Average Liver Iron Concentration Research Articles

Mitapivat Improves Iron Overload in Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. Iron overload is highly prevalent in patients (pts) with PK deficiency regardless of transfusion requirements, suggesting dyserythropoietic features. Iron overload can lead to serious complications including liver cirrhosis, cardiomyopathy, arrhythmia, sudden cardiac death, and endocrine dysfunction. In pts with PK deficiency, ineffective erythropoiesis combined with chronic hemolysis contributes to the manifestation of iron overload. Increased erythropoietic drive leading to erythroferrone-induced hepcidin suppression results in increased iron absorption and abnormal iron metabolism in PK deficiency. Furthermore, transfusions increase the existing burden of iron overload in PK deficiency. Mitapivat (AG-348) is a first-in-class, oral, allosteric activator of the red blood cell wildtype and mutant PK enzyme (PKR) that is approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, which has been shown to improve ineffective erythropoiesis and hemolysis. Previously reported data from ACTIVATE (NCT03548220) and its long-term extension (LTE) study (NCT03853798) also showed that treatment with mitapivat improved markers of iron homeostasis in adults with PK deficiency (up to 72 weeks [wks]). Here, we provide longer-term data from the LTE study on the impact of mitapivat on iron homeostasis and iron overload, and also assess liver iron concentration (LIC) changes in pts with iron overload at baseline (BL). Methods: In ACTIVATE (double-blind, placebo [PBO]-controlled study), pts with PK deficiency who were not regularly transfused were randomized 1:1 to receive mitapivat or PBO. Pts who had demonstrated clinical benefit from mitapivat on completion of the fixed-dose period for ACTIVATE (24 wks), or who were assigned to the PBO arm in ACTIVATE, were eligible to continue in the LTE. All pts enrolled in the LTE received mitapivat. Pts from ACTIVATE who continued in the LTE were categorized into the mitapivat-to-mitapivat arm (M/M) or PBO-to-mitapivat arm (P/M). The ACTIVATE/LTE analysis assessed changes from BL over time (up to 96 wks), for both study arms, in markers related to iron homeostasis and overload, including erythroferrone, soluble transferrin receptor (sTfR), hepcidin, and LIC by magnetic resonance imaging. LIC changes over time in pts with evidence of iron overload at BL, were also assessed; pts were considered to have iron overload at BL if they met at least 1 of 3 criteria: BL ferritin >1000 mg/L, BL average LIC >3 mg Fe/g dry weight (dw), or chelation therapy within the last year before study start. For this calculation, BL was defined as the last assessment before start of treatment with mitapivat, and LIC data from pts in the M/M arm were pooled together with data from pts in the P/M arm and summarized over the time they were treated with mitapivat. Results: 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40). Meaningful improvements in hepcidin, erythroferrone, sTfR, and LIC values were observed with mitapivat treatment previously; here, we confirm these meaningful improvements are continued up to 96 wks (Table). These measurements were improved early-on, within 24 wks of starting treatment in the M/M arm, but remained relatively unchanged in the P/M arm while on PBO. Similar improvements to the M/M arm were seen in the P/M arm after switching to mitapivat in the LTE. Among pts treated with mitapivat (N=78), 55.1% (n=43) met the criteria for iron overload at BL. These pts showed clinically meaningful and continued improvements in iron overload over time as measured by LIC (median [Q1, Q3] decrease from BL to Wk 96 of mitapivat treatment of -1.95 [-4.85, -0.70] mg Fe/g dw) (Figure). Conclusions: Activation of PKR with mitapivat was associated with meaningful long-term improvements in iron homeostasis and overload. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload in pts with PK deficiency. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Advances in Biomagnetic Liver Susceptometry Allow the Measurement of Liver Iron Concentration with a Room Temperature Sensor

