Oral Chelator Research Articles

Neutropenia in Children Treated with Deferiprone or Deferasirox: A Report of the Largest Randomized Trial of Oral Chelators in Transfusion-Dependent Pediatric Patients

Introduction: Agranulocytosis/severe neutropenia is an established adverse event during deferiprone (DFP) use. Less is known about milder episodes, which are frequently transient despite continuous deferiprone use. To provide further insight into this topic, we compared the incidence of neutropenia during DFP or deferasirox (DFX) treatment in the randomized Deferiprone Evaluation in Paediatrics (DEEP-2) trial, where blood neutrophil count was regularly monitored in patients randomized to be treated with DFP or DFX. Methods: DEEP-2 was a multicenter, randomized, 12-month, open-label trial comparing DFP vs DFX in pediatric (<18 years old) patients with transfusion-dependent hemoglobinopathies. 390 patients from 22 centers in 7 countries were randomized (1:1 DFP:DFX) and received at least one dose of the study medication (193 on DFP and 197 on DFX). Neutrophil count was regularly assessed every 7 +/-7 days in all patients. Neutrophil counts <500/mm3 were classified as agranulocytosis/severe neutropenia, 500 - <1,000 /mm3 as moderate neutropenia, and 1,000 - <1,500 /mm3 as mild neutropenia. The incidence of neutrophil counts below the threshold of neutropenia (1,500/mm3) and the rate of reported episodes of neutropenia as identified by the treating physician were compared between the two treatments. An ANOVA model was used to compare the time to neutropenia and time for its resolution between the two treatment groups. To compare the cumulative hazard curves was used the Kaplan-Meier log rank test. Results: 3579 and 4027 neutrophil counts were available for DFP- and DFX-treated patients, respectively. 47 (1.3%) of the total counts in 24 (12.4%) of the 193 DFP-treated patients versus 48 (1.2%) of the total counts in 27 (13.7%) of the 197 DFX-treated patients were below 1,500/mm3. Of these, 28 cases in 23 DFP-treated patients and 15 cases in 11 DFX-treated patients were reported by the treating physician as neutropenia, corresponding to a global incidence rate 11.9% for DFP and 5.6% for DFX (p=0.081, Chi-Square test). 23 (82.1%) of the 28 episodes of neutropenia during DFP use were considered drug related vs 2 (13.3%) of the 15 episodes during DFX use (p-value < 0.001, Fisher Exact test) (table 1). The mean (SD) treatment duration with either DFP or DFX prior to diagnosis of mild or moderated neutropenia was 127 (96.1) days and 101 (85.7) respectively. All those episodes, except for 2, resolved within a mean time of 13 days (1 - 42 days) in DFP-treated patients and 18 days (6 - 46 days) in DFX-treated patients. The 2 cases where neutropenia did not resolve were diagnosed as constitutional neutropenia and bone marrow suppression. There was no significant difference in those results between the two treatment groups as assessed by one-way ANOVA(p = 0.379), Log-Rank test (p = 0.065) or cumulative-hazard and Kaplan-Meier. During the study 3 events of agranulocytosis occurred, all in patients treated with DFP and not included in the present analysis. All 3 episodes resolved. Conclusion: Data from the largest randomized trial of oral chelators in transfusion-dependent pediatric patients provide evidence that, a drop in the neutrophil count below the threshold for mild neutropenia is very common (>10% of patients) for both DFP and DFX treated patients. All episodes of neutropenia, except for 2 with specific etiology, resolved, irrespective of their severity and of chelator used. A causal relationship of neutropenia to chelator use varied based on the chelator; the majority of events observed during DFP use were assessed by the clinician as drug related, whereas the majority of events observed during DFX use were assessed unrelated to its use. These data indicate that while agranulocytosis rate in DFP patients is not changed from previous reports, moderate/mild neutropenia represent discrete events in patients undergoing oral iron chelation therapy. Disclosures Tricta: ApoPharma: Employment. Della Pasqua:GlaxoSmithKline: Employment. Kattamis:Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reggiardo:CVBF: Consultancy. Spino:ApoPharma: Employment. Tsang:Apotex Inc.: Employment.

