Use Of Iron Chelation Therapy Research Articles

Utilization Patterns and Outcomes from Iron Chelation in Elderly Patients with Low-Risk Myelodysplastic Syndrome

Introduction: Iron overload from red blood cell (RBC) transfusions is a source of morbidity and mortality in patients with myelodysplastic syndromes (MDS). Evidence supporting iron chelation therapy (ICT) in Low-Risk MDS (LR-MDS) is controversial on account of studies conducted in highly selected patients and limited clinical trial data. We conducted a large population analysis aimed at defining real-world ICT utilization in LR-MDS and associated outcomes. Methods: We included patients diagnosed with MDS from 2007 to 2017 in SEER-Medicare using ICD-O-3 codes, aged 66 or older, with continuous Medicare parts A, B, and D. Exclusion criteria included patients with high-risk histology (MDS with excess blasts), less than 2-year survival, without complete follow-up, or enrolled in HMO. ICT eligibility was defined as ICD-9/10 codes for transfusion-related iron overload and/or cumulative ≥20 RBC units within ≤2 years of MDS diagnosis. ICT was identified from HCPCS codes for deferoxamine or prescription records for deferasirox or deferiprone. Explanatory variables included age, sex, race, rurality, socioeconomic quintile, marital status, geographic region, MDS histologic subtype, year of diagnosis, Charlson comorbidity index (CCI), and MDS therapies, including erythropoietin-stimulating agents (ESA), hypomethylating agents (HMA), and lenalidomide, identified from HCPCS codes and prescription records. Outcomes were identified through validated algorithms using ICD-9/10 codes and included overall survival (OS), progression to acute myeloid leukemia (AML), and complications related to iron overload, comprising heart failure, non-ischemic heart disease, atrial fibrillation/flutter, and liver disease/cirrhosis. To control for confounding, we implemented 3 approaches: multivariable Cox-proportional hazards regression, propensity score matching (PSM) by conditional probability of receiving ICT, and cause-specific regression with competing risk of death. Results: We analyzed 2,564 LR-MDS patients who were eligible for ICT. The mean ± SD age was 81 ± 6 years and 56.2% were male. Only 393 (15.3%) of these patients received ICT. The initial agent of choice was deferasirox in 203 (51.7%), deferoxamine in 188 (47.8%), and deferiprone in 2 (0.5%). Median ICT duration was 7 months (IQR 1-20). Chelated patients were younger (median age 79 vs 81, p<0.01), more likely to have histology with ringed sideroblasts [RS] (17.8% vs 7%, p<0.01), had less comorbid burden (median CCI 1 vs 2, p<0.01), and were more frequently treated with ESA (42.8% vs 33%, p<0.01), HMA (59% vs 49.8%), and lenalidomide (27% vs 11.1%, p<0.01), than those not treated with ICT. Their median monthly RBC transfusion density was 4 (IQR 2-6). Factors predicting ICT use were histology with RS (OR=1.9, 95%CI 1.4 - 3.8), RBC transfusion density (OR=1.1 per 4 units/month, 95%CI 1.1-1.2), and therapy with ESA (OR=1.5, 95%CI 1.2-1.9), HMA (OR=1.3, 95%CI 1.1-1.8), or lenalidomide (OR=2.6, 95%CI 1.9-3.5). Among patients who received ICT, 352 (89.6%) were considered transfusion dependent (≥2 RBC units within 8 weeks before starting ICT). Of them, 278 (78.9%) achieved hematologic response (≥50% decrease in RBC units following ICT). ICT was associated with decreased risk of death (HR=0.52, 95%CI 0.46-0.59) in the multivariable model adjusting for all listed covariates. The PSM matched 379 chelated (96.4% case rate) with 729 non-chelated patients and yielded similar results for OS benefit from ICT (HR=0.53, 95%CI 0.46-0.61). Table 1 shows results for other outcomes. Across models, ICT was associated with 43-49% decreased risk of AML transformation and 23-32% reduced risk of adverse cardiac outcomes. Cardiac benefit was predominantly driven by a lower risk of heart failure. No significant association was observed between ICT and hepatic outcomes. Conclusions: Our results suggest that ICT is associated with fewer transfusions, improved OS, lower risk of AML, and less adverse cardiac outcomes in LR-MDS. Our older, unselected cohort better reflects real-world LR-MDS patients and builds upon OS benefit reported in more restricting settings. Given the link between clonal hematopoiesis, cardiovascular disease and LR-MDS, defining ICT's effect on molecular and clonal dynamics could clarify the mechanism behind improved cardiac outcomes.

