scholarly journals Combination iron chelation therapy with deferiprone and deferasirox in iron-overloaded patients with transfusiondependent β-thalassemia major

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hossein Karami ◽  
Mehrnoush Kosaryan ◽  
Arash Hadian Amree ◽  
Hadi Darvishi-Khezri ◽  
Masoomeh Mousavi
Keyword(s):  
Combination Therapy ◽  
Cardiac Mri ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Liver Mri ◽  
Duration Of Treatment ◽  
Liver Iron ◽  
Significant Difference ◽  
Before And After

There are few papers on the combination therapy of deferiprone (DFP) and deferasirox (DFX) in iron-overloaded patients with transfusion-dependent β-thalassemia major (β-TM). A total of 6 patients with β-TM (5 males and 1 female) with a mean age of 23.8±5.8 years (ranging from 17 to 31) used this treatment regimen. The mean doses of DFP and DFX were 53.9±22.2 and 29.3±6.8 mg/kg/day, respectively. The duration of treatment was 11.5±4.6 months. Their serum ferritin levels were measured to be 2800±1900 and 3400±1600 ng/mL before and after treatment, respectively (p&lt;0.6). Their cardiac magnetic resonance imaging (MRI) T2* values were 16.69±15.35 <em>vs</em> 17.38±5.74 millisecond (ms) before and after treatment, respectively (p &lt; 0.9). Although there was no significant difference between their cardiac MRI T2* values before and after treatment statistically, the values improved after combination therapy with DFP and DFX in most of the patients. Liver MRI T2 * values were changed from 2.12±0.98 to 3.03±1.51 ms after treatment (p &lt; 0.01); Further, their liver T2* values and liver iron concentration (LIC) were improved after treatment. Our study found that cardiac MRI T2* values, liver MRI T2* values, and LIC were improved after combination therapy with DFP and DFX in β-TM patients and that DFP and DFX combination therapy could be used to alleviate cardiac and liver iron loading.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

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.

Safe and Efficient Chelation by Deferasirox In Thalassemia Major Patients with Low Liver and Cardiac Iron Concentrations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5168-5168
Author(s):  
Regine Grosse ◽  
Gritta Janka ◽  
Andrea Jarisch ◽  
Peter Nielsen ◽  
Jin Yamamura ◽  
...  
Keyword(s):  
Side Effects ◽  
Conflicts Of Interest ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Transfusion Rate ◽  
Liver Iron Concentration ◽  
Measurement Interval ◽  
Liver Iron ◽  
Rbc Transfusion

Abstract Abstract 5168 Chelation treatment of iron overload from chronic blood (RBC) transfusion is still a challenge to both, patients and medical caretakers. Different treatment regimes have been recommended so far, especially for chronically transfused patients with low or even normal liver iron concentration. We report the results from 16 regularly transfused patients with thalassemia major (TM) who were on iron chelation treatment under normal to mild liver iron concentration (LIC). All patients received deferoxamine (DFO) treatment before they changed to deferasirox (DSX) treatment. 16 TM patients (mean age 13.6 y) were treated with DSX (median dose 18 mg/kg/d, range: 7 – 33 mg/kg/d) for 6 to 71 months. Liver iron measurements by biomagnetic susceptometry (BLS) and/or MRI-R2 as well as cardiac MRI-R2* were performed in intervals of 6 to 12 months. The median LIC was 782 μ g/g-liver wet weight (range: 460 μ g – 1122 μ g). Median RBC transfusion rate was 8500 ml/y, equivalent to about 2 erythrocyte concentrates per 3 weeks or a daily iron influx of 16.2 mg/d. For each measurement interval, the ratio of daily iron influx and DSX dose rate was calculated. This represents the equilibrium molar efficacy for iron balance. In all 16 TM patients no severe side effects were observed and creatinine was in the normal range of < 0.9 mg/d throughout the treatment with DSX. From baseline DFO treatment interval to the endpoint of DSX treatment, liver iron decreased by 124 – 4689 μ g/g-liver (conversion factor of 6 for mg/g-dry-wgt), while serum ferritin decreased by -596 to 8283 μ g/l. For all measurement intervals, molar chelation efficacies between 18 % and 56 % were calculated at equilibrium with a median efficacy of 31 % (interquartile range = 16 %). This agrees with molar efficacies of DSX reported earlier, but for relatively higher LIC and chelation doses (Blood 2005; 106(11):#2690 and Blood 2007; 110(11):#2776). The cardiac R2* (median R2* = 38 s-1) was either below the normal threshold of 50 s-1 (T2* > 20 ms) or decreased by about 24 %/y under DSX treatment. In these few patients at low LIC, this was even higher than recently reported. Conclusion: Even in patients with normal to mild LIC iron chelation treatment with DSX is safe, does not result in increased creatinine levels or severe side effects and is as efficient as in patients with higher LIC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Association Between Iron Over Load and Tanner Stage Retardation in the Females with B-Thalassemia Major

