Liver MRI Is Better Than Biopsy For Assessing Total Body Iron Balance: Validation By Simulation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 958-958
Author(s):  
John C. Wood ◽  
Pinggao Zhang ◽  
Hugh Y. Rienhoff ◽  
Walid Abi-Saab ◽  
Ellis J. Neufeld
Keyword(s):  
Standard Deviation ◽  
Liver Biopsy ◽  
Sampling Error ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Sampling Variability ◽  
Body Iron ◽  
Equity Ownership ◽  
Total Body ◽  
Better Than

Abstract Introduction Liver iron concentration (LIC) represents the best surrogate of total body iron balance for guiding iron chelation therapy. Liver biopsy was formerly used to determine LIC, but has gradually been replaced by magnetic resonance imaging (MRI) relaxometry because relaxometry is noninvasive and has lower sampling variability. Since neither liver biopsy nor MRI relaxometry can be considered a “gold standard”, there is a need for an independent mechanism to validate their accuracy and reproducibility. In this study, we use serial estimates of iron chelation efficiency calculated by R2 and R2* MRI as well as simulated liver biopsy results to demonstrate that MRI is fundamentally more accurate that liver biopsy in determining iron balance. Methods All patients were participating in a phase 2 clinical trial of SPD602 (formerly known as FBS0701) and had strict documentation of iron chelator and blood intake. MRI R2 and R2* LIC estimates were performed at baseline, 12, 24, 48, 72, and 96 weeks. Forty-nine patients completed 24 weeks, 39 completed 48 weeks, and 26 completed 96 weeks of the trial. Liver biopsy LIC results were simulated (by Monte Carlo simulation) using sampling errors having a coefficient of variation (CoV) of 0%, 10%, 20%, 30%, and 40%, and iron assay variability of 12%. LIC estimates by R2, R2*, and simulated biopsy were used to calculate chelation efficiency estimates over time. Bland–Altman limits of agreement were compared across observation timescales of 12, 24, and 48 weeks. Results Table 1 summarizes the standard deviation for chelation efficiency estimates performed at 12, 24, and 48 week intervals. For 48 week intervals, R2, R2*, and “perfect” liver biopsy exhibited statistically identical variance (indicated by italic type), and were superior to any “realistic” sampling error for liver biopsy (CoV 10–40%). At shorter measurement intervals, R2* produced the lowest variance estimates. For 12 week intervals, R2* efficiency estimates were confounded by two outliers; exclusion of these two points reduced the standard deviation of 12 week R2* efficiency estimates to 15.6% (p < 0.01). Figure 1 (top row) demonstrates simulated efficiency estimates by “perfect” liver biopsy performed on 12, 24, and 48 week timescales. While “perfect” liver biopsy approaches ideal behavior at 48 week intervals, many non-physiologic estimates (> 100%, < 0%) are produced during shorter term observations. Figure 1 (middle and bottom row) compares the identical relationships for chelation efficiency estimates generated by R2 and R2*, respectively. R2 demonstrates similar scatter as observed for liver biopsy. R2* efficiency estimates are better, with a slope near unity and all points residing in the upper right hand quadrant for 24 and 48 week timescales. Thus both R2 and R2* produce chelation efficiency estimates at least as good as “perfect” liver biopsy and better than biopsy performed with any reasonable estimate of sampling variability. Discussion Even if liver biopsy is assumed to have no sampling variation, which is unrealistic in clinical practice, MRI relaxometry is superior for tracking of total body iron balance. R2 and R2* are equally robust on annual evaluations, but R2* more closely tracks iron balance on shorter timescales. We conclude that MRI relaxometry should replace liver biopsy for the determination of LIC for both clinical and regulatory purposes. Disclosures: Wood: Shire: Consultancy, Research Funding; Apopharma: Honoraria, Patents & Royalties; Novartis: Honoraria. Zhang:Shire: Employment. Rienhoff:Shire: Consultancy, Milestone Payments Other. Abi-Saab:Shire: Employment, Equity Ownership, Patents & Royalties; AbbVie: Equity Ownership, Patents & Royalties; Novartis: Equity Ownership, Patents & Royalties; Abbott: Equity Ownership, Patents & Royalties; Pfizer: Equity Ownership, Patents & Royalties. Neufeld:Shire: Consultancy.

