Comparison Of Two Combination Iron Chelation Regimens, Deferiprone and Deferasirox Versus Deferiprone and Deferoxamine, In Pediatric Patients With β-Thalassemia Major

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 559-559 ◽  
Author(s):  
Mohsen Saleh Elalfy ◽  
Yasser Wali ◽  
S Tony ◽  
Ahmed Samir ◽  
Amira Adly
Keyword(s):  
Adverse Events ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Cardiac Mri ◽  
Treatment Satisfaction ◽  
Short Form ◽  
Infusion Pump ◽  
Thalassemia Major ◽  
Serious Adverse Events ◽  
Patient Reported

Abstract Background Patients with severe iron overload may require a more rapid and efficient therapy for reduction in iron burden than what can be provided with chelation monotherapy. Combined chelation using deferoxamine (DFO) and deferiprone (DFP) is widely used to treat such patients, but the inconvenience of parenteral administration of DFO reduces the effectiveness of this regimen in many patients. Minimal data are available on the safety and efficacy of combined two orally active chelator agents. Aim To compare the safety, efficacy, compliance, treatment satisfaction, and quality of life (QoL) associated with two combination chelation regimens: DFP and DFO versus DFP and deferasirox (DFX). Methods This was a randomized, open-label trial registered as (NCT01511848) conducted at 2 treatment centers in patients aged 10 to 18 years with β-thalassemia major and severe iron overload (serum ferritin > 2500 μg/ L on chelation monotherapy, with 50% uptrend over the last 12 months). Patients were randomly allocated to one of two 12-month treatment regimens. All patients received DFP at a dose of 75 mg/kg/day, divided into 2 doses taken orally at 8 am and 3 pm. Those in Arm 1 additionally received DFO at a dose of 40 mg/kg/d delivered via subcutaneous infusion pump, starting at 10 pm, while those in Arm 2 additionally received a dose of DFX 20 mg/kg/d, taken orally at 10 pm. The primary efficacy endpoints were the difference between treatment groups in the change from baseline to 12 months of serum ferritin (SF) levels, liver iron concentration (LIC), and cardiac MRI. Secondary efficacy endpoints were the change from baseline to 12 months in QoL, using the Medical Outcomes Study Short Form health survey (SF-36). Serum ferritin was measured every 3 months, and liver and cardiac MRI T2* assessments were conducted every 6 months. Changes in all 3 measures were compared using 2-way ANOVA for repeated measures. The safety endpoint was the occurrence of serious adverse events during the study period. In addition, patients had complete blood count every 2 weeks, and monthly detailed clinical examinations that included blood sampling for serum creatinine, albumin/creatinine ratio, and liver function tests. Audiometric and ophthalmological assessments were conducted at baseline and 12 months. Assessments of compliance and of patient-reported outcomes (PROs) were assessed at weeks 424 and at end of study. Results A total of 96 patients were randomized. The arms were comparable with respect to baseline demographics, with a mean age of 14.9±1.8 years in Arm 1 and 15.1±1.9 years in Arm 2 (p=0.27), and with 65.2% males in Arm 1 and 66.6% males in Arm 2 (p=0.76). Forty of 46 patients (87%) in Arm 1 and 46 of 48 patients (92%) in Arm 2 completed all 12 months of treatment. Reasons for discontinuation were skin infection and pain at infusion sites in Arm 1,and decrease in SF < 1000 μg/ L in Arm 2. Efficacy findings: Table 1 shows the changes in SF, LIC, and cardiac MRI values at baseline and at completion of 1 year on therapy. Safety findings: No serious adverse events were reported during the study in either treatment group. The number of adverse effects reported was comparable in both arms. Compliance: Treatment compliance was significantly higher in Arm 2 than in Arm 1(95% vs. 80%, respectively<0.001). Satisfaction: Significantly more patients in Arm 2 than in Arm 1 reported being satisfied with treatment at both 6 months (92% vs. 64%, respectively; p<0.001) and 12 months (88% vs. 59%, respectively; p<0.001). QoL: Improvement in QoL was seen in significantly more patients in Arm 2 than in Arm 1 (85% vs. 60%, respectively; p<0.001). Conclusion Data from this randomized prospective study show that while both forms of combination therapy, DFP with DFX and DFP with DFO, were effective in reducing iron overload in multi-transfused β-thalassemia major, patients who received DFP and DFX showed a higher decline in serum ferritin, greater improvement in cardiac T2*, higher treatment satisfaction, better compliance, and more improvement in QoL than did patients who received DFP and DFO, with no increased toxicity. Disclosures: No relevant conflicts of interest to declare.

