Randomized Controlled Trial of the Efficacy and Safety of Deferiprone: Subgroup Analysis of Pediatric Patients in Iron-Overloaded Patients with Sickle Cell Disease and Other Anemias

Abstract Children with sickle cell disease (SCD) who have their disease managed with frequent blood transfusions often require iron chelation therapy to prevent iron overload. Deferoxamine (DFO) is an iron chelator approved for pediatric use that is often administered via infusion; however, postmarketing research revealed that adherence to treatment in pediatric populations is a key challenge experienced by patients and caregivers due to the burdensome nature of the administration route. Deferiprone (DFP), an oral iron chelator, has recently been approved as a first-line treatment for transfusional iron overload in pediatric and adult patients with SCD and other anemias. We previously reported that DFP is noninferior to DFO in patients with SCD and iron overload (as assessed by liver iron concentration [LIC]) and has an acceptable safety profile. Here, we report a subgroup analysis of the FIRST (NCT02041299) study to assess whether the efficacy and safety of DFP are comparable to DFO in children with SCD. In this phase 4, multicenter, 2-arm, randomized, open-label study, eligible patients were randomized in a 2:1 ratio to receive DFP or DFO for 12 months. The subgroup analysis included children (2-16 years of age) with SCD or another rare anemia who were treated for transfusional iron overload. Children received either DFP orally tid or DFO by subcutaneous infusion 5-7 days a week. Iron load was monitored during the trial and dosage adjustments were allowed when necessary. The primary efficacy endpoint was the change in LIC from baseline to month 12, and data were analyzed for all patients who had a baseline and a follow-up LIC assessment (efficacy population). Absolute neutrophil counts were assessed weekly for the first 6 months, and then every 2 weeks until the end of the study. Additional safety assessments were done monthly with analysis including all patients who received at least 1 dose of the study drug (safety population). Statistical significance between DFP- and DFO-treated groups was calculated via t-test for continuous variables and Fisher's exact test for discrete variables. Of the 228 patients in the safety population, 128 (n=86 in DFP; n=42 in DFO) were children. Five children withdrew from the study due to adverse events (AEs) and 19 withdrew for other reasons. Most children in each treatment group (DFP, 75.6 %; DFO, 80.9%) had a primary diagnosis of SCD (HbS); the remainder had another form of anemia that required chronic transfusions. At the time of first exposure, mean ages (SD) in the DFP- and DFO-treated groups were 9.9 (3.7) years and 10.9 (3.0) (P=0.09), respectively. There were no significant differences between the DFP- and DFO-treatment groups in sex (males 59.3% vs 57.1%; P=0.85), ethnicity (P=0.68), or race (P=0.34). Children treated with DFP or DFO showed no significant differences in overall incidence of AEs (P=0.77) (including neutropenias (P=0.30)), severe AEs (P=0.10), serious AEs (P=0.16), or withdrawals due to an AE (P=0.17). However, a difference in the overall incidence of nonserious AEs considered at least possibly related to DFP treatment (59.3% vs 33.3%; P=0.01) was found. Table 1 shows the most common (≥5%) AEs in children by treatment group. The only individual AE for which the rate was significantly higher in the DFP group vs the DFO group was elevated liver enzymes (P=0.03), a known transient reaction to DFP that typically resolves with continued DFP therapy. In DFP-treated children, there were no AEs observed that had not been previously reported in other patient populations; 1 child developed agranulocytosis; and children <6 years of age treated with DFP demonstrated a comparable safety profile to that of older children (6-16 years of age) treated with DFP. In the efficacy population, after 12 months of treatment, there was no significant difference in the mean (SD) LIC change from baseline in children treated with DFP (n=78) compared to DFO (n=40) (-3.39 ± 4.24 mg/g vs -2.99 ± 3.16 mg/g, respectively; P=0.57). This subgroup analysis of children receiving chronic transfusion therapy for SCD or other anemias corroborates previous findings that treatment with DFP is comparable to DFO in reducing LIC. No new safety concerns were observed in children that have not been previously noted in other populations. Thus, the present findings may benefit children and their healthcare providers when considering effective iron chelation therapy that may also address treatment-adherence concerns. Figure 1 Figure 1. Disclosures Hamdy: Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; ApoPharma: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria. Kwiatkowski: Terumo BCT: Research Funding; Sangamo: Research Funding; Bluebird Bio: Research Funding; Novartis: Research Funding; ApoPharma: Research Funding; Agios: Honoraria; Silence Therapeutics: Honoraria; Celgene: Honoraria; Imara: Other: Consultancy Fees; Bluebird Bio: Other: Consultancy Fees. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Lee: Chiesi Canada Corp: Current Employment. Temin: Chiesi Canada Corp: Current Employment. Fradette: Chiesi Canada Corp: Current Employment. Tricta: Chiesi Canada Corp: Current Employment.

