Transfusion-dependent Iron Overload Research Articles

Surrogate Markers of Subclinical Atherosclerosis and Its Associated Factors in Patients with β-Thalassemia Major

β-Thalassemia major (β-TM) is a severe genetic hemoglobin (Hb) disorder with cardiovascular complications such as atherosclerosis due to transfusion-dependent iron overload. We aimed to determine the associated factors with surrogate markers of subclinical atherosclerosis in these patients. Sixty subjects with β-TM referred to the Thalassemia Clinic of the Iranian Blood Transfusion Organization (IBTO) were included in our study. The blood samples were collected for laboratory measurements. The carotid intima-media thickness (CIMT), was measured by ultrasonography, and ankle-brachial index (ABI) was calculated. The multivariate linear analysis was performed to determine the appropriate indicators of subclinical atherosclerosis in β-TM. There was no significant difference in baseline characteristics between the study groups. In multivariate linear analysis, age and systolic blood pressure (SBP) were negatively associated with inverse-transformed CIMT [unstandardized β coefficient (B): −0.024, 95% confidence interval (95% CI): −0.032- −0.010, p < 0.001; B: −0.009, 95% CI: −0.017- −0.001, p 0.031, respectively]. There was also a significant correlation between the serum level of high-density lipoprotein cholesterol (HDL-C) and insulin with higher ABI, after adjustment for confounding variables (B: 0.003; 95% CI: 0.000–0.005; p = 0.030, and B: 0.004, 95% CI: 0.000–0.009, p = 0.037, respectively). Our results show that advancing age and increased SBP, HDL-C and insulin, associated with higher CIMT or ABI, are appropriate indicators of subclinical atherosclerosis in β-TM patients.

Impact of medication adherence on the effectiveness of deferasirox for the treatment of transfusional iron overload in myelodysplastic syndrome.

Regular blood transfusions in the management of myelodysplastic syndrome (MDS) often lead to iron overload. The main objective of this study was to evaluate the impact of medication adherence on the effectiveness of deferasirox for the treatment of transfusional iron overload in patients with MDS. Secondary objectives were to describe treatment effectiveness and safety in daily clinical practice. A longitudinal, retrospective, observational study was carried out in a university hospital. The inclusion criteria were age over 18 years, MDS diagnosis and treatment with deferasirox for transfusion-dependent iron overload during the period of study (from January 2011 to April 2015). Treatment effectiveness was estimated by serum ferritin (SF), and adherence was measured by medication possession ratio (MPR). Clinically relevant analytical alterations during the treatment and reasons for treatment discontinuation were also assessed. Thirty-five patients were included in the study. Median SF at baseline was 1636 μg/L, and it decreased to 1399 μg/L during follow-up. The median adherence rate was 92%, although only 54·8% of the patients maintained deferasirox adherence ≥90% during the whole duration of treatment. Adherence rate was inversely correlated to SF (r = -0·288, P = 0·004). The median (p25, p75) duration of treatment was 11 (3·0, 37·8) months. The most common reasons for treatment discontinuation were renal toxicity (35%) and patient's death (25%). Deferasirox's effectiveness, measured by the decrease in SF, was significantly better in adherent patients. The most frequent reason for treatment discontinuation was renal toxicity. Developing strategies to improve deferasirox treatment adherence and monitoring renal function in those patients should be key points in pharmaceutical care.

Assessment of Cardiac Iron Overload in Chonically Transfused Patients with Thalassemia, Sickle Cell Anemia, and Myelodysplastic Syndromes

