therefore, iron chelation alone is likely insufficient to improve erythropoiesis. Additional experiments are in progress to further elucidate this mechanism. Our second conclusion is that use of Tmprss6-ASO together with DFP combines the best effects of these two drugs, in particular on erythropoiesis and organ iron content. In animals that received the combined treatment, kidney and liver iron concentrations were further decreased compared to the single treatments. This indicates that Tmprss6-ASO might be extremely helpful in the treatment of NTDT and it could further improve iron related-chelation therapies. Disclosures Casu: Merganser Biotech LLC: Employment; Isis Pharmaceuticals, Inc.: Employment. Aghajan:Isis Pharmaceuticals, Inc.: Employment. Guo:Isis Pharmaceuticals, Inc.: Employment. Monia:Isis Pharmaceuticals, Inc.: Employment. Rivella:bayer: Consultancy, Research Funding; isis Pharmaceuticals, Inc.: Consultancy, Research Funding; merganser Biotech LLC: Consultancy, Research Funding, Stock options , Stock options Other.

Download Full-text

Insights into Relationships Between Serum Ferritin and Liver Iron Concentration Trends during 12 Months of Iron Chelation Therapy with Deferasirox – a Post-Hoc Analysis from the Epic Study

Blood ◽

10.1182/blood.v124.21.52.52 ◽

2014 ◽

Vol 124 (21) ◽

pp. 52-52 ◽

Cited By ~ 2

Author(s):

John B Porter ◽

Mohsen Elalfy ◽

Ali T Taher ◽

Lee Lee Chan ◽

Szu-Hee Lee ◽

...

Keyword(s):

Board Of Directors ◽

Serum Ferritin ◽

Research Funding ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Intake ◽

Advisory Committees ◽

Liver Iron ◽

Baseline Serum ◽

Post Hoc

Abstract Background Serum ferritin is regularly used to assess response to chelation therapy and correlates significantly with liver iron concentration (LIC) particularly when LIC is <7 mg Fe/g dry weight (dw) and serum ferritin is <4000 ng/mL. The absence of a serum ferritin decrease in the first months of a new chelation regime may be interpreted as a lack of response with respect to decreasing body iron load. However, sequential LIC determination (where available) has indicated that many of these patients do indeed have a decrease in LIC. This clinical experience requires greater understanding, particularly the nature of the LIC and serum ferritin relationship at baseline serum ferritin values ≥4000 ng/mL. The aim of this post-hoc analysis of the EPIC study was to gain insight into the relationship between serum ferritin and LIC in response to deferasirox over 1 year, in a large patient cohort, so that serum ferritin trends can be more clearly interpreted and evidence-based practical guidance be given for patients with transfusion-dependent thalassemia (TDT). Methods TDT patients were recruited from 25 sites, received 1-year of deferasirox treatment and had serum ferritin and R2 magnetic resonance imaging (R2-MRI)-assessed LIC measurements at baseline and 1 year. Summary statistics are provided for serum ferritin and LIC responders (decrease, any change from baseline <0) and nonresponders (increase or no change, any change from baseline ≥0), and for baseline serum ferritin categories (≥4000 vs <4000 ng/mL). Results Of the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. Importantly, after 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was –5.4 (–38.5, –11.7, –0.9, 15.4) in serum ferritin responders and –0.2 (–18.4, –2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [0.01–1.49]) and nonresponders (0.37 [0.02–1.00]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [9.8–40.4] vs 23.7 [9.7–37.9]). Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/mL also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin ≥4000 ng/mL (70.3% [n=78]). However, serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/mL; 50.0% [n=14], ≥4000 ng/mL; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value (–0.3 [–13.5–18.7] for <4000 ng/mL and 0.2 [–18.4–19.6] for ≥4000 ng/mL). Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [480–9725] ng/mL; 11.9 [1.8–37.5] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [9.7–36.0] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/mL (n=172) than in those with serum ferritin ≥4000 ng/mL (–2.8 [–38.5–18.7] vs –4.9 [–31.1–19.6]; n=139). Median iron intake was similar between groups. Discussion and conclusions A decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/mL. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Overall, serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body. Figure 1 Figure 1. Disclosures Porter: Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Sutcharitchan:Novartis: Research Funding. Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chakravarty:Novartis: Employment. El-Ali:Novartis: Employment.

Download Full-text

Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia

Blood ◽

10.1182/blood-2009-04-217455 ◽

2010 ◽

Vol 115 (12) ◽

pp. 2364-2371 ◽

Cited By ~ 119

Author(s):

Dudley J. Pennell ◽

John B. Porter ◽

Maria Domenica Cappellini ◽

Amal El-Beshlawy ◽

Lee Lee Chan ◽

...

