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

Blood ◽  
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.

scholarly journals Efficacy and Safety of Deferasirox in Chinese Patients with Non-Transfusion-Dependent Thalassemia: 1-Year Results from the Thetis Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4570-4570
Author(s):  
Yong-Rong Lai ◽  
Rong Rong Liu ◽  
M Domenica Cappellini ◽  
Yesim Aydinok ◽  
John B Porter ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Chinese Patients ◽  
Relative Reduction ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Absolute Change

Abstract Background: Although non-transfusion-dependent thalassemias (NTDT) and non-transfusion-dependent congenital or chronic anemias are found in Southern China, they are relatively rare diseases in China and there are little data evaluating iron chelation in Chinese patients. This 1-year analysis from the THETIS study investigated the efficacy and safety of deferasirox in a large subpopulation of Chinese patients. Early escalation of deferasirox doses (max: 30 mg/kg/day) was evaluated according to liver iron concentration (LIC). Methods: THETIS is an open-label, single-arm, multicenter, Phase IV, 5-year study with the primary endpoint after 1 year of treatment. For this subanalysis, Chinese patients ≥10 years 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 >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 deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox 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, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 (max 10 mg/kg/day). This sub-analysis evaluated absolute change in LIC and SF from baseline to week 52. Results: 68 Chinese patients were enrolled (median age 26.0, range 10-63 years) with Hb H disease (n=35), β thalassemia intermedia (n=21) or Hb E/β thalassemia (n=12). Most patients received prior transfusions (n=56/68, 82.4%); 20/68 (29.4%) patients received prior chelation. 57/68 (83.82%) patients completed 1 year. Patients who discontinued were most commonly lost to follow-up (n=4) or withdrew consent (n=3, personal or logistical reasons). Mean actual daily deferasirox dose ± standard deviation (SD) over 1 year (considering dose adjustments), was 16.21 ± 5.61 mg/kg/day. Mean LIC ± SD at baseline was 17.75 ± 12.37 mg Fe/g dw in Chinese patients, which decreased to 9.35 ± 6.83 mg Fe/g dw at week 52 (absolute change from baseline, -8.51 ± 8.58 mg Fe/g dw [95% CI -10.69 to -6.33]). Patients with higher LIC at baseline experienced a greater reduction in LIC by week 52 (Figure). Furthermore, 48 (70.6%) Chinese patients achieved an absolute decrease in LIC of ≥3 mg Fe/g dw, and 46 (67.6%) patients achieved a ≥30% relative reduction in LIC at the last assessment. At week 52, LIC was <3 mg Fe/g dw in 5 (7.4%) patients. Median SF (range) decreased in Chinese patients from a baseline of 1580 (333-6638) ng/mL to 872 (267-4315) ng/mL at week 52 (absolute median change, -423 [-5307 to -1669] ng/mL). At week 52, SF was <300 ng/mL in 1 (1.5%) patient. Adverse events (AE) regardless of causality were reported in 40 (58.8%) Chinese patients. Drug-related AEs were reported in 18 (26.5%) Chinese patients, most commonly gastrointestinal (abdominal discomfort, n=2; diarrhea and hematochezia, n=1 each) or skin related (rash, n=3; eczema, n=1). No patients discontinued because of AEs. One death occurred during the study (pneumonia leading to cardiac failure) that was not suspected to be drug-related. No patient had two consecutive serum creatinine increases of >33% above baseline or >ULN. No patient discontinued treatment due to notable liver or renal laboratory values. Conclusions: Deferasirox at 10 mg/kg/day escalated to a maximum of 30 mg/kg/day effectively reduced iron burden in Chinese patients. AEs were consistent with the known safety profile for deferasirox. Early dose escalation at week 4 and further adjustment at week 24 ensured that patients with iron overload achieved clinically relevant reductions in iron burden. These results were in alignment with the THETIS primary efficacy analysis, supporting early dose escalation of deferasirox to optimize chelation in more heavily iron-overloaded Chinese NTDT patients. Figure 1. Figure 1. Disclosures 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. Zhu:Novartis: Employment. Wang:Novartis: Employment. Qi:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1514-1514 ◽  
Author(s):  
Pradyumna D. Phatak ◽  
Pierre Brissot ◽  
Herbert Bonkovsky ◽  
Mark Wurster ◽  
Lawrie Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Advisory Committees ◽  
The Core ◽  
Upper Limit ◽  
Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1288-1288
Author(s):  
Yesim Aydinok ◽  
Metin Delebe ◽  
Gunes Basol ◽  
Selen Bayraktaroglu ◽  
Nihal Karadas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Thalassemia Major ◽  
Average Dose ◽  
Advisory Committees ◽  
Baseline Characteristics ◽  
Labile Iron ◽  
The Impact

Abstract Background Ascorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment. Objectives Perform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity. Patients and Methods Enrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched). Results 22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year. At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1). In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS. A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2). Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo). Conclusions TM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. Table 1 Baseline characteristics of patients based on AA status Table 1. Baseline characteristics of patients based on AA status Table 2 Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Table 2. Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Disclosures Aydinok: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

scholarly journals 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 ◽  
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 &lt;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.

