scholarly journals LONG-TERM EFFECTIVENESS, SAFETY, AND TOLERABILITY OF TWICE-DAILY DOSING WITH DEFERASIROX IN CHILDREN WITH TRANSFUSION-DEPENDENT THALASSEMIAS UNRESPONSIVE TO STANDARD ONCE-DAILY DOSING

2021 ◽  
Vol 13 (1) ◽  
pp. e2021065
Author(s):  
Jassada Buaboonnam ◽  
Chayamon Takpradit ◽  
Vip Viprakasit ◽  
Nattee Narkbunnam ◽  
Nassawee Vathana ◽  
...  
Keyword(s):  
Safety Profile ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Liver Iron ◽  
Once Daily ◽  
Treatment Interruptions ◽  
Inadequate Responders

Background: Patients with transfusion-dependent thalassemia (TDT) risk iron overload and require iron chelation therapy. Salvage therapy is warranted for patients demonstrating poor chelation responses. Patients and methods: We retrospectively studied the serum-ferritin (SF) and liver-iron-concentration (LIC) outcomes of patients with TDT treated with twice-daily dosing of deferasirox (TDD-DFX) for > 24 months, after failing to respond to once-daily deferasirox (OD-DFX). Results: We enrolled 22 patients (14 males and 8 females; median age, 9.2 [3–15.5] years). The median erythron transfusion was 216 (206–277) ml/kg/year. The median TDD-DFX treatment period was 30 (24–35) months. Before initiating TDD-DFX, the median SF level was 2,486 (1,562–8,183) ng/ml, while the median LIC was 6.5 (3.2–19) mg/g dry wt. There were 18 responders (81.8%) and 4 nonresponders. The median SF-level change was -724 (-4 916 to 1,490) ng/mL. The median LIC change was -2.14 (-13.7 to 6.8) mg/g dry wt. The 1-year and end-of-study SF levels and LICs were statistically significant (SF, P = 0.006/0.005; and LIC, 0.006/0.005, respectively). There were no treatment interruptions secondary to adverse events. In the follow-up of the TDD-DFX-responder group, 11 of the 18 had a reduced dose, whereas the remaining 7 continued with the same dose. Conclusions: TDD-DFX appears to be an alternative treatment approach for patients refractory to OD-DFX, with a favorable long-term safety profile. Further studies with larger groups and pharmacogenetic analyses of inadequate responders are warranted to better determine the efficacy and safety profile of TDD-DFX.

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.

Long Term Efficacy, Safety and Tolerability (>24 Months) of Twice Daily Dosing of Deferasirox in Transfusion Dependent Thalassemias Who Were Unresponsive to Standard Once Daily Dose

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 958-958
Author(s):  
Bunchoo Pongtanakul ◽  
Vip Viprakasit
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Once Daily ◽  
Term Efficacy ◽  
Before And After ◽  
Baseline Levels ◽  
Median Change

