scholarly journals Multi-Center, Multi-Vendor Reproducibility and Calibration of MRI-Based R2* for Liver Iron Quantification

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2010-2010
Author(s):  
Diego Hernando ◽  
Ruiyang Zhao ◽  
Qing Yuan ◽  
Mounes Aliyari Ghasabeh ◽  
Stefan Ruschke ◽  
...  
Keyword(s):  
Field Strength ◽  
Iron Overload ◽  
Roc Curve ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Breath Hold ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Stores ◽  
Privately Held

Abstract Introduction: Excessive accumulation of iron is caused by a variety of conditions, including hereditary hemochromatosis and transfusional hemosiderosis. If untreated, iron overload can lead to damage in those organs where iron accumulates. Therefore, accurate and reproducible evaluation of body iron stores is needed to guide diagnosis, grading, and treatment monitoring of iron overload. While serum ferritin is the simplest means to assess body iron, it is also an acute phase reactant and therefore is not a reliable biomarker of body iron. Liver iron concentration (LIC) is directly and linearly related to total body iron stores. As such, LIC is widely recognized as a useful surrogate biomarker for the evaluation of iron overload. Liver biopsy is limited by its invasive nature and is contraindicated in many patients (eg. thrombocytopenia) due to bleeding risk. Magnetic resonance imaging (MRI) is a standard of care tool to measure LIC. Arguably the most practical method is R2* MRI due to its speed and ease of use, but the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Therefore, we evaluated the reproducibility and calibration of R2*-based LIC measurement via a single-breath-hold, confounder-corrected R2*-MRI at both 1.5T and 3T, through a multi-center, multi-vendor study. Methods: Four centers (University of Wisconsin-Madison, University of Texas-Southwestern, Johns Hopkins University, and Stanford University) using MRI scanners of different vendors (GE, Philips, and Siemens) participated in this HIPAA-compliant IRB-approved prospective cross-sectional study. This study recruited subjects with known or suspected iron overload from a variety of etiologies, including hereditary hemochromatosis, transfusional hemosiderosis (due to non-malignant or malignant conditions), and chronic liver disease. Subjects with were recruited for same day multiecho gradient-echo MRI for R2* mapping at both 1.5T and 3T (UW, UTSW, Stanford: 3.0T; JHU: 2.89T). R2* maps were reconstructed from the raw multiecho images and analyzed at a single center. Spin-echo MRI were also performed at 1.5T according to a standardized protocol (FerriScan, Resonance Health, Australia) and processed by a commercial algorithm to obtain FDA-approved reference standard LIC estimates. R2*-vs.-LIC calibrations were generated across centers and field strengths using linear regression and compared using F-tests. A predicted 2.89T calibration was interpolated from the 1.5T and 3.0T calibrations, and compared to the measured (JHU) calibration. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic accuracy of R2* MRI for detection of clinically relevant LIC thresholds. Results: A total of 200 subjects were recruited and successfully scanned for this study. We confirmed a linear relationship between R2* and LIC. All calibrations within the same field strength (see Figure 1) were highly reproducible showing no statistically significant center-specific differences (F > 3.0461). Pooled calibrations for 1.5T, 2.89T, and 3.0T were generated. At either field strength and for each of the LIC thresholds under consideration (1.8, 3.2, 7.0, 15.0 mg/g), estimated areas under the ROC curve (AUCs) of 0.98 or higher were observed. Discussion and Conclusions: In conclusion, confounder-corrected R2* MRI enables accurate and reproducible quantification of liver iron overload, over clinically relevant ranges of LIC. The data generated in this study provide the necessary calibrations for broad dissemination of R2*-based LIC quantification. Figure 1 Figure 1. Disclosures Hernando: Calimetrix: Current holder of individual stocks in a privately-held company. Pedrosa: Merck: Honoraria; Bayer Healthcare: Honoraria; Health Tech International: Current holder of stock options in a privately-held company. Vasanawala: HeartVista: Current holder of individual stocks in a privately-held company; InkSpace: Current holder of individual stocks in a privately-held company; Arterys: Current holder of individual stocks in a privately-held company. Reeder: Bayer: Research Funding; Pfizer: Research Funding; Calimetrix, LLC: Current holder of individual stocks in a privately-held company; Reveal Pharmaceuticals: Current holder of individual stocks in a privately-held company; Elucent Medical: Current holder of individual stocks in a privately-held company; Cellectar Biosciences: Current holder of individual stocks in a privately-held company; HeartVista: Current holder of individual stocks in a privately-held company.

