Intensive Iron-Chelation Therapy with Desferrioxamine in Iron-Loading Anaemias

1978 ◽  
Vol 54 (1) ◽  
pp. 99-106 ◽  
Author(s):  
M. J. Pippard ◽  
S. T. Callender ◽  
D. J. Weatherall
Keyword(s):  
Chelation Therapy ◽  
Iron Chelation ◽  
Mean Value ◽  
Linear Increase ◽  
Total Iron ◽  
Iron Loading ◽  
Iron Load ◽  
Excretion Rates ◽  
Kinetics Of ◽  
Iron Excretion

1. Urinary iron excretion after desferrioxamine has been examined in nine patients with different iron-loading anaemias. Particular attention has been paid to individual variation in response and the kinetics of iron removal in order to determine the most efficient and convenient method of administration. 2. Twelve-hour subcutaneous infusions of desferrioxamine were comparable with intravenous infusions and gave a mean value of 62% more iron excretion than similar intramuscular bolus doses (range 20–125%). 3. Increasing doses as 12 h subcutaneous infusions produced a linear increase in iron excretion, which was followed by a tendency to reach a plateau. Iron excretion varied greatly between patients, was not related solely to age or estimated iron load, and in most cases was increased by ascorbic acid saturation. 4. Maximum iron-excretion rates were achieved after 3–6 h and then maintained throughout an infusion. With bolus injections excretion rates declined rapidly after the first 6 h, during which approximately 60% of the total iron excretion occurred. 5. The dose and method of administration should be ‘tailor-made’ for each patient. Overnight 12 h subcutaneous infusions can be both as effective as similar doses given over 24 h and a practical way of achieving substantial negative iron balance. 6. Since children receiving regular blood transfusions for congenital anaemias such as thalassaemia usually die at the end of the second decade, this approach to iron chelation offers the possibility of alleviating what have hitherto been fatal iron-loading states.

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4632-4639 ◽  
Author(s):  
Peter D. Jensen ◽  
Finn T. Jensen ◽  
Thorkil Christensen ◽  
Hans Eiskjær ◽  
Ulrik Baandrup ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Myocardial Iron ◽  
Resonance Imaging ◽  
Liver Iron ◽  
Iron Pool ◽  
Iron Excretion

Abstract Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2sD) was 2.8 μmol/g in the controls (day-to-day) and 4.0 μmol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 μmol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R2 = 0.69, P = .0014) and still after 6 months of iron chelation (R2 = 0.76, P = .001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity.

scholarly journals Erythrocytapheresis therapy to reduce iron overload in chronically transfused patients with sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1136-1142 ◽  
Author(s):  
HC Kim ◽  
NP Dugan ◽  
JH Silber ◽  
MB Martin ◽  
E Schwartz ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Cell Disease ◽  
Donor Blood ◽  
Iron Load ◽  
Blood Usage ◽  
Hb S

Abstract Chelation therapy with deferoxamine is effective in preventing the risk of transfusional iron overload, but treatment failure is common because of noncompliance. To reduce the transfusional iron load, we have evaluated longterm erythrocytapheresis in 14 subjects with sickle cell disease and stroke (11) or other complications (3) as an alternative to simple transfusion. Subjects were treated with erythrocytapheresis using the Haemonetics V50 (Haemonetics Corp, Braintree, MA) to maintain the target pretransfusion hemoglobin S (Hb S) level less than 50% for 6 to 71 months. The transfusional iron load and the donor blood usage were analyzed for a 6- to 36-month study period and were compared with similar data from a subset of 7 subjects previously treated with conventional (target Hb S < 30%) and modified (target Hb S < 50%) simple transfusion protocols. The effect of erythrocytapheresis on iron accumulation was determined by assessment of serum ferritin levels in the absence of iron chelation. The mean transfusional iron load and donor blood usage with erythrocytapheresis were 19 +/- 14 mg iron/kg/yr (range, 6 to 50) and 188.4 +/- 55.2 mL packed-red blood cells (RBC)/kg/yr (range, 107 to 281), respectively. Of 6 subjects receiving no iron chelation therapy, 5 maintained normal or nearly normal serum ferritin levels during 11 to 36 months of erythrocytapheresis. In comparison with conventional simple transfusion and modified simple transfusion, erythrocytapheresis reduced iron loading by 87% (P < .01) and 82% (P < .01), respectively, but increased donor blood usage by 23% and 73%, respectively. Subjects with pre-erythrocytapheresis Hb levels > or = 8.0 g/dL had lower iron accumulation (P < .001) and less donor blood usage (P < .005) than subjects with Hb levels < or = 8.0 g/dL. Although donor blood usage is increased in comparison with simple transfusion, long-term erythrocytapheresis markedly reduces or prevents iron accumulation. This form of transfusion therapy allows the cessation of iron chelation in well-chelated subjects and, if used as the initial form of transfusion therapy, may prevent long-term complications of sickle cell disease without risk of iron overload and the need for chelation therapy.