Iron Overload and Treatment Outcome in an Adult Sickle Cell Disease Cohort

Objective. Blood transfusion plays a prominent role in the management of patients with sickle cell disease (SCD) and has a compounded effect on iron overload, especially when simple top-off transfusions are given. Adults with sickle cell anemia (SCA: HbSS or HbSβ 0-thalassemia), often require episodic blood transfusions on a chronic basis and, hence, are at risk of developing transfusional iron overload. We monitored 83 adult SCD patients with a diagnosis of iron overload during routine treatment and follow up at our clinical center. The aim of this study was to observe and describe treatment outcomes for individuals with iron overload seen at the University of Illinois adult sickle cell center between 2010 and 2023. Method. Patients eligible for the study were aged 18 years or above at the time of their initial visit. Patients were identified from our institutional clinical and translational research informatics data warehouse using computable phenotype algorithms as well as SCD outpatient encounter information to improve accuracy of abstracted data. Results of our queries were abstracted in the form of identified patient data and subsequently reviewed in Epic electronic health record (Epic, Verona, WI). We retrospectively studied adult subjects with SCD seen during routine clinical care between 2010 and 2023. Selected subjects had a diagnosis of iron overload, determined by 2 consecutive ferritin levels >1000ng/ml in steady state plus a significant transfusion history. We extracted data on clinical laboratory markers, abdominal imaging, use of iron chelation at baseline and in the final year of follow up, whether patients were receiving chronic erythrapheresis treatment at baseline and at end of follow up, and if alive at the end of the follow up period. Subjects have variable start date and follow up period, beginning at the start of diagnosis of iron overload and ending in June 2023 or last identifiable follow up visit, or mortality. Result. Baseline characteristics of 83 adult patients included in our study are summarized in table 1. Seventy percent of the patients were female and just about everyone had HbSS disease. The females had older median age (39.5year; IQR 32-50 years) than males. The mean ferritin value was significantly higher than the initial measure after a median follows up period of 5.3 years. During the follow up period, 40% of male patients discontinued iron chelation therapy whereas only 5.6% of females did the same. Multivariable analyses were performed for association between change in ferritin measure (between follow up period) with demographic data and other covariates presented in Table 1. Covariates were eliminated by backward selection. Predictors retained in the final model include follow-up period, initial ferritin value, gender, ALT, AST, and albumin. Females had a higher drop in their follow up ferritin, but this was not significant. Neither use of iron chelation therapy at baseline nor erythrapheresis at baseline predicted a change in ferritin value, however we did not collect information on compliance or duration of therapy. Patients followed up for longer duration, or who have higher ALT, had subsequent higher measure for follow up ferritin. Higher albumin predicted a lower ferritin at follow up. The effects of liver markers on ferritin are likely correlative only. After a median follow up period of 5.3years, about 22% of the patients were confirmed to be deceased. Some patients lost to follow up have an indeterminate alive status. Predictors of mortality in multivariate analysis include follow up ferritin value, albumin, and HCV status. Positive HCV status had a strong association with cirrhosis (p=0.001) as 71% of HCV positive individuals had cirrhosis. In turn 53% of the cirrhotic patients died in the follow up period. Conclusion. Here we present an overview of the clinical outcomes of adult patients with SCD and iron overload during a median follow up period of 5.3 years. Despite limitations of a typical retrospective study, our study illustrates the difficulty associated with the management of transfusional iron overload during routine treatment follow up, especially in patients continuing to undergo episodic transfusion treatment. We also continue to underline the low adherence with chelation therapy in adult populations with SCD and iron overload, and the high mortality associated with the condition.

Betibeglogene Autotemcel; A New Hope For Transfusion Dependent Beta-Thalassaemia.

Respected Editor, Beta thalassaemia is an autosomal recessive disorder that leads to abnormal production of functional adult haemoglobin because of either inadequate or absent production of the B globin chain (beta+/beta0).1 Transfusion-dependent thalassemia (TDT) is a rare and most severe form requiring life-long blood transfusions. To mitigate the effects of TDT, life-long blood transfusions every 2-5 weeks are required, which can elicit transfusion-based reactions and lead to an iron overload state, which can further cause widespread organ damage despite the use of iron chelation therapy.2 Continue...

Economic and clinical burden of managing transfusion-dependent β-thalassemia in the United States

AimsTo describe clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with transfusion-dependent β-thalassemia (TDT) in the United States.Materials and methodsMerative MarketScan Databases were used to identify patients with β-thalassemia between 1 March 2010, and 1 March 2019. Patients were eligible for inclusion with ≥1 inpatient claim or ≥2 outpatient claims for β-thalassemia and ≥8 red blood cell transfusions (RBCTs) during any 12-month period after and including the date of the first qualifying β-thalassemia diagnosis code. Matched controls consisted of individuals without β-thalassemia. Clinical and economic outcomes of patients were assessed during ≥12 months of follow-up, defined as the period from the index date (i.e. the first RBCT) to either the end of continuous enrollment in benefits, inpatient death, or 1 March 2020.ResultsOverall, 207 patients with TDT and 1035 matched controls were identified. Most patients received iron chelation therapy (ICT) (91.3%), with a mean of 12.1 (standard deviation [SD] = 10.3) ICT claims per-patient-per-year (PPPY). Many also received RBCTs, with a mean of 14.2 (SD = 4.7) RBCTs PPPY. TDT was associated with higher annual ($137,125) and lifetime ($7.1 million) healthcare costs vs. matched controls ($4183 and $235,000, respectively). Annual costs were driven by ICT (52.1%) and RBCT use (23.6%). Patients with TDT had 7-times more total outpatient visits/encounters, 3-times more prescriptions, and 33-times higher total annual costs than matched controls.LimitationsThis analysis may underestimate the burden of TDT, as indirect healthcare costs (e.g. absenteeism, presenteeism, etc.) were not included. Results may not be generalizable to patients excluded from this analysis, including those with other types of insurance or without insurance.ConclusionsPatients with TDT have high HCRU and direct healthcare costs. Treatments that eliminate the need for RBCTs could reduce the clinical and economic burden of managing TDT.

5613341 REAL-WORLD CHANGES IN KIDNEY FUNCTION FOR PATIENTS WITH SICKLE CELL DISEASE OR OTHER ANAEMIAS RECEIVING IRON CHELATION THERAPY IN THE US