Is Ferriscan - a Useful Tool for Diagnosing and Monitoring Tissue Iron Load after Acute Iron Intoxication?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4828-4828
Author(s):  
Mohamed A. Yassin ◽  
Ashraf Tawfiq Soliman ◽  
Abdulqadir Nashwan ◽  
Abbas Moustafa ◽  
Sandra Abousamaan
Keyword(s):  
Iron Overload ◽  
Serum Iron ◽  
Iron Concentration ◽  
Iron Toxicity ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Body Iron ◽  
Elemental Iron ◽  
Iron Stores ◽  
Tissue Iron

Abstract Almost 16,000 iron exposures annually are reported in children less than six years of age in the United States. Deferoxamine is the iron-chelating agent of choice. Deferoxamine binds absorbed iron, and the iron-deferoxamine complex is excreted in the urine. Indications for treatment include shock, altered mental status, persistent GI symptoms, metabolic acidosis, pills visible on radiographs, serum iron level greater than 500 µg/dL, or estimated dose greater than 60 mg/kg of elemental iron. No clear end point of therapy is distinguished. Infusion of deferoxamine for 6-12 hours has been suggested for moderate toxicity. For severe toxicity, administer deferoxamine for 24 hours. Because these end points are arbitrary, observe the patient for the recurrence of toxicity 2-3 hours after the deferoxamine has been stopped. Complications of iron toxicity include the following: Infection with Yersinia enterocolitica, acute respiratory distress syndrome (ARDS) and fulminant hepatic failure, hepatic cirrhosis, pyloric or duodenal stenosis. Systemic toxicity is expected with an ingestion of 60 mg/kg. Ingestion of more than 250 mg/kg of elemental iron is potentially lethal. Although a low serum ferritin is an accurate measure of iron deficiency, there is no accurate serum or plasma marker for acute body-iron overload. Serum iron concentration and transferrin saturation do not quantitatively reflect body iron. Stores and should therefore not be used as surrogate markers of tissue iron overload. Liver iron concentration provides the best measure of total body iron stores and is a validated predictor of the risks a particular patient faces from the complications of iron toxicity. Several imaging noninvasive techniques are available for measuring liver iron concentration (LIC) . There are two validated MRI methods for quantitating the liver iron burden: the FerriScan and T2 methods. The noninvasive R2-MRI technique (FerriScan) is highly sensitive and specific for estimating LIC and is approved by the Food and Drug Administration for routine clinical use. However, it was not used to diagnose and monitor LIC in cases of acute iron intoxication. This 27 year old female nurse by profession self-referred to hematology clinic for evaluation of Iron overload after self injecting herself with 20 ampoules of IV iron Ferro sac (each ampoule containing 200 mg of iron, (4000 mg elemental iron, 60 mg/kg) . Her CBC on presentation showed Hb of 12.5 g/dl her baseline Hb 9 g/dl with serum iron of 28 (NR 9.0 - 30.4 umol/L) ,TIBC of 42 NR(45 - 80 umol/L ), ferritin 1001 (NR 24-336 mcg/l) Her clinical exam was unremarkable. Her MRI showed severe iron overload. 9 mg /g dray tissue (NR 0.17-1.8) Patient received chelation with deferasirox at dose of 30 mg /kg for 6 months when her ferriscan showed almost normal LIC of 2 mg /g dry tissue. This case report showed the value of ferriscan in diagnosing the degree of tissue iron overload and in monitoring chelation to a safe level of hepatic iron content. Disclosures No relevant conflicts of interest to declare.

A New Model for Predicting Venesection Therapy Requirements in Hereditary Hemochromatosis Using Non-Invasive Liver Iron Concentration Measurement.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3596-3596 ◽  
Author(s):  
Timothy G. St. Pierre ◽  
Gary P. Jeffrey ◽  
Enrico Rossi ◽  
Adam J. Fleming ◽  
Wanida Chua-anusorn ◽  
...  
Keyword(s):  
Blood Volume ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Liver Volume ◽  
Newly Diagnosed ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Stores ◽  
Straight Line ◽  
Total Body

Abstract Newly diagnosed hereditary hemochromatosis subjects are treated with venesection therapy in order to reduce body iron stores. Liver iron concentration (LIC) is the most reliable indicator of body iron stores. Proton transverse relaxation rate imaging (FerriScan®) enables a highly specific and sensitive measurement of LIC [St. Pierre TG, Clark PR, Chuaanusorn W, Fleming A, Jeffrey GP, Olynyk JK, Pootrakul P, Robins E, Lindeman R. Blood105 (2005) 855–861]. In this study FerriScan® was used to follow the LIC and liver volume in 7 newly diagnosed homozygous C282Y hereditary hemochromatosis patients. Baseline LIC values ranged from 3.4 to 16.7 mg Fe/g dry tissue. The total number of venesected units of blood required to lower the LIC of each subject to the upper end of the normal range was initially estimated from body mass and LIC [Angelucci, E., Brittenham, G.M., McLaren, C.E. et al. (2000) New Eng. J. Med.343, 327–331]. The LIC of each subject was measured again after approximately half the estimated total number of units of blood had been removed, and a third time near completion of the venesection therapy. For each subject, a straight line was fitted to the LIC versus venesected blood volume data. The coefficient of variation of the differences between the measured LIC values and the fitted lines (a measure of the precision of the LIC measurements) was found to be 7 %. Total body iron stores were measured by extrapolating the straight line fit through the LIC vs venesected blood volume to zero LIC and using a value of 0.473 mg Fe/mL for the blood iron concentration. Total liver iron content was determined by simultaneous measurement of LIC and liver volume with MRI. The data indicated that the higher the LIC at diagnosis, the higher was the fraction, α, of the total body iron store located in the liver. Hence a linear model relating α to LIC is proposed, α = β x LIC + α0. Linear regression was used on the 21 measurements of LIC in the study to find the following optimum model parameters α0 = 0.169 and β = 0.0274 g wet liver/mg Fe. Using these parameters the total blood volume (TBV) to be removed from a patient to bring the LIC down from an initial value (LICi) to a target value (LICf) can be calculated using TBV = [(LICi – LICf) x V]/(β x LICi + α0) where V is the liver volume. Using the 21 measurements in this study a straight line relationship between measured and predicted numbers of units of blood to bring LIC to 1 mg Fe/g dry tissue was found to have slope 0.99 and Pearson’s correlation coefficient of 0.97. The data suggest that simultaneous measurement of LIC and liver volume with MRI (data acquisition time less than 30 minutes) can be used to predict venesection requirements in hereditary hemochromatosis. The measurement of baseline LIC also enables an estimate of the possible visceral or metabolic consequences of the iron burden. For example, in the absence of other complicating factors, a measurement of the LIC multiplied by the age of the subject gives a good predictor of iron induced liver damage [Olynyk, J.K, St. Pierre, T.G., Britton, R.S., Brunt, E.M., and Bacon, B.R. (2005) Am. J. Gastro., 100, 837–841].