Influence of Iron Chelation Therapy on R1 and R2 Calibration Curves in Gerbil Liver and Heart.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1775-1775
Author(s):  
John C. Wood ◽  
Michelle I. Aguilar ◽  
Maya Otto-Duessel ◽  
Hanspeter Nick ◽  
Marvin D. Nelson ◽  
...  
Keyword(s):  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelators ◽  
Mongolian Gerbils ◽  
Iron Loading ◽  
Longitudinal Assessment ◽  
Relaxation Rates ◽  
Iron Distribution ◽  
Calibration Curves

Abstract Introduction: MRI is gaining increasing importance for the noninvasive quantification of organ iron burden. To date, MRI validation studies have not systematically examined the effects of different iron chelators. Since transverse relaxation rates depend on iron distribution as well as iron concentration, physiologic and pharmacologic processes that alter iron distribution could change MRI calibration curves. This paper compares the effect of three iron chelators, deferoxamine, deferiprone, and deferasirox on R1 and R2 calibration curves according to two loading and chelation strategies. Methods: 33 Mongolian gerbils underwent iron dextran 500 mg/kg/wk for 4 weeks followed by 4 weeks of chelation therapy using deferoxamine, deferiprone and defersirox. An additional 32 animals received less aggressive iron loading (200 mg/kg/week) for 10 weeks, followed by 12 weeks of chelation therapy. R1 and R2 measurements were obtained immediately post euthanasia using an NMR relaxometer. Calibration curves from 28 unchelated animals loaded with 200 mg/kg/week from 2 to 48 weeks were used as the reference standard for both chelated groups, using Bland-Altman analysis. Results: In the liver, R2-iron calibration became more variable over time regardless of whether chelation was performed or not (mean COV 28% versus 12%); no significant changes were observed in the heart R2-iron relationship. Variability in R1 measurements did not change for either heart or liver. Two systematic chelator-specific changes in liver iron calibration curves were noted:deferiprone treated animals exhibited signficantly higher R1 values (Figure 1) anddeferasirox treated animals demonstrated lower R2 values for given iron concentration (Figure 2). Both changes were associated with obvious changes in water content or iron distribution. Discussion: The acuity of the iron loading process affects the variability but not the bias of MRI-iron calibration curves. In contrast, iron chelation can produce systematic shifts in MRI calibration curves compared with the unchelated state, reflecting gross changes in tissue hydration and iron distribution. Since the rate of iron-loading and extraction performed in animals is more extreme than occurs in humans, limiting tissue requilibration, it is possible that the present studies overestimate the potential for chelator-specific calibration bias. Nonetheless, caution should be used in extrapolating calibration curves derived from patients using deferoxamine therapy to others being treated with deferiprone and deferasirox. Careful, longitudinal assessment of MRI calibration curves of patients receiving oral chelation therapies is warranted. Figure Figure Figure Figure

Iron Chelation Therapy in Transfusion Dependent Patients with Thalassemia and Minimal Liver Iron Load

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4270-4270
Author(s):  
Antonios Kattamis ◽  
Konstantinos Stokidis ◽  
Theoni Petropoulou ◽  
Dimitra Kyriacopoulou ◽  
Polyxeni Delaporta ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Research Funding ◽  
Chelation Therapy ◽  
Combined Therapy ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Iron Load ◽  
Low Levels

