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

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.

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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.

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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.

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Efficacy and Safety of Deferasirox (Exjade®) in β-Thalassemia Patients with Myocardial Siderosis: 2-Year Results From the EPIC Cardiac Sub-Study.

Blood ◽

10.1182/blood.v114.22.4062.4062 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4062-4062 ◽

Cited By ~ 3

Author(s):

Dudley J. Pennell ◽

John B. Porter ◽

M. Domenica Cappellini ◽

Lee Lee Chan ◽

Amal El-Beshlawy ◽

...

Keyword(s):

Board Of Directors ◽

Serum Ferritin ◽

Research Funding ◽

Extension Phase ◽

Left Ventricular Ejection ◽

Advisory Committees ◽

Off Label ◽

The Core ◽

Cardiac Siderosis

Abstract Abstract 4062 Poster Board III-997 Background Over 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. Methods Patients aged ≥10 years with myocardial T2* >5–<20 ms (indicating cardiac siderosis) by cardiovascular magnetic resonance (CMR), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin >2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. Results Out of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was <10 ms (severe cardiac siderosis) in 39 patients (39%) and 10–20 ms (mild-to-moderate cardiac siderosis) in 61 (61%). 67.0% had received prior deferoxamine (DFO) and 33.0% prior DFO/deferiprone combination therapy. Mean actual deferasirox dose increased from 33.1 ±3.7 mg/kg/day in the core 1-year phase to 36.1 ±7.4 mg/kg/day during the extension. Continued improvement in myocardial T2* was observed in the extension phase so that after 2 years of deferasirox treatment, T2* had significantly increased from a baseline geometric mean of 11.2 to 15.3 ms (P<0.001). Significant increases from 7.3 to 9.3 ms (P<0.001) and from 14.6 to 19.9 ms (P<0.001) were respectively noted in patients with baseline T2* <10 and 10–20 ms (Figure). LVEF remained stable in both subgroups throughout the 2-year follow up period. Both mean LIC and median serum ferritin were significantly reduced from baseline by 10.7 ± 12.8 mg Fe/g dw and 2343 ng/mL (range –12795 to 25127), respectively (P<0.001; based on last-observation-carried-forward analysis). Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. Conclusions This is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures: 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. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

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A Decade Follow-up of a Thalassemia Major (TM) Cohort Monitored by Cardiac Magnetic Resonance Imaging (CMR): Significant Reduction In Patients with Cardiac Iron and In Total Mortality

Blood ◽

10.1182/blood.v116.21.1011.1011 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1011-1011 ◽

Cited By ~ 7

Author(s):