R2 and R2* Are Equally Effective In Evaluating Chronic Response To Iron Chelation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3437-3437
Author(s):  
John C. Wood ◽  
Pinggao Zhang ◽  
Hugh Y. Rienhoff ◽  
Walid Abi-Saab ◽  
Ellis J. Neufeld
Keyword(s):  
Clinical Trials ◽  
Los Angeles ◽  
Liver Biopsy ◽  
Dynamic Range ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Phase 2 ◽  
Limits Of Agreement ◽  
Liver Iron ◽  
Equity Ownership

Abstract Introduction Magnetic resonance imaging (MRI) relaxometry, using either R2 or R2* measurements, has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation therapy, but there have been no longitudinal studies comparing R2 and R2* techniques. We used R2 and R2* liver iron concentration (LICR2 and LICR2*) estimates, transfusional iron burdens, and drug adherence data to calculate iron chelation efficiency in patients undergoing a phase 2 trial of SPD602 (formerly known as FBS0701), a tridentate iron chelator in development. We hypothesized that chelation efficiency estimates derived from LICR2 and LICR2* measurements would be in better agreement than baseline LIC assessments using the two techniques. Methods In the phase 2 clinical trial of SPD602, 51 patients underwent a baseline examination, 39 patients completed 48 weeks, and 26 patients completed 96 weeks. MRI assessment of liver R2 and R2* were performed at baseline, 12, 24, 48, 72, and 96 weeks, analyzed by experienced reference laboratories (Ferriscan R2 by Resonance Health Western Australia; R2* by Children's Hospital Los Angeles, CA), and converted to LIC using established calibrations. Efficiency was calculated according to the following equation: where TII is the transfusional iron intake in mg/kg, ΔLIC is the change in LIC in mg/g dry weight, MWdrug and MWFe are the molecular weights of SPD602 and iron respectively, and drug is the total SPD602 consumed in mg/kg. Results Figure 1 shows a scattergram of LICR2 versus LICR2* at baseline; both axes were log-transformed to normalize the variance. Resulting linear fit had a slope of 0.996, a scaling factor of 0.114 and an r2 of 0.76 (p< 0.0001). 95% limits of agreement were broad, measuring -53.8% to 53.8%. However, chelation efficiency estimates across the two techniques compared more favorably, with r2 values 0.76 and 0.83 when calculated over 0–48 and 49–96 weeks, respectively. Figure 2 demonstrates the LICR2 and LICR2* chelation efficiency estimates in patients completing 96 weeks. The r2 value was 0.89 with excellent 95% limits of agreement [-3.5 to 3.5%]; elimination of two outliers improved the r2 value to 0.95. Discussion Taken together, these data illustrate two important points for individual hematology practitioners. First, while R2 and R2* methods are individually as accurate as liver biopsy in predicting true LIC, large discrepancies between LICR2 and LICR2* can be observed for any given individual as shown by the baseline measurements. These discrepancies do not reflect intrinsic deficiencies of either technique, but arise because R2 and R2* are differentially sensitive to pattern and scale of iron deposition in the liver. Thus LICR2 and LICR2* cannot be used interchangeably in an individual. Secondly, however, longitudinal assessments decrease systematic errors between and within techniques, just as paired statistics often provide greater statistical power than unpaired statistics. As a result, both LICR2 and LICR2* produce chelation efficiency estimates that are internally consistent and physiologically reasonable. The choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, including cost, the expected dynamic range of iron burden, and the availability of trained, experienced personnel for image quality control and analysis. In summary, the present study demonstrates that well-performed LICR2 and LICR2* measurements yield comparable longitudinal monitoring of chelator effectiveness, suitable for clinical trials and for clinical practice. Disclosures: Wood: Shire: Consultancy, Research Funding; Apopharma: Honoraria, Patents & Royalties; Novartis: Honoraria. Zhang:Shire: Employment. Rienhoff:Shire: Consultancy, Milestone Payments Other. Abi-Saab:Shire: Employment, Equity Ownership, Patents & Royalties; AbbVie: Equity Ownership, Patents & Royalties; Novartis: Equity Ownership, Patents & Royalties; Abbott: Equity Ownership, Patents & Royalties; Pfizer: Equity Ownership, Patents & Royalties. Neufeld:Shire: Consultancy.

Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results

2015 ◽  
Vol 33 (6) ◽  
pp. 761-767 ◽  
Author(s):  
John C. Wood ◽  
Pinggao Zhang ◽  
Hugh Rienhoff ◽  
Walid Abi-Saab ◽  
Ellis J. Neufeld
Keyword(s):  
Liver Biopsy ◽  
Liver Mri ◽  
Body Iron ◽  
Total Body

Hepatic iron concentration and total body iron burden in genetic hemochromatosis (GH)

1991 ◽  
Vol 13 ◽  
pp. S49
Author(s):  
C. Mandelli ◽  
L. Cesarini ◽  
A. Pipemo ◽  
S. Fargion ◽  
A.L. Fracanzani ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Hepatic Iron ◽  
Body Iron ◽  
Total Body ◽  
Hepatic Iron Concentration ◽  
Genetic Hemochromatosis

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

Blood ◽  
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.

Hepatic Iron Concentration and Total Body Iron Stores in Thalassemia Major

2000 ◽  
Vol 343 (5) ◽  
pp. 327-331 ◽  
Author(s):  
Emanuele Angelucci ◽  
Gary M. Brittenham ◽  
Christine E. McLaren ◽  
Marta Ripalti ◽  
Donatella Baronciani ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Thalassemia Major ◽  
Hepatic Iron ◽  
Body Iron ◽  
Iron Stores ◽  
Total Body ◽  
Hepatic Iron Concentration

Intraindividual Comparison between Deferasirox and Deferoxamine in Thalassemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2776-2776
Author(s):  
Roland Fischer ◽  
Regine Grosse ◽  
Rainer Engelhardt ◽  
Peter Nielsen ◽  
Oliver Leismann ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Concentration ◽  
Compartment Model ◽  
Blood Transfusions ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Body Iron ◽  
Dose Rates ◽  
Total Body ◽  
Rbc Transfusion

Abstract In patients with iron overload from chronic blood (RBC) transfusion a new era of chelation treatment has been started with the availability of 3 chelators, their combinations, and other potential modifiers of tissue iron distribution. The decision about the chelator type and its dose would be facilitated if a mean chelation response could be forecasted. With the knowledge of a chelator’s molar efficacy, one could calculate the dose necessary to compete with the iron influx from blood transfusions. An open compartment model as developed for deferoxamine (DFO) and deferiprone (DFP) (Brit J Haematol2003;121:938–48) would additionally allow to forecast the total body iron store for a given blood transfusion and chelator dose rate over time, also for deferasirox. In a prospective study of the oral chelator deferasirox (DSX, Exjade®), 17 patients with b-thalassemia (age: 4 – 32 y) have been followed for 8 to 38 months by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months. Retrospectively, the same patients were followed in the past during s.c. DFO treatment. Liver iron concentration LIC, liver volumes, RBC transfusion and chelation dose rates were assessed. Of major importance was the stability of the hematocrit in the RBC units used in our department of 60 ± 3% over more than 6 years. Total body iron stores were calculated from total liver iron taking into account that 80 ± 10% of the total body storage iron is accumulated in the liver. For each measurement interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron stores per interval time, and the molar dose rate of DFO or DSX. Additionally, total body iron elimination (TBIE) rate constants were calculated for each interval and fitted as function of the chelatable iron pool. LIC values, liver volumes, and ferritin levels were measured in the range of 498–8009 μg/g-liver, 654-3208 ml, and between 787 and 14866 μg/l. During DSX and DFO treatment, molar chelation efficacies of 11.2–53.1% and 6.1–23.7% were found for mean dose rates of 0.5–3.2 mmol/d (21–39 mg/kg/d) and 0.9–5.2 mmol/d (25–53 mg/kg/d) applied to iron influx rates of 7.6–30.6 mg/d and 9.7–28.5 mg/d from blood transfusion, respectively. In 6/17 (13/15 for DFO) patients with at least 3 treatment intervals, the intraindividual the molar efficacy ranged from 13.3±1.9% to 39.0±7.2% for DSX and from 7.8±2.0% to 19.4±2.9% for DFO in the same patients. Compliance assessed from tablet count protocols (> 90%) did not influence these data significantly. The mean molar efficacies of 29±10% and 15±5% in our patient group agreed with reference values (Blood2005;106(11):#2690 and Brit J Haematol2003;121:938–48) for DSX and DFO, respectively. In contrast to DFO and DFP, the compartment model calculations resulted in a linear function of the TBIE rate constant for DSX with no saturation effect over the whole range of chelator doses and LIC. In summary, deferasirox was as efficient as deferoxamine at only half the molar dose even on an intraindividual patient basis. Once the individual molar efficacy has been assessed, a minimum chelator dose can be calculated to compete with the daily iron input from blood transfusions. The compartment model parameters of the total body iron elimination rate constant for deferasirox may allow to forecast the gross time pattern of liver iron concentration changes for practical treatment periods.