Background: Clinical efficacy, safety and tolerability of deferasirox (DFX); a once daily oral iron chelator in transfusion dependent thalassemias (TDT) with iron overload can be achieved by appropriate dosage adjustment based on iron burden and ongoing transfusion iron overload. However, even with recommended DFX dosage, at least 40% of our Thai TDT patients did not appropriately respond to DFX. Patients with unresponsiveness to DFX (UR) was defined as (1) having a rising serum ferritin (SF) trend or (2) having a reduction of SF < 30% of baseline levels (BL) at least 3 consecutive mths, with more than two SF measurements >1500 ng/mL; and (3) receiving once daily DFX at an average dosage > 30 mg/kg/day for at least 6 mths. Previously, twice daily dosing (TWD) of DFX was shown to be effective in patients with UR (Pongtanakul B, et al. Blood Cells Mol Dis. 2013) but long term efficacy, safety and tolerability of TWD of DFX is still lacking. Methods: Patients with UR who received TWD of DFX with the same total dose per day > 24 mths were included. CBC, renal function, urine analysis were performed every 3 wks to monitor possible side effect. SF and liver function test were checked every 6 wks. Tolerability and compliance to DFX were evaluated by direct history taking and drug account prescribed. Responsiveness to TWD of DFX (RP) was defined as the patients who showed a decrease of SF or reduction of liver iron concentration (LIC) by MRI > 30% of the BL at 6 or 12 mths. Results: Twenty four TDT patients received TWD of DFX; 4 patients were excluded due to poor compliance and a short follow up period and 4 patients did not meet RP criteria. Sixteen patients were enrolled; 9 male (56%) with a mean (± SD) age of 9.08 ± 3.84 yrs (range 2.1-24.2 yrs). Clinical diagnoses include; Hb E/β thalassemia. (n=12), β thalassemia major (n=3) and Hb Barts hydrops (n=1). Mean follow up time before switching dose were 17.3 ± 7.3 mths. Average SF at BL before DFX and before TWD were 3,039 ± 1,713.7.02 and 3,500 ± 1,403.2 ng/mL, with median % change of SF was +27.58 % (range; -13.4 to +104%). Mean actual DFX dose during 6 mths before switching was 36.3 ± 2.2 mg/kg/day. None had symptoms of gastrointestinal irritation. After TWD, 13 (81.25%) and 16 patients (100%) showed a significant decrease of SF (> 30% of the baseline levels) at 6 and 12 months. Mean SF and median % change of SF at 6 and 12 months after switching were 2,527.56 ± 1,191.80 ng/mL; -29.24 % and 1,695.83 ± 859.16 ng/mL; -53.14%, with statistical significance compared to BL and before switching (p <0.05). Mean transfusion iron load before and after switching were not different (range 0.2-0.4 mg/kg/day). One patient had a SF reduction < 30%, but LIC was significant reduction at 12 months. Nine out of 16 patients were evaluated for LIC; average LIC at BL and at the end of study were reduced from 6.7 to 3.2 mg/g dry wt. None had cardiac T2* < 20 msec. All patients except one tolerated well with DFX at before and after switching (>24 months) with minor adverse events. One patient had severe transaminitis (ALT > 3 times of ULN) but after investigation, this was thought to be result from acute viral hepatitis. This patient could be successfully restarted DFX at the same TWD. Five patients could decrease DFX dosage to < 20 mg/kg/day and switched back to daily dosing (mean dosage was 17.04 mg/kg/day). However, 4 patients, after decreased DFX dosage and switched back to daily dosing; their SF increased and required to increase DFX dosage with TWD to maintain SF. Seven patients continued to receive TWD of DFX with mean dosage was 36.4 mg/kg/day. Mean follow up time after TWD of DFX was 44.1 + 9.8 mths (range 24 - 72 mths). Conclusion: Herein, we show that TWD of DFX effectively reduced iron burden in TDT with iron overload. Safety and tolerability of this dosing are not different from once daily dosing. Most patients could decrease DFX dosage and switched back to once daily dosing when iron burden decreased. However, 25% (4/16) of these patients still required twice daily dosing with higher dosage to maintain optimal body iron levels. Interestingly, 16% (4/24) of our patients who received TWD could not achieve effective iron chelation. This group of patients may represent those who have different pharmacogenetic background that affect directly to efficacy of DFX causing a resistant to iron chelation therapy. This population confirms for improving iron chelation measures by means of a newer iron chelation agent or a combination of DFX with other iron chelation. Disclosures Off Label Use: Twice daily dosing instead of standard daily dosing.

Iron Chelation Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine Is Effective in Reducing Iron Overload in Patients with Advanced Fibrosis and Cirrhosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2696-2696 ◽  
Author(s):  
E. Angelucci ◽  
B. Turlin ◽  
D. Canatan ◽  
A. Mangiagli ◽  
V. De Sanctis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Advanced Fibrosis ◽  
Liver Iron ◽  
Once Daily ◽  
Tissue Iron