Update in Combined Chelation Therapy with Deferoxamine and Deferiprone in Brazilian Patients with Thalassemia Major: Assessment of Three Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5415-5415
Author(s):  
Sandra Regina Loggetto ◽  
Mônica Veríssimo ◽  
Antônio Fabron Júnior ◽  
Giorgio Roberto Baldanzi ◽  
Nelson Hamerschlak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Combined Therapy ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Cardiac Iron Overload

Abstract Introduction: Cardiac failure is a main cause of morbidity and mortality in patients with thalassemia major (TM) who are receiving regular blood transfusion due to iron overload. So, effective and adequate iron chelation is extremely important. Deferoxamine (DFO), the most widely used iron chelator, has poor compliance. Combined therapy with Deferiprone (DFP) increases chelation efficacy, decreases iron-induced complications, improves compliance increasing survival in thalassemia. Objectives: Assessment of efficacy and safety in combined chelation with DFP and DFO in thalassemic patients with iron overload. Methods and results: We have 50 thalassemia major patients in 4 Brazilian Centers (Boldrini Hospital, Sao Paulo Hematology Center, HEMEPAR and FAMEMA) receiving combined chelation therapy with follow up to three years. DFP (75–100 mg/kg/daily) and DFO (30–60 mg/kg, 4–7 days/week) are being administered during one to three years. Median age of this group is 21,5 y/o (range 8–35), with 48% female. Median age to start regular transfusions was 12 months (range 2–140) and to begin chelation therapy was 57 months (range 17–216). All patients were screened for Hepatitis C and 26% had positive sorology and/or PCR. Statistical analysis were made with Spearman test and Fisher test. All patients, except two, did cardiac and liver MRI in the initial phase of the study, resulting in 60,5% with cardiac iron overload (T2*&lt;20ms), being severe in 31,2%. Assessment of liver iron concentration (LIC) showed 95,7% with liver iron overload (&gt;3ug/g dry weight), being severe in 17,4%. During follow up, only 43 patients (86%) was screened with MRI. From these, 67,4% had cardiac iron overload (severe in 32,5%) and 78,6% had liver iron overload (severe in 11,9%). Mean serum ferritin before and after three years were 3095,7 ±1934,5 ng/ml and 2373,9±1987,6 ng/ml, respectively. Our data showed positive correlation between serum ferritin, LIC and ALT, even in initial data and after combined chelation therapy (p&lt;0,001), but there is no correlation between cardiac T2* and LIC and between cardiac T2* and ferritin. DFP adverse events included 8% agranulocytosis, 22% neutropenia, 20% arthralgia and 38% gastric intolerance. DFO adverse events were 2,6% deafness, 2,0% cataract and 12% growth deficit. Hepatic toxicity was found in 6%, but without necessity to stop treatment. Compliance in this group was excellent in 48%, good in 22% and poor in 30%. Conclusions: This is the first multicenter study to evaluate combined chelation therapy in Brazil based on cardiac MRI and LIC. Most patients had cardiac and hepatic iron overload probably because they began iron chelation lately, due to difficult access to iron chelators in the past. Cardiac iron overload didn’t have correlation with ferritin and LIC and these data need more understanding. Age of initial regular blood transfusion, increased transfusional requirement, inadequate chelation or delayed chelation may play a role in this question. Combined therapy with DFO and DFP is effective to decrease serum ferritin and LIC. Follow up and improving compliance may decrease cardiac iron overload. Adverse events are similar to literature. Combined therapy is safety in TM patients with transfusional iron overload.