▪Background. Cardiac iron overload is the major cause for death in regularly transfused thalassemic (Thal) patients. Its impact in myelodysplastic syndrome (MDS) patients is debated. Heart seems to be spared in regularly transfused patients with sickle cell anemia (SCA), which is supposed to be related to a later onset on transfusions and to the use of erythrocytapheresis rather than simple transfusion. Our aim was to assess the prevalence of cardiac iron overload, defined as a T2*cardiovascular magnetic resonance (MR) <20ms, and to look for predisposing factors.Patients and methods. Patients were enrolled if they were regularly followed in a center where the exact number of erythrocyte concentrates (EC) could be obtained, had received in the previous year more than 8 EC, were older than 6 years (limit for MRI without sedation), had no known heart disease related to another pathology, and had given informed consent.All patients underwent 1.5T myocardial T2*MR imaging after validation of the procedures in the different sites. Assessment of Liver Iron Content (LIC) used two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. Serum Non-Transferrin Bound Iron (NTBI) was measured by the FeROSTM eLPI kit, and serum hepcidin by LC-MSMS.Results. 20 Thal, 41 SCA and 25 MDS patients were evaluable. We divided SCA in 2 groups, according to the procedure recorded at the time of the study, manual exchange transfusion (G1, N = 30 patients), or erythrocytapheresis (G2, N=11 patients).We found cardiac overload in 0, 3 (15%), and 4 (16%) of SCA, Thal, and MDS patients respectively. Serum ferritins at beginning of chelation were not statistically different in all categories of patients, as well as Ferritin and LIC at the time of the study. Increased LIC and abnormal T2* were associated in Thal and MDS patients (p=0.04), with no correlation between abnormal T2* and parameters of transfusion and chelation.Plasmatic iron level was increased in Thal and MDS patients but remained at normal range in SCA patients. NTBI level was high in Thal and MDS but completely absent in SCA groups.The major discrepancy was in the values of hepcidin, which were collapsed in Thal, at normal range in SCA, and highly elevated in MDS patients.Discussion and conclusion.We confirm that SCA patients are relatively protected from cardiac iron overload. This results probably from massive consummation of iron through effective erythropoiesis, making toxic free iron (NTBI) less available in the circulation. In addition, since iron overload in SCA results from a massive outflow of hemoglobin (Hb) due to intravascular hemolysis and transfusion, the heme/Hb-bound iron must be efficiently handled in liver macrophages, limiting its release in the bloodstream.In Thal patients, underlying defects in erythropoietic processes, together with low hepcidin that stimulates intestinal iron absorption and increases NTBI, must provoke more organ damages. Hepcidin levels were high in MDS patients, suggesting that transfusion-dependent iron overload was a more effective regulator of hepcidin production than dyserythropoiesis. The % of T2*<20 ms we observed in MDS patients (16%) was quite comparable with previous publications.Finally, we observe that, in opposition with previous reports, SCA patients undergoing eythrocytapheresis may experience severe iron overload and need iron chelation.Table 1ThalSCA G1SCA G2MDSpAge at beginning of transfusion (yrs)8.5[0-45]7[0-45]16.5[1-55]66[38-83]<0.001Duration of transfusion (yrs)10[1-39]7[1-22]10.5[0-25]3[1-10]<0.001N EC since diagnosis359[21-1360]139[24-791]201[14-888]77[16-544]0.0005N CE/yr24[8-67]21[4-62]35[17-58]27[7-65]0.09G1vsG2=0.03% patientschelated959072.7720.12Age at beginning of chelation (yrs)11[1-48]9[2-47]18[6-31]68[38-84]<0.0005Ferritin at beginning of chelation (ng/ml)1148[713-2400]2075[448-3670]1500[905-2804]2398[482-5140]0.22N T2*<20 ms3(15%)004(16%)0.01LIC (mg/g d.w.)10.4[0.8-20.2]10.7[0.8-37.1]14[0.8-19.7]15.2[3.0-45.3]0.29Plasmatic iron(μmol/l)36.9[31-57]22.5[6-42.2]21[13-46]38.2[11.9-72]<0.001NTBI (mg/ml)7.1[0-31.1]0[0-18.3]0[0-12.4]4.45[0-25.5]0.0005Ferritin (ng/ml)870[169-4339]2739[393-5596]2404[33-20030]1611[223-6813]0.08Hepcidin (ng/ml)1.35[0-12.3]9.95[0-67.9]2.10[0-52.4]36.35[3-143.2]<0.001Deferasirox dosage<0.5 μg/ml3/8(38%)3/10(29%)3/5(60%)0/11(0%)0.03 DisclosuresDe Montalembert:Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau.

Deferasirox chelation therapy in patients with transfusion-dependent MDS: a 'real-world' report from two regional Italian registries: Gruppo Romano Mielodisplasie and Registro Basilicata.

Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion-dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large 'real-world' MDS population. One hundred and eighteen patients with transfusion-dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion-dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients.

A Case of Yersinia Enterocolitica Sepsis in a Beta Thalassemia Patient on Deferasirox

We report a case of Yersinia enterocolitica sepsis in a 23 year old woman with transfusion-dependent beta-thalassemia major and iron overload treated with deferasirox. Although yersiniosis is a recognized complication of iron overload syndromes treated with desferrioxamine, Y. enterocolitica sepsis has not previously been reported in association with deferasirox. This case underscores the importance of considering iron-avid organisms as potential pathogens and initiating appropriate broad empiric antimicrobial coverage as well as discontinuing chelating agents in iron-overloaded patients. Given the current paucity of evidence and lack of consensus regarding appropriate antibiotic regimens for Yersinia sepsis, which we review briefly, we highlight the importance of consulting an Infectious Diseases specialist early in the course of illness.