Abstract Introduction: Although the direct measurement of iron from a liver biopsy is the reference standard method to determine liver iron concentration (LIC), results are highly unreliable in patients with advanced fibrosis and cirrhosis. As a result, chelation therapy is difficult to monitor in this patient population where effective chelation therapy may be critical. It is therefore important to assess parameters additional to LIC in order to accurately assess body iron in these patients. Aim: To analyze the efficacy of chelation with deferoxamine (DFO) and the investigational once-daily, oral iron chelator deferasirox (DSX) in patients with advanced fibrosis participating in DSX registration studies. Methods: A subgroup of patients from DSX Studies 0107 and 0108 were selected based on a staging result according to the Ischak scale of 5 (incomplete cirrhosis) or 6 (probable or definite cirrhosis), measured either at baseline or after 1 year of chelation therapy. The subgroup of patients with β-thalassemia participating in Study 0107 received DSX (n=26) or DFO (n=30). In Study 0108, the subgroup of patients with β-thalassemia unable to be treated with DFO (n=12) or patients with anemias other than β-thalassemia (n=7) were treated with DSX only. In both studies, patients received chelation therapy according to baseline LIC. Results: In Study 0107, treatment with DSX or DFO led to a decrease in semi-quantitative tissue iron score (TIS) and LIC, which were paralleled by changes in serum ferritin. TIS, LIC and serum ferritin in a subgroup of patients with advanced fibrosis and cirrhosis treated with DSX and DFO (Study 0107) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) *Median (min, max) Baseline* 35.5 (4,39) 34 (10,52) 25.5 (2.4,45.9) 19.5 (3.9,55.1) 4195 (321,12646) 4144 (653,15283) Change from baseline* −2 (−43,20) −2 (−25,16) −9.4 (−42.2,13.1) −3.1 (−24.5,12.4) −1269 (−7082,3609) −951 (−8259,1264 Similarly, in Study 0108, DSX treatment produced a decrease in all 3 parameters in patients with β-thalassemia or rare anemia. TIS, LIC and serum ferritin in a subgroup of β-thalassemia and rare anemia patients with advanced fibrosis and cirrhosis (Study 0108) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL β-thalassemia (n=12) Rare anemia (n=7) β-thalassemia (n=12) Rare anemia (n=7) -thalassemia β (n=12) Rare anemia (n=7) *Median (min, max) Baseline* 35 (4,48) 41 (32,49) 29.4 (3.8,37.4) 26.3 (15,51.3) 4813 (440,11698) 2385 (1553,9099) Change from baseline* 2 (−19,27) −3 (−20,1) −1.6 (−18,9.9) −10 (−13.9,8.8) −986 (−4453,2131) −1322 (−2609,1901) Conclusions: Chelation therapy with DSX or DFO is effective in reducing iron overload in patients with advanced fibrosis and cirrhosis. The trends observed in TIS and LIC were closely mirrored by changes in serum ferritin, highlighting the validity of this method for monitoring chelation therapy in this population.

Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3825-3825
Author(s):  
Nelson Hamerschlak ◽  
Laercio Rosemberg ◽  
Alexandre Parma ◽  
Fernanda F. Assir ◽  
Frederico R. Moreira ◽  
...  
Keyword(s):  
Iron Overload ◽  
Ventricular Function ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Inverse Correlation ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

Iron Chelation in Regularly Transfused Patients with Aplastic Anemia: Efficacy and Safety Results from the Large Deferasirox EPIC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 439-439 ◽  
Author(s):  
Jong Wook Lee ◽  
Sung-Soo Yoon ◽  
Zhi Xiang Shen ◽  
Hui-Chi Hsu ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Aplastic Anemia ◽  
Iron Reduction ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Efficacy And Safety ◽  
Iron Intake ◽  
Liver Iron ◽  
Transfusion Requirements