Regulation of Iron Homeostasis By PTG-300 Improves Disease Parameters in Mouse Models for Beta-Thalassemia and Hereditary Hemochromatosis

Hepcidin-Ferroportin axis dictates optimal absorption of dietary iron as well as systemic iron levels. This is crucial for providing sufficient iron needed for cellular functions while also preventing iron toxicity. PTG-300 (currently in a Phase 2 clinical study for beta-thalassemia) is a peptide mimetic of natural hepcidin that targets the major iron transporter, ferroportin, and causes its internalization & subsequent degradation. The pharmacodynamic effects of PTG-300 are the reductions in serum iron and transferrin-saturation (TSAT) due to reduced ferroportin expression on cells that store or recycle iron. We chose to demonstrate in two mouse models with iron dysregulation, that our hepcidin mimetics improve disease parameters by correcting dysregulated iron homeostasis. Beta-thalassemia is characterized by an imbalance in alpha-beta globin ratio in erythrocytes due to underlying beta-globin gene mutations. The excess alpha-globin, along with associated heme and iron, form "hemichrome" aggregates that integrate into the membranes of RBCs. The labile iron in these hemichromes generate ROS and are toxic to the cells, causing premature hemolysis of circulating RBCs and reduction in their lifespan. In a mouse model for beta-thalassemia, Hbbth3/+, we investigated the efficacy of a hepcidin mimetic in reducing hemichrome aggregation by limiting iron in the erythroid progenitors, and thereby reducing iron toxicity in RBCs. Subcutaneous injections of 1 mg/kg PN-8772 (analog of PTG-300 which has similar in vitro and in vivo potency) were administered every other day (Q2D) for a period of 4 weeks. At the end of the study, hemichrome aggregates were extracted from RBC membranes, and then analyzed on a TAU gel to quantify the cytoskeleton α-globin band intensities (Casu et al, Blood 2016). Hemichrome aggregates were reduced in groups treated with PN-8772 as compared to untreated controls, with concurrent improvements in hemoglobin and reductions in reticulocytes. Treatment with oral chelator Deferasirox (200 mg/kg; daily) did not show reduction in hemichrome aggregation, while it significantly lowered liver iron-overload. RBCs in Hbbth3/+ mice express aberrant morphologies due to the underlying hemichrome toxicity, similar to the phenotypes expressed in human beta-thalassemia. Chronic treatment with PN-8772 (as described above) also resulted in a significant reduction in aberrant morphologies that are indicative of hemolysis, viz. spherocytes & schistocytes. In a separate study, flow cytometry was used to monitor the survival of RBCs in Hbbth3/+ mice. At the end of 4 weeks of PTG-300 treatment (1 mg/kg, Q2D) the RBCs were marked by an in-life biotinylation method (Schmidt et al, Blood 2013) and subsequently followed over 49 days with continued treatment. There was a significant increase in survival of RBCs as compared to untreated controls. In summary, we demonstrate that by limiting iron in the developing erythroblasts and iron toxicity in RBCs, PTG-300 therapy has the potential to improve the quality of the RBCs and their oxygen carrying capacity, thereby ameliorating anemia. In beta-thalassemia, the clinical presentation includes secondary iron overload in various organs because of hyperabsorption of dietary iron, exacerbated by frequent blood transfusions that are required for management of anemia. Similarly, in hereditary hemochromatosis (HH) there is hyperabsorption of dietary iron leading to primary iron overload. We used a hemochromatosis mouse model (HFE) to demonstrate the effectiveness of PTG-300 therapy in limiting systemic iron toxicity by regulating TSAT and in preventing hyper-iron absorption. The model is characterized by homozygous deletion of HFE with severely low hepcidin levels and consequently very high TSAT (~100%). In this model, a single dose of PTG-300 at 2.5mg/kg reduced TSAT by ~60% at 10-hour post-dose, as compared to untreated controls. Sustained TSAT reduction by chronic treatment will therefore mitigate toxic effects of labile iron. Two weeks of chronic treatment with PTG-300 (2.5 mg/kg, Q2D) effectively prevented iron deposition in the liver. Overall our data suggests that PTG-300 has the potential to be an effective treatment in hemoglobinopathies, like beta-thalassemia, and Hereditary Hemochromatosis, by reducing systemic labile iron toxicity by limiting TSAT, preventing organ iron deposition & improving anemia (in case of thalassemia). Disclosures Taranath: Protagonist Therapeutics: Employment. Bourne:Protagonist Therapeutics: Employment. Zhao:Protagonist Therapeutics: Employment. Frederick:Protagonist Therapeutics: Employment. King:Protagonist Therapeutics: Employment. Liu:Protagonist Therapeutics: Employment.