Concomitant Medications and Gastrointestinal Events in Thalassemia and MDS Patients Receiving Deferasirox for Transfusional Iron Overload: Data From the EPIC Study

AbstractAbstract 5182 Background:The 1-yr open-label, single-arm, multicenter EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) trial assessed the efficacy and safety of deferasirox in patients with transfusion-dependent iron overload, including patients with thalassemia and with myelodysplastic syndromes (MDS). The most frequent adverse events (AEs) in the EPIC trial were gastrointestinal (GI) disturbances. Here, we qualitatively examine concomitant medication (con med) use in thalassemia and MDS patients with/without GI events to consider the impact of con med use on GI events. Methods:Thalassemia and MDS patients from the EPIC study were included. A GI event was defined as an investigator-reported AE with the system organ class ‘GI disorders' after start of treatment. Data are reported here for the most frequently received con meds of interest, by preferred term, which also had notable differences in their frequency among patients with/without GI events; con meds that may have been prescribed to treat GI events are excluded from interpretation: propulsives, antipropulsives, proton pump inhibitors, laxatives and electrolyte solutions. Results:Among thalassemia patients (n=1115; 48. 3% male; aged 18. 2 yrs [range 2–72]), 345 (30. 9%) patients experienced a GI event. Mean deferasirox dose was 23. 8 ± 5. 4 mg/kg/d in patients with a GI event and 24. 3 ± 5. 5 mg/kg/d in patients with no GI event; median serum ferritin (SF) at end of study (EOS) was 2734 ng/mL (391–23997) and 3223 ng/mL (259–17644), respectively. 28. 9% of thalassemia patients did not receive any con meds; 15. 7% received ≥7 different types of con meds. Thalassemia patients with a GI event received a mean of 6. 0 different types of con meds, vs 2. 1 in patients without a GI event. Con meds were received in 91. 9% of patients with a GI event vs 61. 8% of patients without a GI event. Anti-inflammatory, antibiotic or antifungal con meds were more frequent in thalassemia patients who experienced a GI event (Figure A). The con med with the largest relative difference in frequency among patients with vs without a GI event was paracetamol/codeine phosphate (7. 2 vs 0. 5%, respectively).Among MDS patients (n=341; 59. 8% male; aged 67. 9 yrs [11–89]), 248 (72. 7%) patients experienced a GI event. Deferasirox dose was 18. 8 ± 4. 9 mg/kg/d in patients with a GI event and 20. 4 ± 6. 4 mg/kg/d in patients with no GI event; SF at EOS was 1977 ng/mL (254–9835) and 2045 ng/mL (141–10155), respectively. 12. 3% of MDS patients did not receive any con meds; 37. 8% received ≥7 different types. Patients with a GI event received a mean of 9. 6 different types of con meds vs 4. 5 in patients without a GI event. Con meds were received in 89. 5% of patients with a GI event, vs 82. 8% of patients without a GI event. In patients with MDS, antibiotic, antifungal or opioid medications were more frequent in patients with GI events (Figure B). The con med with the largest relative difference in frequency among patients with vs without a GI event was tramadol hydrochloride (7. 7 vs 1. 1%, respectively).Most frequent con med in both populations was paracetamol (acetaminophen; Figure). In patients receiving paracetamol who had a GI event, the most frequent types of GI events in thalassemia patients were diarrhea, abdominal pain and nausea; in MDS patients these were diarrhea, constipation and abdominal pain. In patients receiving paracetamol, mean alanine aminotransferase level at EOS in thalassemia patients with a GI event was 49. 0 vs 46. 3 U/L in patients with no GI event; and 38. 9 vs 27. 2 U/L in MDS patients, respectively. Discussion:In both thalassemia and MDS patients, concomitant use of antifungal and antibiotic medications was more frequent in patients with GI events, although it should be considered that GI events are also the most frequent AEs of, for eg, amoxicillin/potassium clavulanate and ciprofloxacin. Paracetamol use was higher in patients who had GI events; types of GI events were typical of those observed during deferasirox treatment and did not appear related to liver toxicity. Anti-inflammatory medications were more frequent in thalassemia patients with GI events, as were opioid medications in MDS patients. Con meds may affect the frequency of GI AEs reported with deferasirox. Further investigation is needed to determine whether these observations result from a potential interaction of the metabolic pathways of con meds and deferasirox – eg, CYP450 metabolism of paracetamol – or the action of the con meds alone. [Display omitted] Disclosures:Cappellini:Novartis: Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Louw:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau.