Background: Treating sickle cell disease (SCD) and other anaemias with frequent blood transfusions increases the bodily iron burden, which can be mitigated through iron chelation therapy (ICT).1 As these populations age, impaired kidney function becomes more prevalent, which is also impacted by disease progression and use of ICT.1 An understanding of how kidney function changes over time for real-world patients on ICT is critical for optimal long-term management. Aims: To evaluate real-world changes in kidney function, specifically in estimated glomerular filtration rate (eGFR) and serum creatinine levels in patients with SCD or other anaemias and who received ICT in the United States (US). Methods: Electronic medical records were gathered from the TriNetX electronic database, representing 46 US healthcare organisations. Records were dated between 1999 and 2021 (data cutoff date: September 7, 2021). The baseline period for each patient was defined as the 365 days prior to the date ICT was first dispensed; the follow-up period was the following 730 days (24 months). eGFR and serum creatinine assessments during the follow-up period were analysed using a mixed model repeated measures approach, adjusted for first iron chelation event, age, sex, race, time of assessment, and baseline eGFR, creatinine, and haemoglobin. Eligible patients had to have at least 2 eGFR measurements during follow-up. Study endpoints were changes in eGFR, serum creatinine level, proteinuria, and albuminuria over time, as well as the proportion of patients with SCD or other anaemias who developed kidney impairment (eGFR <60 mL/min/1.73m2) during follow-up. Results: Analyses of eGFR and creatinine levels were conducted on a total of 1527 patients diagnosed with SCD (n = 1510) or other anaemias (n = 17). More patients were first dispensed deferasirox (n =1237) than deferoxamine (n = 223) and deferiprone (n = 67). Compared to baseline, eGFR values remained stable over 24 months after patients were dispensed deferiprone, while there were statistically significant decreases in eGFR over the same period for those given deferasirox or deferoxamine (Table 1). The proportions of patients with SCD or other anaemias who developed kidney impairment during follow-up were 13.9% (deferasirox), 9.2% (deferoxamine), and 11.9% (deferiprone). There were statistically significant reductions in eGFR and statistically significant increases in serum creatinine over 24 months from baseline among patients who first received deferasirox and deferoxamine (Table 1). Proteinuria and albuminuria analyses were not completed due to insufficient data; similarly, a small number of patients in the database were diagnosed with other anaemias to support distinct, formal analysis for this patient group. Summary/Conclusion: The data from this real-world US analysis indicate patients who were prescribed deferiprone had worse baseline kidney function prior to initiation of ICT. The data also indicate that deferiprone has a lesser detrimental impact on kidney function as measured by eGFR and serum creatinine level. This study could not assess treatment adherence. Although there are limitations owing to the retrospective nature of the data, the results may assist clinicians should in their choice of ICT for patients who have or are at risk for developing kidney impairment.Reference 1. Bhandari, Galanello, Eur J Haematol 2012; 89:187

Effect of Luspatercept on Red Blood Cell (RBC) Transfusion Burden, Iron Chelation Therapy (ICT), and Iron Overload in Adults with Transfusion-Dependent β-Thalassemia (TDT) from the BELIEVE Trial: A Long-Term Analysis

Effect of Luspatercept on Red Blood Cell (RBC) Transfusion Burden, Iron Chelation Therapy (ICT), and Iron Overload in Adults with Transfusion-Dependent β-Thalassemia (TDT) from the BELIEVE Trial: A Long-Term Analysis

S272: SAFETY AND PRELIMINARY PHARMACODYNAMIC EFFECTS OF THE FERROPORTIN INHIBITOR VAMIFEPORT (VIT-2763) IN PATIENTS WITH NON-TRANSFUSION-DEPENDENT BETA THALASSEMIA (NTDT): RESULTS FROM A PHASE 2A STUDY

Background: NTDT is characterized by an imbalanced α/β-globin chain ratio, ineffective erythropoiesis, increased intestinal iron absorption and iron overload. Vamifeport inhibits ferroportin-mediated iron export into plasma and has been shown to decrease serum iron and transferrin saturation (TSAT) levels in relevant animal disease models and healthy volunteers. Aims: The primary objective of this multicenter, Phase 2a, double-blind, randomized, placebo-controlled study (NCT04364269) was to assess the safety and tolerability of vamifeport (given once [QD] or twice [BID] daily) versus placebo in patients with NTDT over a 12-week treatment period. A secondary objective was to assess preliminary efficacy of vamifeport versus placebo with respect to pharmacodynamic effects on iron parameters (serum iron, ferritin, hepcidin and TSAT) in these patients. Methods: Adults (18–65 years) with documented NTDT (including β-thalassemia intermedia) who provided informed consent, were included. NTDT was defined as receipt of <5 units of red blood cells during the 24 weeks prior to randomization. Patients also required a mean baseline hemoglobin of ≤11 g/dL on two consecutive measurements ≥1 week apart within 6 weeks prior to randomization. Use of iron chelation therapy (ICT) within 4 weeks prior to randomization was not permitted; patients with TSAT <30%, serum ferritin <150 ng/mL and/or liver iron content ≤1 mg/g (<300 ng/mL/3 mg/g, respectively, for those recently on ICT) were also excluded. Patients received vamifeport at a dose of 60 mg if their body weight was 40–59 kg or 120 mg if their weight was 60–100 kg. Results: Twenty-five patients were included (vamifeport QD n=9, BID n=12, placebo n=4; median age 42.0, 31.0 and 40.5 [range 18–61] years, respectively). Overall, 64% were male, 56% had a body weight <60 kg and 16% had received prior ICT. At baseline, mean (standard deviation [SD]) serum iron concentrations were 27.2 (11.6) µmol/L and mean TSAT was 76.2 (27.6)% for the population as a whole. Mean (SD) serum ferritin concentrations were 746.7 (1431.7) µg/L. There were no differences between groups in treatment-emergent adverse event (TEAE) rates (vamifeport QD 66%, BID 58%; placebo 75%). All TEAEs were mild or moderate intensity, and each was reported only once. There were no deaths or serious AEs (1 patient receiving vamifeport QD had an acute hemolytic event); one TEAE (increased creatine kinase and transaminase levels, not drug-related) led to drug discontinuation in the vamifeport BID group. There were also no clinically relevant changes in any assessed safety parameter. Serum iron concentrations decreased 3 h after first vamifeport dose (Day 1) in all vamifeport-treated patients (mean [SD] decrease: QD -11.3 [7.2] µmol/L; BID -17.0 [9.6] µmol/L) and were maintained below baseline levels at 3–4 h post vamifeport administration at each visit throughout the remaining treatment period. Mean (SD) TSAT also decreased at Day 1 (3 h post dose; QD -32.6 [19.6]%; BID -46.8 [22.6]%) and were below baseline levels 3–4 h post-dose at each subsequent visit in the vamifeport groups (Figure). There were no clinically meaningful changes from baseline in serum iron or TSAT levels in the placebo group, or in ferritin or hepcidin levels in any treatment group. Image:Summary/Conclusion: In this 12-week Phase 2a study, vamifeport had a favorable safety and tolerability profile and showed promising target engagement and pharmacodynamic effects on serum iron and TSAT levels versus placebo in adults with NTDT.