Abstract Background: Patients with aplastic anemia (AA) can be effectively treated with bone marrow transplantation or immunosuppressive/immunomodulatory therapy, but many will require repeated blood transfusions to manage symptoms of severe anemia and are subsequently at risk of accumulating excessive body iron. Reduction in iron burden across a range of transfusion-dependent anemias, including AA, has been previously demonstrated with deferasirox (Exjade®). More recently, the EPIC trial enrolled the largest cohort of patients with AA undergoing iron chelation to date. The efficacy and safety of deferasirox in these patients are presented. Methods: Enrolled patients had transfusion-dependent AA and serum ferritin (SF) levels of □1000 ng/mL, or &lt;1000 ng/mL with a history of multiple transfusions (&gt;20 transfusions or 100 mL/kg of red blood cells) and an R2 MRI-confirmed liver iron concentration (LIC) &gt;2 mg Fe/g dry weight. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of SF trends and safety markers indicative of iron toxicity. SF was assessed every 4 weeks and the primary efficacy endpoint was the change at week 52 from baseline. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: In total, 116 AA patients (67 males, 49 females; mean age 33.3 years) were enrolled. Median baseline SF was 3254.0 ng/mL; patients received a mean of 115.8 mL/kg of blood in the year prior to enrollment. Approximately two-thirds of patients (68.1%) had received no prior chelation therapy. Of those who had, patients received deferoxamine (DFO; n=31, 26.7%) or combination DFO/deferiprone (n=6, 5.2%). After 12 months, median SF decreased significantly by 964.0 ng/mL from baseline median of 3254.0 ng/mL (P=0.0003). This occurred at an average actual deferasirox dose of 17.6±4.8 mg/kg/day. The median change in SF from baseline was –970.0 ng/mL (P&lt;0.0001; 3263.0 ng/mL [baseline]; 0.20 mg/kg/day [mean iron intake]) in patients receiving a mean actual deferasirox dose &lt;20 mg/kg/day (n=75) and −883.8 ng/mL (P=0.27; 3238.0 ng/mL [baseline]; 0.29 mg/kg/day [mean iron intake]) in those receiving 20–&lt;30 mg/kg/day (n=40). Overall, 88 patients (76%) completed the study; reasons for discontinuation included AEs (n=13, 11%), consent withdrawal (n=6, 5%), lost to follow-up (n=1, 1%) and various other reasons (n=3, 3%). In addition, five patients (4%) died during the study (one death related to pneumonia, three due to sepsis and one as a result of hepatic adenoma rupture). No death was suspected by investigators to be treatment related. The most common drug-related AEs (investigator-assessed) were: nausea (n=26, 22%), diarrhea (n=18, 16%), rash (n=13, 11%), vomiting (n=10, 9%), dyspepsia (n=9, 8%), abdominal pain (n=7, 6%), upper abdominal pain (n=7, 6%), and anorexia (n=7, 6%). Most AEs were mild or moderate in severity (&gt;95%). 29 patients (25.0%) had an increase in serum creatinine &gt;33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. One patient (0.9%) had an increase in alanine aminotransferase (ALT) that exceeded &gt;10xULN on two consecutive visits; ALT levels were elevated in this patient at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent, iron overloaded patients with AA. Despite the high iron burden, most patients had received no prior chelation therapy, indicating a clear need for iron chelation in this patient population. Overall, deferasirox was generally well tolerated in these AA patients with the majority of AEs being mild to moderate.

Correlation of Hepatocyte Iron Score and Liver Iron Ratio with Alanine Aminotransferase in Patients with Beta Thalassemia Receiving Iron Chelation Therapy for at Least 3 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2156-2156
Author(s):  
M Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Silverio Perrotta ◽  
Leyla Agaoglu ◽  
Antonis Kattamis ◽  
...  
Keyword(s):  
Liver Function ◽  
Board Of Directors ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Advisory Committees ◽  
Liver Iron ◽  
Absolute Change ◽  
The Mean ◽  
Relative Change

