Decrease In Liver Iron Concentration Research Articles

Long-Term Efficacy and Safety of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent β-Thalassemia: Results in Patients with up to 6 Years of Follow-up

Long-Term Efficacy and Safety of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent β-Thalassemia: Results in Patients with up to 6 Years of Follow-up

Jadenu® Substituting Exjade® in Iron Overloaded β-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles.

IntroductionDue to the chronic nature of chelation therapy and the adverse consequences of iron overload, patient adherence to therapy is an important issue. Jadenu ® is a new oral formulation of deferasirox (Exjade ®) tablets for oral suspension. While Exjade® is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, Jadenu ® can be taken in a single step, with or without a light meal, simplifying administration for the treatment of patients with chronic iron overload. This may significantly improve the compliance to treatment of patients with β-thalassemia major (BMT). The aim of this study was to evaluate the drug tolerability and the effects of chelation therapy on serum ferritin concentration, liver iron concentration (LIC) and biochemical profiles in patients with BMT and iron overload.Patients and MethodsTwelve selected adult patients BMT (mean age: 29 years; range:15–34 years) were enrolled in the study. All patients were on monthly regular red cell transfusion therapy to keep their pre-transfusional hemoglobin (Hb) level not less than 9 g/dL. They were on Exjade® therapy (30 mg/kg per day) for two years or more before starting Jadenu® therapy (14–28 mg/kg/day). The reason for shifting from Deferasirox® to Jadenu® therapy was lack of tolerability, as described by patients, such as nausea, vomiting, diarrhea, stomach pain. Most of them also reported that Deferasirox® was not palatable. Lab investigations included monthly urine analysis and measurement of their serum concentrations of creatinine, fasting blood glucose (FBG), serum ferritin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transferase (AST) and albumin concentrations. LIC was measured using FerriScan ®. Thyroid function, vitamin D and serum parathormone, before and one year after starting Jadenu ® therapy, were also assessed.ResultsApart from some minor gastrointestinal complaints reported in 3 BMT patients that did not require discontinuation of therapy, other side effects were not registered during the treatment. Subjectively, patients reported an improvement in the palatability of Jadenu® compared to Exjade® therapy in 8 out of 12 BMT patients. A non-significant decrease in LIC measured by FerriScan® and serum ferritin levels was observed after one year of treatment with Jadenu®. A significant positive correlation was found between serum ferritin level and LIC measured by the FerriScan® method. LIC and serum ferritin level correlated significantly with ALT level (r = 0.31 and 0.45 respectively, p < 0.05). No significant correlation was detected between LIC and other biochemical or hormonal parameters.ConclusionsOur study shows that short-term treatment with Jadenu ® is safe but is associated with a non-significant decrease in LIC and serum ferritin levels. Therefore, there is an urgent need for adequately-powered and high-quality trials to assess the clinical efficacy and the longterm outcomes of new deferasirox formulation.

Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia

▪Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014).Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients.Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week follow-up (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg.Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks.A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw.Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia.Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile. Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433). DisclosuresZhang:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Leneus:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership.

Association of Liver Iron Concentration Levels with Myocardial T2* Responses in Transfusion-Dependent Thalassemia Major Patients Treated with Deferasirox and Deferoxamine- Extension of Cordelia Study

Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC The LIC levels for pts categorized by LIC For pts with BL LIC The mT2* responses for pts categorized according to visit specific LIC levels (LIC Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell:Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Efficacy and Safety of Deferasirox in Chinese Patients with Non-Transfusion-Dependent Thalassemia: 1-Year Results from the Thetis Study