2020 ◽  
Vol 11 (1) ◽  
pp. 546-552
Author(s):  
Suzan Sabbar Mutlag
Keyword(s):  
Serum Ferritin ◽  
Iron Concentration ◽  
Growth Failure ◽  
Iron Chelation ◽  
Tanner Stage ◽  
Thalassemia Major ◽  
The Body ◽  
Liver Iron ◽  
Iron Stores ◽  
Female Patients

Despite optimal therapy of patients with B- major thalassemia included repeated transfusion of blood program and iron chelation agents helped by increasing survival of these patients  but remained a major problem in adolescents of these patients such as growth failure and hypogonadism. This study was aimed to determine the relationship between iron overload and tanner stage retardation among female  patients with B- major thalassemia in Thalassemia Hospital in Diwaniyah Governorate. The current study occurred on all female patients diagnosed β-thalassemia major depends on the blood tests, with their age range from 13years to 16 years who registered in Thalassemia unit in Al- Diwaniyah  Governorate, Republic of Iraq. In the physical examination, the patients were assessed for weight, height, Tanner stages, and body mass index(BMI), which recorded. S. Ferritin value was used to assess the iron load, and pelvic ultrasound was checked to assess the size of the uterus and both ovaries.  The results of the currents study revealed that the total numbers of B- thalassemia major female patients are 31 patients, aged 13-16 years. Age of patients at which diagnosed of B- major thalassemia range from 0.17 to 5 year. The frequency of Blood transfusion (time/Year) ranges from 6 to 33 times/Year. The level of serum ferritin of the patients was ranged from 913-12000 ng/ml with. Tanner stage I was predominant, accounting for 87%, whereas stage II and III accounted for 10% and 3%, respectively. There was a significant negative relation between times transfusion of blood and Tanner. There was a significant correlation between Uterus size, ovarian size, and Tanner stage. Because of inflammation falsely increase serum ferritin or due to the relation between body iron in the body and level of serum ferritin is not always within the linear range, especially in the condition of inflammation or tissue damage. So that level of serum ferritin is not an adequate measure of iron stores in patients with major thalassemia. Therefore, we needed another indicator to measure iron stores in patients with thalassemia major such as liver iron concentration.

Monitoring Cardiac Siderosis in Patients with Beta-Thalassemia Major on Various Chelation Regimens,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3177-3177
Author(s):  
Srikanth R. Ambati ◽  
Rachel Randolph ◽  
Kevin Mennitt ◽  
Dorothy A Kleinert ◽  
Patricia Giardina
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Liver Iron ◽  
Beta Thalassemia Major ◽  
Cardiac Siderosis ◽  
Hepatic Iron Overload