Download Full-text

Clinical Parameters in 391 Iron-Overloaded Patients with Lower-Risk MDS Enrolled in a Prospective, Non-Interventional Multicenter Registry.

Blood ◽

10.1182/blood.v114.22.4834.4834 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4834-4834

Author(s):

Guillermo Garcia-Manero ◽

Billie J. Marek ◽

Roger M. Lyons ◽

Noelia Martinez-Lopez ◽

Carole Paley ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Serum Ferritin ◽

Lower Risk ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Advisory Committees ◽

The Impact

Abstract Abstract 4834 Introduction Despite recent improvements in therapies for patients with myelodysplastic syndromes (MDS), 60–80% will require continuing packed red cell blood (pRBC) transfusions for prolonged periods. Complications resulting from the iron burden may, therefore, become clinically significant for many patients during the course of their disease. Patients with lower-risk MDS have a greater chance of developing the long-term toxicity of iron overload because of their prolonged survival, and are more likely to benefit from effective iron chelation therapy. This report describes data from a registry designed to study the impact of iron overload and iron chelation therapy on organ function and survival in patients with lower-risk MDS. Methods This is an ongoing, prospective, non-interventional, multicenter 5-year registry in 107 US centers, enrolling 600 patients (aged ≥18 years) with lower-risk MDS (by WHO, FAB and/or IPSS criteria) and transfusional iron overload (defined as serum ferritin ≥1000 μg/L and/or having received ≤20 cumulative pRBC units and/or an ongoing transfusion requirement ≥6 units every 12 weeks). Follow-up will be performed at least every 6 months for a maximum of 60 months or until death. Recommended assessments include serum ferritin, creatinine, calculated creatinine clearance, echocardiograms, and endocrine and hematological status. Results As of May 31 2009, 391 patients have enrolled in the registry. Demographic data are available from 389 patients. Median age: 74.4 years (range 21–99); male: 218, female: 171; ethnicity: 331 Caucasian (85%), 25 African-American (6%), 24 Hispanic (6%), five Asian (1%), two Native American (0.5%), and two other (0.5%). The median time since diagnosis (n=385) was <3 years in 217 patients (56%); ≥3–<5 years in 72 (19%); ≥5–<7 years in 48 (12%); and ≥7 years in 48 (12%). The MDS classification of the patients by WHO, FAB and IPSS, as well as patients' serum ferritin and transfusion burden, are summarized in the table. The most frequent concomitant conditions classified by organ (n=384 patients) were: 205 (53%) patients with vascular, 160 (42%) endocrine, and 171 (45%) cardiac dysfunction. At registry entry, 249 patients were receiving erythropoietin; 61 granulocyte colony stimulating factor; seven hydroxyurea; 25 thalidomide (Thalomid); 147 5-azacytidine (Vidaza); 95 lenalidomide (Revlimid) and 90 decitabine (Dacogen). 137 of 391 (35%) patients were on iron chelation therapy at study entry: 34 (9%) received deferoxamine for mean and median treatment durations of 803 and 383 (range 1–4386) days, respectively, while 117 (30%) received deferasirox for mean and median durations of 488 and 396 (9–1269) days, respectively. Calculated creatinine clearance was normal (>80 mL/min) in 37 (9%) patients; mildly abnormal (51–80 mL/min) in 30 (8%); and moderately abnormal (30–50 mL/min) in nine (2%) patients. Conclusions These baseline data indicate the demographic distribution as well as the co-morbidities associated with lower-risk MDS patients. In spite of recent guidelines, fewer than 50% of iron-overloaded patients are receiving any iron chelation treatment, despite the presence of cardiac, vascular and endocrine concomitant conditions in 40-54% of patients. Recent retrospective data highlights the impact of chelation on mortality in lower-risk MDS patients. This ongoing registry will prospectively assess the impact of iron chelation on survival and organ function in iron-overloaded patients with lower-risk MDS. Disclosures Lyons: Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Research Funding. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Improved Survival with Iron Chelation Therapy for Lower IPSS Risk MDS Appears to Have a Stronger Association in Patients with a Non-RARS Diagnosis