Alison S Thomas ◽

Maciej Garbowski ◽

Ai Leen Ang ◽

Farrukh T Shah ◽

J. Malcolm Walker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Thalassemia Major ◽

Iron Loading ◽

Myocardial Iron ◽

Advisory Committees ◽

Cardiac Iron

Abstract Abstract 1011 Background. CMR was introduced in London to assess myocardial iron loading in 1999 and some of these patients now have 10 years of follow-up, most with contemporary CMR determinations. The impact of long-term monitoring of myocardial iron loading in thalassemia major (TM) on the proportion of patients with increased myocardial iron (cT2* <20ms) and on patterns of mortality has not been previously described in a longitudinal cohort over this duration. Patients and Methods. All patients regularly attending two London thalassemia centres, who received their first CMR Jan 1999 - Dec 2000 were analyzed as a cohort. Patients underwent initial CMR at the Royal Brompton Hospital and received CMR follow up (FU) either there or at the Heart Hospital (UCLH). 132 patients were identified as having received a CMR in 1999–2000. A minimum 7 years CMR FU was required for inclusion in the long-term CMR analysis. 109 patients had at least 7 years of CMR follow up (range 7.0–10.6 years, median 9.2). The median age at 1st CMR was 27.9 years (range 7.7 – 49.5 years). At baseline, patients were receiving chelation with deferoxamine (DFO) monotherapy (70%), deferiprone (DFP) monotherapy (21%), or a combination of these agents (9%). At latest FU, patients were receiving DFO (32%), deferasirox (DFX) (28%), DFP (22%), or combined DFP and DFO therapy (18%). Results: Improvement in cardiac iron: In 1999–2000, 60% of TM patients had cT2* values ≤20ms and 17% had cT2* values <10ms. By contrast, at long term FU, only 23% now have cT2* ≤20ms, 7% have cT2* values <10ms (p<0.001). Changes to chelation therapy: 31% of patients stayed on the same chelator; 33% had 1 chelator switch, 26% 2 switches and 11% 3 or more switches. 18 switches in chelation therapy were due to side-effects (12 DFP, 5 DFX, 1 DFO). There were 9 breaks in chelation therapy during pregnancy in 8 different women. The proportions of patients with T2* < 20ms fell significantly for those who remained on DFO or DFP monotherapies throughout, or who changed chelation modalities on only one (p=0.002) or two (p=0.02) occasions. Patients who received had 3 or more switches did not show a improvement in this respect. The latter group was also the only subset that showed significant deterioration in myocardial iron (p<0.001). Mortality rates: the overall mortality rate for the initial cohort was 1.65 per 1000 patient years (95% CI 0.71 – 3.24); median age at death 35.6 years (range 27.3–48.4). This is a substantial improvement in the mortality index compared with the UK thalassemia registry data, of 4.3 per 1000 patient years during the period 2000–2003 (Modell et al, JCMR, 2008). The incidence rate ratio is 0.387 (95% CI 0.11–0.961), p<0.05, with patients in our cohort 61% less likely to die than those in the 2000–2003 cohort. Causes of death: there were 8 deaths during the FU period: 3 with complications of hepatitis C (all with cT2* > 20ms), 3 with sepsis (2 with cT2* <10ms and impaired ejection fraction, 1 with cT2* of 18ms), 1 with breast cancer, 1 with sudden unexplained death (cT2* > 20ms). Thus in only 2 patients could excessive cardiac iron loading be considered a causal/contributory factor. There was no significant difference in the baseline cT2* between those who died and those currently still alive (p= 0.2), meaning that death as a drop-out cause does not explain iron loading trends over FU. Chelators at death: DFO (4), DFP (2), DFX (1), combination (1). Conclusions: Over a decade we have seen an almost 3 fold fall in the proportion of patients with myocardial iron overload. Mortality has become substantially lower and cardiac iron overload is no longer the leading cause of mortality. In addition to CMR, this decade has seen the advent of two new oral iron chelators and many patients switched chelation regimen, sometimes several times, during the follow up period. Whilst the contribution of the individual components of this practice to the improved outcome cannot be concluded without randomized studies, it is clear that this modern management of TM is associated with reduced TM mortality. Disclosures: Off Label Use: Deferiprone is off label in the USA but licensed in Europe. Shah:Novartis: Honoraria, Speakers Bureau; Apotex/ Swedish Orphan: Honoraria. Pennell:Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardiovascular Imaging Solutions: Director of CVIS, Equity Ownership. Porter:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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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

Blood ◽

10.1182/blood-2021-148064 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 762-762

Author(s):

Mona Hamdy ◽

Amal El-Beshlawy ◽

Fatma Soliman Elsayed Ebeid ◽

Janet L. Kwiatkowski ◽

Julie Kanter ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Subgroup Analysis ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelator ◽

Advisory Committees ◽

Safety Population ◽

Efficacy Population

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.

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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.

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Deferasirox–Deferoxamine Combination Therapy Reduces Cardiac Iron With Rapid Liver Iron Removal In Patients With Severe Transfusional Iron Overload (HYPERION)

Blood ◽

10.1182/blood.v122.21.2257.2257 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2257-2257 ◽

Cited By ~ 4

Author(s):

Yesim Aydinok ◽

Antonis Kattamis ◽

M Domenica Cappellini ◽

Amal El-Beshlawy ◽

Raffaella Origa ◽

...

Keyword(s):