Abstract Background: Chronic blood transfusions impact the liver due to accumulation of iron, leading to tissue damage, collagen formation and portal fibrosis. Long-term chelation therapy has been shown to be associated with stability or improvement of liver fibrosis and necroinflammation in heavily iron-overloaded patients with β thalassemia, independently of reductions in liver iron concentration (LIC) (Deugnier et al Gastroenterology 2011;141:1202-1211). It was also shown that changes in alanine aminotransferase (ALT, an indicator of hepatocellular damage) mirrored changes in LIC, with significant decreases in ALT seen in LIC responders. Here, we evaluated the effect of long-term chelation therapy on hepatocyte iron score (HIS), and the correlation of HIS and liver iron ratio (LIR) with ALT, to determine if the location of iron within the liver impacts liver function. Methods: Study design, inclusion and exclusion criteria for studies 107 and 108 have been described previously (Deugnier et al, 2011). β thalassemia patients who had liver biopsy assessment at start of deferasirox treatment and after at least 3 years, were included in this analysis. Iron deposits were assessed according to size, cellular and lobular locations in Rappaport's acinus leading to three different scores: HIS (range 0-12), sinusoidal iron score (SIS, range 0-4) and portal iron score (PIS, range 0-4). The LIR, used to assess the relative amount of hepatocytic to total liver iron, was calculated as HIS/(HIS + SIS + PIS) x 100%. LIC was determined by liver biopsy. Correlation between ALT and HIS, and ALT and LIR was assessed using Pearson correlation coefficients. Baseline (BL) in these analyses refers to start of deferasirox treatment. Patients who received deferoxamine during the first year are referred to as the crossover cohort. Assessments were performed according to LIC response (see Table). Results: Of 671 β thalassemia patients enrolled, 470 received chelation therapy for at least 3 years. Of these patients, 219 had histological biopsy data at BL and after at least 3 years of treatment. For all patients (n=219), mean absolute change ± standard deviation (SD) in HIS from BL (16.7 ± 7.4) to end of study (EOS; 11.8 ± 7.8) was -5.0 ± 9.3 (95% confidence interval [CI]; -6.3, -3.8), with a mean relative change of -18.1% (95% CI; -27.7, -8.5). In the crossover cohort (n=94), the mean absolute change in HIS from BL (15.1 ± 7.1) to EOS (11.6 ± 8.0) was -3.8 ± 9.3 (95% CI; -5.8, -1.8), with a mean relative change of -10.4% (95% CI; -26.8, 6.0). Among LIC responders, the mean absolute change of HIS from BL (18.6 ± 7.4) to EOS (9.9 ± 7.2) was -8.7 ± 7.6 (95% CI; -10.1, -7.4); mean relative change -43.5% (95% CI; -51.7, -35.4). Among LIC non-responders, the mean absolute change of HIS from BL (13.0 ± 5.9) to EOS (14.4 ± 7.9) was 1.6 ± 8.2 (95% CI; -0.3, 3.5); mean relative change 26.9% (95% CI; 6.9, 47.0; Table). Correlation of HIS versus ALT: At BL and EOS, HIS showed a weak positive correlation with ALT in LIC responders (n=125, R=0.27 and n=126, R=0.31, respectively) and moderate correlation in non-responders (n=72, R=0.36 and n=72, R=0.43). Similarly, absolute change in HIS showed a weak correlation with change in ALT in LIC responders (n=125; R=0.17) with a moderate correlation in non-responders (n=72; R=0.44; Figure). Correlation of LIR versus ALT: At BL and EOS, LIR showed no correlation with ALT in LIC responders (n=121; R=-0.07 and n=122; R=0.04, respectively) and non-responders (n=70; R=-0.14 and n=70; R=-0.05, respectively). Absolute change in LIR showed a weak negative correlation with change in ALT in LIC responders (n=121; R=-0.25) and no correlation in non-responders (n=70; R=0.02). Discussion: Long-term iron chelation therapy is associated with improvement of liver function as measured by ALT in iron-overloaded patients with β thalassemia. Absolute change in HIS correlated with change in ALT in both LIC responders and non-responders. Although this correlation was weak to moderate, this finding supports the importance of excess iron removal from hepatocytes in order to improve ALT levels. By contrast, LIR which represents the proportion of HIS to total liver iron, showed no correlation. These results suggest that the improvement in liver function seen during chelation therapy may partly be due to the decrease in iron stored in hepatocytes. Further studies are warranted to investigate the mechanisms by which iron chelation therapy may improve liver function. Disclosures Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kattamis:ApoPharma: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Han:Novartis: Employment. El-Ali:Novartis: Employment. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Long-Term Iron Chelation Therapy with Deferiprone in Patients with Thalassemia Major and Low Iron Load

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3626-3626 ◽  
Author(s):  
Shahina Daar ◽  
Murtadha K. Al-Khabori ◽  
Khalil Al Farsi ◽  
Bader Abdulla Al-Rawahi ◽  
Arwa Z. Al-Riyami
Keyword(s):  
Iron Overload ◽  
Safety Profile ◽  
Chelation Therapy ◽  
Conflicts Of Interest ◽  
Serum Magnesium ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
P Value ◽  
Patient Reported