Myoglobin knockout mice experience less damage and more immune infiltration in muscle pressure injury

IntroductionMuscle pressure ulcers are slow to heal and classified as “chronic” wounds, but the reasons for slow healing are not well understood. Elevated levels of extracellular hemoglobin have been implicated in the pathogenesis and impaired healing of sickle cell and vascular ulcers. We question whether extracellular release of myoglobin after muscle pressure injury might contribute to a hostile wound environment, analogous to hemoglobin. We hypothesise that knockout of myoglobin will decrease tissue damage and improve the microenvironment of muscle pressure ulcers.MethodsWe developed germline Myoglobin knockout (Mb–/–) mice via CRISPR deletion. Similar to previous studies, our adult Mb–/– mice show no phenotypic differences to Mb‐wildtype (Mb+/+) mice. Pressure injuries were created in mice by applying a pair of 12 mm magnets to the dorsal skinfold and panniculus carnosus muscle, in two intervals of 12 hours. We compared pressure ulcers in elderly 20‐month‐old mice carrying Mb–/– or Mb+/+. Ex vivo wound tissues were analysed at day 3 after injury.ResultsMb‐wildtype mice had high levels of ferric iron in the wound localized to the extracellular space and infiltrating cells (presumably macrophages). In knockout mice, iron was undetectable. The knockout mice had smaller pressure ulcers post‐injury and 50% less tissue damage at the wound centre (p &lt; 0.01), compared to control Mb+/+ mice. In addition, the wounds of Mb–/– mice show a marked decrease in protein nitration (2.7‐fold decrease in nitrotyrosine levels; p &lt; 0.0001) compared to Mb+/+ mice. Furthermore, Mb‐knockout wounds exhibited an almost 21‐fold decrease in DNA oxidation, measured by oxidised guanine (8‐oxoguanine; p &lt; 0.0001) compared to Myoglobin+/+. We found 3.5‐fold greater infiltration of immune cells (p &lt; 0.01) and higher CCL7 chemokine expression (p &lt; 0.01) in Mb‐knockout tissues than Mb‐wildtype. Furthermore, Mb–/– wounds displayed a four‐fold decrease in citrullinated histone 3 (p &lt; 0.0001), a marker of extracellular traps, compared to Mb+/+.ConclusionIn the absence of myoglobin, pressure‐injured tissues displayed less oxidative and nitrosative damage. Interestingly, they also showed higher immune infiltration and decreased extracellular traps, meaning that increased immune infiltration co‐occurred with decreased oxidative stress. We conclude that extracellular myoglobin contributes to oxidative stress and immune dysfunction in muscle pressure ulcers, and its removal causes less tissue death. This has important implications for the use of iron chelation therapy in the treatment of muscle pressure ulcers.

Effect of Iron Chelator on Renal Function in Thalassemia Patients who Undergo Regular Transfusion

Background: The thalassemia family of genetic disorders is characterized by an abnormal synthesis of the hemoglobin chain, resulting in chronic anemia in some people and clinically asymptomatic in others. There have been very few studies conducted on the effects of thalassemia on the kidneys, which typically included patients treated with deferoxamine having both glomerular and tubular dysfunction. Objective: This research aimed to determine whether kidney dysfunction is observed in young thalassemic individuals manipulating both conventional and primitive markers of kidney dysfunction, and to associate the results to the use of iron chelation therapy. Methods: We measured serum cystatin C (Cys C), tubular phosphorus reabsorption (TPRA), fractional sodium excretion (FNE), and 2-microglobulin, urine calcium, protein, and glucose levels in addition to the usual renal biochemistry. Results: A whole of 42 individuals, ranging in age from 4 to 23, were included in this study and were split into two groups for study (group A taking deferoxamine alone, and group B taking deferiprone coupled with deferoxamine). An increased Cys C level (36%) and proteinuria (24%) were seen in a large percentage of patients, as were tubulopathy with hypercalciuria (35.5 %) and point out 2-MG excretion (33.5 %). Conclusion: Patients with -thalassemia seem to suffer from renal dysfunction even when they are young, so it is important to monitor early signs of renal dysfunction. There is a need for further research into the effect of novel chelators on parameters tubular function. Keywords: Deferiporin, iron chelator, thalassemia, Peshawar, dfo

From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox.

Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage. This therapeutic approach is already widely used in thalassemic patients and in low-risk Myelodysplastic Syndrome (MDS) patients. More recently, ICT has been proposed for high-risk MDS, especially when an allogeneic bone marrow transplantation has been planned. Furthermore, other hematological and hereditary disorders, characterized by considerable transfusion support to manage anemia, could benefit from this therapy. Meanwhile, data accumulated on how iron toxicity could exacerbate anemia and other clinical comorbidities due to oxidative stress radical oxygen species (ROS) mediated by free iron species. Taking all into consideration, together with the availability of approved oral iron chelators, we envision a larger use of ICT in the near future. The aim of this review is to better identify those non-thalassemic patients who can benefit from ICT and give practical tips for management of this therapeutic strategy.

Relationship between transfusion burden, healthcare resource utilization, and complications in patients with beta-thalassemia in Taiwan: A real-world analysis.