Abstract Abstract 4270 Background: Recent advances in the treatment of iron overload in patients with transfusion- dependent thalassemia have dramatically changed iron related morbidity and mortality. Intensive chelation therapy by using combination therapy or monotherapy at high doses had led to total clearing of the iron in many patients. The best approach for chelation treatment in patients with low levels of iron overload is debatable. Patients and Methods This study included all the patients with thalassemia major with minimal liver iron overload, followed in our unit. More precisely, to be eligible for this observational study, the patients needed to have liver iron concentration (LIC) <1.5 mg Fe/gram dry weight tissue, defined by MRI, and to have at least a subsequent MRI evaluation after this time. The mean observation time, which was the time between the two MRIs, was 16.9±5.2 months. Results Fourty five patients (22 females, 30 non-splemectomized, 21 HCV seropositive, mean age: 31±5.6 years) have reached minimal levels of iron overload in any time point after 2004. Thirty one of them have been treated with combined therapy of desferrioxamine (DFO) and deferiprone (DFP) and 5, 6 and 3 with monotherapy of deferasirox (DFX), DFP and DFO, respectively. After reaching these levels, 42% of the patients changed therapy, with the most frequent change being from combined therapy to monotherapy (15 patients). Baseline ferritin levels at the time of the first MRI range from 43 to 4336 ng/ml (median 230 ng/ml) and they were not affected by spleen, gender or HCV status. Baseline LIC (mean 1.2 ± 1.7 mgFe/g.d.w.) correlated well with ferritin levels (Spearman's rho = 0.47, p<0.005), as did ferritin changes to LIC changes (Spearman's rho = 0.67, p<0.005). The results on the follow up evaluation, stratified according to the actual treatment, are shown in the table Deferiprone was less efficacious in controlling both LIC and ferritin levels compared to combination therapy (p=0.016 and 0.031, respectively). Fifteen out of 17 patients treated with DFP showed an increase in LIC, despite using the recommended dose. Six out of 9 patients treated with DFX, most at a low dose, showed an increase in LIC. There were no differences in changes in the cardiac parameters (LVEF, cardiac T2*) in between treatment groups. The efficiency of DFP and DFX, which represents the ratio of iron excreted to the theoretical maximum of iron that could be bound by the chelators, was calculated at 1.8±0.9 % and 15.2 ± 3.6 %, respectively. Conclusions Current iron chelation therapy regimens are able to render iron load-free many patients with thalassemia major. As iron accumulation from transfusions continues, a fine balance needs to be found in which neither worsening of iron overload nor toxicity from excessive dose of iron chelators will occur. This study showed that at low levels of iron overload both combination therapy and DFX can control iron accumulation, whether monotherapy with DFP may be insufficient to achieve iron balance in many patients. The dose of the chelators needs to be adjusted according to the needs and the clinical course of the patients, which can be predicted by the trend of the ferritin levels. Furthermore, it should be kept in mind that at low levels of iron overload, the iron chelators' efficiency may be lower than previously described. Disclosures: Kattamis: NOVARTIS ONCOLOGY: Honoraria, Research Funding, Speakers Bureau; APOPHARMA: Honoraria. Ladis:NOVARTIS ONCOLOGY: Honoraria, Research Funding; APOPHARMA: Honoraria, Research Funding.

Multiple Packed Red Blood Cell (PRBC) Transfusions In Pediatric Patients With Acute Myeloid Leukemia (AML) Result In a Large Transfusional Iron Dose With The Potential For Long-Term Organ Dysfunction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2660-2660
Author(s):  
Mohammed Al-Darwish ◽  
Asim F Belgaumi ◽  
Neameh A Farhan ◽  
Ali Al-Ahmari ◽  
Amal Al-Seraihy ◽  
...  
Keyword(s):  
Organ Dysfunction ◽  
Pediatric Patients ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Left Ventricular Ejection ◽  
Hepatic Iron ◽  
Iron Chelation Therapy ◽  
Body Iron ◽  
Iron Load