PRO136 PATIENT-REPORTED BURDEN OF TRANSFUSION-DEPENDENT BETA-THALASSEMIA IN THE USA AND UK MEASURED USING A DIGITAL APP

Evaluate real-world management and symptom burden of transfusion-dependent β-thalassemia (TDT) in the United States and United Kingdom. Individuals with TDT were recruited to a 3-month study to investigate the time and symptom burden of TDT and its impact on health-related quality of life (HRQoL). Adult participants or caregivers for individuals with TDT aged 12–17 years, provided data via MyThalLog – a bespoke smartphone app. Daily burden assessments were made via the following: • Time burden questionnaire • Brief Fatigue Inventory (BFI) ‘worst fatigue’ question. • Brief Pain Inventory - Short Form ‘worst pain’ question Participants also completed the Transfusion-dependent quality of life (TranQoL) questionnaire and full BFI monthly. The time burden of TDT was substantial on transfusion days (mean: 8.8 hours, median: 8.2, Interquartile Range [IQR]: 3.4). The average weekly time burden in non-transfusion weeks was 41.4 hours (median: 10.2, IQR: 87.5 - variation driven by time for chelation preparation) for participants on non-oral chelators and 2.87 hours (median: 1.2, IQR: 1.2) for those on oral chelation only. Worst fatigue and pain scores observed in the five-day, pre-transfusion period were high (mean: 5.6 and 4.8, respectively; 10-point scale; 10 = worst symptoms). There was a clinically relevant reduction in fatigue post-transfusion (mean reductions versus transfusion day, over days one to three: 1.2, 1.4, 1.8 points, respectively; minimal clinically important difference [MCID]: 1 point). Pain remained persistent post-transfusion (mean reductions over days one to three: 0.9, 1.1, 1.4 points, respectively; MCID: 2 points). TranQoL (mean: 62.9, median: 63.7, IQR: 23.9; 100-point scale; 100 = best HRQoL) and BFI (mean: 5.5, median: 6.2, IQR: 4.0; 10-point scale; 10 = worst symptoms) scores were lower (i.e., worse) than reported previously in TDT and oncology populations from TranQoL and BFI validation studies, respectively. Time managing disease, fatigue, pain, and HRQoL impairment contributed to participant reported TDT burden.

Evaluation of Renal Function Disorder With Urinary Neutrophil Gelatinase-associated Lipocalin Level in Patients With β-Thalassemia Major.

Neutrophil gelatinase-associated lipocalin (NGAL) is found in the granules of human neutrophils, with many diverse functions. Expression of NGAL is induced under various pathophysiological conditions, for example, infection, inflammation, kidney injury, cardiovascular disease, burn injury, and intoxication, and it has an important antiapoptotic and anti-inflammatory role. A total of 37 patients with thalassemia disease β-thalassemia major (24 male and 13 female individuals) and 37 healthy controls (17 male and 20 female) were enrolled in this study. All patients were regularly transfused, and all of them were using oral chelator, deferasirox. NGAL and cystatin C levels were significantly higher in the case group than in the control group. In patients with β-thalassemia major, renal damage can occur owing to regular blood transfusion. Urinary NGAL levels in these patients may be considered as a marker for early renal injury.

Treatment of iron overload syndrome: a general review.

Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

Soil Lead Concentrations in Dareta Village, Zamfara, Nigeria.