Abstract Introduction and Objectives: Iron chelators are effective in reducing iron burden and in improving clinical outcomes in patients with transfusional iron overload. However, limited data are available on their efficacy and safety in transfusion-dependent patients with low iron overload, due mainly to concerns of chelation toxicity observed with deferoxamine (DFO) in patients with serum ferritin (SF) < 1500ug/L. Deferiprone (DFP) has markedly lower affinity for iron (pFe3+ log stability constant = 19.9) than that of deferoxamine (26.6), and may provide a better safety profile in patients with low iron overload. The objective of this study is to evaluate the safety and efficacy of DFP in patients with thalassemia major (TM) and SF <500 ug/L. Methods: A total of 32 patients with TM (15 males) who had achieved SF <500 ug/L while on chelation with combined DFO and DFP (n=30) or on deferasirox (DFX) (n=2) had their chelation switched to DFP monotherapy (75-100mg/kg/day). All patients received 50 mg of oral zinc sulfate once a week for the duration of the study. Iron overload was assessed using SF and MRI T2* of liver and heart within 3 months of switch and then 6-12 monthly thereafter. Renal and liver function tests were performed monthly and trace elements (serum magnesium, copper, zinc and selenium) were also assessed. Results: Patients were followed for a median of 4.5 years (Range: 1-11 years). The median age at time of switch was 22.7 years (Range 11-28). The mean packed red blood cell volume transfused during the study was 197 mL/kg/year (Range: 157-282 mL). There was no significant increase in the SF (Baseline 392 ug/L; Last assessment 418 ug/L; p value 0.55) or the liver iron concentration (Baseline 3.44 mg/g dw; Last assessment 3.1 mg/g dw; p value 0.54) during the follow up. On the contrary, there was a statistically significant improvement in the cardiac T2* (Baseline 30 ms; Last assessment 38 ms; p <0.001). DFP was discontinued in 28% of patients (Ineffective in 3; Agranulocytosis in 1; Pregnancy in 1; Bone marrow transplantation in 2; Deaths in 2). The two deaths were unrelated to the chelation therapy (Decompensated HCV related liver cirrhosis and severe hypoglycaemia in a patient with diabetes mellitus). Two patients had mild asymptomatic hypocalcemia, and one had low copper levels. All three patients normalized their results with no treatment and without stopping DFP. No patient reported gastrointestinal disturbances or arthralgia, and none had elevation of liver enzymes or serum creatinine. Conclusion: Long-term DFP therapy in patients with TM and low iron overload was effective in stabilizing SF and LIC and was associated with improvement in the myocardial iron. The safety profile was consistent with those observed during therapy in patients with more severe iron burden and there were no increase in the unexpected adverse drug reactions. Disclosures No relevant conflicts of interest to declare.

Deferasirox (Exjade®, ICL670) Treatment of Inadequately Chelated β-Thalassemia Patients from the Middle East: The ESCALATOR Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3840-3840 ◽  
Author(s):  
Ali Taher ◽  
Amal El-Beshlawy ◽  
Abdullah Al Jefri ◽  
Mohsen El Alfy ◽  
Kusai Al Zir ◽  
...  
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Oral Iron ◽  
Study Cohort ◽  
Liver Iron ◽  
Transfusion Therapy ◽  
Once Daily ◽  
Oral Iron Chelator