Deferasirox Treatment for up to 3 Years in Iron-Overloaded Pediatric Patients Reduces Serum Ferritin with a Manageable Safety Profile

AbstractAbstract 1028 Background:To prevent complications associated with iron overload in patients with transfusion-dependent anemias, iron chelation therapy is required throughout life starting from early childhood. Long-term studies of iron chelation therapy are therefore required, particularly in pediatric patients. The 1-year open-label, single-arm, multicenter EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) trial evaluating the efficacy and safety of deferasirox in patients with transfusion-dependent iron overload enrolled 577 pediatric patients across 23 countries. In an extension period of up to 18 months, or until deferasirox was available locally, patients completing the core study could continue to receive deferasirox, thus providing long-term efficacy and safety data of deferasirox in iron-overloaded pediatric patients. Methods:At enrolment, transfusion-dependent pediatric patients (defined as ≥2–<16 years at enrollment) had serum ferritin ≥1000 ng/mL OR <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg red blood cells transfused) and liver iron concentration >2 mg Fe/g dw confirmed by R2 magnetic resonance imaging. Deferasirox starting dose was 10–30 mg/kg/day depending on frequency of blood transfusions, with protocol-specified adjustments of 5–10 mg/kg/day (range 0–40 mg/kg/day) based on 3-monthly serum ferritin trends and safety. Biochemistry analysis including serum ferritin was performed on a monthly basis, and growth was monitored every 12 weeks, with continuous assessment of safety parameters. Creatinine clearance was calculated using the Schwarz formula for pediatric patients. Changes from the start of deferasirox treatment (core baseline) are presented. Results:267 pediatric patients aged 2–<6 (n=68), 6–<12 (n=114) and 12–<16 (n=85) years entered the extension period (n=141 [52.8%] male; n=248 [92.9%] with underlying thalassemia; n=33 [12.4%] with a history of hepatitis B and/or C). Median duration of deferasirox exposure was 101.3 weeks (range 55.6–159.9) with mean ± SD deferasirox dose 25.7 ± 5.8 mg/kg/day (13.4–40.0). Median serum ferritin decreased from a baseline of 3222 ng/mL (951–16,944) to 2431 ng/mL (238–29,681) at the end of the extension (absolute change from baseline –528 ng/mL [–6354 to 25,127]; P<0.0001; last observation carried forward).Overall, 257/267 (96.3%) patients completed the extension; main reasons (more than two patients) for discontinuation were unsatisfactory therapeutic effect (n=4, 1.5%) and consent withdrawal (n=3; 1.1%). The most common (>5%) investigator-assessed drug-related AEs were increased alanine aminotransferase (ALT; n=47, 17.6%), increased aspartate aminotransferase (AST; n=44, 16.5%), increased blood creatinine (n=24, 9.0%) and rash (n=23, 8.6%). ALT and AST increases were mostly mild in severity, transient, non-progressive and managed with dose adjustments. There were no reported drug-related serious AEs and no deaths occurred.45/267 (16.9%) patients had two consecutive ALT values >5 × upper limit of normal (ULN). Of these 45 patients, 40 had high ALT levels at baseline and 30 had ALT or AST >2.5 × ULN at baseline; 13/45 had a history of hepatitis B and/or C. 6/267 (2.2%) patients had two consecutive serum creatinine values >33% above baseline and >ULN; all had normal values at baseline. The relative change in creatinine clearance from baseline to end of the extension was between –10 and –20% for the majority of patients (n=52, 19.5%), although changes in both directions were variable.Stature, growth and weight assessments indicated positive growth velocity. For all patients combined, mean ± SD growth velocity at end of extension was 5.9 ± 43.3 cm/year (median 2.6 cm/year). Conclusions:Deferasirox therapy for up to 3 years in pediatric patients significantly decreased serum ferritin, similar to previous reports. The majority of patients with elevated liver enzymes during the study also had elevated levels at baseline; renal safety was consistent with previous reports. While patient age and gender will influence individual growth rates, positive growth velocity was nonetheless maintained during treatment. Disclosures:Lin:Novartis: Honoraria. Aydinok:Novartis: Honoraria, Research Funding, Speakers Bureau; Ferrokin: Research Funding. Galanello:Novartis: Research Funding, Speakers Bureau; Apopharma: Research Funding, Speakers Bureau; Ferrokin: Research Funding. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69years who were treated with DFX for a median duration of 354days. Mean daily dose of DFX was 19mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447ng/mL and decreased to 1,685ng/mL (reduction by 31%) at end of study (p = 0.01). In 7 (13%) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8mg/g dry tissue weight (± 8.3mg/g dry tissue weight) at study entry to 10,8mg/g dry tissue weight (± 10.4mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52%) did not complete the 12month study period most commonly due to AEs in 28% (n = 15) and abnormal laboratory values in 7% (n = 4), respectively. The most common adverse events (≥ 10% of all patients) with suspected drug relationship were diarrhea (n = 25, 46%), nausea (n = 13, 24%), upper abdominal pain (n = 8, 15%), serum creatinine increase (n = 16, 30%) and rash (n = 5, 9%). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61%). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11%). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.