Background. Acute widespread lead poisoning took place in Zamfara State, Nigeria in 2010. Over 735 children were reported dead and thousands sickened by the neurotoxin. The source was traced to artisanal gold mining and processing in the villages. An immediate medical response protocol was developed to provide oral chelation therapy to the vulnerable population. In order not to compromise the efficacy of the chelation therapy, immediate remediation of the affected villages was carried out. An over 95% reduction in soil lead levels was reported immediately after the remediation exercise.Objectives.The aim of the present study was to perform a general audit of soil lead concentrations, conducted between June and July 2013 in Dareta village (one of the most affected villages), to evaluate the soil pollution status of the village three years after the remediation exercise.Methods.Soil samples were collected from residential compounds, cultivated farmlands and other common areas. Lead contents of the samples were determined using atomic absorption spectrophotometer (Shimadzu, model AA-6800, Japan) after wet digestion. Speciation of lead in soil was done following standard analytical methods.Results.Mean soil lead concentrations for residential areas were 1029.42±98.50 mg/kg, 1523.99±201.00 mg/kg, 1404.57±141.00 mg/kg and 6724.68±84.00 mg/kg for residential compounds, market square, old grinding mills and new grinding mills, respectively. The concentrations exceeded both the Dutch target and intervention values and US Environmental Protection Agency limit for soil lead levels in residential areas. Based on the index of geo-accumulation, the ranking of intensity of lead (Pb) pollution of Dareta soils ranged from strongly polluted to extremely polluted, indicating they pose a range of moderate to very high potential ecological risk to the other components of the environment. At the current rate of accumulation, by the year 2025, soil Pb levels of Dareta common areas are expected to exceed the pre-remediation levels associated with several deaths.Conclusions.Findings of this study indicate that the problem of lead poisoning is ongoing in Dareta village. Zamfara State authorities should address the challenge through sustained periodic assessment and cleanup of affected areas. Implementation of safer mining practices should be enforced immediately.Competing Interests.The authors declare no competing financial interests

PF504 LONG‐TERM SEQUENTIAL DEFERIPRONE AND DEFERASIROX THERAPY IN TRANSFUSION‐DEPENDENT THALASSEMIA PATIENTS: A PROSPECTIVE CLINICAL TRIAL

Background:Iron overload is the main risk factor for morbidity and mortality in patients (pts) with transfusion dependent thalassemia (TDT). Therefore, life‐long iron chelation therapy is necessary for prevention of morbidities and long‐term survival. Three different chelating agents are currently available to treat iron burden in TDT pts: Deferoxamine (DFO) which is given subcutaneously, and 2 oral agents, Deferasirox (DFX) and Deferiprone (DFP). The possibility of using both oral chelators in a sequential manner remains of interest based on evidence that DFX and DFP have the liver and heart as their main target organ, respectively. Since the sequential administration of both oral chelators in monotherapy could be associated with a lower rate of adverse events (AEs), a prospective clinical trial to study this hypothesis was conducted.Aims:The aim was to assess the safety and effectiveness of the sequential DFP and DFX treatment in TDT pts, as measured by changes in SF, liver and cardiac MRI‐T2∗, over time.Methods:This was a multicenter prospective clinical trial to assess effectiveness and safety of sequential DFP and DFX treatment in TDT pts. Data were collected at the coordinating centre (A.O.V. Cervello, U.O.C. di Ematologia II, Palermo, Italy). A total of 21 consecutive patients were followed at 6 Italian centres between 2010 and 2014. Trial interventions included sequential treatment with oral DFX dispersible tablet at the dose of 30 mg/kg/day for 3 days a week and oral DFP at a dose of 75 mg/kg/day every 6–8 hours for the remaining 4 consecutive days. The planned duration of the study was 5 years. However, since sample size was not reached, it was interrupted on April 10, 2014. Data consisted of repeated measurement on the same patient over time. Linear mixed‐effects (LME) models for repeated measurements were used to assess the effect of the sequential DFX and DFP therapy on SF levels, septum cardiac MRI‐T2∗, and liver MRI‐T2∗ over time.Results:Overall, 21 TDT pts (8 [38.1%] males and 13 [61.9%] females) were enrolled in this trial. Patients’ median age was 32 years (range: 16 to 50). Mean total blood transfusion was 159.2 ± 35.3 ml/kg/year with a mean iron intake of 9.6 ± 0.6 mg/year. The median follow‐up was 32.2 months (range: 1 to 57). Results from the fitted LME model suggested a non‐statistically significant linear increase over time of the mean SF level (Coeff. 0.33 [SE 5.77], 95% CI −10.9 to 11.6, p‐value = 0.954), as shown in Figure 1. The mean values of septum cardiac MRI‐T2∗ was 31.3 ms and 37.3 ms at baseline and at the end of follow‐up, respectively. The estimated results of the LME model for the mean liver T2∗ suggested that there is a statistically signficant linear increase over time (Coeff. 0.13 [SE 0.04], 95% CI 0.05 to 0.21, p‐value = 0.001). Similarly, for the mean septum cardiac MRI‐T2∗, results suggested that there is a statistically signficant linear increase over time (Coeff. 0.22 [SE 0.06], 95% CI 0.09 to 0.33, p‐value< 0.001). None of the patients developed iron overload in the liver or heart during sequential DFX and DFP iron chelation treatment. No moderate/severe adverse events were observed over 36 months.Summary/Conclusion:In our trial, sequential regimen of DFP and DFX maintained SF levels and removed iron from the heart and liver as evident from improvement in MRI‐T2∗ values. None of the pts experienced moderate or severe adverse events. Our data suggest the need to design new and wider studies to check this daily sequential therapy as an effective treatment option in those TDT pts who do not tolerate either mono or combined therapy.image