Serum Metabolite Profiles Are Reflective of Iron Overload in Thalassemia Major Patients on Chelation Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2112-2112
Author(s):  
Farzana Sayani ◽  
Niloufar Abdolmohammadi ◽  
Anne Marie Lauf ◽  
Aalim Weljie
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Cardiac Mri ◽  
Chelation Therapy ◽  
Thalassemia Major ◽  
Multivariate Regression Analysis ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Metabolic Systems ◽  
Metabolite Profiles

Abstract Abstract 2112 Introduction: Iron overload (IO) either through blood transfusions or increased gastrointestinal absorption is associated with organ dysfunction and increased morbidity and mortality in patients with various hematological disorders including thalassemia. Despite improved methods of iron load detection and chelation therapy, patients still continue to be at risk for iron-associated toxicities. Methods for predicting IO include serum ferritin, liver iron content by MRI, and cardiac MRI T2*. Limited information is available regarding the effects of IO on the different metabolic systems in the liver and heart, which may change with chelation therapy. Different chelators, including deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX), chelate iron at different rates and effectiveness from the liver and heart. The liver is involved in maintenance of glucose and lipid homeostasis, and iron-triggered injury increases secondary metabolites including triacylglycerols and glucose. IO alters the stability of hepatic and myocardial lysosomal membranes releasing higher levels of lysosomal enzymes in liver compared to heart in animal models. These and other metabolic pathways have not been studied extensively in iron-overloaded patients. The new technology of metabolomics allows for the concurrent measurement and analysis of multiple metabolites and has the potential to provide more valuable information on the metabolic systems affected by iron overload that could have clinical relevance. Aim: To determine if novel metabolomics technologies can identify specific metabolites and pathways affected by iron overload including energy, carbohydrate, and lipid metabolism. Methods: In this pilot project, we included twelve iron overloaded patients (thalassemia major N=7, thalassemia intermedia N=2, hemoglobin H disease N=2, pure red cell aplasia N=1) (age > 18 years) and 12 sex and age-matched controls. Clinical parameters including age, sex, chelator therapy, pre-transfusion hemoglobin, serum ferritin, liver iron content, and cardiac MRI T2* were collected on patient samples. The metabolite profile on fasting serum samples was analyzed in triplicate using gas chromatography-mass spectrometry (GC-MS) along with MetaboliteDetector a software. Significant metabolites were identified using multivariate regression analysis by supervised projection methods (two-way orthogonal partial least squares discriminant analysis, O2PLS-DA) using Simca-P (Umetrics). Results: A total of 291 analytes were detected and quantified for each samples by GC-MS metabolomics. Clear differences were detected in serum metabolite profiles between patients with iron overload and control samples (p = 0.03) (Figure 1). Metabolite differences between the two groups consisted of amino acids, their breakdown products, and sugars. Multivariate regression analysis showed correlation between the different metabolite profiles and diagnosis of thalassemia major (p = 0.02). No significant differences were seen comparing age, sex, pre-transfusion hemoglobin, serum ferritin, LIC, and cardiac MRI T2*. There was a non-significant but detectable difference observed in the metabolic profile of the 3 patients on combination therapy with DFO and DFP (p<0.3) suggesting possible differences related to the presence DFP. Conclusion: We conclude that metabolomics is a valid and useful tool to detect differences in the iron-associated metabolic changes in iron overloaded patients, specifically, thalassemia major. Combination therapy with DFO and DFP has a possibly different metabolic profile compared to other chelators. Further work is needed to delineate the specific metabolic changes due to iron chelation, specifically, effects on oxidative damage, as chelation therapy is known to reduce the levels of non-transferrin bound iron and reactive oxygen species. A larger sample size may also be needed to further detect any metabolite differences in relation to organ iron load. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis

2015 ◽  
Vol 3 (2) ◽  
pp. 287-292 ◽  
Author(s):  
Khaled M. Salama ◽  
Ola M. Ibrahim ◽  
Ahmed M. Kaddah ◽  
Samia Boseila ◽  
Leila Abu Ismail ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Viral Hepatitis ◽  
Serum Ferritin ◽  
Liver Enzymes ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Elevated Liver Enzymes ◽  
Hcv Antibody