Blood ◽

10.1182/blood.v118.21.1732.1732 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1732-1732

Author(s):

Heather A Leitch ◽

Christopher Chan ◽

Chantal S Leger ◽

Lynda M Foltz ◽

Khaled M Ramadan ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Advisory Committees

Abstract Abstract 1732 Background: Several retrospective analyses suggest that transfusional iron overload portends inferior survival in lower risk MDS and that iron chelation therapy (ICT) is associated with improved survival in this group of patients. However an analysis of 126 patients with RARS from the Mayo Clinic showed no association between elevated ferritin level at diagnosis or transfusion burden on overall survival (OS). We performed a retrospective analysis of 268 MDS patients seen at our center to determine whether an association between transfusional iron overload or receiving iron chelation therapy (ICT) and survival differed between RARS and other lower risk MDS. Methods: Patients were identified from the clinical database of the hematology practice. Patients with a diagnosis (dx) of MDS confirmed by bone marrow biopsy (bmbx) were included. Clinical and laboratory data were collected by retrospective chart review. Survival analyses were performed using SPSS version 19. Results: 268 patients with a bmbx confirmed diagnosis of MDS by WHO or FAB criteria were identified. The following patients were excluded: uncertain IPSS score, n=35; intermediate-2 risk, n=33; high risk, n=16; RAEB-t, n=3; concomitant diagnosis of advanced stage non-Hodgkin lymphoma of uncertain type, n=1. The remaining 182 patients had the following characteristics: median age 69.5 (range 30–94) years and 109 (69.9%) were male. Specific MDS dx were: RA, n=27; RARS, n=53; RCMD, n=34; RAEB, n=15; MDS-U, n=22; hypocellular MDS, n=6; 5Q- syndrome, n=6; CMML, n=21. IPSS scores for all patients were: intermediate-1, n=101; low, n=74; uncertain (but IPSS score not >1.0), n=7. The marrow blast count was 6–9 x109/L in 4 patients and <5 x109/L in all others. Specific MDS treatment (rx) was: supportive care, n=82; erythropoiesis stimulating agents (ESA), n=22; immunosuppressive therapy (IST), n=10; lenalidomide, n=7; and chemotherapy, n=6. 137 patients received RBC transfusions and 38 received ICT: deferasirox (DFX), n=19; deferoxamine (DFO), n=9; DFO followed by DFX, n=9; and DFX followed by DFO, n=1. The median duration of ICT was 10.5 (range 0.5–64) months. Clinical features significantly associated with OS in univariate analyses of all 182 patients included: specific MDS dx; IPSS score; total number of red blood cell (RBC) units transfused over the course of follow-up; receiving ICT; specific MDS rx received; requirement for hospitalization; experiencing at least one episode of infection; and AML transformation (P</=0.01 for all); serum ferritin level >1000ng/mL was not significant in this analysis (P=not significant [NS]). In a multivariate analysis (MVA), the following factors remained significant for OS: specific MDS dx; IPSS score; receiving ICT; specific MDS rx; and AML transformation (P</=0.01 for all). In an MVA stratified for RARS, significant were: specific MDS dx (P<0.0001); IPSS score (P=0.005); specific MDS rx (P=0.038) and receiving ICT (P=0.039). At a median follow-up of 28 (0.1–245.9) months, 121 patients were alive (non-RARS, n=83 [64.3%]; RARS, n=38 [71.6%]) and the projected median OS for all patient was 99 months. The projected median OS for non-RARS patients without ICT and with ICT was 44 months and not reached (NR), respectively, and for RARS without and with ICT was 99 and 134.4 months (P<0.0001). The 5 year OS in these four groups was 39.2% and 91.7% (P=0.04); and 72.4% and 76.3%, respectively (P=NS). However, when RARS ICT patients were compared to only RBC transfusion dependent RARS patients not receiving ICT, the median OS was 73.8 vs 134.4 months, respectively, and 5 year OS was 59.9% and 76.3%, respectively (P=0.025). Conclusions: These results suggest an association between receiving iron chelation therapy and survival in lower IPSS risk MDS, in keeping with prior analyses. However, the association between ICT and OS in non-RARS MDS appeared to be stronger than in RARS, in keeping with data from Mayo suggesting transfusional iron overload may not have a major association with outcome in RARS. The median follow-up in the current study was just over 2 years, and median duration of ICT only 10.5 months; longer follow-up may be needed in RARS to determine whether ICT is potentially beneficial in this subgroup of patients with a relatively long expected survival. As with all retrospective analyses, these results must be considered hypothesis generating, and prospective trials are needed for firm conclusions to be drawn. Disclosures: Leitch: Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Iron chelation agents for the treatment of transfusional iron overload in MDS. Vickars:Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Relative Trends in Myocardial T2* Versus Myocardial Iron Concentration As Representations of Myocardial Iron Chelation Efficacy in Patients with β Thalassemia Major Treated with Deferasirox for up to 3 Years