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].

Chelator Efficacy of Deferasirox and Deferoxamine Determined by SQUID Biosusceptometry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1779-1779 ◽  
Author(s):  
Regine Grosse ◽  
Gisela Janssen ◽  
Rainer Engelhardt ◽  
Marketa Groeger ◽  
Oliver Leismann ◽  
...  
Keyword(s):  
Dose Rate ◽  
Iron Concentration ◽  
Prospective Trial ◽  
Reference Value ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Stores ◽  
Dose Rates ◽  
Total Body ◽  
Rbc Transfusion

Abstract Chelation treatment of patients with iron overload from chronic blood (RBC) transfusion needs continuous monitoring of iron stores, iron influx rates from RBC, chelation dose rates, and compliance. Molar chelator efficacy depicts the combined effect from these variables. Treatment should always aim to maximize the efficacy of a certain chelator in an individual patient in order to reduce organ damage from iron toxicity. In a prospective trial on the oral chelator deferasirox, a total of 12 patients with b-thalassemia major have been followed by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months over a time period of up to 38 months under deferasirox. Patients were initially on deferoxamine (DFO, Desferal®) and then participated in an international multi-center trial randomized for s.c. DFO and the oral chelator deferasirox (DSX, Exjade®). Liver iron concentration LIC (μg/g-liver wet weight), liver volumes, RBC transfusion rates, chelation dose rates, and compliance from tablet counts were assessed. Total body iron stores were calculated from total liver iron taking into account that 70 – 90 % of the total body storage iron is accumulated in the liver. For each chelation interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron per interval time (= mobilized iron rate), and the molar dose rate of DFO or DSX (Fischer et al: Ann N Y Acad Sci2005; 1054: 350–7), equation 1. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[Molar\ efficacy\ [\%]\ =\ mobilized\ iron\ rate/molar\ chelator\ dose\ rate\] \end{document} LIC values were in the range of 836 to 8404 with a median value of 2424 μg/g-liver, while ferritin levels were between 911 and 13609 μg/l with a median ratio of ferritin-to-LIC of 1.0 ((μg/l)/(μg/g)) (range: 0.4 to 3.2). The median molar dose rates for DFO and DSX were 3.2 and 1.6 mmol/d, respectively. For each patient, the molar efficacies for DFO and DSX were averaged. From these averaged values, a mean molar efficacy ± SD of 13.2 ± 3.4 % and 23.6 ± 10.3 % was found for DFO and DSX, respectively. Relative to DFO, in each patient an increase between 5.5 and 27.1 % was found for DSX (mean: 11.7 ± 7.3 %). Patients with a low efficacy on DFO also had a low molar efficacy on DSX and vice versa (e.g., 8.0 and 13.5 % versus 16.0 and 31.9 %). Compliance assessed from tablet count protocols was larger than 90% and did not change these data significantly. On a larger scale in highly compliant thalassemia patients, a molar efficacy of 17.6 ± 4.8 % was observed (Fischer et al: Brit J Haematol2003; 121: 938–48). In comparison to that reference value, the molar efficacy of DFO for this patient group was decreased. The reported molar efficacy of 27.9 ± 13.8 % for DSX obtained from biopsy results (Porter et al: Blood2005; 106(11): 755a) is only insignificantly higher than our value. In summary, we found deferasirox to be two times more efficient than deferoxamine on the same molar dose level, even for patients with a relatively low efficacy under both chelator treatment regimens.

Deferasirox (Exjade®) Significantly Improves Cardiac T2* in Heavily Iron-Overloaded Patients with β-Thalassemia Major

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5417-5417
Author(s):  
Shahina Daar ◽  
Anil Pathare ◽  
Ali Taher
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Dose Titration ◽  
Total Study Population ◽  
Body Iron ◽  
Cardiac Iron ◽  
Cardiac Siderosis ◽  
Total Body