Abstract Abstract 3177 Background: Patients with Beta-thalassemia major develop progressive iron overload in various organs. Cardiac siderosis is a major cause of mortality and morbidity in these patients, and also poses a significant treatment challenge. Methods: We have reviewed 101 beta-thalassemia major patients 39 Male (M) 62 Female (F) with a mean age of 27.9 (range: 2 to 60 years). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and all received iron chelation initially with deferoxamine (DFO) and subsequently treated with deferasirox (DFX) or deferiprone (DFP) in combination with DFO. Each patient was monitored yearly for iron excess by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC (or weekly if on DFP), and urinalysis. Annual EKG, ECHO, hearing and vision testing and endocrine evaluations were also performed. The patients were grouped according to the severity of cardiac siderosis. Mild to moderate cardiac siderosis was defined as a T2* 12–20 msec and severe cardiac siderosis T2*≤ 11 msec. Annual studies were compared using paired student T test and repeated measures Analysis Of Variance (ANOVA) when necessary. Patient population: Twenty one of the 101 patients (7M and 14F) with a mean age of 30.6 yr, age range 15 to 56 yr, had abnormal cardiac T2* of <20 msec and three or more subsequent annual cardiac T2* measurements. Thirteen patients, 3 M 10 F with a mean age of 33 (range: 19 to 60), had severe cardiac siderosis and 8 patients, 3 M 5 F with mean age of 38 (range: 25 to 49), had mild-moderate cardiac siderosis. During the course of the observation their iron chelation therapy was optimized to reduce serum ferritin levels < 1500 μg/dl and to reduce or maintain liver iron concentration (LIC) ≤ 7 mg/gm dw. Data analysis: At the time of their first annual MRI study (baseline), 8 patients were on DFO of which 6 were switched to DFX, 13 patients were on DFX, 11 patients were dose escalated on DFX, and 4 patients were switched to combination chelation with DFO and DFP. At baseline, patients with severe cardiac siderosis had a mean cardiac T2* level = 7.4 ± 0.47 SEM (range: 4.6 to 11msec). Over the treatment course of 6 years annual cardiac T2* levels consistently improved and by 6 years cardiac T2* reached a mean level =14.3 ±1.5 SEM (range: 12 to 17 ms) (Fig 1). Those patients who at baseline had a mild to moderate cardiac siderosis with mean cardiac T2* of 14.6 ± 1.02 SEM (range: 12 to 19 msec) improved by 3 years of treatment when they achieved a mean cardiac T2* of 26.3 ± 3.4 SEM (range of 16 to 42 msec) (Fig 2). Liver iron concentration (LIC) was measured annually by MRI. Initially the majority, 16 out of 21 of patients, had hepatic iron overload LIC ≤ 10 mg/ gm dw of whom 56% (9 of the 16) had severe cardiac siderosis. 5 of 21 patients had a LIC > 15 mg/ gm dw of whom 80% (4 out of 5) patients had severe cardiac siderosis (Fig 3). Patients with LIC ≤10 mg/ gm dw had ferritin levels ranging from 166 to 3240 μg/ dl and patients with LIC >15 mg/ gm dw had elevated serum ferritin levels of 1180 to 17,000 μg/ dl. Patients with severe cardiac siderosis had mean MRI ejection fraction (EF)= 55.8% (range: 31 to 70%) while patients with mild to moderate cardiac siderosis had mean MRI EF= 60% (range: 53 to 66%). One patient with severe cardiac siderosis was recovering from symptomatic congestive heart failure. Conclusion: Cardiac siderosis can be noninvasively diagnosed utilizing MRI T2* techniques and subsequently to monitor treatment. The majority of patients improve cardiac T2* over time with optimal chelation therapy. Severe cardiac siderosis occurs even with mild to moderate hepatic iron overload. Left ventricular EF may not predict severe cardiac siderosis. Therefore it is important to annually monitor cardiac siderosis with MRI T2*. Disclosures: No relevant conflicts of interest to declare.

Impact of Iron Assessment by MRI

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 443-450 ◽  
Author(s):  
John C. Wood
Keyword(s):  
Chelation Therapy ◽  
Hypogonadotropic Hypogonadism ◽  
Iron Concentration ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
The Body ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Kinetics Of Uptake

Abstract The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.