Blood ◽

10.1182/blood.v124.21.4040.4040 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4040-4040

Author(s):

John B Porter ◽

Ali T Taher ◽

Yesim Aydinok ◽

Amal El-Beshlawy ◽

Mohsen Elalfy ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Myocardial Iron ◽

Advisory Committees ◽

Post Hoc

Abstract Background: Heart failure due to iron-induced cardiomyopathy is rare yet remains one of the leading causes of death in patients with β thalassemia. Using myocardial T2* (mT2*) cardiovascular magnetic resonance (CMR) to estimate myocardial iron burden has improved the management of cardiac siderosis. Myocardial T2* >20 ms is considered normal and as iron accumulates, mT2* reduces, with values <10 ms associated with an increased risk of heart failure. As reported by Carpenter et al (2011), a calibration for CMR R2* against atomic emission spectroscopy-measured myocardial iron concentration (MIC), showing a curvilinear relationship between R2* and MIC, actual MIC can now also be assessed and affords an additional efficacy measure for patients undergoing iron chelation therapy. In a previous post-hoc analysis of the 3-year EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) cardiac substudy, the long-term effects of deferasirox on mT2* and MIC were reported. Here, we report relative trends between mT2* and MIC as a representation of myocardial chelation efficacy by determining how far the patient has progressed from baseline toward reaching normal levels, in order to further understand the interpretation of these two parameters. Methods: Patients aged ≥10 years with mT2* >5 to <20 ms by CMR, left ventricular ejection fraction ≥56%, serum ferritin >2500 ng/mL, MR (R2) liver iron concentration >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Cardiac iron removal was analyzed over 3 years in patients with mT2* at baseline and each considered time point. Post-hoc calculation of MIC from mT2* values was conducted using the formula described by Carpenter et al as follows: [Fe] = 45.0 x (mT2*)−1.22 where [Fe] is measured in milligrams per gram dw and mT2* is measured in milliseconds. Data are presented descriptively as the percentage of the progression of the patients toward achieving normalization of mT2* (>20 ms) or MIC (>1.16 mg Fe/g dw as derived from the formula based on normal mT2*) by mT2* at baseline: >5 to <10 ms, 10 to <15 ms and 15 to <20 ms. Results: Data were analyzed at Month 12 (n=67: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=19; 15 to <20 ms, n=24), Month 24 (n=66: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=18; 15 to <20 ms, n=24) and Month 36 (n=63: baseline mT2* >5 to <10 ms, n=22; 10 to <15 ms, n=18; 15 to <20 ms, n=23). As previously reported (Pennell et al. 2012), geometric mean mT2* in the overall population significantly increased from 12.0 ms at baseline to 13.9 ms at Month 12, 15.6 ms at Month 24 and 17.1 ms at Month 36. In parallel, mean MIC significantly decreased from 2.43 mg Fe/g dw at baseline to 2.10 mg Fe/g dw at Month 12, 1.94 mg Fe/g dw at Month 24 and 1.80 mg Fe/g dw at Month 36. The median percentage progression of patients towards normalizing mT2* and MIC by baseline mT2* category are presented in the Figure. In patients with severe myocardial iron overload at baseline, the percentage toward normalization in mT2* in the first, second and third year was less than the percentage towards normalization in MIC. This difference was less pronounced, but still evident, in patients with mild-to-moderate myocardial iron overload. Figure 1 Figure 1. Discussion: The calibration of the relationship between CMR measurements and MIC by Carpenter et al allows an additional assessment to mT2* to determine chelator efficacy in terms of the actual concentration of iron in the myocardium. Here we show that, particularly in patients with severe myocardial iron overload, when analyzing the progression towards normalization, improvement in MIC is proportionally greater than that seen with mT2*. It could be interpreted that a small improvement (ie 1 ms) in mT2* when baseline values are >5 to <10 ms is not equivalent in terms of myocardial iron removal to a small improvement in patients with less severe myocardial iron overload at baseline; a consequence of the reciprocal relationship between mT2* and MIC. Therefore, analysis of mT2* only may underestimate the efficacy of iron chelation with respect to the myocardium in patients with severe myocardial iron loading (mT2* <10 ms) and thus MIC may better reflect response to chelation therapy. It would therefore be valuable if MIC were calculated and reported in parallel with mT2* when assessing and monitoring patients on iron chelation therapy across a range of baseline mT2* values. Disclosures Porter: Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Barbier:Novartis: Employment. Cappellini:Novartis: Honoraria, Speakers Bureau; Genzyme: Honoraria.