BACKGROUND: Beta Thalassemia is the most common chronic hemolytic anemia in Egypt (85.1%) with an estimated carrier rate of 9-10.2%. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of Alanine transaminase (ALT) and Aspartate transaminase (AST).AIM: Evaluating the potentiating effect of iron overload & viral hepatitis infection on the liver enzymes.PATIENTS AND METHODS: Eighty (80) thalassemia major patients were studied with respect to liver enzymes, ferritin, transferrin saturation, HBsAg, anti-HCV antibody and HCV-PCR for anti-HCV positive patients.RESULTS: Fifty % of the patients were anti-HCV positive and 55% of them were HCV-PCR positive. Patients with elevated ALT and AST levels had significantly higher mean serum ferritin than those with normal levels. Anti-HCV positive patients had higher mean serum ferritin, serum ALT, AST and GGT levels and higher age and duration of blood transfusion than the negative group. HCV-PCR positive patients had higher mean serum ferritin and serum ALT and also higher age and duration of blood transfusion than the negative group.CONCLUSION: Iron overload is a main leading cause of elevated liver enzymes, and presence of HCV infection is significantly related to the increased iron overload.

scholarly journals LONGITUDINAL STUDY ON LIVER FUNCTIONS IN PATIENTS WITH THALASSEMIA MAJOR BEFORE AND AFTER DEFERASIROX (DFX) THERAPY

2014 ◽  
Vol 6 (1) ◽  
pp. e2014025 ◽  
Author(s):  
Ashraf Tawfik Soliman ◽  
Mohamed Yassin ◽  
Fawzia AlYafei ◽  
Lolwa Al-Naimi ◽  
Noora Almarri ◽  
...  
Keyword(s):  
Liver Function ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Negative Correlation ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Growth Potential ◽  
Igf I ◽  
Liver Functions

With regular blood transfusion and iron chelation therapy, most patients with thalassemia major (BTM) now survive beyond the third decade of life . Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are important causes of liver pathology. Iron chelation with desferrioxamine (Desferal)  reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox (Exjade- DFX ), an  oral single dose therapy has improved the compliance to chelation therapy.Aims: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX therapy in relation to ferritin level and IGF-I level.Methods: Liver function tests including: serum bilirubin, alanine transferase (ALT), aspartate transferase (AST) , albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every 6 months in 40 patients with BTM, with hepatitis negative screening (checked every year), for at  least   five years of DFO therapy and 4-5 years of DFX therapy .Results: DFX  therapy (20 mg/kg/day)  significantly decreased serum ferritin level in patients with BTM, this was associated with significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum  ferritin concentrations ( r = 0.45 and 0.33 respectively , p < 0.05) . IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.The negative correlation between serum ferritin concentrations and ALT suggests that impairment of hepatic function negatively affects IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.Conclusions: Some impairment of liver function can occur in hepatitis negative BMT patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

Safety and Efficacy of Alternate Desferrioxamine and Deferiprone Compared to Desferrioxamine Alone in the Treatment of Iron Overload in Transfusion-Dependent Thalassemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3611-3611 ◽  
Author(s):  
Renzo Galanello ◽  
Antonios Kattamis ◽  
Antonio Piga ◽  
Fernando Tricta
Keyword(s):  
Adverse Events ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Comparable Efficacy ◽  
Liver Iron ◽  
Safety And Efficacy ◽  
Alternate Therapy ◽  
Significant Difference ◽  
Wet Weight