Lack of Correlation between Serum Ferritin and Liver Iron Concentration in Beta-Zero Thalassemia Intermedia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3620-3620 ◽  
Author(s):  
Renzo Galanello ◽  
Nicolina Giagu ◽  
Susanna Barella ◽  
Liliana Maccioni ◽  
Raffaella Origa
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Regulatory Protein ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Thalassemia Intermedia ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract Serum ferritin and liver iron concentration (LIC) are the most commonly used methods for assessment of iron overload in thalassemia. While in patients with thalassemia major a significant correlation has been found between these two parameters, data are lacking in patients with thalassemia intermedia. In this study we measured the serum ferritin and LIC in 22 adult patients with beta-zero thalassemia intermedia never transfused (14 patients) or sporadically transfused, i.e. less than 10 units in total (8 patients), who maintained a mean hemoglobin of 8.8 ± 1.1 g/dl. Serum ferritin levels were measured by an automated chemiluminescence immunoassay analyzer, whereas LIC was determined by atomic absorption in liver biopsies. We compared the results obtained in those patients with those obtained in 22 regularly transfused (mean annual Hb = 11.3 ± 0.3 g/dl) and iron chelated thalassemia major patients, matched by sex, age and liver iron concentration. We also determined serum erythropoietin (s-epo) and serum transferrin receptor (s-TfR) in a cohort of the two patient groups (12 thalassemia intermedia; 15 thalassemia major). Mean LIC was 11.3 ± 6 mg/g dry weight tissue in thalassemia intermedia, and 11.8 ± 7 mg/g d.w. in thalassemia major group. Mean serum ferritin (at least 2 determinations from each patient within ± 2 months of liver biopsy) was 627 ± 309 ng/ml in thalassemia intermedia and 2748 ± 2510 ng/ml in thalassemia major. The difference was statistically significant (p = 0.0001). LIC was weakly correlated with serum ferritin in thalassemia major patients (r2=0.46; p=0.001) and uncorrelated in patients with thalassemia intermedia (r2=0.04; p=0.37) (Figure). S-epo and s-TfR were significantly higher in thalassemia intermedia than in thalassemia major [s-epo 467 ± 454 mU/ml versus 71 ± 44 mU/ml (p<0.001); s-TfR 43 ± 13 mU/ ml versus 13 ± 6 mU/ml (p<0.0001)]. The discrepancy between LIC and serum ferritin in thalassemia intermedia patients may be due to the higher levels of s-epo (secondary to anemia) in those patients, which through the iron regulatory protein 1 determine an up-regulation of s-TfR and a repression of ferritin translation (Weiss et al 1997). The mechanism of iron overload may also be mediated by hepcidin, whose synthesis could be suppressed as a consequence of anemia. The observation reported has important implications for iron chelation in patients with thalassemia intermedia. In such patients serum ferritin levels have little value for the monitoring of iron overload. Figure Figure

Transfusion History, Iron Chelation Practices and Status of Iron Overload across Various Transfusion-Dependent Anemias: Data from the Large- Scale, Prospective, 1-Year EPIC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3880-3880
Author(s):  
Maria Domenica Cappellini ◽  
Norbert Gattermann ◽  
Vip Viprakasit ◽  
Jong Wook Lee ◽  
John B Porter ◽  
...  
Keyword(s):  
Iron Overload ◽  
Large Scale ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Baseline Characteristics ◽  
Transfusion History

Abstract Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naïve (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias All (n=1744) TM (n=937) TI (n=84) MDS (n=341) AA (n=116) SCD (n=80) Rare (n=43) DBA (n=14) *Mean ± SD; **Median Age, yrs* 30.6±23.3 18.4±10.8 19.2±14.4 67.9±11.4 33.3±17.1 23.9±13.2 39.5±22.7 17.3±13.2 Transfusions in last yr* 17.8±12.5 17.5±8.8 13.5±7.1 24.3±17.7 12.5±13.0 10.7±8.2 21.0±18.7 19.0±18.7 Total transfused in last yr, mL/kg* 159±136 190±139 155±87 116±123 116±179 84±57 153±142 185±148 Total yrs on transfusions* 12.3±10.4 16.8±10.4 10.2±7.8 3.6±4.6 6.1±5.7 13.0±9.6 10.9±11.8 13.3±10.0 % of lifetime on transfusions* 62.9±39.4 89.8±15.2 61.2±28.8 5.7±8.4 27.1±29.3 59.5±30.1 44.3±41.5 87.5±23.2 LIC in last yr, mg Fe/g dw* 10.7±9.0 9.5±7.8 9.7±5.5 14.4±8.5 12.0±4.3 11.8±8.4 – 8.8±4.2 SF, ng/mL** 3135 3157 3493 2730 3254 3163 3161 2289 Prior chelation, % DFO 58.6 66.7 78.6 40.2 26.7 62.5 55.8 71.4 Deferiprone 1.6 1.3 – 4.1 – 1.3 2.3 – DFO/deferiprone 16.7 25.0 4.8 7.0 5.2 12.5 11.6 14.3 Other 0.3 0.4 – 0.3 – – – – None 23.0 7.0 16.7 48.4 68.1 23.8 30.2 14.3 Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naïve despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4058-4058
Author(s):  
Ali Taher ◽  
Mohsen Saleh Elalfy ◽  
Amal El-Beshlawy ◽  
Dunhua Zhou ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Advisory Committees ◽  
Liver Iron ◽  
Transfusion Requirements