▪Background: Although non-transfusion-dependent thalassemias (NTDT) and non-transfusion-dependent congenital or chronic anemias are found in Southern China, they are relatively rare diseases in China and there are little data evaluating iron chelation in Chinese patients. This 1-year analysis from the THETIS study investigated the efficacy and safety of deferasirox in a large subpopulation of Chinese patients. Early escalation of deferasirox doses (max: 30 mg/kg/day) was evaluated according to liver iron concentration (LIC).Methods: THETIS is an open-label, single-arm, multicenter, Phase IV, 5-year study with the primary endpoint after 1 year of treatment. For this subanalysis, Chinese patients ≥10 years of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw] and serum ferritin [SF] ≥300 ng/mL) were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed), Hb S/β thalassemia, active hepatitis B/C, cirrhosis, history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase >5× the upper limit of normal (ULN), serum creatinine >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC >15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC >7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC <3 or SF <300, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 (max 10 mg/kg/day). This sub-analysis evaluated absolute change in LIC and SF from baseline to week 52.Results: 68 Chinese patients were enrolled (median age 26.0, range 10-63 years) with Hb H disease (n=35), β thalassemia intermedia (n=21) or Hb E/β thalassemia (n=12). Most patients received prior transfusions (n=56/68, 82.4%); 20/68 (29.4%) patients received prior chelation. 57/68 (83.82%) patients completed 1 year. Patients who discontinued were most commonly lost to follow-up (n=4) or withdrew consent (n=3, personal or logistical reasons). Mean actual daily deferasirox dose ± standard deviation (SD) over 1 year (considering dose adjustments), was 16.21 ± 5.61 mg/kg/day.Mean LIC ± SD at baseline was 17.75 ± 12.37 mg Fe/g dw in Chinese patients, which decreased to 9.35 ± 6.83 mg Fe/g dw at week 52 (absolute change from baseline, -8.51 ± 8.58 mg Fe/g dw [95% CI -10.69 to -6.33]). Patients with higher LIC at baseline experienced a greater reduction in LIC by week 52 (Figure).Furthermore, 48 (70.6%) Chinese patients achieved an absolute decrease in LIC of ≥3 mg Fe/g dw, and 46 (67.6%) patients achieved a ≥30% relative reduction in LIC at the last assessment. At week 52, LIC was <3 mg Fe/g dw in 5 (7.4%) patients. Median SF (range) decreased in Chinese patients from a baseline of 1580 (333-6638) ng/mL to 872 (267-4315) ng/mL at week 52 (absolute median change, -423 [-5307 to -1669] ng/mL). At week 52, SF was <300 ng/mL in 1 (1.5%) patient.Adverse events (AE) regardless of causality were reported in 40 (58.8%) Chinese patients. Drug-related AEs were reported in 18 (26.5%) Chinese patients, most commonly gastrointestinal (abdominal discomfort, n=2; diarrhea and hematochezia, n=1 each) or skin related (rash, n=3; eczema, n=1). No patients discontinued because of AEs. One death occurred during the study (pneumonia leading to cardiac failure) that was not suspected to be drug-related. No patient had two consecutive serum creatinine increases of >33% above baseline or >ULN. No patient discontinued treatment due to notable liver or renal laboratory values.Conclusions: Deferasirox at 10 mg/kg/day escalated to a maximum of 30 mg/kg/day effectively reduced iron burden in Chinese patients. AEs were consistent with the known safety profile for deferasirox. Early dose escalation at week 4 and further adjustment at week 24 ensured that patients with iron overload achieved clinically relevant reductions in iron burden. These results were in alignment with the THETIS primary efficacy analysis, supporting early dose escalation of deferasirox to optimize chelation in more heavily iron-overloaded Chinese NTDT patients. [Display omitted] DisclosuresCappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Zhu:Novartis: Employment. Wang:Novartis: Employment. Qi:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

Insights into Relationships Between Serum Ferritin and Liver Iron Concentration Trends during 12 Months of Iron Chelation Therapy with Deferasirox – a Post-Hoc Analysis from the Epic Study

▪BackgroundSerum ferritin is regularly used to assess response to chelation therapy and correlates significantly with liver iron concentration (LIC) particularly when LIC is <7 mg Fe/g dry weight (dw) and serum ferritin is <4000 ng/mL. The absence of a serum ferritin decrease in the first months of a new chelation regime may be interpreted as a lack of response with respect to decreasing body iron load. However, sequential LIC determination (where available) has indicated that many of these patients do indeed have a decrease in LIC. This clinical experience requires greater understanding, particularly the nature of the LIC and serum ferritin relationship at baseline serum ferritin values ≥4000 ng/mL.The aim of this post-hoc analysis of the EPIC study was to gain insight into the relationship between serum ferritin and LIC in response to deferasirox over 1 year, in a large patient cohort, so that serum ferritin trends can be more clearly interpreted and evidence-based practical guidance be given for patients with transfusion-dependent thalassemia (TDT).MethodsTDT patients were recruited from 25 sites, received 1-year of deferasirox treatment and had serum ferritin and R2 magnetic resonance imaging (R2-MRI)-assessed LIC measurements at baseline and 1 year. Summary statistics are provided for serum ferritin and LIC responders (decrease, any change from baseline <0) and nonresponders (increase or no change, any change from baseline ≥0), and for baseline serum ferritin categories (≥4000 vs <4000 ng/mL).ResultsOf the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. Importantly, after 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was –5.4 (–38.5, –11.7, –0.9, 15.4) in serum ferritin responders and –0.2 (–18.4, –2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [0.01–1.49]) and nonresponders (0.37 [0.02–1.00]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [9.8–40.4] vs 23.7 [9.7–37.9]).Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/mL also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin ≥4000 ng/mL (70.3% [n=78]). However, serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/mL; 50.0% [n=14], ≥4000 ng/mL; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value (–0.3 [–13.5–18.7] for <4000 ng/mL and 0.2 [–18.4–19.6] for ≥4000 ng/mL).Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [480–9725] ng/mL; 11.9 [1.8–37.5] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [9.7–36.0] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/mL (n=172) than in those with serum ferritin ≥4000 ng/mL (–2.8 [–38.5–18.7] vs –4.9 [–31.1–19.6]; n=139). Median iron intake was similar between groups.Discussion and conclusionsA decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/mL. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Overall, serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body. [Display omitted] DisclosuresPorter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity’s Board of Directors or advisory committees; Alnylam: Membership on an entity’s Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Sutcharitchan:Novartis: Research Funding. Aydinok:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chakravarty:Novartis: Employment. El-Ali:Novartis: Employment.