Introduction: Iron overload is frequently observed in diverse states ranging from thalassemia, sickle cell disease, hereditary hemochromatosis, transfusion-dependent anemias, cancer chemotherapy and chronic liver disease. Management of iron overload depends on the ability to quantify and monitor the patient's iron stores with precision. Organ iron measurement by relaxometry-based MRI techniques has become the current standard. MRI is expensive and has the added limitations of multiple existing methods and reduced dynamic range with 3 Tesla scanners. Liver iron measurements by magnetic susceptometers using superconductive quantum interference device (SQUID) technology are expensive and have limited availability. In this study an improved low-cost device, the room-temperature susceptometer (RTS, Insight Magnetics, San Diego, CA), was tested against the Model 5700 Ferritometer ® 3-Channel SQUID BioSusceptometer System (Tristan Technologies, Inc. San Diego, CA). Both systems quantify liver iron concentration (LIC) using bulk magnetic susceptibility.Where the SQUID uses an ultra-stable sensing system immersed in liquid helium, the RTS cancels the temperature and magnetic-field fluctuations inherent in an apparatus that works at room temperature. The RTS uses three main techniques to sense the very weak magnetic field produced by liver iron: (a) oscillatory magnetic fields that can be detected with high sensitivity using coils of ordinary copper wire, (b) field-producing and field-sensing coils to cancel the signal due to the applied magnetic field, and (c) movement of the sensing unit periodically toward and away from the patient so as to distinguish the patient's magnetic field response from the interfering signal caused by temperature fluctuations in the sensing system.Methods: This study compared measurements of LIC from RTS to those by the SQUID. The RTS in this study was modified from an earlier model to make the baseline reading more stable, and to increase the accuracy of the water reference measurement to which the patient's magnetic response is compared. The magnetic-field source and sensing coils were enlarged to increase the signal of the liver compared with that of the overlying tissue.LIC was measured once on the SQUID and once on the RTS at a single visit. Using ultrasound imaging, optimum liver measurement position was determined and marked with an x-y-positioning and z-distance sensing Locator Loop (Positronic Systemtechnik GmbH, Germany). The locator loop remained attached to the patient for measurements with both devices to preserve measurement location. LIC calculation was corrected for the susceptibility and geometry of the overlying tissue. Measurement results from SQUID and RTS were analyzed independently by two investigators.Results: Thirteen adults (10 with transfusion-dependent thalassemia and 3 controls) with body mass index (BMI) <25 were enrolled. All measurements were completed at a single visit with no failures. LIC values (µg/g wet-liver weight), ranged from -33 to 6493 with SQUID, and -305 to 7237 with RTS. In the three controls, the LIC was -33, 144 and 427 µg/g with SQUID, and -305, 451 and 230 µg/g with RTS. The overall correlation between the two methods was excellent, yielding an r2 = 0.976 and slope = 1.037 ± 0.068 (p<0.001, Fig 1). Bland-Altman analysis of percent-difference versus the average of the two methods showed bias -2.72 (95% limits of agreement -149.1 to 143.6) for all subjects, which improved to 1.94 (95% limits of agreement -41.1 to 45.3) when the average values below 350 µg/g (n=4) were excluded (Fig 2). The percent difference between the two methods was influenced by the subject's BMI (p=0.050 for all subjects; p=0.031 after excluding average LIC <350 µg/g), with the least difference observed in the BMI range of 20-23 Kg/m2.Conclusion: This study shows that, with the recent improvements in the RTS technology, LIC measurements now closely align with those using SQUID. The remaining difference between the two methods likely results from the models used to compensate for the overlying tissue. Further comparison of RTS to SQUID and MRI-based methods in diverse iron overload states is warranted in a larger study. This work may ultimately make low-cost noninvasive measurement of iron overload accessible to the large number of patients in the US, and to resource-limited countries around the world. DisclosuresLal:Bluebird Bio: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Novartis: Research Funding; Celgene Corporation: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding. Avrin:Insight Magnetics: Employment, Other: Proprietor of company developing the study device, Patents & Royalties: Own rights to patents on the study device. Weyhmiller:Insight Magnetics: Research Funding.

Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

▪Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely.Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes.Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment.Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3).A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA.An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin.Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. DisclosuresRogers:Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

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

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

In-Accuracy Of Bone Density Measurements By DXA In Patients With Hemoglobinopathies and Iron Overload