Abstract Introduction: Iron overload currently remains a major cause of morbidity and mortality in patients (pts) with thalassemia major (TM), despite the availability of iron chelation therapy. Magnetic resonance imaging (MRI) can be used to measure tissue iron levels and identify pts with iron overload. The aim of this study was to monitor cardiac siderosis using MRI T2* in a cohort of Omani pts with TM. Methods: Cardiac MRI T2* was assessed in 19 pts enrolled at a single center in Oman. All pts had transfusional iron overload and had received chelation therapy (16/19 pts DFO + deferiprone; 2/19 DFO; 1/19 deferiprone) prior to enrollment in the ESCALATOR study. After completing a 1-year core phase of the ESCALATOR study, cardiac iron was evaluated as part of the site standard of care. Hence, pts had been receiving once-daily oral deferasirox starting with 20 mg/kg/day with subsequent dose adjustments for 12 months prior to the first cardiac T2* assessment (baseline [BL]). Pts continued on deferasirox throughout the 18-month period of this present evaluation. Results: All 19 pts (11 male; 8 female) completed 18 months of evaluation. Mean age (±SD) was 18 years (±4.5; range 10–29). At BL, pts had a mean cardiac T2* (±SD) of 17.2 (±10.8) ms (table) indicative of cardiac iron loading, (normal &gt;20 ms) and a high median BL serum ferritin (SF) of 5497 ng/mL, signifying a high total body iron burden (r = −0.35). Pts also had a high liver iron concentration (LIC), which was correlated with both BL cardiac T2* and SF levels (r = −0.52 and 0.53, respectively). When the data were analyzed by BL cardiac T2* subgroups (&lt;10 ms [n=6], 10–20 ms [n=7], &lt;20 ms [n=13] and &gt;20 ms [n=6]), all subgroups demonstrated a high BL SF. Mean deferasirox dose (±SD) in all pts was 25.9 (±2.3) mg/kg/day at BL, 32.0 (±4.4) mg/kg/day at 6 months and 37.7 (±5.5) mg/kg/day at 18 months, with dose adjustments carried out as per ESCALATOR study protocol. Overall, deferasirox significantly improved mean cardiac T2* by 3.6 and 4.3 ms at 6 (P=0.007) and 18 months (P=0.02), respectively. Further analysis showed a significant improvement in T2* (P&lt;0.05) at 18 months in all subgroups except those pts with normal BL T2* (&gt;20 ms), who only showed an improvement at 6 months. Moreover, deferasirox significantly reduced SF (P=0.001) and LIC (P=0.01) in the total study population at 18 months. Additional subgroup analyses for the changes at 6 and 18 months relative to BL are shown in the table. Table. Efficacy of deferasirox after 6 and 18 months of therapy All pts (n=19) &lt;10 ms (n=6) 10–20 ms (n=7) &lt;20 ms (n=13) &gt;20 ms (n=6) Mean cardiac T2*, ms (±SD) †These values were measured 6 months prior to BL T2* MRI; ‡significantly improved (P&lt;0.05) compared with BL BL 17.2 (10.8) 6.3 (2.2) 14.9 (3.1) 10.9 (5.2) 30.8 (5.1) 6 months 20.8 (13.7)‡ 6.2 (2.6) 19.2 (6.8) 13.2 (8.5) 37.2 (4.9)‡ 18 months 21.5 (12.8)‡ 7.8 (3.2)‡ 21.4 (8.7)‡ 15.1 (9.6) ‡ 35.2 (6.0) Median SF, ng/mL BL 5497 6385 5497 5497 4733 6 months 4128 6100 4803 4803 3031‡ 18 months 4235‡ 5937 4655 4674‡ 1793‡ Mean LIC, mg/g dw (±SD) Pre-BL† 24.17 (8.96) 29.57 (11.21) 24.81 (7.69) 27.01 (9.38) 18.02 (3.44) 6 months 19.71 (11.42)‡ 25.23 (10.73) 23.34 (11.16) 24.22 (10.55) 9.93 (5.89)‡ 18 months 17.62 (12.93)‡ 20.02 (10.85) 23.97 (13.96) 22.15 (12.28) 7.82 (8.50)‡ Conclusions: Deferasirox therapy significantly improved cardiac T2* in these heavily iron-overloaded pts with TM. Improvement was seen in pts with various degrees of cardiac siderosis, including those pts with BL cardiac T2* &lt;10 ms, indicative of high cardiac iron burden. SF and LIC were also significantly reduced in all pts, indicating that deferasirox reduced both cardiac and total body iron burden in these pts. That deferasirox dose was increased in all pts over the 18 months of the study highlights the importance of dose titration to achieve treatment goals.

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