Combination Therapy ◽

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Iron Removal ◽

Advisory Committees ◽

Liver Iron ◽

Off Label ◽

Cardiac Iron ◽

Cardiac Siderosis

Abstract Background Transfusion-dependent patients with severe cardiac siderosis often require intensive iron chelation therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move from a high-risk (cardiac T2*<10 ms) to lower risk (≥10 ms) status for heart failure. Oral deferasirox (DFX) monotherapy has been shown to improve cardiac T2*, but data on the combined use of DFX and deferoxamine (DFO) are limited. Aim To evaluate efficacy and safety of investigational DFX–DFO in combination followed by DFX monotherapy in patients with severe transfusional cardiac siderosis. Methods The prospective, Phase II, open-label, multinational HYPERION study evaluated DFX–DFO in combination followed by DFX monotherapy in transfusion-dependent patients with severe cardiac siderosis (NCT01254227). Patients enrolled were ≥10 years with CMR-measured cardiac T2* 5–<10 ms, left ventricular ejection fraction (LVEF) ≥56%, R2-MRI liver iron concentration (LIC) ≥7 mg Fe/g dw. Starting dose was DFX 20 mg/kg/d, 7 d/wk, plus DFO 40 mg/kg/d, 5 d/wk for ≥8 hrs/d. DFX dose could be increased to 30 and 40 mg/kg/d after Month 1 and 6, respectively. Patients achieving cardiac T2* ≥10 ms and a relative T2* increase of ≥10% from baseline (BL) any time after 6 months were switched to DFX monotherapy. Combination therapy was resumed if cardiac T2* fell to <10 ms with a relative decrease of ≥10% from previous T2* value. Dose adjustments were based on efficacy and safety parameters. Primary efficacy endpoint was change in geometric mean cardiac T2* at Month 12 divided by that at BL. A key secondary objective was the proportion of patients achieving T2* ≥10 ms and a ≥10% relative increase from BL after 6 and 12 months. Efficacy was analyzed for all evaluable patients in the full analysis set (FAS) who received ≥1 dose of study drug and had a BL and post-BL assessment; cardiac T2* is also reported for patients with T2* at BL and Month 12 (12-month completers). Results 60 patients were enrolled (59 β-thalassemia major, 1 Diamond–Blackfan anemia; mean age 22.8 years; 46.7% male) with severe iron overload (geometric mean [Gmean] cardiac T2* 7.03 ms, mean LIC 33.4 ± 14.5 mg Fe/g dw, median serum ferritin 5551 ng/mL [range 1163, 11,317]). Overall, 20 patients discontinued; 5 consent withdrawals, 4 adverse events (AEs: pruritus, arthritis, abdominal pain, drug rash with eosinophilia and systemic symptoms), 4 abnormal test procedure results (all T2* <5 ms), 4 lost to follow-up, 2 administrative problems, 1 death (central nervous system infection, suspected relationship to DFO). Mean dose was DFX 29.6 ± 6.3, 7 d/wk, and DFO 37.4 ± 5.8 mg/kg/d, 5 d/wk. In the evaluable FAS (n=52, last observation carried forward) cardiac T2* increased 9% and LIC decreased 46% (Fig); serum ferritin levels decreased by 2174 ng/mL (–6138, 1570). Among 12-month completers (n=36), cardiac T2* increased from 7.24 at BL to 8.24 ms (14% improvement). In patients with BL LIC <30 and ≥30 mg Fe/g dw, cardiac T2* improvement was 17% (7.85 to 9.15 ms, n=16) and 6% (6.69 to 7.11 ms, n=36), respectively. Overall, 12.5 and 19.2% of patients achieved T2* ≥10 ms and ≥10% relative increase from BL at Month 6 and 12, respectively. Mean LVEF remained stable and no patient had cardiac failure. AEs with suspected relationship to study drug (≥5%) were abdominal pain, nausea (both 6.7%); increased blood creatinine, diarrhea, increased urine protein/creatinine ratio (all 5.0%). 1 patient had serum creatinine >33% increase from BL and >upper limit of normal at 2 consecutive visits. Discussion Cardiac T2* improved during 12 months of treatment with DFX–DFO in patients with severe transfusional body iron burden. High BL LIC levels decreased considerably with DFX–DFO. Overall, as LIC decreased cardiac T2* increased, most notably after 6 months. The higher DFX dose permitted after Month 6 possibly influenced this trend. Cardiac T2* improvements were observed irrespective of BL LIC value, but were most marked in those with BL LIC <30 mg Fe/g dw, consistent with previous data showing that cardiac iron removal follows liver iron removal (Noetzli Blood 2008). Safety of DFX–DFO was consistent with established monotherapy profiles, with no unexpected findings. 2-year follow-up for HYPERION will evaluate the impact of longer-term DFX–DFO in combination on liver and cardiac iron removal. Disclosures: Aydinok: Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Deferasirox and deferoxamine are both indicated as a monotherapy for the treatment of chronic iron overload due to frequent blood transfusions. Patients with severe cardiac iron overload are at increased risk of heart failure and are often treated by off-label combination therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move to a lower-risk status. This abstract describes off-label use of the combination of deferasirox and deferoxamine to treat patients with severe transfusional cardiac iron overload. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Cappellini:Genzyme: Honoraria; Novartis: Honoraria, Speakers Bureau. Perrotta:Novartis: Research Funding. Karakas:Novartis: Honoraria, Research Funding. Viprakasit:GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Habr:Novartis: Employment. Wegener:Novartis: Employment. Shen:Novartis: Employment. Porter, MD on behalf of the HYPERION investigators:Shire: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.