IntroductionWhen monitoring bone health in patients with hemoglobinapathies, it is unknown if iron in surrounding tissues can lead to inaccuracies in the 2-dimensional assessment by Dual Energy X-ray Absorptiometry (DXA). ObjectiveThe aims of this study were: 1) to determine if the accuracy of lumbar spine assessment by DXA is affected by high liver iron concentration in patients with Sickle Cell Disease (SCD) or Thalassemia (Thal), 2) to test the effect of high tissue iron on vertebral Z-scores using phantoms, 3) to explore the ability to account for potential high-iron content effects when performing DXA examinations. MethodsThis study consisted of a retrospective chart review of data collected by the Children's Hospital & Research Center Oakland, Bone Density Clinic and Iron Measurement Program. Data from both DXA and Super Conducting Quantum Interference Device (SQUID) examinations collected between 2002 and 2013 from were abstracted. Only those patients with a diagnosis of SCD or Thal, who had a DXA and SQUID measurement within the same year were divided into an iron overload group (liver iron concentration (LIC) >3,000 µg Fe/g wet) and low iron (LIC <500 µg Fe/g wet) group. These patients were compared with healthy controls of which only 13 had both DXA and SQUID tests, 34 had DXA only. The 34 healthy controls without a SQUID test were included because it was assumed, based on their health screen that their liver-iron content would not interfere with DXA. In order to explore aim 1, a lumbar spine scan, by DXA, of each subject was re-analyzed to compare the derived areal bone mineral density (aBMD) Z-scores of lumbar vertebrae that are covered by the liver (presumed L1 or L1/L2) with the Z-scores of the lumbar vertebrae not covered by the liver (L3/L4). To explore aim 2, phantoms were designed to mimic the geometry of iron loaded tissues in order to explore the contribution of iron in specific tissues on the accuracy of DXA assessments. Phantoms were constructed using KNOX® brand gelatin and iron(II) sulfate heptahydrate and had concentrations ranging from 3,000 to 7,000 ug Fe/g gelatin. The iron-loaded phantoms were positioned obtusely overlying L1/L2 of the DXA daily quality control phantom to mimic the position of the liver. All data were analyzed by STATA ver.9.2 and were considered significant with a p<0.05. ResultsData from 102 total visits abstracted from 88 subjects [19 SCD (13 F), 24 Thal (12 F), age: 30.1 ± 11.9 years, mean ± SD], and 45 healthy controls (24 F, age: 25.4 ± 11.0 yrs) were analyzed. The SCD and Thal group had an average LIC by SQUID of 4651 ± 2079 µg Fe/g wet tissue and serum ferritin of 5408±2706 ng/mL; while the healthy controls, with both a DXA and a SQUID (n=17), had an average LIC of 251±144. Average aBMD Z-score of the lumbar spine L1-L4 in the Thal group was -2.0 ± 1.1 , the SCD was -2.0 ± 1.6 and the healthy controls: -0.3 ± 0.9. However, when individual vertebrae are analyzed separately, a significant difference was observed between the lumbar spine L1 BMD Z-scores compared to the combined means of L3/L4 Z-scores in the iron loaded population (Table 1). The discrepancy was even greater in subjects with LIC >5000 ug/g wet tissue. These findings were reproduced using heavily iron loaded phantoms.Table1Summary of Vertebrae Analysis by DXA in Controls, Patients and PhantomsSubject groupL1 aBMD Z-ScoreAvgL3/L4 aBMD Z-scoreMean difference L1 vs AvgL3/L4Difference (L1 vs AvgL3/L4)p-valueControls (n=52)-0.29 ± 0.16-0.50 ± 0.170.21 ± 0.08-0.42 ± 0.12<0.001SCD & Thal (n=50)-1.60 ± 0.18-2.21 ± 0.180.63 ± 0.09Controls (n=52)-0.29 ± 0.16-0.50 ± 0.170.21 ± 0.080.70 ± 0.16<0.001LIC >5000 (n=18)-1.43 ± 0.28-2.35 ± 0.260.91 ± 0.15Control Phantom (n=10)0.76 ± 0.08-0.17 ± 0.070.93 ± 0.03-1.0 ± 0.16< 0.001Iron Phantom (n=10)1.70 ± 0.47-0.22 ± 0.101.92 ± 0.15 ConclusionsInitial results for this study show that there is a relationship between liver iron content and lumbar spine aBMD Z-scores when evaluated by DXA. The BMD Z-score for L1 appears to be more significantly affected by the liver iron content then L2, which was unanticipated. When evaluating patients with liver iron content >3,000 ug/g wet tissue, it is important to consider the effects of iron contribution from the liver on the DXA spine scans and delete L1 and/or L2 from the total Z-score prior to making an interpretation. Failing to do so may under diagnose low bone mass in this at risk patient population. Disclosures:No relevant conflicts of interest to declare.

Twice Daily Dosing of Deferasirox Significantly Improves Clinical Efficacy in Transfusion Dependent Thalassemias Who Were Inadequate Responders to Standard Once Daily Dose