S144 A MULTICENTRE, RANDOMIZED, NON‐INFERIORITY TRIAL COMPARING THE EFFICACY OF DEFERIPRONE VERSUS DEFERASIROX IN PEDIATRIC PATIENTS AFFECTED BY TRANSFUSION‐DEPENDENT HEMOGLOBINOPATHIES (DEEP‐2 TRIAL)

Background:While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion‐dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.Aims:We report results of DEferiprone Evaluation in Pediatrics‐2 (DEEP‐2), (EudraCT Number 2012‐000353‐31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).Methods:DEEP‐2 was a non‐inferiority, 12‐months, active‐controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to < 18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI‐T2∗) (patients >10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI‐T2∗, liver iron concentration‐R2 (LIC‐R2) and safety profile. Non‐inferiority (NI) was based on the 2‐sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than −0.125. In the intention‐to‐treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.Results:21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients < 6 years of age (30%), 38 with non β‐thalassemia TDH (mainly SCD) and 54 chelation‐naïve. DFP was non‐inferior to DFX based on the PP population (n = 271) while the NI criterion was not met for the ITT population (n = 390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2∗ values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = −20, CIU = 317 ng/ml; NI criterion: <400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI‐T2∗ and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug‐related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX‐treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.Summary/Conclusion:This FP7‐sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP‐2 trial provide evidence to support the use of DFP in pediatric patients.image

PB2047 COMPARATIVE ANALYSIS OF DEFERASIROX DISPERSIBLE TABLETS VS FILM‐COATED TABLETS IN SEVERE CONGENITAL ANEMIAS: RESTROSPECTIVE STUDY IN A TERTIARY HOSPITAL

Background:Several congenital anemias are defined by ineffective erythropoiesis, sometimes even exarcerbated by chronic hemolysis, which in combination with periodic transfusions required on the most severe forms lead to iron overload in the organism, which settle on body tissues leading to their disfunction, with significant impact on morbimortality.Iron chelators aim to decrease iron load, as well as prevent or delay long term complications. Deferasirox (DF) is an oral chelator whose efficacy and security had been well defined since its approval. New film‐coated formulation proved similar efficacy as well as better palatability and tolerance on the ECLIPSE trial, achieving better treatment compliance.Aims:Conducting a comparative study between deferasirox dispersable tablets (DF‐D) versus film‐coated tablets (DF‐FC) amidst severe congenital anemias, analyzing chelating capacity as well as treatment compliance and side effects in both formulations.Methods:Retrospective case series. We collected data from patients diagnosed with severe congenital anemias and active follow up visits in our hospital, who were treated with DF‐D as well as DF‐FC over 12 months each. Qualitative variables are presented as absolute frequencies and percentages; and the quantitative ones as median and standard deviation. Exact Fisher test was performed when comparing qualitative variables, and Mann Whitney test when analyzing quantitative ones. Data was analized by SPSS Statistics.Results:We collected data from 7 patients: 6 of them diagnosed as thalassemia major and 1 as Blackfan Diamond anemia. 85,7% of our patients were female and 14,3% were male, median age 44 years old.Mean red blood cells concentrates tranfused were 20 units per year for both formulations. Median DF dosing was 1500 mg over DF‐D treatment and 1080 mg over DF‐FC treatment, which translates into equivalent dosing given DF‐FC better bioavailability.We got 6,2% mean increasing percentage of serum ferritin levels with DF‐D versus 1,3% with DF‐FC; however, when analyzing liver iron concentration (LIC) we observed an 8,3% decrease in iron load with DF‐D as opposite to 39,7% with DF‐FC, as well as a similar decrease in cardiac iron concentration (CIC) comparing both formulations (9,5% with DF‐D vs 6,5% with DF‐FC).71,4% patients showed poor treatment compliance over DF‐D treatment, due to the development of side effects, outlining digestive disturbances (80%) and less frequently renal impairment or nonspecific disturbances (10% each), conditioning a change in therapy in 40% of cases. We did not find adherence problems with DF‐FC formulation, side effects rate decreased to 28,6% and no patient required a change in therapy.Summary/Conclusion:Our data revealed a high rate of side effects associated with DF‐D, mainly digestive disturbances, conditioning poor therapeutic adherence as well as changes to treatment in 40% of our patients. New formulation substantially decreased side effects rate, no patients required a change in treatment and we found a 100% therapy compliance.imageSerum ferritin levels showed an slight increase over both treatments, with hardly any diffence between the two, which did not correlate with LIC levels, that showed a significant decrease in iron load, or cardiac deposits. In our opinion this data could be explained given ferritin low specificity quantifying iron load, whose levels fluctuate with inflammatory or infectious states; as compared to LIC and CIC estimation by magnetic resonance imaging, which have shown higher reliability when quantifying iron burden.