BackgroundThis study utilized a population‐based claims database to identify patients with beta‐thalassemia and evaluate associations between transfusion burden, healthcare resource utilization (HCRU), and complications.Study design and methodsTaiwan's National Health Insurance Research Database was used to identify patients with beta‐thalassemia (ICD‐10 D56.1) in 2016. Patients with a beta‐thalassemia claim in 2016 were indexed into the study at their first claim on or after January 1, 2001 in the dataset through to December 31, 2016 and followed until the end of study. During the follow‐up period, red blood cell transfusion (RBCT) units, HCRU, iron chelation therapy use, and beta‐thalassemia‐related complications incidence were recorded. Patients were grouped into transfusion burden severity cohorts based on average number of RBCT units per 12 weeks during follow‐up: 0 RBCT units, >0 to <6 RBCT units (mild), ≥6 to <12 RBCT units (moderate), and ≥12 RBCT units (severe).ResultsA total of 2984 patients were included with mean follow‐up of 6.95 years. Of these, 1616 (54.2%) patients had no claims for RBCT units, 1112 (37.3%) had claims for >0 to <6 RBCT units, 112 (3.8%) for ≥6 to <12 RBCT units, and 144 (4.8%) for ≥12 RBCT units per 12 weeks. Transfused patients had significantly more all‐cause HCRU and iron chelation therapy compared with non‐transfused patients during follow‐up. Thalassemia‐related HCRU and risk of liver, endocrine, cardiac, and renal complications were significantly and positively correlated with increases of RBCT units.DiscussionClinical and healthcare resource burden of patients with beta‐thalassemia is closely related to transfusion burden.

A Systematic Review and Meta-Analysis of the Effect of Iron Chelation Therapy on Survival in Patients with Lower Risk Myelodysplastic Syndrome

Background: Anemia is the most common cytopenia among patients with myelodysplastic syndromes (MDS) often necessitating regular red blood cell (RBC) transfusions. As a result, most patients develop iron overload (IO). RBC transfusion dependency and IO have been associated with worse clinical outcomes, including inferior overall survival (OS), in MDS patients. While iron chelation therapy (ICT) is recommended by most clinical guidelines and experts for select MDS patients, the use of ICT remains controversial in the absence of published, randomized controlled trials. To evaluate the impact of ICT on survival among lower risk MDS patients, we performed a systematic review and meta-analysis (SRMA) of the literature.Methods: We conducted an SRMA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. PubMed and Embase electronic databases were searched through October 2016 with search terms “MDS” OR “myelodysplastic syndrome” AND “iron chelation” OR “iron chelating” OR “iron overload” AND “survival” OR “death” AND “study” OR “trial.” Additionally, the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry, and abstracts from recent American Society of Hematology annual meetings (years 2014-2016) were searched. One study, published in 2014, had an updated analysis in 2017 that was used for the current analysis. Information abstracted included data relating to study and patient characteristics, outcome measures (mortality and progression to acute myeloid leukemia [AML]), and measures of effect (calculated odds, hazard ratios [HRs], and confounding variables for adjustment). A Random Effects model was used to compute an adjusted HR (aHR) among the different studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. Study heterogeneity was assessed using the Cochran Q and the I2 statistic. Publication bias was assessed through visual examination of a funnel plot and with the Egger's test for small-study effects.Results: Of the 331 records screened, 23 were assessed for eligibility, and 9 were included (Figure 1). Of these 9 studies, 6 were considered to be of high quality based on the NOS. All 9 were observational studies (4 prospective and 5 retrospective); 8 were identified as including patients with the International Prognostic Scoring System (IPSS)-defined low and intermediate-1 risk MDS. In these 8 studies, ICT was associated with an overall lower risk of mortality (aHR 0.43; 95% confidence interval [CI] 0.30-0.60; p < 0.01) (Figure 2). The pooled estimate of the ratio of median unadjusted survival times was 2.02 (95% CI 1.64-2.49), indicating that the median OS for patients receiving ICT was approximately twice that for patients who did not receive ICT. There was evidence of significant heterogeneity across studies for this outcome measure with I2 = 64% and Cochran's Q statistic = 19.8 (p = 0.006). Although the direction of effects did not change, heterogeneity was significant in prospective studies (I2 = 73%; Cochran's Q statistic = 7.4, p = 0.02), but not in retrospective studies (I2 = 9.8%; Cochran's Q statistic = 4.4, p = 0.35). In the 2 studies that reported on benefits of adequate chelation, any degree of chelation was found to confer a survival benefit, but this was to a lesser degree than the survival benefit accrued by those who received higher adequate doses. ICT seemed to decrease the risk of progression to AML (odds ratio 0.526; 95% CI 0.37-0.74; p < 0.001) in the studies that reported on this outcome (Figure 3); these studies displayed no significant heterogeneity. The impact of ICT on end organ damage could not be assessed due to non-uniform reporting of studies.Conclusions: This SRMA suggests a significant reduction in the adjusted risk of mortality among IPSS low and intermediate-1 risk MDS patients treated with ICT. Furthermore, our analysis suggests that ICT is associated with delayed progression to AML, although the causality of these associations cannot be established based on this study. Randomized controlled studies are needed to confirm these findings. [Display omitted] DisclosuresBallas:Novartis: Honoraria, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Direct Medical Care Cost Associated with β-Thalassemia Care in Turkey