The safety and efficacy of alternating desferrioxamine and deferiprone for the treatment of iron overload in patients with transfusion-dependent anemias was studied in 60 thalassemia patients regularly treated with desferrioxamine. Patients were randomized to continue desferrioxamine alone (20–60 mg/kg/day, 5–7 days/week) or to alternate desferrioxamine (20–60 mg/kg/day, 2 days/week) with oral deferiprone (25 mg/kg tid, 5 days/week). Both treatment groups were similar for age (19.8 ± 6.1 years for desferrioxamine alone and 18.7 ± 4.8 years for alternate therapy) as was gender distribution and mean standard dose of desferrioxamine at the time of study initiation. Over the following 12 months, all patients were monitored weekly for adverse events and for their white blood cell count. Efficacy of the chelation was evaluated by measurement of the serum ferritin, liver iron concentration (magnetic susceptometry by SQUID), and by Non-Transferrin Bound Iron (NTBI). Compliance was comparable for both arms (96.1 ± 5.0% for alternate therapy vs 95.7 ± 5.7 % for desferrioxamine alone; p=0.7883). There was no significant difference in the proportion of patients with adverse events in the two therapy groups but the chelation regimens were associated with distinct adverse events. The alternate therapy was associated with transient gastrointestinal symptoms, such as vomiting in 5 patients (17%), abdominal pain in 3 patients (10%), or diarrhea in one patient (3%), or transient increase of serum ALT levels in one patient (3%), occurring mainly in the first weeks of therapy and were mild/moderate in severity. Daily infusions of desferrioxamine were associated with abscess at the site of infusion in one patient (3%), and allergic reactions in another patient (3%). Mean serum ALT levels were not significantly different between the two therapies. There were no episodes of agranulocytosis and only one patient, treated with desferrioxamine alone, experienced milder neutropenia. Both therapies resulted in similar decreases of serum ferritin (−349 ± 573 mg/L for the desferrioxamine arm; −248 ± 791 for the alternate arm; p=0.5802), and of liver iron concentrations (−239 ± 474 μg/g wet weight for the desferrioxamine arm; −65 ± 615 μg/g wet weight for the alternate therapy arm; p=0.2263) by the end of the treatment period. No significant changes in NTBI were observed between the two treatment arms (1.10 ± 7.19 μmol/L for the desferrioxamine arm; −0.03 ± 8.13 μmol/L for the alternate arm; p=0.5775). In conclusion, this 12 month study in transfusion-dependent thalassemia demonstrated that the alternating therapy with deferiprone and desferrioxamine is not associated with a significant increase in the incidence of adverse events and that it has comparable efficacy to desferrioxamine alone in controlling iron overload.

Efficacy of the Novel Oral Iron Chelator Deferitrin in Metabolic Iron Balance Studies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2775-2775
Author(s):  
Robert W. Grady ◽  
Maria Sitarou ◽  
Renzo Galanello ◽  
Hannah Tamary ◽  
Eliana Lai ◽  
...  
Keyword(s):  
Adverse Events ◽  
Animal Studies ◽  
Drug Evaluation ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Thalassemia Major ◽  
Total Iron ◽  
Tridentate Ligand ◽  
Serious Adverse Events ◽  
Iron Excretion