Download Full-text

Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽

10.1182/blood-2019-130237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3542-3542 ◽

Cited By ~ 1

Author(s):

Natalia Scaramellini ◽

Carola Arighi ◽

Alessia Marcon ◽

Dario Consonni ◽

Elena Cassinerio ◽

...

Keyword(s):

Clinical Practice ◽

Liver Function ◽

Iron Overload ◽

Board Of Directors ◽

Chelation Therapy ◽

Iron Chelation ◽

Published Data ◽

Iron Chelation Therapy ◽

Iron Intake ◽

Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p<0.001) and for SF<500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT> 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value < 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Improvement in Right Ventricular Function Following 1 Year of Deferasirox Therapy in Patients with β-Thalassemia.

Blood ◽

10.1182/blood.v114.22.5106.5106 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5106-5106

Author(s):

Gillian Smith ◽

Dudley J. Pennell ◽

John B. Porter ◽

M. Domenica Cappellini ◽

Lee Lee Chan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Left Ventricular ◽

Myocardial Iron ◽

Advisory Committees ◽

Off Label ◽

Cardiac Siderosis ◽

Rv Function

Abstract Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction ≥56%, serum ferritin (SF) levels of >2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%) patients. Mean baseline LIC was 28.2 ± 10.0 mg Fe/g dw, median serum ferritin was 5235 ng/mL, and the mean amount of transfused blood in the previous year was 185 mL/kg. 68% of patients had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination chelation therapy. Mean actual deferasirox dose over 12 months was 32.6 mg/kg/day. RVEF increased significantly from a mean ± SD baseline of 65.8 ± 6.2% to 67.6 ± 6.4% at 6 months (P=0.013) and 68.7 ± 5.7% at 12 months (P<0.0001; Figure). RVESV significantly decreased from 35.0 ± 14.5 mL at baseline, to 33.4 ± 12.8 mL (P=0.034; Figure) by 12 months and RVEDV significantly increased from 101.0 ± 31.8 mL at baseline to 105.7 ± 33.4 mL (P=0.04; Figure) by 12 months. There were no significant correlations between any of the RV function parameters assessed and T2*. There was a borderline significant reduction in RVM from 46.8 ± 14.6 g at baseline to 44.9 ± 12.4 g at 12 months (P=0.088). Reference RVEF, RVESV, RVEDV and RVM have been defined in healthy subjects as 66 ± 6 %, 50 ± 14 mL, 144 ± 23 mL and 48 ± 12 g, respectively (A M Maceira et al. Eur Heart J 2006;27:2879–88), although values were shown to vary significantly by gender, body surface area and age. Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Download Full-text

Combined Chelation Therapy with Deferasirox and Deferoxamine In Transfusion-Dependent Thalassemia

Blood ◽

10.1182/blood.v116.21.4269.4269 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4269-4269 ◽

Cited By ~ 1

Author(s):

Ashutosh Lal ◽

Nancy Sweeters ◽

Vivian Ng ◽

Drucilla Foote ◽

Patricia Evans ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Liver Weight ◽