Abstract Iron overload is a potentially life-threatening consequence of multiple blood transfusions. Effective iron chelation therapy reduces morbidity and saves lives. Many patients are unable to comply with current treatments, deferoxamine (DFO) or deferiprone (L1), because they cannot tolerate the parenteral infusion regimen required for DFO, because of adverse events (AEs), or because they do not respond to treatment. The objective of the ESCALATOR trial is to evaluate the effectiveness of deferasirox, an investigational once-daily oral iron chelator in advanced clinical development, in reducing liver iron concentration (LIC) in patients with β-thalassemia unable to be properly treated with DFO and/or L1. During a 1-year treatment period, patients will receive deferasirox at a daily dose of 20 mg/kg. Reduction of LIC is the primary endpoint, as assessed by biopsy at baseline and study end. Secondary efficacy variables include serum ferritin (SF) and other potential surrogate markers of iron overload such as concentration of labile plasma iron (LPI) in a subgroup of patients. Safety assessments include AEs and comprehensive laboratory evaluations. To date, 232 patients have initiated treatment at seven centers in five countries (Egypt, Saudi Arabia, Lebanon, Oman, Syria). Demographics, relevant medical history and baseline iron burden parameters are described in the table. Importantly, baseline SF values were significantly correlated with LIC (R=0.63; P&lt;0.0001). The last patient’s last visit will be in June 2006. Age 2 to &lt;16 years (n=159) Age ≥16 years (n=73) All patients (n=232) Mean ± SD; †n=14 Female:male, n 79:80 35:38 114:118 Race (caucasian:oriental:other), n 59:81:19 11:41:21 70:122:40 BMI*, kg/m2 17.4 ± 2.6 21.6 ± 3.2 18.7 ± 3.4 Weight*, kg 29.4 ± 9.9 54.7 ± 9.7 37.3 ± 15.3 Hepatitis B or C, n 43 29 72 Splenectomy, n 46 53 99 Transfusions in previous year*, n 15.5 ± 4.5 14.3 ± 3.7 15.1 ± 4.3 Total volume transfused in previous year*, mL 5265 ± 2469 7446 ± 2953 5873 ± 2784 Years on chelation therapy*, n 6.2 ± 3.5 12.7 ± 4.8 8.2 ± 4.9 Proportion of life on transfusion therapy*, % 89.3 ± 13.9 89.0 ± 14.1 89.2 ± 14.0 Liver pathology grading (modified HAI scale)     Grade 0–6 143 64 207     Grade 7–12 4 0 4     Grade 13–18 0 0 0 LIC, mg Fe/g dw     Mean ± SD 17.1 ± 8.5 20.0 ± 10.0 18.0 ± 9.1     Median (min, max) 16.6 (2.9, 38.2) 19.0 (2.9, 48.9) 17.5 (2.9, 48.9) SF, ng/mL     Mean ± SD 3957 ± 2342 4564 ± 4117 4148 ± 3019     Median (min, max) 3356 (914, 13539) 3335 (956, 23017) 3346 (914, 23017) LPI†,μmol/L     Mean ± SD - - 1.03 ± 0.80     Median (min, max) - - 0.82 (0, 2.65) The ESCALATOR study cohort is a highly challenging population with varied chelation response and transfusion history. The magnitude of LIC and SF, which were well correlated, reflects the severity of iron overload in patients unable to maintain adequate chelation using DFO or L1. This study will provide important insights into the clinical management of iron overload with the well tolerated, once-daily oral iron chelator deferasirox in this difficult-to-treat population.

Deferasirox Safety Profile in Patients with Transfusion-Dependent Anaemias:Results From the Interim Analysis of a Hellenic Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3183-3183
Author(s):  
Vassilis Ladis ◽  
Marouso Drossou ◽  
Dimitria Vini ◽  
Ersi Voskaridou ◽  
Miranda Athanasiou-Metaxa ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Safety Profile ◽  
Interim Analysis ◽  
Pediatric Patients ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Liver Iron ◽  
Liver Iron Overload