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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.

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Ferritin Levels Do Not Reflect the Severity of Iron Overload in Diamond Blackfan Anemia

Blood ◽

10.1182/blood-2021-152730 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3078-3078

Author(s):

Jonathan de Wilde ◽

Birgit van Dooijeweert ◽

Elise Huisman ◽

Frans Smiers ◽

Eduard J. Van Beers ◽

...

Keyword(s):

Board Of Directors ◽

Serum Ferritin ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Diamond Blackfan Anemia ◽

Transfusion History

Abstract Introduction: Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by hypoplastic anemia, congenital malformations and an increased risk to develop malignancies.Until now, treatment of DBA consists of red blood cell (RBC) transfusions, glucocorticoids (GC) and allogeneic hematopoietic stem cell transplantation in a selection of patients. Whereas RBC transfusions are the main cause of IO, elevated iron parameters have also been reported in non-transfusion-dependent DBA patients. Here we investigated the incidence and severity of IO in a well-described cohort of transfusion-dependent and non-transfusion-dependent DBA patients in order to gain more insight in the regulation of iron metabolism in DBA, and to provide clinical guiding to improve the diagnosis and management of IO in DBA. Methods: In this retrospective, observational study we have included twenty-nine pediatric and adult DBA patients for whom at least one serum ferritin level and/or MRI result was available. Ten patients (34%) were classified as transfusion-dependent (TD) (ten or more transfusions during the twelve months prior to evaluation). Non-transfusion-dependent (NTD) patients (66%) were treated with either GC, incidental transfusions or received no treatment. Transfusion burden (transfusion history) was assessed via medical records. Serum ferritin levels ≥250 ng/mL in males and ≥150 ng/mL in females were considered to be elevated. Results of MRI were expressed as liver iron content (LIC) and as cardiac T2* in milliseconds (ms). LIC ≥3 mg/g indicates significant hepatic IO, and LIC ≥7 mg/g is associated with clinical morbidity. Cardiac T2* ≤20 ms indicates significant cardiac IO. Results: In 15/29 (52%) MRI analysis of IO was performed. Hepatic IO (LIC >3 mg/g) was present in 9/29 (31%) of DBA patients, of which 8/9 (89%) had moderate to severe IO (LIC>7mg/g), despite the fact that all but one were treated with chelation therapy. Overall serum ferritin levels and LIC correlated significantly (r=0.7907, p<0.001), and all TD patients with LIC ≥7 mg/g had serum ferritin levels ³400 ng/mL, however, none of the patients had a serum ferritin >1000 ng/mL (Figure 1A). Interestingly, in the NTD group, hepatic IO was present in 2/7 patients (29%), who both only had mildly elevated serum ferritin levels (263 ng/mL and 277 ng/mL) and were not treated with iron chelation therapy. Based on total transfusion burden since birth, patients were classified in distinct groups: nine patients who received ³10 transfusions during life (9/10) were diagnosed with hepatic IO, whilst none of the patients who received <10 transfusions were diagnosed with hepatic IO. Both mean serum ferritin levels and mean LIC values were significantly higher in patients with ³10 transfusions compared to all with <10 transfusions (Figure 1B-C). Discussion: We demonstrate that IO is common in DBA yet can be easily overlooked in NTD patients that were treated with transfusions in the past. While serum ferritin levels significantly correlated with LIC values, this parameter cannot be used exclusively to screen for IO or titrate iron chelation therapy. We conclude that in clinical practice, biochemical parameters in combination with transfusion history justify a low-threshold to perform an MRI-based evaluation of IO, and to start adequate chelation therapy. Figure 1 Figure 1. Disclosures Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding. Wijk: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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.

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