Myocardial Iron ◽

Advisory Committees ◽

Single Drug ◽

Median Plasma ◽

Group B

Abstract Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC <15 mg/g dry liver-weight (group A), adults with LIC >15 mg/g (group B), and children 8–18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3–7 days/week (as 8–12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* <20 msec at study entry (range 6.5–19.5 msec at week 0) showed an average improvement of +2.43 msec following treatment (range 8.8–21.3 msec at week 52, p=0.027). All 3 subjects with left ventricular ejection fraction below 60% at baseline (47.5-58.1%) showed improvement at end of study (60.6-64.4%). There was progressive decline in median plasma NTBI level during the study from 3.26 μM (1.79-5.79 μM) at baseline to 2.38 μM (1.59-3.08 μM) at 12 months (p=0.008). DSX produced immediate and significant decline in plasma NTBI when administered during infusion of DFO. The median plasma NTBI measured on DFO alone was 2.46 μM (0.92-5.90 μM), which decreased to 1.96 μM (0-3.50 μM) following administration of the dose of DSX (p<0.001). A sustained control of the LPI fraction was also demonstrated throughout the study period. At baseline the median LPI was 0.87 μM (0-2.43 μM) which decreased to 0.05 μM (0-1.20 μM) during the study period (p=0.004). No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. Disclosures: Harmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

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

Blood ◽

10.1182/blood.v128.22.1018.1018 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1018-1018 ◽

Cited By ~ 1

Author(s):

Banu Aygun ◽

Nicole Mortier ◽

Zora R. Rogers ◽

William Owen ◽

Beng Fuh ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Chelation Therapy ◽

Venous Access ◽

Study Entry ◽

Iron Loading ◽

Advisory Committees

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

Download Full-text

Iron Overload Is Highly Prevalent in All Disease Severity States in Pyruvate Kinase Deficiency (PKD)

Blood ◽

10.1182/blood.v128.22.2430.2430 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2430-2430

Author(s):

Eduard J van Beers ◽

Wilma Barcellini ◽

Stefan W. Eber ◽

Janet L Kwiatkowski ◽

Jennifer A Rothman ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Chelation Therapy ◽

Iron Status ◽

Compound Heterozygous ◽

Advisory Committees ◽

Cardiac Iron ◽

Significant Difference

Abstract Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values <0.05 were considered statistically significant. Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p<0.0001. However, of 29 patients with an LIC measurement and a mean ferritin <1000 ng/mL, 15 (52%) had a LIC >3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p<0.0001), even after controlling for transfusion history (p<0.0001). Age was associated with iron overload (p=0.046); although, the age range of patients with iron overload was broad (1.3-69.9 years). The frequency of iron overload was significantly higher in those with a lower baselineHb(p=0.004) and higher bilirubin (p=0.03). Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2*<20ms); they were age 5 (T2* 17.8ms, LIC 5 mg/g) and 22 years (T2* 19.7ms, LIC 14 mg/g) at the time of the MRI. Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p<0.0001) and proportion who had been historically transfused (79% vs 32%, p<0.0001). Despite these differences, the Amish patients had a lower prevalence of iron overload (34% vs. 51%). There was no significant difference inHbor enrollment age between the Amish and non-Amish cohorts. Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin <1000 ng/ml does not exclude hepatic iron overload. Therefore, we recommend that all patients with PKD starting at age 1 year should be screened annually for iron overload using ferritin and, at least once, using MRI. Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Optimizing Iron Chelation Therapy with Deferasirox for Non-Transfusion-Dependent Thalassemia Patients: 1-Year Results from the Phase IV, Open-Label Thetis Study

Blood ◽

10.1182/blood.v126.23.2153.2153 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2153-2153

Author(s):

Ali T Taher ◽

M Domenica Cappellini ◽

Yesim Aydinok ◽

John B. Porter ◽

Zeynep Karakas ◽

...

Keyword(s):

Serum Creatinine ◽

Iron Overload ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Iron Chelation ◽