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al. , 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC 15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p -values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC 15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC 15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p =0.0016) and 46% (7.3 ±7.3 ms, p 15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC 15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC 15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase ( p 15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. ![Graphic][1] Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher: Novartis Pharma: Honoraria, Research Funding. Aydinok: Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini: Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis: Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali: Novartis Pharma: Employment. Martin: Novartis Pharma: Employment. Pennell: Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. [1]: /embed/inline-graphic-1.gif

Safety, Tolerability and Dose Response of FBS0701, a Novel Iron Chelator for Treatment of Transfusional Iron Overload: Results of a 24-Week Multicenter, International Phase 2 Study

Abstract 690▪▪This icon denotes a clinically relevant abstract BACKGROUND:The iron chelators in current clinical use - deferoxamine, deferasirox, deferiprone - are useful for many but not all patients with transfusion-dependent anemias. FBS0701 is a novel, orally available tridentate iron chelator in clinical development. Pre-clinical studies demonstrated a >4-fold higher no-observable-adverse-effect level compared to deferasirox (Exjade®) suggesting a favorable clinical safety profile, especially with respect to gastrointestinal and renal toxicity. Multi-dose safety and PK studies in transfusional iron-overloaded patients established the acute safety of FBS0701 and support once-a-day dosing. OBJECTIVES:To assess the long term safety, tolerability, dose-response and pharmacodynamics of FBS0701 in adults with transfusional iron overload. METHODS:This was a 24 week, multi-center study of FBS0701 at two once-daily dose levels: 14.5 (16 mg of the salt form) and 29 (32 mg salt) mg/kg/d. These doses are the molar equivalent of 13.5 and 27 mg/kg of deferasirox. Adults under age 60 y, with liver iron concentration (LIC) measured by R2 (Ferriscan®) MRI at baseline between 3.5 and 30 mg/g dry weight and cardiac T2* >10 ms were eligible for enrolment. Fifty-one patients were stratified on the basis of historical mean daily transfusion iron intake and then randomized to dose. Patients were evaluated at Weeks 1, 2, 3, 4, 6, 8 and then monthly to 24 wks. Assessments included history and physical exam, vital signs, clinical pathology, adverse events (AEs), ECG and LIC by R2 MRI at baseline, 12 and 24 weeks. All results shown are from the safety population (patients who received at least one dose FBS0701) RESULTS:All patients had a primary hemoglobinopathy, the majority (75%) with β-thalassemia syndromes. Twenty-four (47%) patients had abnormal transaminases prior to dosing and 16 patients (31%) had a history of viral hepatitis. FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study; two withdrew for reasons unrelated to drug. There were no serious AEs related to FBS0701. No AEs showed dose-dependency in frequency or severity. Fewer than 5% had nausea, vomiting, abdominal pain, or diarrhea deemed related to FBS0701. The most common AE deemed related to FBS0701 was an increase in transaminases (15%, N=8). Three of these patients acquired HCV on-study from a single blood bank source. None of the remaining patients exceeded their baseline transaminases by 5X. Mean serum creatinine (Cr) in the two dose groups were not statistically different from each other or from baseline values (Figure 1). Only three (5%) patients, each with GFR <100 mL/min at baseline, had an abnormal Cr on-study and none exceeded 50% above ULN. All changes in Cr were reversible. At Week 24 there was a statistically difference between the two doses in the change in LIC compared to baseline (Figure 2). The low dose cohort had a mean LIC gain of 3.1 mg/g (dw), with 29% achieving a net decrease in LIC in the intent to treat population. The high dose cohort (29 mg/kg) had a mean change of −0.3 mg/g (dw), with 50% achieving a net decrease in LIC over 24 weeks. (P value <0.04 for the difference in mean LIC). CONCLUSIONS:FBS0701 for 24 weeks was equally well tolerated at both doses: AEs related to drug were each <5% - nausea, vomiting, abdominal pain, or diarrhea. Cr was stable in 95% of patients even in the majority with moderate renal impairment (GFR <100 mL/min) at baseline. Transaminases were elevated in 15% and reversible. Patients with a history of hepatitis were more likely to have elevated transaminases (80%) compared to patients without (20%), but there were no differences in the magnitude or duration of elevations between the two groups. The low frequency, short duration and generally mild nature of AEs at therapeutic doses compares favorably to other oral iron chelators. FBS0701 was also generally well tolerated in patients with common co-morbidities including infectious hepatitis and renal impairment. FBS0701 was effective at clearing hepatic iron in a majority of patients receiving 29 mg/kg/d. Higher doses of FBS0701 might be expected to safely induce negative iron balance in a greater proportion of iron overloaded patients. [Display omitted] [Display omitted] Disclosures:Neufeld:Ferrokin BioSciences: Research Funding; Novartis: Research Funding. Galanello:Apopharma: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ferrokin Biosciences: Research Funding. Viprakasit:Ferrokin BioSciences: Research Funding; Novartis: Research Funding, Speakers Bureau; GPO-L-ONE: Research Funding; National Research University, Thailand: Research Funding. Aydinok:Ferrokin Biosciences: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Piga:Ferrokin BioSciences: Research Funding. Harmatz:Novartis: Research Funding. Forni:Ferrokin BioSciences: Research Funding; Fondazione Carige, Genoa, IT: Research Funding; Novartis: Research Funding, Speakers Bureau. Shah:Swedish Orphan Biovitrum: Speakers Bureau; Novartis: Speakers Bureau; Ferrokin Biosciences: Research Funding. Grace:Ferrokin BioSciences: Research Funding. Porter:Ferrokin BioSciences: Research Funding. Vichinsky:Apopharma: Research Funding; Ferrokin Biosciences: Research Funding; Novartis: Research Funding. Wood:ApoPharma: Consultancy; Novar: Research Funding; Ferrok: Consultancy. Peppe:Ferrokin BioSciences: Employment. Jones:Ferrokin BioSciences: Employment. Rienhoff:Ferrokin BioSciences: Employment, Equity Ownership.