AbstractAbstract 1026 Background:Clinical efficacy of deferasirox (DFX); a once daily oral iron chelator in patients with transfusional iron overload depends on factors such as iron burden, rate of transfusion and appropriate dose. At present, the recommended dose approved as a label indication is 30 mg/kg/day, though doses up to 40 were studied in patients with cardiac siderosis with acceptable safety profiles. Recent several studies have shown in a non-clinical trial setting that a proportion of patients could not achieve satisfactory iron balance at 30 mg/kg/day or even at higher dose. These patients were labeled as inadequate responder (IR). In our center, surprisingly 44.2% of transfusion dependent thalassemia patients were classified as IR to DFX since the drug was registered in 2007. Difference in bioavailability with a lower area under the curve (AUC) of each IR individual was the only main mechanism identified earlier (Neufeld E, et al. Blood 2009). We hypothesize that adjusting DFX dose from once daily into two dividing dose per day might improve drug exposure and chelating efficacy in such patients. Methods:Patients with IR was primarily defined as (1) having a rising serum ferritin (SF) trend or (2) having a reduction of SF less than 30% of baseline levels (BL) at least 3 consecutive months, with more than two SF measurements higher than 1500 ng/mL; and (3) receiving once daily DFX at an average dosage > 35 mg/kg/day for at least 6 months. DFX administration schedule was switched to twice daily with the same total dose per day. CBC, renal function, urine analysis were performed every 3 weeks to monitor possible adverse effects. SF and liver function test were checked every six weeks. Tolerability and compliance to DFX were evaluated by direct history taking and drug account prescribed during study period. Results:Nineteen patients were met inclusion criteria; 2 patients were excluded from further study due to poor compliance and a short follow up period. Total 17 patients (7 male, 41%) were eligible with a mean (± SD) age of 10.22 ± 4.1 yrs (range; 2.1–18 yrs). Clinical diagnoses include; Hb E/β thal. (n=13), β thal. major (n=3) and Hb Barts hydrops (n=1). Mean follow up time before and after switching dose admin were 15.3 ± 6.3 and 20.8 ± 10.3 mths. Average SF at baseline (BL) before DFX and before switching regimen were 3,632 ± 2,031.02 and 3,844 ± 2,144.3 ng/mL, respectively with median % change of SF was +15.8 % (range; −29.8 to +104%). Mean actual DFX dose during 6 mths before switching was 37.22 ± 2.3 mg/kg/day. None of studied patients was DFX intolerance as they had no symptoms of gastrointestinal (GI) irritation. After twice daily dose, 10 (58.8%) and 14 patients (82.4%) showed a significant decrease of SF (> 30% of the baseline levels) at 6 and 12 mths. Mean SF and median % change of SF at 6 and 12 months after switching were 2,380.53 ± 1,774.62 ng/mL; −38.08 % and 1,588.12 ± 1,373.22 ng/mL; −58.7%, respectively with statistical significance compared to BL and before switching (p <0.05). Mean transfusion iron load before and after switching were not different (range 0.2–0.4 mg/kg/day). Although 3 patients had a SF reduction < 30%, all showed a reducing trend; −11.5%, −25.7% and −25.6% at 12 mths. Five from 17 patients were evaluated for liver iron concentration (LIC); average LIC at BL and at the end of study (EOS) were significantly reduced from 11.2 to 5.85 mg/g dry wt. None had cardiac T2* < 20 msec. All patients except two tolerated well with DFX at before and after switching (up to 12 months) with minor adverse events (AEs). One patient had significant proteinurea after 6 months and one with severe transaminitis (ALT > 3 times of ULN). They were temporarily discontinued with DFX and both AEs were completely resolved and did not recur when they were resumed on the twice daily regimen. Conclusion:Previously, twice daily DFX was shown to be effective in patients with DFX intolerance. We show herein that patients with IR might also be beneficial from a twice daily dosing with clinically well-tolerance and acceptable compliance. Dividing DFX into twice daily dose might provide a better bioavailability in selected patients with sustainable therapeutic levels of DFX throughout 24 hr-exposure resulting in a better clinical efficacy. Further pharmacokinetic and pharmacogenetic study in IR patients is warranted and this can provide additional insights on the next level of tailoring iron chelation therapy in patients with transfusional iron overload. Disclosures:No relevant conflicts of interest to declare.

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.

Concentration of Liver Iron in Calves and Response to Dietary Iron and Desferrioxamine

Twenty-four grade Holstein male calves were used to study the effects of iron, desferrioxamine (DFO) and age oil the concentration of liver iron as sampled by biopsy. Blood hemoglobin was also studied. A gradual decrease in liver iron was observed between the age of 15 and 60 days. The rate of decrease, however, was different depending upon whether the calf had low or high reserves at 15 days. Feeding iron to provide 50 mg. per calf daily was insufficient to prevent a gradual decline in liver iron, and to maintain, after 55 days of treatment, a concentration of liver iron significantly higher than in control animals. The calves receiving DFO in their diet had an average liver iron concentration, on a fresh weight basis, 16 ppm lower than control animals. A positive correlation was found between blood hemoglobin and liver iron, suggesting that liver reserves may be one factor partially controlling blood hemoglobin concentration at birth and also at 8 wk. of age. Because DFO may lower liver iron and consequently blood hemgolobin, it may find application in the raising of veal calves.