Relative Reduction ◽

Average Dose ◽

Advisory Committees ◽

Absolute Change

Abstract Background: Efficacy and safety of iron chelation with deferasirox (Exjade®; DFX) 5 and 10 mg/kg/day (escalated to max: 20 mg/kg/day) in non-transfusion-dependent thalassemia patients, was established in the placebo-controlled, THALASSA study; Taher et al Blood 2012;120:970-977. THETIS added to this evidence by investigating a broader patient population, including non-transfusion-dependent congenital anemia patients and those treated with concomitant medications (eg hydroxyurea) and by evaluating early escalation with higher DFX doses according to liver iron concentration (LIC; max: 30 mg/kg/day). Methods: Patients ≥10 yrs of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw]) and serum ferritin (SF) ≥300 ng/mL were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed); Hb S/β thalassemia; active hepatitis B/C; cirrhosis; history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase (ALT) >5×the upper limit of normal (ULN), serum creatinine >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started DFX at 10 mg/kg/day. At week 4, DFX was increased according to baseline (BL) LIC: LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day. At week 24, DFX was adjusted further: LIC >15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC >7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC <3 or SF <300 ng/mL, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 ng/mL (max 10 mg/kg/day). The primary efficacy endpoint was absolute change in LIC from BL to week 52. Secondary endpoints included absolute change in LIC from BL to week 24 and change in SF from BL to week 52. Results: 134 patients were enrolled consisting of β thalassemia intermedia (n=69), Hb H disease (n=40), Hb E/β thalassemia (n=24) and congenital dyserythropoietic anemia (n=1) patients. Mean actual daily DFX dose ± SD over 1 yr (considering dose adjustments) was 14.70 ± 5.48 mg/kg/day. Mean LIC ± SD decreased significantly from 15.13 ± 10.72 mg Fe/g dw at BL to 8.46 ± 6.25 mg Fe/g dw at week 52 (absolute change, ‒6.68 ± 7.02 mg Fe/g dw [95% CI: -7.91, -5.45]; P <0.0001). At the last assessment, an absolute decrease in LIC of ≥3 mg Fe/g dw was observed in 86 (64.2%) patients and a ≥30% relative reduction in LIC in 81 (60.4%) patients. Reduction in LIC was greater in patients with higher BL LIC, with these patients receiving a higher than average dose (Figure). Median SF (range) decreased from 1001 (232-6638) ng/mL at BL to 669 (200-4315) ng/mL at week 52 (absolute median change, -304 [-5307 to -1669] ng/mL). 112 (83.58%) patients completed 1 yr. Patients discontinued primarily because of withdrawal of consent (n=10, personal/logistical reasons). Adverse events (AE) regardless of causality were reported in 97 (72.4%) patients and were unaffected by average dose. AEs with a suspected relationship to DFX were reported in 42 (31.3%) patients; most commonly, gastrointestinal (abdominal discomfort, diarrhea, nausea; n=6 each). One patient had a suspected drug-related serious AE (pancreatitis) that lasted 11 days; DFX was withheld for the duration, then restarted. One patient discontinued because of an AE (extramedullary hematopoiesis) and one death occurred (pneumonia leading to cardiac failure); neither suspected as drug-related. One patient had an elevated BL ALT 2×ULN that increased to >5×ULN on one occasion; BL bilirubin levels were 2×ULN and alkaline phosphatase 1.5×ULN; without dose adjustment or interruption, all parameters improved better than baseline values by week 52. No patient had two consecutive serum creatinine increases >33% above BL or >ULN. All patients with notable renal or liver laboratory values continued treatment. Conclusions: DFX 10 mg/kg/day (escalated to max: 30 mg/kg/day) resulted in significant and clinically relevant reductions in iron overload, with a similar safety profile as reported in THALASSA (in both DFX- and placebo-treated patients). With early dose escalation at week 4 with further adjustment at week 24, patients with a higher iron burden received higher DFX doses. These results support early dose escalation of DFX to optimize chelation in more heavily iron-overloaded patients with non-transfusion-dependent anemias. Disclosures Taher: Novartis: Honoraria, Research Funding. Cappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Karakas:Novartis: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Wang:Novartis: Employment. Zhu:Novartis: Employment. Joaquin:Novartis: Employment. Uwamahoro:Novartis: Employment.

Download Full-text

Deferasirox (Exjade®) ≥30 Mg/Kg/Day Is Effective in Reducing Iron Burden in Thalassemia Major Patients Previously Chelated with Monotherapy or Combination Therapy.

Blood ◽

10.1182/blood.v114.22.4058.4058 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4058-4058

Author(s):

Ali Taher ◽

Mohsen Saleh Elalfy ◽

Amal El-Beshlawy ◽

Dunhua Zhou ◽

Lee Lee Chan ◽

...