Transfused Myelodysplastic Syndromes (MDS) Patients Have Severe Iron Overload and Relevant Improvements in Iron Burden and Liver Function with Deferasirox Treatment: Results From a Pooled Analysis

Abstract 5019 Background:MDS patients receiving chronic transfusions can develop significant iron accumulation in key organs such as the liver following 10–20 transfusions (Porter et al. BJH 2001). The diagnosis and monitoring of iron overload, as well as the effect of iron chelation therapy in MDS patients, is often based on serum ferritin (SF), with limited data on liver iron concentration (LIC), primarily due to the biopsy-related increased risk of bleeding and infections in these patients. However, LIC is clinically a more robust and direct measure of body iron burden and with the availability of non-invasive determination of LIC by MRI, LIC assessment has become more practical in MDS patients. This pooled analysis focuses on LIC assessments from a population of 71 MDS patients who completed 1 year of treatment with deferasirox (Exjade®), including assessment of the relationship between LIC vs SF and alanine aminotransferase (ALT). Methods:Analysis is based on 1-year pooled data from iron-overloaded patients with MDS who were enrolled in 4 open-label single-arm deferasirox studies: US02 (Low/Int-1 MDS patients, starting dose 20 mg/kg/day); 2409 (MDS patients with life expectancy >1 yr, starting dose 10–30 mg/kg/day); 108 (MDS patients with life expectancy >1 yr, dosing 5–40 mg/kg/day), and 2204 (Low/Int-1 MDS patients, starting dose 10–30 mg/kg/day). LIC was assessed in the US02, 2409 and 2204 studies using R2 MRI (St Pierre et al. Blood 2004). In the 108 study, LIC was assessed by magnetic liver susceptometry using a superconducting quantum interference device (SQUID) or ultrasound-guided percutaneous liver biopsy; LIC values obtained by SQUID were multiplied by a factor of 2 to correct for the underestimation of LIC by SQUID compared to biopsy (Porter et al. EJH 2008). Datasets were pooled for baseline (BL) characteristics, as well as LIC, SF and ALT at BL and end of study (EOS). Correlations were evaluated on a Pearson’s correlation coefficient. Results:71 patients (56.3% male) were assessed with a mean age of 65 years (range 16.5–82.0). Mean transfusional iron intake ± SD was 0.31 ± 0.12 mg/kg/day. Mean actual deferasirox dose was 19.6 ± 6.5 mg/kg/day. At BL, mean ± SD LIC was 20.5 ± 14.6 mg Fe/g dw (BL LIC <7 mg Fe/g dw, 21.1%; ≥7 mg–≤15 mg Fe/g dw, 23.9%; and >15 mg Fe/g dw, 54.9%). Median BL SF was 2620 ng/mL (range 538–12,639) (BL SF ≤2500 ng/mL, 47.9%; >2500–≤5000 ng/mL, 32.4%; and >5000 ng/mL, 15.5%). With 1 year of DFX, mean ± SD LIC decreased to 13.9 ± 13.1 mg Fe/g dw (mean absolute change –6.6 mg Fe/g dw). In patients with BL LIC <7 mg Fe/g dw (n=15), LIC was maintained with a mean absolute change of 1.0 ± 2.8 mg Fe/g dw, whereas in patients with BL LIC ≥7 mg Fe/g dw (n=56), LIC was reduced by –8.6 ± 10.7 mg Fe/g dw from BL. The proportion of MDS patients with LIC ≥7 mg Fe/g dw reduced from 78.9% at BL to 59.2% at EOS, with 50.7% of patients achieving a decrease in LIC of ≥30%.Median SF decreased to 2035 ng/mL (range 158–10520 ng/mL) with median absolute change from baseline of –630 ng/mL. There was a significant correlation between BL LIC and SF (R=0.548; P<0.0001). Change in LIC significantly correlated with change in serum ferritin (R=0.336; P=0.0042, Figure A). Mean ALT decreased from 55.9 to 38.9 U/L (absolute change –17.0). The change in LIC correlated with the change in ALT (R=0.397, P=0.0006, Figure B). [Display omitted] Conclusions:This pooled analysis in a large cohort of transfusion-dependent MDS patients with LIC assessment shows significantly elevated LIC, with a high proportion of patients (55%) having severely elevated LIC of >15 mg Fe/g dw, a level known to markedly increase liver dysfunction and other iron overload-related complications. One year of treatment with deferasirox produced relevant reductions in LIC, an outcome possibly indicative of a clinical benefit. SF and ALT (an important indicator of liver function) also decreased, with reductions correlating with those of LIC. These findings indicate that correction of moderate-to-severe iron overload in MDS patients is associated with a parallel improvement in liver function. Disclosures:Gattermann:Novartis Pharma: Honoraria, Research Funding. Greenberg:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharma: Employment. Kpamegan:Novartis Pharma: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Trends in Ferritin Can Be Dramatically Different From Trends in Total Body Iron and Could Lead to Erroneous Decisions in Iron Chelation Management and Discourage Adherence in Chronically Transfused Patients,