Improved efficacy and tolerability of oral deferasirox by twice‐daily dosing for patients with transfusion‐dependent β‐thalassemia

Deferasirox is an oral iron-chelating agent taken once-daily by patients with transfusion-dependent iron overload. However, some patients are unresponsive or unable to tolerate once-daily deferasirox. The current study evaluated whether twice-daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients. Patients from two Taiwanese hospitals with transfusion-dependent β-thalassemia, including those who showed increasing serum ferritin levels for six consecutive months, with at least one level >2,500 ng/dl, while treated with >30 mg/kg/day of once-daily deferasirox (unresponsive) or developed deferasirox-related adverse events (AEs) at the dosage required to maintain the iron burden balance (intolerant) and were treated twice-daily with the same total daily dose of deferasirox since 2008, were enrolled in the study and evaluated retrospectively by medical record review. Eighteen patients were included for analysis. A statistically significant median decrease in serum ferritin levels was detected in the 11 unresponsive patients after 6 months of continuous twice-daily deferasirox treatment. Five out of the seven intolerant patients experienced either no deferasirox-related AEs or less severe AEs. The 12 patients from both groups (11 unresponsive, 1 intolerant) who received continuous twice-daily deferasirox for 6 months showed a mild but significant median increase in serum creatinine levels. Twice-daily deferasirox dosing is effective in iron chelation and improves tolerability in transfusion-dependent β-thalassemia patients who are unresponsive to or intolerant of once-daily deferasirox. Future studies with greater patient numbers will be required to confirm the results reported herein.

An instrument assessing satisfaction with iron chelation therapy: Psychometric testing from an open-label clinical trial

The Satisfaction with Iron Chelation Therapy (SICT) instrument was developed based on a literature review, in-depth patient and clinician interviews, and cognitive debriefing interviews. An, open-label, single arm, multicenter trial evaluating the efficacy and safety of deferasirox in patients diagnosed with transfusion-dependent iron overload, provided an opportunity to assess the psychometric measurement properties of the instrument. Psychometric analyses were performed using data at baseline from 273 patients with a range of transfusion-dependent iron overload conditions who were participating in a multinational study. Responsiveness was further evaluated for all patients who also had subsequent satisfaction domain scores collected at week 4. Baseline SICT domain scores had acceptable floor and ceiling effects and internal consistency reliability (Cronbach's alpha: 0.75-0.85). Item discriminant and item convergent validity were both excellent although one item in each analysis did not meet the specified criterion. Small to moderate correlations were observed between SICT and Short Form 36 Health Survey (SF-36) domain scores. Patients with the highest levels of serum ferritin at baseline (>3100 ng/mL) were the least satisfied about the Perceived Effectiveness of ICT and vice versa. Satisfaction improved in all patients, although there were no clear differences observed between groups of patients defined according to changes in serum ferritin levels from baseline to week 4 (stable, improved, or worsened). The SICT domains are reliable and valid. Further testing using a more specific criterion (such as assessing patient global ratings of change in satisfaction domains that correspond to the SICT domains) could help to establish with greater confidence the responsiveness of the instrument.

Iron chelation therapy for patients with sickle cell disease and iron overload

A 21-year-old male with sickle cell disease (SCD) presented with severe pallor. He had received a total of 100 red blood cell (RBC) units in his lifetime, had a mean serum ferritin level of 3133 ng/ml, and liver iron concentration (LIC) of 12 mg Fe/g dry weight (dw). He was started on subcutaneous deferoxamine (DFO) infusions at a dose of 56 mg/kg/d, five days a week (equivalent to 40 mg/kg/d, seven days a week) and continued to receive 8–10 RBC units/year as treatment for pain. During the first six months of chelation therapy, his serum ferritin levels fell by around 50% of the pretreatment value, but then started to increase back up to the baseline values. The patient was noncompliant with DFO therapy. He experienced pain at the site of injection, could not sleep and was concerned about carrying a pump and not being accepted by his peers. He dropped out of college and abstained from all social activities. He was referred to a psychologist; however, this failed to improve compliance and he opted to stop DFO therapy altogether.