Abstract The treatment of AML in children utilizes intensive chemotherapy and often myeloablative hematopoietic cell transplant (HCT). This results in significant myelosuppression, necessitating blood product transfusions. Repeated PRBC transfusions result in an increase in the body iron load which can lead to secondary hemochromatosis and organ dysfunction, particularly the heart and liver. Patients with hemoglobinopathies on chronic PRBC transfusions require iron chelation therapy usually after 10-20 units transfused. While patients with AML receive multiple transfusions, there is little data on the number or volume of PRBC transfused or the estimate of the iron load received. This retrospective study evaluated the number and volumes of PRBC transfusions administered to pediatric (<14 years) patients with AML, and calculated an estimate of the iron infused. Twenty-two patients with AML were diagnosed and treated at our institution between January 2010 and December 2012. There were 13 girls and 9 boys with a median age at diagnosis of 7.5 years (mean 6.95; range 0.4-13.2). One patient died early of sepsis without achieving complete remission (CR), and another died in CR following her last course of chemotherapy. Eight patients underwent HCT following myeloablative conditioning with busulfan, cyclophosphamide and etoposide; the remaining received chemotherapy alone. For patients who completed their chemotherapy the cumulative anthracycline dose was 450 mg/m2. Patients received a median of 17.5 PRBC transfusions (mean 16.6; range 3-28) during the course of their treatment. The cumulative PRBC transfusion volume was 185.4 ml/kg (mean 175.8; range 24.87 – 311.58), which translates to a median iron dose of 129.8 mg/kg (mean 123.1; range 17.4 – 218.1). The median serum ferritin level for those patients who were tested (n=12) was 1794.5 mg/L (mean 9074.5; range 699 – 78500). The median projected hepatic iron content, based on the transfused iron burden was 12.24 mg/g liver dry weight (mean 11.61; range 1.64 – 20.58); 17 (77.3%) patients had projected hepatic iron concentrations in excess of 7.0 mg/g, and none were <1.6 mg/g. Ten patients have developed a > 10 percentage point reduction in their left ventricular ejection fraction (LVEF; range -11% to -45%) however only one patient is on cardiac failure medications. Cardiac T2* MRI studies are being conducted to evaluate cardiac iron status for patients in this cohort. 13 patients were alive in CR at a median follow-up duration of 1.83 years (mean 2.16; range 0.27 – 3.43). Pediatric patients with AML receive large volumes of PRBC transfusions during their treatment and as a consequence accumulate high total body iron. This is in excess of the threshold for chelation therapy, used to prevent organ dysfunction, in patients with hemoglobinopathies. In addition, AML patient also receive significant cardio-toxic medications which may compound the effect of iron on the myocardium. With improvements in long term survival for patients with AML the addition of iron chelation therapy must be studied in order to prevent long term toxicity of AML therapy. Disclosures: No relevant conflicts of interest to declare.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox in Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 MRI

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3649-3649 ◽  
Author(s):  
Yoo-Hong Min ◽  
Hyeoung Joon Kim ◽  
Kyoo Hyung Lee ◽  
Sung-Soo Yoon ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Dry Weight ◽  
Mean Value ◽  
One Year

Abstract Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a median of 30 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (10.3%), 20 (69.0%), and 4 cases (13.8%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64%) were severe form. Mean value of serum ferritin level in enrolled patients was 4,417 ± 3,378 (4,788 ± 3,996 in MDS, 4,185 ± 2,962 in AA) ng/ml at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 23.9 ± 13.8 (26.1 ± 15.0 in MDS, 22.8 ± 13.2 in AA) mg Fe/g dry weight. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. A consistent decrease in the serum ferritin level was demonstrated during the first 6 months in vast majority of patients despite of continued transfusion (209.7 ± 159.9 ng/ml and 324.0 ± 289.4 ng/ml per month in MDS and AA, respectively). Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 6 months of medication, a slower decrease in the serum ferritin level was observed in MDS patients. In 30 cases, one-year medication of deferasirox was completed. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,085 ± 2,150 ng/ml (64.4% of baseline level) and 2,913 ± 2,232 ng/ml (69.6% of baseline level, p<0.01) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 24 cases, and LIC was significantly decreased to the level of 19.3 ± 13.6 mg Fe/g dry weight (67.4% of baseline value, p=0.01). Decrease in the level of LIC at EOS in MDS (64.3% of baseline) was comparable to that in AA cases (68.5% of baseline). The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 28 (35.4%) cases because of death (7 in MDS and 6 in AA), patient refusal (11 cases), and decrease in the serum ferritin level below 500ng/ml (4 cases). All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient’s transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients.