Abstract 3203Ferritin trends are used as surrogates for change in total body iron in patients with transfusional iron overload who are on chelation therapy. They are often used to infer patient adherence with prescribed therapy and for recommending changes. Population studies of ferritin show a 70% correlation with liver iron. The aim of this study was to determine whether the trends in ferritin adequately reflect the change in liver iron concentration (LIC) in individual patients. We retrospectively evaluated ferritin and LIC for 10 years in 40 patients with transfusion dependent anemia (23 with transfusion dependent thalassemia, 12 with sickle cell anemia, 2 with congenital dyserythropoetic anemia, 2 with Diamond Blackfan Anemia and one with sideroblastic anemia). Ferritin levels are evaluated every three weeks at each transfusion and liver iron concentration (LIC) by MRI at approximately annual intervals. The LIC values in mg/g dry weight (dw) are derived by MRI. The trends for both LIC and ferritin were evaluated at each period between the sequential MRIs. We used the average of all ferritins in a four month window centered on the date of the MRI for comparison to the LIC. The overall correlation between ferritin and LIC was similar to other published results (r2=0.69).When ferritin and LIC were plotted against time for each patient, the ferritin trend clearly predicted the LIC trend during certain periods of time (Example figure 1 segment A) and did not during other periods (Figure 1 segment B). [Display omitted] The trend in ferritin correctly predicted the trend in LIC all of the time in 55% of patients (22/40). In 45 % of the patients (18/40) the ferritin trend did not correlate with the LIC in over half of the observational periods. In 37.5 % (15/40) of patients during at least one observation period the direction of change was dramatically different. Of these, the direction of change was opposite in 12.5% (5/40). In 22.5 % (9/40) the changes were disproportionate. Six of these patients showed a period during which there was a slight decrease in ferritin but a significant decrease in LIC. In two there was a significant increase in LIC with only a minimal rise in ferritin. In one, with a significant increase in ferritin the LIC increased minimally.While the ferritin was decreasing the LIC and ferritin trends correlated much better than when the ferritin was increasing. This implies that when ferritin levels increase it is a particularly poor tool for assessing change in iron overload.It is clear from this analysis that over certain periods of time, even up to four years, the trends in ferritin can be opposite in direction to the change in total body iron, as derived from LIC. This could lead to inappropriate changes in therapy and incorrect assumptions by health care providers about patient adherence. It is accepted that poor compliance with chelation therapy is the greatest barrier to effective management of iron overload. If only ferritin is used to assess changes in total body iron, patients could be discouraged by their apparent poor response to therapy even though their LIC may actually be decreasing. Serial assessment of total body iron burden by direct measurement of LIC is essential for proper management of patients with transfusional iron overload. Disclosures:Berdoukas:ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.

Therapeutic Phlebotomy in Children with Sickle Cell Anemia, Stroke, and Iron Overload: The SWiTCH Experience

Abstract 1044▪▪This icon denotes a clinically relevant abstract Background:Stroke With Transfusions Changing to Hydroxyurea (SWiTCH Clinical Trials.gov NCT00122980), an NHLBI-sponsored Phase III multicenter trial, compared chronic blood transfusions/chelation to hydroxyurea/phlebotomy for the reduction of recurrent stroke and improvement in iron overload management in children with sickle cell anemia (SCA) and history of overt stroke. To date, however, phlebotomy to manage iron overload has not been commonly performed in children, especially those with SCA. Objective:To describe the experience with SWiTCH phlebotomy procedures, including success rate, associated adverse events, and effect on liver iron stores. Methods:Quantitative liver iron concentration (LIC) was measured by liver biopsy at study entry. Only subjects with LIC > 5 mg Fe/gram dry weight liver (DWL) were eligible for randomization. Those randomized to hydroxyurea/phlebotomy received decreasing volumes of monthly transfusion during hydroxyurea dose escalation, which lasted 4–9 months. Phlebotomy was performed every 4±1 weeks after discontinuation of transfusions. The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) for Hb ≥ 8.0 gm/dL, and 5 mL/kg for Hb 7.0–7.9 gm/dL. Phlebotomy was held if Hb was <7.0 gm/dL. Phlebotomy was performed over 30 minutes with immediate normal saline replacement, typically using peripheral venous access. Exit LIC by liver biopsy was obtained in those completing 30 months of therapy. Ferritin was monitored monthly in all subjects using a centralized laboratory. Results:Sixty-seven children (mean age 13.0 ± 4.0 years; range 5.2–19.0 years) with history of previous stroke and transfusion therapy for an average of 7.4 ± 3.8 years (range 1.5–15.5 years) were randomized to the hydroxyurea/phlebotomy arm. Most of them had also received chelation therapy: 47 (71%) with deferoxamine for an average of 4.8 ± 3.2 years, and 57 (86%) with deferasirox for 1.5 ± 0.8 years prior to study entry. Their average entry LIC was 16.5 ± 9.4 mg/gram DWL. Sixty of 67 children (90%) successfully transitioned to hydroxyurea after 7.2 ± 2.4 months of transfusion overlap; one subject had a stroke during overlap and six failed to demonstrate adequate response/compliance to hydroxyurea to safely discontinue transfusions. These 60 subjects received an average of 8 ± 3 transfusions providing 63 ± 44 mL/kg PRBCs before completing transition and commencing phlebotomy, and 3 ± 3 transfusions providing 19 ± 20 mL/kg PRBCs after starting phlebotomy, for various clinical indications. During the course of the study, a total of 935 phlebotomies were performed (mean 16 per subject) removing an average total volume of 127 ± 74 mL/kg per subject. The mean pre-phlebotomy Hb level on hydroxyurea (9.1 gm/dL) was not significantly different than the mean pre-transfusion Hb during the transfusion overlap period (9.0 gm/dL). Mean ferritin for these 60 subjects on the hydroxyurea/phlebotomy arm decreased from 3523 ± 2150 ng/mL at study entry to 2227 ± 1646 ng/mL (p<0.0001) at exit; and decreased in 50 of 60 subjects. For the 23 patients on the hydroxyurea/phlebotomy arm who completed 30 months of study treatment, the average LIC was unchanged (18.5 mg Fe/gram DWL at entry compared to 18.1 mg Fe/gram at exit, p=0.817). However, average ferritin level for these subjects was significantly lower at exit (4216 ± 2799 ng/mL vs 2356 ± 2032 ng/mL, respectively, p=0.0003). Of 968 protocol-directed phlebotomy procedures, 935 (97%) were performed; 94% of which were at full prescribed volume. Of the 33 phlebotomy procedures that were not performed, 11 were held due to Hb < 7.0 gm/dL and 9 due to poor venous access. There were only 33 grade 2 adverse events (3.5% prevalence) reported in 12 subjects and no serious adverse events. The most common complication was hypotension (9 events; 5 subjects) followed by dizziness, syncope, headache and weakness. Six subjects had a recurrent stroke but there was no temporal relationship to the phlebotomy procedures. Conclusions:Therapeutic phlebotomies were well-tolerated and did not result in worsening anemia or stroke recurrence in this cohort of children with SCA and previous stroke switched to hydroxyurea. Although ferritin levels decreased significantly, we did not demonstrate an overall decrease in LIC in this heavily iron overloaded cohort, most likely due to continued iron loading with transfusions in the overlap period and subsequent short duration of phlebotomy. Disclosures:Off Label Use: Use of hydroxyurea in children with sickle cell anemia.