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.

Trends in Ferritin Can Be Dramatically Different From Trends in Total Body Iron and Could Lead to Erroneous Decisions in Iron Chelation Management and Discourage Adherence in Chronically Transfused Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3203-3203
Author(s):  
Mammen Puliyel ◽  
Adam Bush ◽  
Vasilios Berdoukas ◽  
Thomas Hofstra ◽  
Susan Claster ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Chelation Therapy ◽  
Patient Adherence ◽  
Iron Concentration ◽  
Response To Therapy ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Body Iron ◽  
Total Body

Abstract Abstract 3203 Ferritin trends are used as surrogates for change in total body iron in patients with transfusional iron overload who are on chelation therapy. They are often used to infer patient adherence with prescribed therapy and for recommending changes. Population studies of ferritin show a 70% correlation with liver iron. The aim of this study was to determine whether the trends in ferritin adequately reflect the change in liver iron concentration (LIC) in individual patients. We retrospectively evaluated ferritin and LIC for 10 years in 40 patients with transfusion dependent anemia (23 with transfusion dependent thalassemia, 12 with sickle cell anemia, 2 with congenital dyserythropoetic anemia, 2 with Diamond Blackfan Anemia and one with sideroblastic anemia). Ferritin levels are evaluated every three weeks at each transfusion and liver iron concentration (LIC) by MRI at approximately annual intervals. The LIC values in mg/g dry weight (dw) are derived by MRI. The trends for both LIC and ferritin were evaluated at each period between the sequential MRIs. We used the average of all ferritins in a four month window centered on the date of the MRI for comparison to the LIC. The overall correlation between ferritin and LIC was similar to other published results (r2=0.69). When ferritin and LIC were plotted against time for each patient, the ferritin trend clearly predicted the LIC trend during certain periods of time (Example figure 1 segment A) and did not during other periods (Figure 1 segment B). The trend in ferritin correctly predicted the trend in LIC all of the time in 55% of patients (22/40). In 45 % of the patients (18/40) the ferritin trend did not correlate with the LIC in over half of the observational periods. In 37.5 % (15/40) of patients during at least one observation period the direction of change was dramatically different. Of these, the direction of change was opposite in 12.5% (5/40). In 22.5 % (9/40) the changes were disproportionate. Six of these patients showed a period during which there was a slight decrease in ferritin but a significant decrease in LIC. In two there was a significant increase in LIC with only a minimal rise in ferritin. In one, with a significant increase in ferritin the LIC increased minimally. While the ferritin was decreasing the LIC and ferritin trends correlated much better than when the ferritin was increasing. This implies that when ferritin levels increase it is a particularly poor tool for assessing change in iron overload. It is clear from this analysis that over certain periods of time, even up to four years, the trends in ferritin can be opposite in direction to the change in total body iron, as derived from LIC. This could lead to inappropriate changes in therapy and incorrect assumptions by health care providers about patient adherence. It is accepted that poor compliance with chelation therapy is the greatest barrier to effective management of iron overload. If only ferritin is used to assess changes in total body iron, patients could be discouraged by their apparent poor response to therapy even though their LIC may actually be decreasing. Serial assessment of total body iron burden by direct measurement of LIC is essential for proper management of patients with transfusional iron overload. 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.

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 Liver iron sensing and body iron homeostasis

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Chia-Yu Wang ◽  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

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.

Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 816-816 ◽  
Author(s):  
Alexis A. Thompson ◽  
Tomas Ganz ◽  
Mary Therese Forsyth ◽  
Elizabeta Nemeth ◽  
Sherif M. Badawy
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in &gt;3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p&lt;0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1514-1514 ◽  
Author(s):  
Pradyumna D. Phatak ◽  
Pierre Brissot ◽  
Herbert Bonkovsky ◽  
Mark Wurster ◽  
Lawrie Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Advisory Committees ◽  
The Core ◽  
Upper Limit ◽  
Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

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