Pharmacokinetics, Metabolism, and Disposition of Deferasirox in β-Thalassemic Patients with Transfusion-Dependent Iron Overload Who Are at Pharmacokinetic Steady State

Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).

Deferasirox (Exjade®) Treatment of Chelation-Naive and Pre-Chelated MDS Patients with Transfusional Iron-Overload in the Medical Practice:Results From the Observational Studies Extend and Exjange.

Abstract 3805Poster Board III-741 BackgroundRed blood cell (RBC) transfusions on a regular basis are unavoidable in a variety of chronic anemias. Unfortunately, chronic transfusion therapy leads to iron overload (IOL) since the body cannot actively remove excess iron. Transfusional IOL can cause severe organ damage, as exemplified by thalassemia major patients in the past. Many patients (pts) with myelodysplastic syndromes (MDS) also need regular RBC transfusions and are thus threatened by secondary hemochromatosis. Deferasirox (Exjade®), an oral iron chelator taken once-daily, has been shown in several clinical trials to maintain or reduce body iron (assessed by liver iron concentration [LIC] or serum ferritin [SF]) in pts with transfusion-dependent IOL. Here we summarize the results of two post-marketing surveillance studies of previously unchelated (Extend; n=123) and pre-chelated (Exjange; n=44) MDS pts with IOL. Pts were analyzed in the daily-routine setting of office-based physicians. MethodsThe Extend and Exjange observation studies cover 1 year of chelation treatment of iron overloaded, transfusion-dependent MDS pts. Deferasirox was prescribed in accordance with the terms of Exjade marketing authorization in Germany (Fachinformation). No inclusion or exclusion criteria or additional diagnostic or monitoring procedures were applied. Hematological parameters, including SF, and adverse events (AEs) were collected in 2-monthly intervals. Results123 MDS pts (65 M, 58 F; mean age 70.4, range 17.6-90.3 yrs) with a median baseline SF of 2679 (range 184-16500) ng/mL without prior chelation and 44 MDS pts (24 M, 20 F; mean age 69.6, range 42.5-88.5 yrs) with a median baseline SF of 2442 (range 521-8565) ng/mL, mainly pre-chelated with Desferal, were observed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. During treatment, median SF levels clearly decreased from first to final visit [-662.3 ng/ml; p<0.0002 (explorative analysis)] in the chelation-naïve and also in the pre-chelated MDS population [-716.0 ng/ml; p<0.0634 (explorative analysis)]. 64.2% of the Extend MDS pts and 47.7% of the Exjange MDS pts completed the 12 months observation period. Reasons for discontinuation included AEs in 19.5% (n=24) and 25% (n=11), respectively. The most common investigator-assessed drug-related AEs were diarrhea (n=13, 10.6% and n=4, 9.1%), nausea (n=11, 8.9% and n=1, 2.3%), and skin reactions (n=8, 6.5 % and n=2, 4.6%), mainly of mild-to-moderate severity. As in previous clinical trials, serum creatinine values showed a minor increase over the study period (median increase until final visit: 0.2 mg/dL in the Extend and 0.1 mg/dL in the Exjange study). ConclusionsWith deferasirox treatment, SF levels declined significantly over the 1-yr observation period in chelation-naïve MDS pts. A similar reduction was also observed in pre-chelated MDS pts. The safety profile of deferasirox was comparable to that previously reported in clinical trials, with mild-to-moderate diarrhea being the most common drug-related AE. Thus, deferasirox is an effective and safe iron chelator for the treatment of IOL in transfusion-dependent MDS pts in the daily-routine situation. The fact that median baseline levels of SF were around 2500 ng/ml in both the Extend and Exjange studies indicates that in everyday clinical practice MDS patients are started relatively late on iron chelation therapy and tend to be inadequately treated with Desferal. Disclosures:Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Leismann:Novartis: Employment. Nass:Novartis: Employment. Germing:Novartis: Honoraria, Research Funding.