Abstract Deferiprone (L1, Ferriprox) and deferasirox (ICL670, Exjade), two orally effective iron-chelating agents, have revolutionized the management of iron overload. Nonetheless, neither drug is effective in all patients, deferoxamine (DFO) still being the only drug capable of placing all affected individuals in net negative iron balance. Deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, GT56-252), is a tridentate ligand with a demonstrated efficacy and an acceptable toxicity profile in preclinical evaluations in primates. In Phase 1 studies, it was well absorbed and no safety issues were identified. Thus, given the need for additional oral chelation options, we explored the efficacy of deferitrin in iron-overloaded patients with β-thalassemia major. Total iron balance studies were carried out wherein the effectiveness of single daily ascending doses of deferitrin (4.5, 6.75, 11 and 17 mg/kg/day) was compared with that of a standard DFO regimen (40 mg/kg infused subcutaneously over 8 hours). Twenty patients were admitted to our clinical research center for 28 days and placed on fixed individualized low-iron diets. On days 5 – 10 they were infused nightly with DFO and on days 15 – 24 given a dose of deferitrin with breakfast. Groups of 4 patients were studied at the three lowest doses of deferitrin, only 2 patients being given 17 mg/kg. Drug-free days allowed for washout of stool iron due to previous treatments, a stool marker being given at the beginning and end of each period of drug evaluation. Safety was assessed by hematology (CBC and coagulation parameters), chemistry (electrolytes, BUN, creatinine, liver function tests), urinalysis, and urinary β-2-microglobulin as well as by EKG, physical examination and monitoring of adverse events. Iron balance due to DFO ranged from 52% – 325% (mean 157%) with 40% – 77% (mean 61%) of total iron excretion appearing in the stool. Only 4 patients failed to achieve net negative iron balance. The response to deferitrin was highly variable at each dose studied, there being patients who responded poorly and others in whom there was a good response. Overall, iron balance ranged from 7% – 42%, nearly all of the iron excreted (0.04 – 0.14 mg/kg/day) appearing in the stool. Of note, total iron excretion appeared to reach a plateau at a deferitrin dose of 11 mg/kg/day. As animal studies suggested that more iron might be excreted upon giving the drug in divided doses, we interrupted our evaluation of 17 mg/kg/day and studied an additional 6 patients at 25 mg/kg/day, the drug being divided t.i.d. with breakfast, dinner and a bedtime snack. Iron balance in these patients ranged from 28% – 62% (mean 43%), stool iron excretion (0.14 – 0.29 mg/kg/day) accounting for 99% of the total. Their DFO-induced iron balance was similar to that of the patients previously studied, ranging from 123% – 233% (mean 173%). At all doses, no significant changes were noted in the EKGs or any hematological, biochemical or urinary parameters. There were no serious adverse events. These results suggest that deferitrin was orally effective and, while less effective than DFO, it was of sufficient efficacy to warrant further evaluation in a longer-term study as an alternative to DFO.

Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels <1000 Ng/Ml during Long-Term Treatment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5423-5423 ◽  
Author(s):  
John B Porter ◽  
Antonio Piga ◽  
Alan Cohen ◽  
John M Ford ◽  
Janet Bodner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Abdominal Pain ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Safety Profile ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Long Term Treatment ◽  
Baseline Characteristics

Abstract Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels &lt;1000 ng/mL. Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level &lt;1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was &lt;1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of &lt;1000 ng/mL, irrespective of future SF levels. Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF&lt;1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level &lt;1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value &lt;1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the &lt;1000 and &gt;1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown). Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels &lt;1000 ng/mL and patients who did not Patients who achieved SF &lt;1000 ng/mL Patients who did not achieve SF &lt;1000 ng/mL *Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase n 174 300 Male:female 85:89 145:155 Mean age ± SD, years 23.8 ± 16.7 23.5 ± 18.2 &lt;16, n (%) 65 (37.4) 123 (41.0) ≥16, n (%) 109 (62.6) 177 (59.0) Enrolled from study 107:108 120:54 175:125 Median exposure to deferasirox, months 56.3 45.2 Mean actual deferasirox dose, mg/kg/day 20.3 22.9 Median baseline SF, ng/mL 1791 2883 Drug-related AEs* (≥5% in either group), n (%) Nausea 26 (14.9) 38 (12.7) Diarrhea 17 (9.8) 42 (14.0) Vomiting 14 (8.0) 25 (8.3) Abdominal pain 12 (6.9) 32 (10.7) Upper abdominal pain 6 (3.4) 20 (6.7) Rash 9 (5.2) 16 (5.3) Audiological abnormalities 7 (4.0) 4 (1.3) Ophthalmological abnormalities 4 (2.3) 5 (1.7) Two consecutive SCr increases &gt;33% above baseline and above ULN 26 (14.9) 36 (12.0) Increase in ALT &gt;10×ULN on at least 1 visit 12 (6.9) 20 (6.7) Baseline levels elevated 6 (3.4) 16 (5.3) Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels &lt;1000 ng/mL was similar to that observed in patients who did not achieve SF levels &lt;1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels &lt;1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases &gt;33% above baseline and ULN or with ALTs &gt;10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.