Abstract Abstract 3183 Background: The introduction of iron chelation treatment has led to a significant improvement in morbidity and overall survival in patients with transfusion-dependent anemias. Deferasirox is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in both adult and pediatric patients. The efficacy and safety of deferasirox in a variety of transfusion-dependent anemias has been established in numerous Phase II/III clinical trials. Since most patients with transfusion-dependent anemias require lifelong iron chelation therapy, there is a need to assess the long-term safety of deferasirox in both adult and pediatric patients. Aim: To assess the safety profile of deferasirox in patients with transfusional iron overload in a real-world clinical setting. To further investigate the safety profile of deferasirox in patients with congenital erythrocyte disorders and transfusional iron overload, with ferritin levels <4000 ng/ml and without severe cardiac siderosis. Methods: Between July 2009 and September 2010, 85 patients with transfusion-induced iron overload treated with deferasirox as per the approved product labeling were enrolled in the study. These data represent the 24-week planned interim analysis of a 12-month observational study on deferasirox safety profile in the treatment of pediatric and adult patients with transfusion-dependent anemias who were newly-treated with deferasirox. Safety was evaluated through the monitoring and recording of all adverse events and serious adverse events, as well as routine laboratory testing, including hematology, blood chemistry and hepatic function assessments. Results: The population had a median age of 37.6 years (range: 5.3–61.4) and a female to male ratio of 1.3. Beta-thalassemia (67.1%) was the most common transfusion-dependent anemia, followed by thalassemia intermedia requiring periodic transfusions (20.0%) and sickle cell anemia (12.9%). Mean baseline ferritin levels were 1502.1±870.5 (pediatric group: 1480.2±522.8 and adult group: 1503.6±891.4), while 53 out of the 85 patients (62.4%) had serum ferritin level above 1000 ng/ml. Mean baseline liver T2* value was 10.4±9.7 ms; 44.4% of patients demonstrated minimal liver iron deposition (MRI T2* > 6.3 ms), 51.4% had mild to moderate liver iron overload (T2* ≤ 6.3 ms), and 4.2% had severe liver iron overload (T2*<1.4 ms). 54 (63.5%) of patients analysed had been pre-treated with iron chelators and 31 (36.5%) were chelation-naïve. The initial average daily dose of deferasirox was 25.9±4.8 mg/kg, and 70.6% of patients had no dose modification during the 24-week follow-up period. A statistical significant decrease in median serum ferritin levels was observed by Week 24 (mean absolute change from baseline:-214.5 ng/mL; p=0.009) [Figure 1]. No statistically significant changes were observed in creatitine levels, creatinine clearance and transaminases by Week 24 [Figure 1]. 37 ADRs were reported by 17 patients (20%) over the 24-week period. Among the most frequently observed ADRs (>5%) were epigastralgia reported by 7.1% of patients (6/85) and loose stools/diarrhoea by 5.9% of patients (5/85). The majority of ADRs reported (nevents=25; 67.6%) were graded as mild in severity, while 21.6% (nevents=8) were graded as moderate and 10.8% (nevents=4) as severe. Most ADRs (nevents=31; 83.8%) resulted in full recovery by Week 24. The overall incidence of SADRs was as low as 1.2% (in particular one patient experienced severe epigastralgia and upper extremity pain which resulted in her withdrawal from the study after four months of treatment). The all-cause discontinuation rate was 9.4% (8/85), while only two patients (2.4%) discontinued the study therapy due to ADR; 1 patient due to increased transaminase levels and 1 patient due to the aforementioned SADR. Conclusions: These data highlight the safety profile of deferasirox in both adult and pediatric patients; the regular monitoring of serum ferritin levels as well as other iron-overload parameters and transfusion requirements play a major role in determining and optimizing the outcome of iron chelation therapy. Disclosures: Ladis: Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Drossou:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Vini:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Athanasiou-Metaxa:Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Vlachaki:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Tigka:Novartis Hellas S.A.C.I.: Employment. Tzavelas:Novartis Hellas S.A.C.I.: Employment. Liakopoulou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Adamopoulos:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Kattamis:Novartis Hellas S.A.C.I.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Beta-Thalassaemia Intermedia: Evaluation of Endocrine and Bone Complications

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
M. Baldini ◽  
A. Marcon ◽  
R. Cassin ◽  
F. M. Ulivieri ◽  
D. Spinelli ◽  
...  
Keyword(s):  
Bone Disease ◽  
Chelation Therapy ◽  
Bone Mineralization ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
X Ray ◽  
Bone Complications ◽  
Thalassaemia Intermedia

Objective. Data about endocrine and bone disease in nontransfusion-dependent thalassaemia (NTDT) is scanty. The aim of our study was to evaluate these complications inβ-TI adult patients.Methods. We studied retrospectively 70β-TI patients with mean followup of 20 years. Data recorded included age, gender, haemoglobin and ferritin levels, biochemical and endocrine tests, liver iron concentration (LIC) fromT2*, transfusion regimen, iron chelation, hydroxyurea, splenectomy, and bone mineralization by dual X-ray absorptiometry.Results. Thirty-seven (53%) males and 33 (47%) females were studied, with mean age41±12years, mean haemoglobin9.2±1.5 g/dL, median ferritin 537 (range 14–4893), and mean LIC7.6±6.4 mg Fe/g dw. Thirty-three patients (47%) had been transfused, occasionally (24/33; 73%) or regularly (9/33; 27%); 37/70 (53%) had never been transfused; 34/70 patients had been splenectomized (49%); 39 (56%) were on chelation therapy; and 11 (16%) were on hydroxyurea. Endocrinopathies were found in 15 patients (21%): 10 hypothyroidism, 3 hypogonadism, 2 impaired glucose tolerance (IGT), and one diabetes. Bone disease was observed in 53/70 (76%) patients, osteoporosis in 26/53 (49%), and osteopenia in 27/53 (51%).Discussion and Conclusions. Bone disease was found in most patients in our study, while endocrinopathies were highly uncommon, especially hypogonadism. We speculate that low iron burden may protect against endocrinopathy development.

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