Satisfaction and Adherence Significantly Improves in Patients with β-Thalassemia and Myelodysplastic Syndromes Treated with Deferasirox (Exjade®)

Introduction: Iron chelation therapy (ICT) is essential for the treatment of iron overload and is routinely used life-long to help extend patients' (pts) lives. Conventional ICT (deferoxamine, Desferal®, DFO) is burdensome to pts in terms of method (subcutaneous infusions) and duration (typically 8–12 hours, 5–7 days per week). Deferasirox (Exjade®) is an oral chelator that offers 24-hour ICT, 7 days a week and consequently is less burdensome to pts. Pt-reported outcomes can augment what is known about ICT from clinical and physiological assessments, and they are important since they represent how a pt feels.Methods: As part of a large, single arm, multicenter, 1-year open-label trial (the EPIC study) to assess the efficacy and safety of deferasirox in pts with transfusion-dependent iron overload, β-thalassemia (n=270) and MDS pts (n=87), previously receiving ICT (DFO, deferiprone [Ferriprox®] or combined), were recruited from sites in Australia, Belgium, France, Germany, UK, Greece and Italy. All pts aged ≥16 years were asked to complete the 19-item Satisfaction with ICT questionnaire (SICT) at baseline and week 52 (end of study [EOS]). The SICT is a validated questionnaire assessing pt satisfaction over 4 domains of ICT: perceived effectiveness; side effects; acceptance; burden. Higher SICT scores represent greater levels of satisfaction with each domain. Mean change domain scores were calculated for all pts who had completed data at both time points. Adherence to deferasirox was assessed by asking pts how often they thought about stopping their ICT, and how often they took their ICT exactly as directed by their doctor. Pts responded from 1 ‘Never’ to 5 ‘Always’, and the frequency of pts responding ‘Never’ and ‘Always’ for each item at baseline and EOS was calculated.Results: Mean age of β-thalassemia pts was 26.2 years (SD=11.36); 45.6% (n=123) were male and 54.4% (n=147) were female. MDS pts had a mean age of 66.4 years (SD=10.75); 57.5% (n=50) males and 42.5% (n=37) females. There were 181 β-thalassemia and 57 MDS pts aged ≥16 years who completed the SICT at study baseline. Baseline and EOS mean SICT scores are presented in Table 1. Significant improvements in mean change domain scores were reported in β-thalassemia (P<0.0001) and MDS (P<0.05) pts at EOS: side effects of ICT (mean=1.42, SD=1.31; mean=0.65, SD=1.14, respectively); acceptance of ICT (mean=1.64, SD=1.20; mean=1.03, SD=1.28, respectively); and burden of ICT (mean=1.36, SD=1.05; mean=0.88, SD=1.19, respectively). No statistically significant differences in mean change scores for the perceived effectiveness of ICT domain were found. At EOS, 67.1% (n=116) of β-thalassemia pts reported ‘Always’ following their ICT regimen, compared to 32.4% (n=58) at baseline. Results were comparable in MDS pts (85.7% [n=36] at EOS versus 62.5% [n=35] at baseline). Similarly, 76.3% (n=132) of β-thalassemia pts reported never thinking about stopping ICT at EOS compared to 40.8% (n=73) at baseline. The frequency of MDS pts reporting that they never thought about stopping ICT, decreased from baseline to EOS (75.9% [n=41] at baseline versus 69% [n=29] at EOS).Table 1. SICT scores at baseline and EOS in β-thalassemia and MDS pts treated with deferasiroxSICT domainsBaseline mean (SD)End of study mean (SD)β-thalassemiaMDSβ-thalassemiaMDSPerceived effectiveness of ICT4.12 (0.71) n=803.95 (0.79) n=563.98 (0.79) n=1733.96 (0.80) n=41Side effects of ICT2.93 (1.18) n=1783.83 (1.16) n=564.41 (0.75) n=1724.17 (0.89) n=42Acceptance of ICT2.67 (0.92) n=1793.23 (0.79) n=564.27 (0.71) n=1714.11 (0.67) n=42Burden of ICT3.26 (0.99) n=1803.77 (0.78) n=554.63 (0.54) n=1724.56 (0.50) n=41Conclusions: Satisfaction and adherence with ICT greatly improves in pts with β-thalassemia and MDS treated with deferasirox compared with previous ICT. This is likely to result in increased quality of life and improved long-term health outcomes, while the perception of respondents regarding the effectiveness of their chelator remained stable.