The Palatability and Tolerability of Deferasirox (Exjade®) Taken with Meals, Different Liquids, or Crushed and Added to Food

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5155-5155
Author(s):  
Stuart L Goldberg ◽  
Patricia Giardina ◽  
Joan Parkhurst Cain ◽  
Deborah Chirnomas ◽  
Jason Esposito ◽  
...  
Keyword(s):  
Adverse Events ◽  
Serum Ferritin ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Iron Chelation Therapy ◽  
Age Group ◽  
Baseline Serum ◽  
Off Label

Abstract Abstract 5155 Introduction: Deferasirox (Exjade®, Novartis Pharmaceuticals) is an oral iron chelator indicated for the treatment of transfusional iron overload. The recommended mode of administration is to be taken on an empty stomach in water, apple juice or orange juice ≥30 minutes before food. However, there have been post-marketing reports of discontinuation or reduced compliance of deferasirox secondary to palatability and gastrointestinal adverse events. Registration trials with deferasirox did not evaluate different food combinations in an attempt to maintain predictable plasma levels. Early single dose studies suggested that the bioavailability of deferasirox is increased when administered with or before meals, and is positively influenced by fat content, but is not affected by degree of dispersion nor type of liquid. Long-term pharmacokinetic and tolerability studies involving a food effect have not been conducted to date, and the ability of alternate methods of administration to improve patient compliance with iron chelation therapy is unknown. Method: This is an ongoing single-arm, open-label, multi-center study designed to evaluate the palatability, safety, tolerability and pharmacokinetics of deferasirox when administered with food, dispersed in any liquid of choice, or crushed and added to food. The patient population includes patients with transfusional hemosiderosis (minimum entry serum ferritin ≥500 μ g/L) aged >2 years with thalassemia major, sickle cell disease (SCD), low or intermediate (INT-1) risk MDS or other anemias, who are on, starting, or resuming treatment with deferasirox. The study began with a 1-month run-in phase with deferasirox dosed according to prescribing information, then a 3-month assessment phase where subjects could choose each week from 5 general administration options including with or without meals, in the morning or evening, crushed and added to a soft food, or mixed in a liquid of choice. Subject diaries are used to record the meal and method of administration at the end of each week. Palatability is assessed with a modified facial hedonic scale, with additional directed questions capturing gastrointestinal side effects. This is a data analysis of the run-in phase. Result: Target enrollment has been met with 65 patients. Baseline data on the first 58 subjects include 8 in the 2 to <10 years of age group (median 7.5 years; range 3–9); 42 in the 10 to <60 years of age group (median 18.5 years; range 10–48); and 8 in the ≥60 years of age group (median 74 years; range71-83). Underlying hematologic diagnoses included SCD (41%), thalassemia major (29%), MDS (12%) and other anemias (17%). Sixty-nine percent of subjects were receiving deferasirox prior to entering the study. The median baseline serum ferritin level was 2405 μ g/L (range 560–8660) and was distributed as shown in Table 1. The most frequent adverse events were diarrhea (19%) and nausea (9%) (Table 2), which were more common in MDS (P=0.23 and P<0.01, respectively). Conclusion: This ongoing trial (NCT00845871) is evaluating whether alternative modes of administration improve palatability and tolerability while maintaining safety. Preliminary data from the assessment phase (deferasirox taken with meals, different liquids, or crushed and added to food) will be presented at the meeting. Disclosures: Goldberg: Novartis Oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Exjade, iron chelation therapy, off-label method of administration. Giardina:Novartis: Research Funding. Parkhurst Cain:Novartis: Research Funding. Chirnomas:Novartis: Research Funding. Esposito:Novartis: Employment. Paley:Novartis: Employment. Vichinsky:Novartis: Consultancy, Research Funding, Speakers Bureau; Hemaquest: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apotex: Consultancy, Research Funding.