Background: β-thalassemia is a common disorder in Turkey relative to many other countries. To our knowledge, there are no recent data in the literature on the direct medical care costs associated with β-thalassemia. We conducted a β-thalassemia treatment center survey and chart review to estimate the numbers of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia currently receiving care and the associated direct medical care costs in Turkey.Methods: A preliminary list of β-thalassemia-treating centers was generated from the IMS Health audit of hospitals and treatment centers across Turkey based on the use of iron chelation therapy (ICT) agents. One or more hematologists or pediatricians in each potential hospital ward were contacted to determine the number of patients managed in their ward with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia. TD status was determined using local definitions by each physician. A geographically stratified sample of 60 physicians was then asked to complete a web-based questionnaire on healthcare resource utilization for the four most recent patients under their care: one patient with β-thalassemia major, one with TD β-thalassemia intermedia, one with NTD β-thalassemia intermedia, and one patient at their discretion. Healthcare resource utilization focused on transfusions, ICT, laboratory work, β-thalassemia-associated complications, and inpatient hospital stay. The unit cost of each healthcare utilization was extracted from relevant literature and published government fee schedules. For prescription drug prices, IMS Health sales data in USD were referenced.Results: We identified 107 treatment centers, 91 (85%) of which were successfully surveyed. A total of 2,637 TD β-thalassemia patients (2,059 with β-thalassemia major plus 578 with TD β-thalassemia intermedia) and 2,040 NTD β-thalassemia intermedia patients were reported. Taking into consideration the sampling frame, missing data, infrequent care for NTD β-thalassemia patients, and errors (including the fact that ICT can be used to manage conditions other than β-thalassemia), we estimated there are approximately 4,000 TD and 4,000 NTD β-thalassemia patients in Turkey. A total of 212 β-thalassemia patient records were reviewed (72 β-thalassemia major, 72 TD β-thalassemia intermedia, and 68 NTD β-thalassemia intermedia). Both the mean and median ages were about 20 years old, and the ages were similar between patients with TD and NTD β-thalassemia. For patients with β-thalassemia major, the total annual direct costs per patient were USD 14,360, of which ICT was the most expensive cost component at USD 9,919, followed by in-hospital stay (USD 1,786), transfusions (USD 1,718), complications (USD 800), and laboratory tests (USD 193). Patients with TD β-thalassemia intermedia incurred nearly identical medical care costs of USD 14,940, of which USD 10,301 was attributable to ICT. Not all TD β-thalassemia patients received transfusions at β-thalassemia treatment centers. For patients who did receive transfusions at β-thalassemia treatment centers (n = 85), patients with β-thalassemia major (n = 45) and TD β-thalassemia intermedia (n = 40) received on average 1.6 and 1.5 red blood cell units per month, respectively. Every patient with TD β-thalassemia received ICT, and deferasirox was the most commonly administered chelation treatment, prescribed to 91 of 144 patients. The annual direct cost per patient with NTD β-thalassemia intermedia was lower at USD 9,286, primarily owing to lower healthcare utilization of ICT and transfusions. Combining the costs of TD and NTD β-thalassemia treatment, we estimated that the total annual direct medical care cost was approximately USD 95,491,900 in Turkey, with TD β-thalassemia patients accounting for USD 58,347,900 (61.1%).Conclusions: β-thalassemia remains a prevalent disease in Turkey where there are an estimated 4,000 TD and 4,000 NTD patients. The disease is associated with significant consumption of healthcare resources, with the total annual direct medical care cost estimated to be over USD 95 million. The costs reported in this study were likely underestimated, as many patients who received transfusions outside of β-thalassemia treatment centers were not captured in the chart review. DisclosuresAntmen:Celgene: Honoraria, Other: Advisory for the project Burden of illness in thalassemia; Novartis: Other: Advisory board; Jazz: Other: Advisory board . Angelucci:Roche: Other: Advisory board: biosimilars; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Jazz: Other: Advisory board: AML; Novartis Oncology: Other: Advisory board: iron toxicity; Celgene: Honoraria, Other: Advisory: research project ; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during . Losi:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Burrows:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Bartiromo:Celgene: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership.

Direct Medical Care Costs Associated with β-Thalassemia Care in Italy

Background: β-thalassemia is a prevalent disease in Italy relative to many other countries. There is a paucity of data in the literature on the direct medical care costs associated with β-thalassemia. We conducted a β-thalassemia treatment center survey and chart review to estimate the numbers of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia currently under care and the associated direct medical care costs in Italy.Methods: A preliminary list of β-thalassemia treatment centers was generated from the IMS Health audit of hospitals and treatment centers across Italy based on the use of iron chelation therapy (ICT) agents. One or more hematologists or pediatricians in each potential hospital ward were contacted, by telephone or in-person interview, and asked about the number of patients with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia managed in their ward. TD status was determined using local definitions by each physician. Subsequently, a geographically stratified sample of 60 physicians was asked to complete a web-based questionnaire on healthcare resource utilization for the four most recent patients under their care: one patient with β-thalassemia major, one with TD β-thalassemia intermedia, one with NTD β-thalassemia intermedia, and one patient at their discretion. Healthcare resource utilization focused on five categories: transfusions, ICT, laboratory work, β-thalassemia-associated complications, and inpatient hospital stay. Unit costs of each healthcare utilization were extracted from relevant literature and published government fee schedules. For prescription drug prices, IMS Health sales data were referenced (values were provided in EUR).Results: We identified 124 treatment centers, 114 (92%) of which were successfully surveyed. A total of 5,748 TD β-thalassemia patients (4,515 with β-thalassemia major plus 1,233 with TD β-thalassemia intermedia) and 1,296 NTD β-thalassemia intermedia patients were reported. Taking into consideration the sampling frame, missing data, infrequent care for NTD β-thalassemia intermedia patients, and errors (such as the fact that ICT can be used to manage conditions other than β-thalassemia), we estimated that there are approximately 6,500 TD and 6,000 NTD β-thalassemia intermedia patients in Italy. A total of 205 β-thalassemia patient records were reviewed (109 β-thalassemia major, 53 TD β-thalassemia intermedia, and 43 NTD β-thalassemia intermedia); the median ages for patients with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia were 37, 44, and 43 years, respectively. For patients with β-thalassemia major, the total annual direct cost per patient was EUR 31,883, of which ICT was the most expensive cost component at EUR 22,519, followed by transfusions (EUR 6,115), complications (EUR 1,427), in-hospital stay (EUR 1,213), and laboratory tests (EUR 392). Patients with TD β-thalassemia intermedia incurred nearly identical medical care costs at EUR 31,183, of which EUR 22,963 was attributable to ICT. Of the 162 TD patient records reviewed, 83 patients required 1-2 red blood cell (RBC) units per month, whereas 78 patients required ≥ 3 RBC units per month (1 patient had missing data). Every patient with TD β-thalassemia received ICT, and deferasirox was the most commonly administered chelation agent, prescribed to 103 of 162 patients. The annual direct cost per patient with NTD β-thalassemia intermedia was lower at EUR 13,496, largely owing to lower healthcare utilization of ICT and transfusions. Combining the costs of TD and NTD β-thalassemia treatment, we estimated that the total annual direct medical care cost was approximately EUR 287,162,500 in Italy, of which TD patients accounted for EUR 204,682,000 (71.3%).Conclusions: β-thalassemia remains a prevalent disease in Italy with about 6,500 TD and 6,000 NTD β-thalassemia patients. Management of the disease consumes significant healthcare resources, with the total annual direct medical care cost for β-thalassemia treatment estimated to be approximately EUR 287 million. DisclosuresAngelucci:Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Roche: Other: Advisory board: biosimilars; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Jazz: Other: Advisory board: AML; Novartis Oncology: Other: Advisory board: iron toxicity; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Celgene: Honoraria, Other: Advisory: research project . Antmen:Jazz: Other: Advisory board; Novartis: Other: Advisory board; Celgene: Honoraria, Other: Advisory for the project Burden of illness in thalassemia. Losi:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Burrows:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Bartiromo:Celgene: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership.