Serial Measurements of Cardiac and Hepatic Iron with MRI T2* In Transfusion Dependent Patients with Beta-Thalassemia Major Receiving Deferasirox

AbstractAbstract 2051 Background:Beta-thalassemia patients on regular transfusions develop progressive iron overload. The introduction of noninvasive measures of hepatic and cardiac iron loading (MRI T2*) has made the monitoring of iron excess in regularly transfused thalassemia patients more accessible and annual assessments are now feasible to assist in chelation management and dose adjustments. Methods:We have retrospectively reviewed 46 beta-thalassemia major patients, 37 female (F) and 20 male (M), with a mean age 30.1yr (range 9–59yr). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and had 2 or more annual MRI T2* studies. All 46 patients were treated with deferasirox. Each patient was monitored yearly for iron concentration by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC, and urinalysis. Annual EKG, ECHO, hearing and vision testing and endocrine evaluations were performed. Patients were divided into 4 groups related to initial liver iron concentration (LIC) in mg/gm dry weight (dw), Group A (<3, n = 14), Group B (3-7, n = 8), Group C (7-15, n = 12) and Group D (>15, n = 12). They were also divided into 3 groups based on the initial cardiac T2*, Group 1 (>20ms, n = 26), Group 2 (10-20ms, n = 9) and Group 3 (<10ms, n = 10). Annual baseline and follow up studies of the patient groups were compared using paired student T test. Data Analysis:Over the course of 1 year, mean baseline LIC was unchanged compared to the mean LIC at 1 year follow-up in Group A (1.6 vs 1.6), and stable in Group B (4.5 vs 3.5, p value 0.4), but significantly decreased for Group C (9.5 vs 4.8, p value 0.003) and Group D (17.6 vs 7.9, p value 0.00003). Mean baseline Cardiac T2* measurements compared to the mean cardiac T2* measurements at 1 year follow-up remained normal in Group 1 (39.4 vs 37.4, p value 0.13), and improved in Group 2 (13.7 vs 22.3, p value 0.1) as well as in Group 3 (7.4 vs 8.9, p value 0.12), however they were not statistically significant. The LIC values within each cardiac T2*group were also examined. In Group 3 (cardiac T2*<10ms), only 2 patients had LIC >15mg/gm dw at baseline. At 1yr follow up both patients had improved LIC (19.8 to 10; 15.1 to 7.24) and improved cardiac T2* (Table 1). In Group 1(cardiac T2*>20ms, n=26), all patients had LIC less than 7.5mg/gm dw of liver. Only one Group 1patient had worsening of LIC (6.19 to 10.8) at 1yr follow up. There was no significant difference in the cardiac T2* at 1yr follow up in Groups C (LIC 7–15) and D (LIC >15) patients, even though there was a significant decrease in LIC. There were 4 patients with cardiac T2*<10ms in Group D, of which only one improved, even though there was improvement in LIC for all the 4 patients at 1 yr follow up. LIC improved significantly when the baseline was above 7mg/gm dw of liver and remained stable in others with lower LIC. None of the patients in Groups 1, 2 and 3 had worsening of cardiac T2* when their LICs improved. Conclusion:Improvement in mean cardiac T2* appears to lag behind improvement in mean LIC at 1yr follow up in all patient groups. However, no statistically significant differences were noted on cardiac T2* at 1yr follow up irrespective of the baseline cardiac T2* and LIC values. Annual monitoring of transfusion iron overload and chelation effect are now available, which raises the question of variable organ responsiveness and the need for targeted chelation therapy.Table 1Cardiac T2* values and their corresponding LIC for patients in Group 3 (cardiac T2*<10ms)PatientsBaseline LIC (mg/gm dry weight)1 yr follow up LIC (mg/gm dry weight)Baseline cardiac T2* (ms)1yr follow up cardiac T2*(ms)18.5105.282225.68319.810.036.4945.61.9671052.10.628.110615.17.248.41471.428.710.781018.28591.784.7887101.290.8497 Disclosures:Giardina:Novartis: Research Funding.