scholarly journals Chelator-facilitated removal of iron from transferrin: relevance to combined chelation therapy

2007 ◽  
Vol 409 (2) ◽  
pp. 439-447 ◽  
Author(s):  
Lakshmi D. Devanur ◽  
Robert W. Evans ◽  
Patricia J. Evans ◽  
Robert C. Hider
Keyword(s):  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Removal ◽  
Spectroscopic Methods ◽  
Iron Chelation Therapy ◽  
Simultaneous Presence ◽  
Iron Transfer ◽  
Iron Load ◽  
Combined Administration ◽  
Orally Active

Current iron chelation therapy consists primarily of DFO (desferrioxamine), which has to be administered via intravenous infusion, together with deferiprone and deferasirox, which are orally-active chelators. These chelators, although effective at decreasing the iron load, are associated with a number of side effects. Grady suggested that the combined administration of a smaller bidentate chelator and a larger hexadentate chelator, such as DFO, would result in greater iron removal than either chelator alone [Grady, Bardoukas and Giardina (1998) Blood 92, 16b]. This in turn could lead to a decrease in the chelator dose required. To test this hypothesis, the rate of iron transfer from a range of bidentate HPO (hydroxypyridin-4-one) chelators to DFO was monitored. Spectroscopic methods were utilized to monitor the decrease in the concentration of the Fe–HPO complex. Having established that the shuttling of iron from the bidentate chelator to DFO does occur under clinically relevant concentrations of chelator, studies were undertaken to evaluate whether this mechanism of transfer would apply to iron removal from transferrin. Again, the simultaneous presence of both a bidentate chelator and DFO was found to enhance the rate of iron chelation from transferrin at clinically relevant chelator levels. Deferiprone was found to be particularly effective at ‘shuttling’ iron from transferrin to DFO, probably as a result of its small size and relative low affinity for iron compared with other analogous HPO chelators.

Dose Response of Deferoxamine, Deferiprone, and ICL670 Chelation Therapy in a Gerbil Model of Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3621-3621 ◽  
Author(s):  
John C. Wood ◽  
Maya Otto-Duessel ◽  
Michelle Aguilar ◽  
Hanspeter Nick ◽  
Thomas D. Coates ◽  
...  
Keyword(s):  
Dose Response ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Loss ◽  
Iron Dextran ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Excretion ◽  
Iron Concentrations