Longitudinal Effect of Luspatercept Treatment on Iron Overload and Iron Chelation Therapy (ICT) in Adult Patients (Pts) with β-Thalassemia in the Believe Trial

Longitudinal Effect of Luspatercept Treatment on Iron Overload and Iron Chelation Therapy (ICT) in Adult Patients (Pts) with β-Thalassemia in the Believe Trial

MDS-171: Effects of Luspatercept on Serum Ferritin in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) with Ring Sideroblasts (RS) in the Phase 3 MEDALIST Trial

Background: Iron overload, resulting from RBC transfusions or ineffective erythropoiesis, is associated with significant morbidity in MDS. Aims: To assess changes from baseline in serum ferritin (SF) and iron chelation therapy (ICT) use in the MEDALIST trial patients ( NCT02631070 ). Methods: Patients (IPSS-R-defined lower-risk MDS with RS; ≥18 years; unsatisfactory response to or ineligible for EPO-based therapy; required regular RBC transfusions) had luspatercept (1.0 mg/kg, titration up to 1.75 mg/kg) or placebo administered subcutaneously every 3 weeks. Results: Of 153 luspatercept-treated patients, 87 (56.9%) had low and 66 (43.1%) high baseline RBC transfusion burden (LTB and HTB; Conclusion: Luspatercept treatment resulted in SF decreases, particularly in HTB patients and those with high baseline SF who experienced significant RBC transfusion reduction. Overall, ICT use was reduced with luspatercept.

A Global Systematic Literature Review on the Burden of Illness in Transfusion-Dependent β-Thalassemia

Introduction: Adults with transfusion-dependent (TD) anemia due to β-thalassemia experience significant side effects and increased mortality due to iron overload resulting from repeated red blood cell (RBC) transfusions. To characterize the burden associated with TD anemia in adults with β-thalassemia, a systematic literature review (SLR) was conducted to gather data on the clinical, health-related quality of life (HRQoL), economic, and epidemiological burdens, as well as treatment patterns for patients with TD anemia due to β-thalassemia. Methods: Systematic searches (covering the period from database inception to April 2019) were executed in MEDLINE®, Embase®, and the Cochrane Library for observational studies on the burden of illness in adult patients with TD anemia associated with β-thalassemia. Conference proceedings from the last 2 years were searched to identify recent data not yet published in full text. References were screened at the abstract and full-text levels by 2 independent reviewers, with methodology following Cochrane guidelines. Results: Searches of electronic databases yielded 1,252 citations. After removing duplicates, 874 abstracts were reviewed, with 72 publications progressing to full-text review. Five publications from database searches that met the eligibility criteria were included. An additional 11 references were identified for inclusion from hand searching and conference proceedings, resulting in 16 total references reporting on 13 unique study populations (Table, Figure). Study population sizes ranged from 14 to 1,548 patients, with mean ages varying from 19 to 43 years when reported. Definitions of transfusion dependence were reported in 5 studies; 3 studies defined transfusion dependence as receipt of ≥ 8 RBC transfusions over a 1-year period. Clinical outcomes were rarely reported across studies; 1 study reported survival over time (overall survival [OS] of 96% at 1 year, 86% at 2 years, and 71% at 3 years, with no significant differences by sex). Use of iron chelation therapy (ICT) varied from 63.6% to 100% in 5 studies; 1 study reported that 72% of patients received oral iron chelators, 30% received injectable iron chelators, and 14% received both oral and injectable ICT. Mean total annual cost per person for treating patients with β-thalassemia who received regular RBC transfusions was $128,062, significantly higher than for matched controls ($5,438; P &lt; 0.001). The main cost drivers were ICT (48%) and RBC transfusions (31%). Hospitalizations related to transfusions varied widely within and across studies. Instruments that were used to assess patient HRQoL included the SF-36, BPI Short Form, TranQoL, and FACT-An; results were inconsistent across studies. Most studies indicated that β-thalassemia impacted HRQoL relative to the general population. Relative to normative US data (50), patients with β-thalassemia had lower SF-36 scores in role-physical (47.33), social functioning (46.79), role-emotional (46.78), physical component summary (46.8), and for general health (41.5). Patients were found to experience transfusion-related pain throughout the transfusion cycle, with increased pain associated with higher transfusion frequency. A cross-sectional study found that families of patients with β-thalassemia experienced substantial caregiver burden, including employment and financial problems affecting nearly half of families and a high level of parental anxiety. Epidemiological studies were limited to sparse mortality and comorbidity data and did not present data on the incidence or prevalence of adults with TD anemia in β-thalassemia. Mortality in patients with thalassemia major was 12.8%; primary comorbidities were osteoporosis (16%-100%) followed by cardiac disease (30%), hypogonadism (22%), hypothyroidism (12%) and depression (2%). Conclusions: TD β-thalassemia affects multiple areas of a patient's life and well-being. Although limited data were available for the adult population, studies suggested a significant burden affecting the HRQoL and economic outcomes of patients with TD β-thalassemia in countries around the world. To better understand the burden of illness in TD β-thalassemia, further high-quality observational studies on treatment patterns and epidemiology, as well as those on the clinical, HRQoL, and economic burdens, are needed to close the evidence gaps identified by this SLR. Disclosures Turner: Evidera: Employment; Celgene Corporation: Consultancy. Deshpande:Celgene Corporation: Consultancy; Evidera: Employment. Chitnis:Celgene Corporation: Consultancy; Evidera: Employment. Byrnes:Evidera: Employment. Pelligra:Evidera: Employment; Celgene Corporation: Research Funding. Rines-MacEachern:Evidera: Employment. Morison:Celgene Corporation: Employment. Tang:Celgene Corporation: Employment, Equity Ownership.

Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.

Beta thalassaemia is a common inherited blood disorder. The need for frequent blood transfusions in this condition poses a difficult problem to healthcare systems. The most common cause of morbidity and mortality is cardiac dysfunction from iron overload. The use of iron chelation therapy has reduced the severity of systemic iron overload but specific, non-toxic treatment is required for removal of iron from the myocardium. To assess the effects of calcium channel blockers combined with standard iron chelation therapy in people with transfusion-dependent beta thalassaemia on the amount of iron deposited in the myocardium, on parameters of heart function, and on the incidence of severe heart failure or arrhythmias and related morbidity and mortality. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials databases, and the reference lists of relevant articles and reviews.Date of last search: 24 February 2018. We included randomised controlled trials of calcium channel blockers combined with standard chelation therapy compared with standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia. Two authors independently applied the inclusion criteria for the selection of trials. Two authors assessed the risk of bias of trials and extracted data and a third author verified these assessments. The authors used the GRADE system to assess the quality of the evidence. Two randomised controlled trials (n = 74) were included in the review; there were 35 participants in the amlodipine arms and 39 in the control arms. The mean age of participants was 24.4 years with a standard deviation of 8.5 years. There was comparable participation from both genders. Overall, the risk of bias in included trials was low. The quality of the evidence ranged across outcomes from low to high, but the evidence for most outcomes was judged to be low quality.Cardiac iron assessment, as measured by heart T2*, did not significantly improve in the amlodipine groups compared to the control groups at six or 12 months (low-quality evidence). However, myocardial iron concentration decreased significantly in the amlodipine groups compared to the control groups at both six months, mean difference -0.23 mg/g (95% confidence interval -0.07 to -0.39), and 12 months, mean difference -0.25 mg/g (95% confidence interval -0.44 to -0.05) (low-quality evidence). There were no significant differences between treatment and control groups in serum ferritin (low-quality evidence), liver T2* (low-quality evidence), liver iron content (low-quality evidence) and left ventricular ejection fraction (low-quality evidence). There were no serious adverse events reported in either trial; however, one trial (n = 59) reported mild adverse events, with no statistically significant difference between groups (low-quality evidence). The available evidence does not clearly suggest that the use of calcium channel blockers is associated with a reduction in myocardial iron in people with transfusion-dependent beta thalassaemia, although a potential for this was seen. There is a need for more long-term, multicentre trials to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should be designed to compare commonly used iron chelation drugs with the addition of calcium channel blockers to investigate the potential interplay of these treatments. In addition, the role of baseline myocardial iron content in affecting the response to calcium channel blockers should be investigated. An analysis of the cost-effectiveness of the treatment is also required.

Overcoming barriers to treating iron overload in patients with lower-risk myelodysplastic syndrome

Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic neoplasms characterized by ineffective erythropoiesis, anemia, and/or cytopenias. Supportive care for patients with MDS involves frequent red blood cell transfusions, which places patients with ongoing transfusional dependence (TD) at risk for iron overload (IO). Development of IO and tissue iron deposition can increase the risk of cardiac, hepatic, and endocrine toxicities, infection, and progression to acute myeloid leukemia. Iron chelation therapy (ICT) is an option for lower-risk MDS patients to reduce their degree of IO and possibly improve survival; use of these agents in thalassemia patients with TD and IO has been associated with reduced IO-associated complications and better survival. At present, there are several barriers to the regular use of ICT, such as a lack of randomized trial evidence and consistent guidance on diagnosis of IO and when to implement ICT, as well as barriers in adherence to/tolerability of ICT.

Qualitative modification and development of patient- and caregiver-reported outcome measures for iron chelation therapy

BackgroundCompliance, palatability, gastrointestinal (GI) symptom, and treatment satisfaction patient- and observer-reported outcome (PRO, ObsRO) measures were developed/modified for patients with transfusion-dependent anemias or myelodysplastic syndrome (MDS) requiring iron chelation therapy (ICT).MethodsThis qualitative cross-sectional observational study used grounded theory data collection and analysis methods and followed PRO/ObsRO development industry guidance. Patients and caregivers of patients with transfusion-dependent anemias or MDS were individually interviewed face-to-face to cognitively debrief the Compliance, Palatability, GI Symptom Diary, and Modified Satisfaction with Iron Chelation Therapy (SICT) instruments presented electronically. Interviews were conducted in sets. Interviews began open-endedly to spontaneously elicit ICT experiences. Item modifications were debriefed during the later interviews. Interviews were audio recorded, transcribed, and coded. Data was analyzed using ATLAS.ti qualitative research software.ResultsTwenty-one interviews were completed (Set 1: 5 patients, 6 caregivers; Set 2: 6 patients, 4 caregivers) in 6 US cities. Mean age was 43 years for patients and 9 years for children of caregivers. Conditions requiring ICT use across groups included transfusion-dependent anemias (85.7%) and MDS (14.3%). Concepts spontaneously reported were consistent with instruments debriefed. Interview analysis resulted in PRO and ObsRO versions of each instrument: Compliance (2 items), Palatability (4 items), GI Symptom Diary (6 items), and Modified SICT (PRO = 13, ObsRO = 17 items).ConclusionQualitative research data from cognitive interviews supports the content validity and relevance of the instruments developed/modified. Quantitative validation of these PRO and ObsRO measures is needed testing for validity, reliability, and responsiveness for future research use with new formulations of oral ICT.