Keyword(s):

Iron Overload ◽

Iron Reduction ◽

Geometric Mean ◽

Iron Concentration ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Cardiac Iron ◽

Cardiac Iron Overload

Cardiac iron overload causes most deaths in β-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with β-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ± coefficient of variation) improved from a baseline of 11.2 ms (± 40.5%) to 12.9 ms (± 49.5%) (+16%; P < .001). LVEF (mean ± SD) was unchanged: 67.4 (± 5.7%) to 67.0 (± 6.0%) (−0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (± 25.6%) to 32.5 ms (± 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (± 4.7%) to 69.6 (± 4.5%) (+1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

Download Full-text

Exjade® Reduces Cardiac Iron Burden in Chronically Transfused β-Thalassemia Patients: An MRI T2* Study.

Blood ◽

10.1182/blood.v110.11.2781.2781 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2781-2781 ◽

Cited By ~ 1

Author(s):

J. Wood ◽

A.A. Thompson ◽

C. Paley ◽

B. Kang ◽

P. Giardina ◽

...

Keyword(s):

Ejection Fraction ◽

Iron Concentration ◽

Iron Chelation ◽

Left Ventricular ◽

Iron Removal ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Cardiac Iron ◽

The Mean

Abstract Introduction: Despite the routine use of iron chelation therapy, cardiac iron overload results in cardiomyopathy, congestive heart failure and death in approximately 71% of pts with β-thalassemia. Recent MRI studies suggest that the kinetics of cardiac iron uptake and elimination differ from that of liver. Furthermore, different chelators appear to exhibit unique profiles of relative heart and liver iron removal. Deferasirox (DFX; Exjade®) is a once-daily oral iron chelator with demonstrated efficacy in reducing liver iron. In addition, preclinical and single-institution clinical studies have demonstrated cardiac iron removal. This study is a prospective, single-arm multi-institutional trial designed to evaluate the effect of DFX on cardiac iron in pts with β-thalassemia major. Here, we report preliminary results from the first 15 pts who completed 6 months of treatment. Methods: This ongoing study will enroll 30 pts at 4 US centers. DFX is administered at 30–40 mg/kg/day for 18 months. Entry criteria include MRI evidence of cardiac iron (T2* <20 ms) and normal left ventricular ejection fraction (LVEF ≥56%). Serum ferritin is assessed monthly and MRI assessments for liver iron concentration (LIC), cardiac T2* and LVEF are assessed every 6 months. Labile plasma iron (LPI), serum creatinine, biochemical and hematological status are being monitored. Results: At the time of this analysis, 15 of 17 pts had 6 months of evaluation; all were dosed at 30 mg/kg/day. One of the excluded pts was found ineligible (LVEF <56% at baseline) and the other developed cardiac failure prior to 6 months and was switched to continuous DFO (deferoxamine). This pt had markedly elevated cardiac iron (T2*=1.8 ms) at enrollment. All results are reported as mean±SEM (range) unless otherwise stated. Baseline: All 15 evaluable pts (3 male, 12 female; aged 10–43 years) received ≥150 lifetime transfusions. Ferritin was 4927±987 ng/mL (395–10751; n=12). Cardiac T2* was 9.8±1.13 ms (5.0–16.1), LIC was 16.6±4.27 mg/g dw (3.6–62.3) and ejection fraction was 61.2±1.83%. LPI was 0.72±0.28 μmol/L (n=11) and 33% of pts started with abnormal LPI (≥0.5 μmol/L). 6 Month results: At 6 months, the mean decrease in ferritin was 516 ng/mL; 14 of 15 (93%) pts had decreases in hepatic and cardiac iron. The mean reductions in cardiac and hepatic iron were 17.8% (P=0.0136) and 27.0% (P=0.0027), respectively (Figure). There was no change in LVEF by MRI. All patients had normal LPI at 6 months; for pts with abnormal LPI at baseline, the mean LPI dropped from 1.6±0.3 to 0.26±0.1 μmol/L (P=0.003). No pts developed creatinine >upper limit of normal. Four pts had abnormal transaminases on ≥2 occasions but all 4 were abnormal at baseline. Conclusions: The 30 mg/kg/day dose was well tolerated and led to negative cardiac and liver iron balance in 93% of pts. These results are encouraging given this heavily iron-overloaded and heavily transfused population of β-thalassemia pts. Ongoing assessments over 12 and 18 months will elucidate if DFX continues to improve cardiac iron burden and maintain/improve cardiac function in severely iron-overloaded pts. Figure Figure

Download Full-text