PF785 CHANGING CAUSES OF MORTALITY IN TDT DURING THE ERA OF ORAL CHELATION THERAPY FROM 2000 TO 2018

Background:Heart disease due to transfusion iron overload has been previously reported as the predominant cause of death in transfusion dependent thalassaemia (TDT), but recent reports suggest that liver disease, malignancy and infection are becoming more frequent. If this is the case, changes in standard treatment may be warranted in order to further improve life expectancy.Aims:We aimed to provide robust evidence of these trends by analysing data from the Cyprus thalassaemia cohort study.Methods:This is a long‐term study of outcomes of TDT in the setting of an endemic Mediterranean population where national treatment policies have been consistent in four thalassaemia centres. The cohort has been described previously (Telfer et al, Haematologica 2006). The study update protocol was agreed between investigators at a series of meetings during 2017. A data spreadsheet was populated at each treatment centre and returned to the study centre. Data were checked, queries resolved and final dataset for each centre validated up to 31stDecember 2018. Inclusion criteria were birth after 1/1/60 and continuous treatment and follow up in the four Greek Cyprus thalassaemia centres. The population included a birth cohort of those born from 1/1/74 onwards who had been carefully tracked from birth as part of the Cyprus thalassaemia control programme. Causes of death were classified cardiac, liver (including hepatocellular carcinoma), malignancy, infection and other. Mortality rates were calculated overall and for periods 1980–89, 1990–99, 2000–09 and 2010–18. Survival analysis replicated the methodology in the 2006 study, and for multivariate analysis of risk factors, the study was divided into two time periods (1980–1999 and 2000–2018) to account for the the introduction of oral chelator therapy in 1999/2000. Risk factors for survival were evaluated as Hazard ratios with 95% CI.Results:538 TDT patients were studied over a total of 19,083 patient years. Median age at 30/12/18 was 40.9 yrs, IQR 38.0‐ 47.6. There were 95 deaths, 47.4% cardiac, 9.5% liver, 8.4% malignancy, 14.7% infection and 20% other. Overall the mortality was 5.0 per 1000 patient years follow up. During recent decades, there have been no overall differences in mortality rate, but causes of death have changed due to a downward trend in cardiac and an increasing trend in liver, malignancy and infection‐ related deaths. In the most recent period (2010–18) there was no difference in mortality rates due to different causes (Figure). Estimated survival during the period 2000–2018 was 94% at age 30 (95% CI: 90 ‐ 99%) and 89% at age 40 (95% CI: 85 ‐ 94%). Survival to age 30 improved 8 percentage points compared with the period 1980–1999. In multivariate analysis, independent predictors of survival between 2000 and 2018 were male sex (HR 2.1 95% CI 1.2–4.1), born after 1974 (HR 0.45, 95% CI 0.20 −0.99) and oral chelation therapy with either deferiprone (DFP): HR 0.11, 95% CI 0.06–0.20; or deferasirox (DFX): HR 0.10, 95% CI 0.03–0.32, compared with desferrioxamine (DFO).Summary/Conclusion:These results demonstrate a shift in mortality to causes not directly related to transfusion iron overload. Nevertheless the strongest protective factor for survival is iron chelation therapy, and our data would suggest that DFX and DFP are equally protective. This may relate to better adherence or improved 24 hr iron control compared to DFO. For clinical practice, it remains important to minimize iron loading of heart and liver and to be vigilant about controlling and treating infection.image

Strategies for managing transfusional iron overload: conventional treatments and novel strategies.