Abstract Introduction: The Mongolian gerbil mimics many of the cardiac functional impairments observed in iron cardiomyopathy, however relatively few chelation studies have been performed in this model. The purpose of this study was to characterize the dose-response of deferoxamine, ICL670, and deferiprone (L1) with respect to liver and cardiac iron chelation in the gerbil Methods: Thirty three adult Mongolian gerbils underwent subcutaneous iron dextran loading with 1500 mg/kg iron dextran divided into three, weekly doses. Chelation began at 4 weeks and continued for 4 weeks. Animals were divided into 9 treatment groups of three animals each(DFO 50, 100, and 200 mg/kg/day (subQ BID), ICL670 25, 50, and 100 mg/kg/day(PO QD), and L1 125, 250, and 500 mg/kg/day(PO TID), 5 days per week). Three control animals were sacrificed at 4 weeks and 8 weeks to estimate sponatenous iron loss. Histology and quantitative iron were performed in all animals. Results: Iron loading yielded liver iron concentrations of 26.6±3.8 mg/g(dry wt) and cardiac iron concentrations of 3.7±0.5 mg/g(dry wt) at 4 weeks (normal < .5 mg/g for both organs). However, organ iron content fell 6.4% in liver and 8.9% in heart per week in animals without chelation therapy, reflecting high spontaneous iron excretion. All three chelators exhibited significant dose-responsiveness for liver iron elimination. However, only ICL670 chelation at 100 mg/kg reduced liver iron content greater than for controls. In fact, animals treated with low dose L1 and DFO had higher iron levels than controls, probably by interfering with spontaneous iron elimination. None of the agents chelated the heart effectively. In fact, 88% of the L1 group, 56% of the ICL670 group and 22% of the DFO group had cardiac iron levels outside the normal range predicted from the 8 wk control animals. Conclusion: Iron chelation in the gerbil model requires doses nearly 3.6 fold greater than in humans to produce discernable iron loss above background iron excretion in short-term studies. Subtherapeutic dosing may actually increase iron levels relative to control animals by decreasing spontaneous iron excretion. Groupwise Iron Concentration and Content HIC(mg/g dry) HIC(mg/g wet) Organ FE(mg) CIC(mg/g dry) CIC(mg/g wet) Organ FE(mg) Control(4wk) 26.6±3.8 7.0±1.4 27.5±2.6 3.74±0.5 0.74±0.1 0.32±0.05 Control(8wk) 23.1±1.1 5.9±0.5 20.5±2.2 2.64±0.19 0.52±0.03 0.20±0.01 DFO 50mg/kg 31.0±3.0 8.2±1.5 28.9±3.4 2.73±0.32 0.56±0.03 0.20±0.02 DFO100mg/kg 25.3±3.3 6.8±1.2 25.0±4.9 3.20±0.46 0.90±0.46 0.33±0.18 DFO200mg/kg 23.5±1.4 5.9±0.4 17.6±2.4 2.77±0.20 0.53±0.07 0.18±0.03 L1 125mg/kg 32.2±1.3 7.7±1.1 23.8±3.4 3.63±0.25 0.79±0.02 0.23±0.02 L1 250mg/kg 29.3±7.4 8.5±2.7 26.7±6.2 3.56±0.85 0.71±0.12 0.21±0.04 L1 500mg/kg 18.5±0.9 5.0±0.6 19.4±1.8 2.68±0.43 0.57±0.08 0.20±0.04 ICL 25mg/kg 24.3±6.3 6.2±1.3 21.5±5.6 3.47±0.09 0.74±0.02 0.25±.02 ICL 50mg/kg 27.6±1.7 6.7±1.1 19.7±4.3 3.22±0.05 0.64±0.14 0.23±0.04 ICL100mg/kg 18.5±3.7 4.1±1.1 13.8±1.8 2.96±0.38 0.59±0.09 0.23±0.04

Deferasirox Improves Liver Pathology In β-Thalassemia Patients with Transfusional Iron Overload

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4274-4274 ◽  
Author(s):  
Yves Deugnier ◽  
Bruno Turlin ◽  
Victor Dong ◽  
Vanessa Giannone ◽  
Yiyun Zhang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Success Rate ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Total Iron ◽  
Iron Chelation Therapy ◽  
Liver Pathology ◽  
Liver Iron ◽  
Group A ◽  
Group B