Deferasirox (Exjade®) Monotherapy Significantly Reduces Cardiac Iron Burden in Chronically Transfused β-Thalassemia Patients: An MRI T2* Study

Introduction: Despite the availability of iron chelation therapy, accumulation of excess iron in the heart results in cardiomyopathy, congestive heart failure (CHF) and death in approximately 71% of transfused patients with β-thalassemia (β-thal) major. In preclinical and single-institution clinical studies, Exjade®(deferasirox, DFX) has demonstrated efficacy in decreasing cardiac iron. This ongoing study evaluates the effects of DFX on cardiac iron and left ventricular ejection fraction (LVEF) in patients (pts) with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. Here, we report preliminary results from patients who have completed 12 or 18 months of treatment.Methods: Twenty-eight pts were enrolled at four US centers. DFX was administered at 30–40 mg/kg/day for 18 months. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Serum ferritin (SF) was assessed monthly and MRI assessments for liver iron concentration (LIC), cardiac T2* and LVEF were done every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean±SE (range) unless otherwise stated.Results: At the time of analysis, 18 pts had 12-month evaluations and 12 pts had 18-month evaluations. Five pts discontinued (one non-compliance, two patient decisions, and two deaths). Both deaths were considered unrelated to DFX treatment; the first patient enrolled with markedly elevated baseline cardiac iron (T2*=1.8 ms) and died secondary to CHF. The second patient death was due to sepsis and multi-organ failure.Baseline: All 18 evaluable pts (three male, 15 female; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4324±912 ng/mL (395–16,249). Cardiac T2* was 9.6±0.97 ms (4.6–16.1), LIC was 18.7±3.8 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.7±1.0%.12-Month results: At 12 months, 7/18 pts were on 40 mg/kg/day. 12/18 pts (67%) had an increase in cardiac T2* with a mean difference of 2.2 ms (18%; P=0.025). 13/18 pts (72%) had a decrease in LIC with a mean difference of 2.4 mg Fe/g dw (25%; P=0.032). LVEF remained stable. SF fell by 583 ng/mL (n=18; 22%; P=0.147).18-Month results: At 18 months, 3/12 pts were on 40 mg/kg/day. 10/12 pts (83%) had an increase in cardiac T2* with a mean difference of 4.1 ms (35%; P=0.001). 11/12 pts (92%) had a decrease in LIC with a mean reduction of 4.7 mg Fe/g dw (50%; P=0.003). Mean LVEF trended upward from 61.5 to 63.3% (n=13; P=0.2). SF fell by 1373 ng/mL (n=11; 46%, P=0.006).Safety data from pts (n=25) treated with 30–40 mg DFX were in line with previous studies. The most common drug-related adverse events (AEs; eight pts; 32%) were gastrointestinal in nature. 1/25 patients experienced a suspected SAE (hospitalization due to abdominal pain and vomiting) but completed the study. One patient developed SCr >upper limit of normal (ULN). Two pts (8%) had abnormal transaminases (≥5×ULN) on ≥2 occasions but both had abnormal values at baseline.Conclusions: DFX monotherapy significantly improved cardiac and liver iron after 12 and 18 months. Overall, doses from 30–40 mg/kg/day were well tolerated. Cardiac T2* improvement rates were 1.5–1.9% per month, which is comparable to other monotherapy trials. A trend towards improved LVEF was seen in patients completing 18 months of therapy; however, a larger, long-term study will be required to confirm whether DFX can significantly improve cardiac function in this population. [Display omitted]

Cumulative Efficacy and Safety of 5-Year Deferasirox (Exjade®) Treatment in Pediatric Patients with Thalassemia Major: A Phase II Multicenter Prospective Trial