For individuals who have transfusion-dependent anemia, iron overload is the long-term complication, which results in significant morbidity. Ameliorating this is now the biggest unmet need. This review specifically addresses this issue. Over the last decade or so, major advances in the treatment of these individuals, has resulted from novel strategies aimed at reducing transfusion requirement as well as optimizing chelation therapy. This review will summarize these advances and provide insights into some of the therapies in the pipeline. Strategies aimed at reducing transfusion requirement include modulation of erythropoietic regulation by reducing ineffective red cell production through activin trapping, as well as stem cell gene modification approaches, which aim for a cure, and transfusion independence. Refined means of assessing tissue iron and the introduction of oral chelators have facilitated tailoring chelation regimens with closer monitoring and improved compliance. Newer approaches to ameliorate iron toxicity have focused on the hepcidin pathway, all of which would result in increased hepcidin levels and reduction of iron absorption from the intestine, sequestration of iron in normal storage sites and reduced exposure of more susceptible organs, such as the heart and endocrine organs, to the toxic effects of increased iron. These advances offer the promise of improved management of transfusion-dependent individuals.

Therapeutic mechanism of combined oral chelation therapy to maximize efficacy of iron removal in transfusion-dependent thalassemia major – a pilot study

ABSTRACTObjectives: Three iron chelators are used to treat transfusion-dependent beta-thalassemia: desferrioxamine (DFO), deferasirox (DFX), and deferiprone (DFP). Compliance is low for DFO as it cannot be administered orally. Combined administration of DFP and DFX is orally available, however, the therapeutic mechanism is unknown. This pilot study investigated the iron removal mechanisms of DFX and DFP treatment in patients with transfusion-dependent thalassemia major.Methods: Each patient received three treatments sequentially: (1) DFX monotherapy, (2) DFP monotherapy, and (3) DFX/DFP combination therapy with a four-day washout period between each treatment. Urine and stool specimens were collected to determine the primary outcome of iron excretion volumes.Results: The mean iron excretion was seven times higher after combination therapy with DFX and DFP. Monotherapies also increased excretions volumes, though to a significantly lesser degree.Combined administration of DFX and DFP achieves maximum iron removal in transfusion-dependent thalassemia major compared to monotherapy with either drug.Conclusions: We suggest combination therapy in chronic severe iron overload cases, especially for patients in poor compliance with DFO/DFP combination therapy or those exhibiting poor iron removal from DFX or DFP monotherapy.

Utility of Labile Plasma Iron Assay in Thalassemia Major Patients.

Labile plasma iron (LPI) levels are proposed as marker of iron overload in thalassemia patients and are also known to be the earliest parameter to indicate efficacy of chelation therapy. It was a prospective study in 35 patients of thalassemia major. Patients were recruited in two groups-group A (n = 13) patients not on chelation therapy and group B (n = 22) patients who were on regular oral chelation therapy. Ten age and gender matched healthy controls were also studied. For all patients, ferritin levels and LPI levels were measured at baseline, 6months and 12months. For group B patients paired samples for LPI were taken (before and 2h after chelator). LPI levels were found to be significantly higher in group B patients versus group A patients versus normal healthy controls at all time-points. (P value-< 0.0001, 0.001) In group A, both LPI levels and ferritin levels follow an upward trend and correlated well with each other (P value-< 0.0001). In group B, the serum ferritin trend was not significant over follow up period of 1year (P value 0.16), however LPI levels showed a significant decreasing trend on continued chelation (P value 0.0347) In patients on chelation therapy, the immediate change (2h) in LPI levels on administration of chelators was not found to be significant (P value 0.22). LPI assay appears potentially attractive alternate to serum ferritin and can serve to monitor the trend of iron overload during long-term follow up.

Hearing loss with oral chelators in thalassemia

Hearing loss with oral chelators in thalassemia

Wrist Deformity in Children and Adolescents with β-thalassemia on Oral Iron Chelation Therapy

To describe a novel wrist deformity in b-thalassemia major patients, and their radiographic and magnetic resonance imaging findings. 30 patients with b-thalassemia major who were noticed to have ulnar deviation at wrist joint were evaluated for previous history of medications, serum ferritin levels, presence of pain and swelling at the wrist joint, and the duration of iron chelation therapy. Radiographs of wrist and limited magnetic resonance imaging (MRI) sequences were obtained in 30 and 15 patients, respectively. Radiographs revealed varying severity of distal ulnar shortening, distal radial slanting and presence of soft tissue distal to the ulna. MRI showed similar deformities along with abnormal marrow signal at distal ulnar ends; in 8 patients, a soft tissue distal to the distal end of ulna was noted. Varying severity of radiological abnormalities, predominantly affecting the distal ulna, are present in children and adolescents with b-thalassemia receiving oral chelation therapy.