Abstract Abstract 4058 Poster Board III-993 Background Despite the availability of effective chelators, many patients (pts) with β-thalassemia major (TM) present with high iron burden and serum ferritin (SF) >2500 ng/mL, demonstrated to be associated with significant negative outcomes including cardiac disease and organ failure. In the large, prospective EPIC trial including 854 TM pts who received prior chelation therapy, median baseline SF was 3139 ng/mL despite 10.8 yrs of therapy; hence the therapeutic goal was to reduce iron burden. Previous studies have shown that in TM pts with high transfusional iron, ≥30 mg/kg/day deferasirox (Exjade®) doses significantly reduce SF, while 20 mg/kg/day doses maintained SF levels. The objective of this analysis was to assess whether a mean actual deferasirox dose ≥30 mg/kg/day is effective in reducing SF in iron-overloaded pts with TM irrespective of prior chelation therapies. Methods Pts with TM (≥2 yrs) and transfusional iron overload as defined by SF levels ≥1000 ng/mL or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight were enrolled. Initial deferasirox dosing (10–30 mg/kg/day) was dependent on transfusion requirements and adjusted according to the protocol by 5–10 mg/kg/day (range 0–40 mg/kg/day) every 3 months based on SF trends and safety markers. Pts previously chelated with monotherapy deferoxamine (Desferal®; DFO) or deferiprone (Ferriprox®; DFP) or a combination of both and who received a mean actual deferasirox dose ≥30 mg/kg/day over 1 yr were included. The primary efficacy endpoint was the change in SF at 1 yr from baseline (BL). Results Overall, 129 TM pts (15%) who were previously chelated with DFO and/or DFP were treated with a mean actual deferasirox dose of ≥30 mg/kg/day during the 1 yr EPIC trial; 83 pts received prior DFO or DFP monotherapy and 46 received a combination of both. Mean age was 19.5±8.2 vs 23.0±7.2 yrs in prior monotherapy and prior combination therapy pts, respectively. A mean of 167 mL/kg vs 191 mL/kg was transfused in the yr prior to study entry and the mean duration of prior chelation therapy was 11.7±7.7 yrs vs 14.5±7.9 yrs, respectively. During the study, mean transfusional iron intake was similar in both groups (0.36±0.2 and 0.34±0.1 mg/kg/day, respectively). In prior monotherapy pts (mean dose 33.9±2.2 mg/kg/day), median SF decreased from 4885 ng/mL at BL to 4282 ng/mL after 1 yr (Figure) resulting in a decrease from BL of 1024 ng/mL (P<0.0001) based on last-observation-carried-forward (LOCF) analysis. In prior combination therapy pts (mean dose 34.1±3.9 mg/kg/day), median SF decreased from 5921 ng/mL at BL to 4327 ng/mL (Figure) resulting in a decrease from BL of 886 ng/mL (P=0.0078; LOCF). In patients with labile plasma iron (LPI) at BL, 1.3±2.1 and 1.7±3.1 μmol/L in the prior monotherapy and combination therapy groups, respectively after 1 yr was reduced to 1.1±2.6 and 1.4±2.7 μmol/L (LOCF). Overall, five pts (3.9%) discontinued therapy. Reasons for withdrawal were adverse events (AEs; cardiac failure), abnormal laboratory values (increased transaminases), consent withdrawal, lost to follow-up and protocol violation (all n=1). The most common investigator-assessed drug-related AEs were rash (n=14, 10.9%) and diarrhea (n=12, 9.3%). One pt (0.8%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits and one pt (0.8%) had increased alanine aminotransferase >10xULN on two consecutive visits; levels were already elevated. Conclusions This heavily transfused subgroup of TM pts, who had received prior chelation therapy with DFO and/or DFP for an average >10 yrs, continued to have high SF levels >4500 ng/mL. Monotherapy with ≥30 mg/kg/day deferasirox for 1 yr led to significant and clinically relevant reductions in SF in these pts irrespective of previous chelation therapies and was well tolerated. Longer-term studies are required to assess whether continued deferasirox could reduce SF <2500 ng/mL to minimize serious complications of iron overload. Disclosures: Taher: Novartis: Honoraria, Research Funding. Chan:Novartis: Honoraria, Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Sutcharitcharan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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