Different Adverse Event Profiles and Significant Hematological Improvement Are Noted When Deferasirox Was Used in Adult Patients with Chronic Transfusion-Related Iron Overload in Taiwan: Results from a Prospective Observational Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4554-4554
Author(s):  
Bor-Sheng Ko ◽  
Ming-Chih Chang ◽  
Tzeon-Jye Chiou ◽  
Te-Kau Chang ◽  
Yeu-Chin Chen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Platelet Response ◽  
Chronic Anemia ◽  
Erythroid Response ◽  
The Mean ◽  
Grade 3

Abstract Background Iron overloading is a common problem for adult with myelodysplastic syndrome (MDS), aplastic anemia (AA) or other chronic anemia. Deferasirox (DFX) has been proven as an effective therapy to chelating iron in these patients. Anyway, the safety of DFX is still a concern, and the information of safety profiles and efficacy are less understood in Taiwan. This study is planned primarily to collect long-term safety data of DFX treatment in iron-overloaded MDS, AA and other chronic anemia patients in Taiwan. Study Design This is an observational, single-arm, and multi-center study. Low-risk MDS or AA patients with transfusion-related iron overload, or patients with other anemia and serum ferritin more than 2000 ug/ml, were enrolled within the 18-month enrolling period if DFX is planned to be prescribed. Exposure of iron chelating agents other than DFX before trial initiation was allowed. The initial dose and subsequent adjustment of DFX were up to investigator¡¦s preference. All patients were followed for 3 years for adverse events (AEs) and disease outcomes. Results From 2009 to 2011, 79 patients were enrolled in this study, including 38 MDS, 23 AA and 18 other chronic anemias. Forty-seven cases (59.5%) were male, with mean age 64.3¡Ó17.8 y/o. Fifty-six (70.9%) subjects failed to complete the 3-year study period, but only 8 (10.1%) of the subjects withdrew DFX due to drug-related AEs. The mean DFX exposure dose during study was 17.7¡Ó4.02 mg/Kg/day. In contrast with those reported in literature, the most frequently reported drug-related AEs were rash (16, 20.3%), diarrhea (11, 14.0%), hypercreatinemia (8, 10.1%), pruritus (7, 8.9%), and so on (as in Table 1). When classified by organ systems, skin disorders were the frequently reported one (26, 32.9%), and followed by GI disorders (n=24, 30.4%). Grade 3-4 drug-related adverse events were rare (n=4, 5.1%). For all subjects, DFX could effectively decrease serum ferritin level from baseline (-985+/-2090 ng/ml (p=0.0154 vs. baseline) and -1710+/-2290 ng/ml (p=0.0424 vs. baseline) at 1 yr and 3 yr, respectively) (as in Figure 1). Notably, after DFX usage, 23 patients (32.4%) developed erythroid response according to IWG 2006 criteria; the mean hemoglobin could increase from 7.77+/-1.63 gm/dl (baseline) to 8.25+/-2.60 gm/dl (at 36 month, p=0.6172 vs. baseline), when the average transfusion amount was decreased from 2.3+/-1.4 units (baseline) to 1.6¡Ó0.5 units (at 36 months, p=0.0406 vs. baseline). (as in Figure 2). Ten patients (10/46, 21.7%) had platelet response. For the 38 MDS patients, DFX also could significantly lower serum ferritin level (-590+/-2490 ng/ml (p=0.4095 vs. baseline) and -1310+/-362 ng/ml (p=0.0013 vs. baseline) at 1 yr and 3 yr, respectively) but seemed to have a less extent than that in overall population. Similarly, 10 patients (21.7%) developed erythroid response after DFX use. The mean hemoglobin increment (from 7.67+/-1.67 gm/dl (baseline) to 8.55+/-3.45 gm/dl (at 36 month, p=0.6012 vs. baseline)) and the decrease of average transfusion amount (from 2.1+/-1.2 units (baseline) to 1.6+/-0.6 units (at 36 months, p=0.2943 vs. baseline) were not significant, probably due to low case number (as in Figure 2). Four (4/19, 21.1%) patients experienced platelet response. Conclusion This study showed that the profiles of AEs regarding DFX use for adult anemic patients with transfusion-related iron overload in Taiwan were significantly different from those reported in Western countries. The AE-related discontinuation rate was also relatively low. An expected efficacy to lowering serum ferritin by DFX, and a significantly degree of hematological improvement was noted, too. Table 1. Drug-related adverse events, for all events with incidences > 5% and all grade 3-4 events: Table 1. Drug-related adverse events, for all events with incidences > 5% and all grade 3-4 events: Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Chang: Novartis: Honoraria.

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