Combination Oral Chelation in Adult Patients With Transfusion-dependent Thalassemia and High Iron Burden

An open-label, pilot study was conducted to evaluate deferasirox/deferiprone combination chelation therapy in adult patients with transfusion-dependent thalassemia and severe iron overload. Enrollment proved difficult. Nine patients (median age, 27.4 y; ferritin, 4965 ng/mL; liver iron concentration, 28.5 mg/g dry weight; cardiac T2*, 13.3 ms) received treatment. Two were withdrawn for treatment-related adverse effects. Arthralgia (4 patients) and gastrointestinal symptoms (5 patients) were common; no episodes of neutropenia/agranulocytosis occurred. Adherence difficulties were common. Of 6 patients with 12 to 18 months follow-up, 3 showed improvement in cardiac T2* and 2 in liver iron. Combination oral chelation may be effective but adverse effects and adherence challenges may limit efficacy.

Long-term improvement in cardiac magnetic resonance in β-thalassemia major patients treated with deferasirox extends to patients with abnormal baseline cardiac function.

The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a "real world" setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2* <20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF >56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation.

Construction of a Glutathione-Responsive and Silica-Based Nanocomposite for Controlled Release of Chelator Dimercaptosuccinic Acid.

Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg2+ or Pb2+. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL−1. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.

PSY177 - HEALTH-RELATED QUALITY OF LIFE OF PATIENTS WITH BETA-THALASSEMIA

Beta-thalassemias are a group of genetic hemoglobinopathies. Those with beta-thalassemia minor typically do not require clinical interventions for anemia whereas beta-thalassemia intermedia or major patients require intermittent or chronic blood transfusions with iron-chelation therapies, respectively. This study aimed to review the humanistic burden of beta-thalassemia on patients and caregivers. Systematic searches were conducted in MEDLINE, EMBASE and Cochrane CENTRAL to identify relevant studies published in English in the past 10 years. No geographic restrictions were applied and all studies with population size N≥100 were considered. 133 publications (of 911 references identified) were selected for full-text screening. This resulted in 25 included full-text publications which evaluated the humanistic burden of beta-thalassemia, as measured by generic health-related quality of life (QoL) instruments such as SF-36, WHOQoL, EQ5D and PedsQL. The majority of studies (n=14) were conducted in beta-thalassemia major only, while eleven studies included patients with beta-thalassemia intermedia or other types of thalassemia. Almost half of the studies (n=12) were conducted in Iran and the remaining studies sampled populations from various geographic areas including North America, Europe, Australia, and Asia. The QoL was negatively impacted in both pediatric and adult patients, compared to age- and sex-matched healthy controls. Conflicting QoL findings emerged in patients who were transfusion-dependent compared to those who were not transfusion-dependent. Between patients requiring iron-chelation, QoL was better in those receiving oral chelation compared to those receiving injectable chelation. Based on the available data, beta-thalassemia has a negative impact on the QoL of affected individuals, and use of oral chelation therapies may be associated with a better QoL relative to injectable chelation therapies.

Diagnosis and Management of Genetic Iron Overload Disorders.

Iron overload disorders lead to excess iron deposition in the body, which can occur as a result of genetic or secondary causes. Genetic iron overload, referred to as hereditary hemochromatosis, may present as a common autosomal recessive mutation or as one of several uncommon mutations. Secondary iron overload may result from frequent blood transfusions, exogenous iron intake, or certain hematological diseases such as dyserythropoietic syndrome or chronic hemolytic anemia. Iron overload may be asymptomatic, or may present with significant diseases of the liver, heart, endocrine glands, joints, or other organs. If treated appropriately prior to end-organ damage, life expectancy has been shown to be similar compared to matched populations. Alongside clinical assessment, diagnostic studies involve blood tests, imaging, and in some cases liver biopsy. The mainstay of therapy is periodic phlebotomy, although oral chelation is an option for selected patients.