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

Blood transfusions represent a main component of supportive care in myelodysplastic syndromes (MDS). To avoid organ damage caused by transfusion-dependent iron overload, an adequate iron chelation therapy is required. Recently, a new oral iron chelator deferasirox (ICL670, Exjade) has become available. A study was conducted to demonstrate the efficacy and tolerability of deferasirox in transfusion-dependent iron-overloaded patients with MDS. The efficacy of deferasirox was monitored by changes in serum ferritin, bone marrow iron, and liver iron concentration (LIC), as determined by T2*-weighted magnetic resonance imaging. Twelve patients with MDS of different subtypes (median age 76 years, range 53-91) were enrolled. Deferasirox administered in a once-daily dose of 20-30 mg/kg for 12 months was effective in reducing median ferritin concentration from 1,515 microg/L (range 665-6,900) to 413 microg/L (range 105-3,052). Within the first 4 weeks of treatment before the continuous decline of ferritin levels, the values markedly rose in eight of 12 patients. The median LIC declined from 315 to 230 micromol/g (p=0.02) at the end of study, accompanied by a reduction of bone marrow siderosis. The most common adverse events were mild and transient gastrointestinal disturbances, skin rash, nonprogressive transient increases in serum creatinine and urine beta2-microglobulin, and a temporary reduction of the creatinine clearance. The renal parameters normalized after end of treatment. No hematologic toxicities were observed. Deferasirox proved to be effective in transfusion-dependent iron overload in MDS by mobilizing iron deposits in liver and at least stabilizing iron stores in bone marrow.

Iron chelation beyond transfusion iron overload

The effects of systemic iron overload in hereditary (e.g., classic HFE hemochromatosis) or acquired disorders (e.g., transfusion-dependent iron overload) are well known. Several other iron overload diseases, with an observed mild-to-moderate increase in iron in selected organs (e.g., the liver or the brain), or with "misdistribution" of iron within cells (e.g., reticuloendothelial cells) or subcellular organelles (e.g., mitochondria), have been recognized more recently. The deleterious impact of any excess iron may be high as active redox iron may directly contribute to cell damage or affect signaling pathways involved in cell necrosis-apoptosis or organ fibrosis and cancer. This article discusses the potential use of iron chelation therapy to treat iron overload from causes other than transfusion overload.

Newly Approved Oral Chelation Therapy May Improve Adherence in Transfusion-Dependent Iron Overload

Newly Approved Oral Chelation Therapy May Improve Adherence in Transfusion-Dependent Iron Overload

Complexities in the Rat Iron Loading Model for Pre-Clinical Testing of Iron Chelators.

Transfusion-dependent iron overload, such as occurs in beta-thalassaemia (Cooley's Anaemia), leads to lethal cardiac toxicity in the second decade of life if not treated by iron chelation, but even with subcutaneous desferrioxamine (DFO) cardiac disease remains a problem, although delayed by 1–2 decades. As we design novel iron chelators, we are testing them in various animal models of iron overload. While assessing outcomes we have observed relatively sparse reports of systematic studies on organs, tissues, cellular, or subcellular iron distribution. Therefore we initiated a series of studies to characterize iron distribution using various approaches. Multiple intraperitoneal injections of iron dextran, 200 mg/kg/week X 4 − 16 weeks, followed by an equilibration period of minimum 1–2 weeks was studied as a means of increasing total body iron load in hundreds of rats under various conditions. Sacrifice varied from 6 weeks to 1 year post iron loading and the concentration of iron in liver, heart, and other tissues, organs, cells and subcellular organelles was examined. Quantitatively, in untreated rats (no chelators), the liver/heart iron ratio was about 10:1, consistent with the accumulation observed in post-mortem studies in humans prior to extensive use of iron chelation. Much less-well described has been the distribution of iron in lymphatic tissues. Our studies revealed that lymph nodes become visibly enlarged. In addition, randomly distributed brown spots appeared in the omentum. Such changes persisted up to one year after iron loading, regardless whether they were treated daily with chelators (DFO or deferiprone) in standard doses for four months. Even after a single intraperitoneal iron-dextran injection of 200 mg/kg, changes were visible. Histopathological analysis (hematoxilin-eosin for general histology and Perl's Prussian Blue for iron) showed extensive iron accumulation in the omentum, and in the cortical and subcortical regions of the enlarged lymph nodes. Electron microscopy revealed cellular (macrophages) and subcellular (mitochondria) iron localization in the lymph nodes. When iron was administered as iron sucrose (single ip dose), iron accumulation was more extensive in the omentum and in the peritoneal fat in comparison to iron dextran, but the enlargement of the lymph nodes was not observed. Quantitative iron measurement (via validated HPLC method) in the liver and heart after a single iron dextran (N=30, up to 29th day) and iron sucrose dose (N=6 up to 50th day) was in agreement with the histological observations. Iron accumulation in the omentum and lymph nodes after four months of chelation treatment and one year after iron loading indicated the resistance of these unusual iron “pools” to chelation therapy. These studies confirm that different iron formulations may result in different patterns of iron distribution and they also raise questions about the suitability of rats as an animal model for transfusional iron overload in humans.

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron‐Chelating Agent in Patients with Transfusion‐Dependent Iron Overload Due to β‐Thalassemia

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.