Keyword(s):

Combination Therapy ◽

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Concentration ◽

Thalassemia Major ◽

Advisory Committees ◽

Liver Iron ◽

Transfusion Requirements

Abstract Abstract 4058 Poster Board III-993 Background Despite the availability of effective chelators, many patients (pts) with β-thalassemia major (TM) present with high iron burden and serum ferritin (SF) >2500 ng/mL, demonstrated to be associated with significant negative outcomes including cardiac disease and organ failure. In the large, prospective EPIC trial including 854 TM pts who received prior chelation therapy, median baseline SF was 3139 ng/mL despite 10.8 yrs of therapy; hence the therapeutic goal was to reduce iron burden. Previous studies have shown that in TM pts with high transfusional iron, ≥30 mg/kg/day deferasirox (Exjade®) doses significantly reduce SF, while 20 mg/kg/day doses maintained SF levels. The objective of this analysis was to assess whether a mean actual deferasirox dose ≥30 mg/kg/day is effective in reducing SF in iron-overloaded pts with TM irrespective of prior chelation therapies. Methods Pts with TM (≥2 yrs) and transfusional iron overload as defined by SF levels ≥1000 ng/mL or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight were enrolled. Initial deferasirox dosing (10–30 mg/kg/day) was dependent on transfusion requirements and adjusted according to the protocol by 5–10 mg/kg/day (range 0–40 mg/kg/day) every 3 months based on SF trends and safety markers. Pts previously chelated with monotherapy deferoxamine (Desferal®; DFO) or deferiprone (Ferriprox®; DFP) or a combination of both and who received a mean actual deferasirox dose ≥30 mg/kg/day over 1 yr were included. The primary efficacy endpoint was the change in SF at 1 yr from baseline (BL). Results Overall, 129 TM pts (15%) who were previously chelated with DFO and/or DFP were treated with a mean actual deferasirox dose of ≥30 mg/kg/day during the 1 yr EPIC trial; 83 pts received prior DFO or DFP monotherapy and 46 received a combination of both. Mean age was 19.5±8.2 vs 23.0±7.2 yrs in prior monotherapy and prior combination therapy pts, respectively. A mean of 167 mL/kg vs 191 mL/kg was transfused in the yr prior to study entry and the mean duration of prior chelation therapy was 11.7±7.7 yrs vs 14.5±7.9 yrs, respectively. During the study, mean transfusional iron intake was similar in both groups (0.36±0.2 and 0.34±0.1 mg/kg/day, respectively). In prior monotherapy pts (mean dose 33.9±2.2 mg/kg/day), median SF decreased from 4885 ng/mL at BL to 4282 ng/mL after 1 yr (Figure) resulting in a decrease from BL of 1024 ng/mL (P<0.0001) based on last-observation-carried-forward (LOCF) analysis. In prior combination therapy pts (mean dose 34.1±3.9 mg/kg/day), median SF decreased from 5921 ng/mL at BL to 4327 ng/mL (Figure) resulting in a decrease from BL of 886 ng/mL (P=0.0078; LOCF). In patients with labile plasma iron (LPI) at BL, 1.3±2.1 and 1.7±3.1 μmol/L in the prior monotherapy and combination therapy groups, respectively after 1 yr was reduced to 1.1±2.6 and 1.4±2.7 μmol/L (LOCF). Overall, five pts (3.9%) discontinued therapy. Reasons for withdrawal were adverse events (AEs; cardiac failure), abnormal laboratory values (increased transaminases), consent withdrawal, lost to follow-up and protocol violation (all n=1). The most common investigator-assessed drug-related AEs were rash (n=14, 10.9%) and diarrhea (n=12, 9.3%). One pt (0.8%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits and one pt (0.8%) had increased alanine aminotransferase >10xULN on two consecutive visits; levels were already elevated. Conclusions This heavily transfused subgroup of TM pts, who had received prior chelation therapy with DFO and/or DFP for an average >10 yrs, continued to have high SF levels >4500 ng/mL. Monotherapy with ≥30 mg/kg/day deferasirox for 1 yr led to significant and clinically relevant reductions in SF in these pts irrespective of previous chelation therapies and was well tolerated. Longer-term studies are required to assess whether continued deferasirox could reduce SF <2500 ng/mL to minimize serious complications of iron overload. Disclosures: Taher: Novartis: Honoraria, Research Funding. Chan:Novartis: Honoraria, Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Sutcharitcharan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Download Full-text