Abstract Abstract 4274 Background: While iron overload is known to cause hepatic toxicity, the effect of iron chelation therapy on liver pathology is not well understood. Data evaluating liver fibrosis during iron chelation therapy are limited to small studies (eg, Wu SF et al. Hemoglobin 2006 [n=17], Berdoukas V et al. Hematol J 2005 [n=49], Wanless IR et al. Blood 2002 [n=56]). In order to address such effects in a more robust patient population, we assessed liver biopsy samples from β-thalassemia patients enrolled in two large clinical studies (Porter J et al. Blood 2005, Cappellini MD et al. Blood 2006) that evaluated the effects of deferasirox on iron burden for up to 5 years. Methods: Patients with β-thalassemia and transfusional hemosiderosis receiving ≥8 blood transfusions/year, with liver biopsy assessment (defined as having either liver iron concentration [LIC], Ishak grading or Ishak staging assessment), after at least 3 years of deferasirox treatment, were included. Deferasirox dose was 5–40 mg/kg/day based upon level of iron overload (Study 107, patients randomized to deferoxamine [DFO] or deferasirox for the first year; Study 108, patients received deferasirox only). Treatment response success was defined according to baseline (start of deferasirox dosing) and end-of-study (EOS) LIC measurements (Table). Histological total iron score (TIS) was derived from the iron load observed in hepatocytes (hepatocytic iron score [HIS] range, 0–12), sinusoidal cells (sinusoidal iron score [SIS] range, 0–4) and main structures of the portal tracts (portal iron score [PIS]). A heterogeneity factor (H = 1, 2 or 3) was then applied, based on the overall appearance of the tissue, to provide TIS, calculated as (HIS + SIS + PIS) × (H/3) [range 0–60]. Hepatocytic to total liver iron ratio was calculated as HIS/(HIS + SIS + PIS) (Deugnier Y et al. Gastroenterol 1992). Fibrosis staging was performed according to Ishak scale from 0 (no fibrosis) to 6 (cirrhosis, probable or definite). Liver inflammation was assessed according to the Ishak necroinflammatory grading system with an overall scoring range from 0–18 (Ishak K et al. J Hepatology 1995). Results: Of 770 patients enrolled in the deferasirox studies, 219 with histological biopsy data at baseline and at the end of at least 3 years of treatment with deferasirox were eligible for analyses. Mean LIC was 15.7 ± 9.9 mg Fe/g dw and median serum ferritin was 2069 ng/mL (range 273–11698) at the start of deferasirox treatment. After at least 3 years of treatment, overall LIC success response rate was 63.8% (n=134), and mean LIC decreased by 5.5 ± 10.6 to 10.1 ± 8.2 mg Fe/g dw. Mean absolute change in TIS and liver iron ratio were -8.2 ± 13.3 and -2.1 ± 27.3, respectively. The range of Ishak necroinflammatory scores at baseline was 0–8 with a mean of 2.0 (2.2 in patients who met success rate criteria [Group A], 1.6 in patients who did not meet the success rate criteria [Group B]). At EOS the necroinflammatory score improved to a mean of 0.8 overall, and in both subgroups, with a mean relative change of -66% (69% in Group A and -61% in Group B). Overall 83.3% (n=175) [85.8% (n=115) in Group A, 78.9% (n=60) in Group B] of patients experienced either stabilization or improvement in their Ishak fibrosis score. Ishak staging remained stable (change of -1, 0 or +1) in 55.7% (n=122) of patients. Fifty-nine patients (26.9%) had an improvement in Ishak grading by a score of ≥2. Similar improvements were observed between Group A (26.1%, n=35) and Group B (30.3%, n=23). Conclusions: This is the first study to assess the effect of iron chelation therapy on liver pathology in a large cohort of iron-overloaded patients with β-thalassemia. In addition to reducing total iron burden, deferasirox led to an improvement in pathological markers of iron overload-induced liver damage in the majority of patients; 83.3% showed stabilization or improvement in Ishak fibrosis staging as well as an overall improvement in necroinflammatory score. These effects were similar in both patients who met the LIC success rate criteria and those who did not, suggesting that the observed effects may be at least partly independent of the drug's chelation effect. These findings are important as stabilization or regression of hepatic fibrosis in the face of chronic insult may prevent progressive liver disease. Disclosures: Deugnier: Novartis: Honoraria. Dong:Novartis: Employment. Giannone:Novartis: Employment. Zhang:Novartis: Employment. Griffel:Novartis: Employment. Brissot:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox In Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 mri.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1125-1125
Author(s):  
Yoo-Hong Min ◽  
Hyeoung Joon Kim ◽  
Kyoo-Hyung Lee ◽  
Jae Hoon Lee ◽  
Hee-Sook Park ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Myelodysplastic Syndromes ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Dry Weight ◽  
Mean Value

Abstract Abstract 1125 Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 97 patients with de novo MDS (n = 44) or idiopathic AA (n = 53) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a mean of 28.6 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (8.3%), 25 (69.4%), and 4 cases (11.1%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64.2%) were severe form. Mean value of serum ferritin level in enrolled patients was 3,482.6±436.7 ng/ml in MDS, and 3,904.4±399.2 ng/ml in AA at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 20.8 ± 3.5 mg Fe/g dry weight in MDS and 22.6 ± 2.2 mg Fe/g dry weight in AA. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. Over the study period, patients with MDS and AA received a mean of 24.2 and 22.0 units RBC per year, respectively. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,045.1±446.5 ng/ml and 2,614.7±311.9 ng/ml (p=0.005) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 55 cases, and at the end of study (EOS), the LIC were significantly decreased to 14.3±2.9 mg Fe/g dry weight (p=0.05) and 15.3±2.3 mg Fe/g dry weight (p=0.001) in MDS and AA, respectively. The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 30.9% cases because of death, patient refusal, and decrease in the serum ferritin level below 500ng/ml. All death was ascribed to disease-related causes. This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient's transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document