Background: Pediatric thalassemia major (TM) patients may begin lifelong iron chelation therapy (ICT) as early as 2 years to avoid potential complications of iron overload, such as impaired growth and the later development of cardiac dysfunction. Deferasirox (Exjade®), administered orally once daily, was developed to improve compliance to long-term ICT in patients with transfusion-dependent anemias. We report cumulative efficacy, safety and development data in pediatric patients with transfusion-dependent TM treated with deferasirox for 5 years (study 106).Methods: Pediatric TM patients stratified into two age groups (children 2-≤12 years; adolescents 12–17 years) were enrolled in study 106 and received deferasirox 10 mg/kg/day for 1 year. Patients completing the 1 year study were able to continue deferasirox treatment for an additional 4 years at adjusted doses, to evaluate long term safety and effect on liver iron concentration (LIC). Safety was assessed by the incidence and type of adverse events (AEs), laboratory parameters and growth/sexual development. Efficacy was evaluated by changes in LIC by SQUID.Results: 20 children (mean age 6.7±2.8 years) and 20 adolescents (mean age 14.1±1.6 years) were enrolled. Children had a greater mean iron intake (0.46–0.49 mg/kg/day) than adolescents (0.39–0.41 mg/kg/day). Median exposure to deferasirox was 5.0 years for children, 5.5 years for adolescents; mean dose in children and adolescents was 18.9±5.7 and 20.9±4.5 mg/kg/day, respectively. On average, 30% of children and 10% of adolescents received <15 mg/kg/day. Mean final dose was 26.3 mg/kg/day for children and 27.8 mg/kg/day for adolescents. Relative change in LIC over the treatment period is shown in Figure 1. [Display omitted] Overall, 24 patients (60.0%; 11 children and 13 adolescents) completed the 5-year study. Reasons for discontinuation were AEs (n=8), consent withdrawal (n=7), unsatisfactory therapeutic effect (n=1). Most common AEs were cough, pyrexia (n=34, 85%) and rhinitis (n=30, 75%); the annual frequency of reported AEs did not increase from year to year and generally occurred in similar proportions for children and adolescents. One child had a serious AE (increased transaminases) assessed as drug-related. Two other patients had an ALT increase >10 × ULN on at least one visit; baseline levels were >8 × ULN in one patient, and normal in the other. Both patients were restarted on deferasirox after 2 week interruptions without further incident. No patient had an increase in serum creatinine >33% above baseline and ULN at two consecutive visits. Neutropenia (neutrophil count <1.5×109/L at two consecutive visits), assessed unrelated to treatment, occurred in one child and two adolescents. There were no clinically significant visual defects and one child had a drug-related audiometric abnormality (hypoacusis). Physical development was normal in both groups; growth velocity was higher in children. Sexual development progressed normally in adolescents.Conclusions: Deferasirox dose-dependently reduced iron overload over 5 years of treatment in these heavily transfused pediatric patients with TM. Dose increases over time, with a stable iron intake, were associated with a decrease in LIC for both groups, but the reduction in LIC was greater in adolescents. Despite having a higher transfusional iron intake, more children than adolescents were on a dose <15 mg/kg/day, highlighting that transfusional iron intake should be considered when selecting deferasirox dose. Deferasirox was generally well tolerated. There was no evidence of progressive renal, hepatic or bone marrow dysfunction. Deferasirox treatment had no negative impact on growth and sexual development.

Is Serum Hepcidin Causative in Hemochromatosis? Novel Analysis from a Liver Transplant with Hemochromatosis

Hepcidin is a circulating hepatic hormone that regulates iron balance. It has been speculated that hepcidin insufficiency or dysregulation may be the primary defect in genetic hemochromatosis. A 62-year-old woman underwent elective liver transplantation for chronic hepatitis C cirrhosis. Genetic testing for hemochromatosis was subsequently performed on the donor and recipient. Liver iron concentration was measured in the donated liver at the time of transplantation, and at day 2 and day 652 post-transplant. Serum hepcidin was measured at day 935 in the recipient and in three other liver transplant recipients. The donor was discovered to have significant iron overload without fibrosis, with a liver iron concentration of 326 micromol/g (normal is 0 micromol/g to 35 micromol/g). Genetic testing confirmed that the 89-year-old female donor was a typical C282Y homozygote for hemochromatosis. The recipient did not carry either the C282Y or the H63D mutation of the HFE gene for hemochromatosis. Liver biopsy was performed on the recipient on day 2 and day 652 post-transplant; the liver iron concentrations were 333 micromol/g and 253 micromol/g, respectively. Serum hepcidin in the recipient was elevated at 111 ng/mL compared with that of the three other ambulatory liver transplant recipients (66 ng/mL, 76 ng/mL and 81 ng/mL). The liver transplant recipient described in the present report demonstrated a slight decrease in liver iron concentration over a 1.8-year follow-up period without specific therapy. Hepcidin insufficiency as a primary cause of genetic hemochromatosis seems unlikely based on the clinical profile of the present patient and the hepcidin measurements.

A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major

The aim of this prospective, randomized, 1-year study was to compare the efficacy and safety of oral deferiprone (DFP) with those of combinations of parenteral desferrioxamine (DFO) with oral DFP. A total of 24 patients with thalassemia major were randomized to receive one of the following two treatments; DFP given at a daily dose of 75 mg/kg in combination with DFO (40-50 mg/kg twice weekly) (n=12) or as single agent (n=12). In addition, 12 patients treated with 40-50 mg/kg DFO 5 days weekly were included as a reference group without randomization. Changes in liver iron concentration (LIC) and serum ferritin (SF) were assessed; total iron excretion (TIE), urinary iron excretion (UIE) and iron balance were calculated. Cardiac function and toxicity were also examined. SF and LIC were significantly reduced after 1 year of combination therapy (p=0.01 and 0.07, respectively). A decrease of LIC was observed in all but one patient (87.5%) following the combination therapy but in only 42% of patients treated with DFP monotherapy. In the DFO reference group, a statistically significant decrease in LIC (p=0.01) associated with a substantial decrease in SF (p=0.08) was observed after 1 year. The combination regimen resulted in greater TIE compared to DFP monotherapy (p=0.08) and was the regimen associated with the highest iron balance compared to DFP monotherapy (p=0.04) or standard DFO treatment (p=0.006). The addition of subcutaneous DFO twice weekly to oral DFP 75 mg/kg is a highly efficacious and safe chelation therapy providing superior chelation activity to that of DFP and likely has an efficacy profile comparable to that of standard DFO.