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

Blood ◽  
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.

Transfused Myelodysplastic Syndromes (MDS) Patients Have Severe Iron Overload and Relevant Improvements in Iron Burden and Liver Function with Deferasirox Treatment: Results From a Pooled Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5019-5019
Author(s):  
Norbert Gattermann ◽  
Peter L. Greenberg ◽  
Akio Urabe ◽  
Dany Habr ◽  
Euloge E. Kpamegan ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Liver Function ◽  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Pooled Analysis ◽  
Advisory Committees ◽  
Absolute Change ◽  
Starting Dose

Abstract Abstract 5019 Background: MDS patients receiving chronic transfusions can develop significant iron accumulation in key organs such as the liver following 10–20 transfusions (Porter et al. BJH 2001). The diagnosis and monitoring of iron overload, as well as the effect of iron chelation therapy in MDS patients, is often based on serum ferritin (SF), with limited data on liver iron concentration (LIC), primarily due to the biopsy-related increased risk of bleeding and infections in these patients. However, LIC is clinically a more robust and direct measure of body iron burden and with the availability of non-invasive determination of LIC by MRI, LIC assessment has become more practical in MDS patients. This pooled analysis focuses on LIC assessments from a population of 71 MDS patients who completed 1 year of treatment with deferasirox (Exjade®), including assessment of the relationship between LIC vs SF and alanine aminotransferase (ALT). Methods: Analysis is based on 1-year pooled data from iron-overloaded patients with MDS who were enrolled in 4 open-label single-arm deferasirox studies: US02 (Low/Int-1 MDS patients, starting dose 20 mg/kg/day); 2409 (MDS patients with life expectancy >1 yr, starting dose 10–30 mg/kg/day); 108 (MDS patients with life expectancy >1 yr, dosing 5–40 mg/kg/day), and 2204 (Low/Int-1 MDS patients, starting dose 10–30 mg/kg/day). LIC was assessed in the US02, 2409 and 2204 studies using R2 MRI (St Pierre et al. Blood 2004). In the 108 study, LIC was assessed by magnetic liver susceptometry using a superconducting quantum interference device (SQUID) or ultrasound-guided percutaneous liver biopsy; LIC values obtained by SQUID were multiplied by a factor of 2 to correct for the underestimation of LIC by SQUID compared to biopsy (Porter et al. EJH 2008). Datasets were pooled for baseline (BL) characteristics, as well as LIC, SF and ALT at BL and end of study (EOS). Correlations were evaluated on a Pearson's correlation coefficient. Results: 71 patients (56.3% male) were assessed with a mean age of 65 years (range 16.5–82.0). Mean transfusional iron intake ± SD was 0.31 ± 0.12 mg/kg/day. Mean actual deferasirox dose was 19.6 ± 6.5 mg/kg/day. At BL, mean ± SD LIC was 20.5 ± 14.6 mg Fe/g dw (BL LIC <7 mg Fe/g dw, 21.1%; ≥7 mg–≤15 mg Fe/g dw, 23.9%; and >15 mg Fe/g dw, 54.9%). Median BL SF was 2620 ng/mL (range 538–12,639) (BL SF ≤2500 ng/mL, 47.9%; >2500–≤5000 ng/mL, 32.4%; and >5000 ng/mL, 15.5%). With 1 year of DFX, mean ± SD LIC decreased to 13.9 ± 13.1 mg Fe/g dw (mean absolute change –6.6 mg Fe/g dw). In patients with BL LIC <7 mg Fe/g dw (n=15), LIC was maintained with a mean absolute change of 1.0 ± 2.8 mg Fe/g dw, whereas in patients with BL LIC ≥7 mg Fe/g dw (n=56), LIC was reduced by –8.6 ± 10.7 mg Fe/g dw from BL. The proportion of MDS patients with LIC ≥7 mg Fe/g dw reduced from 78.9% at BL to 59.2% at EOS, with 50.7% of patients achieving a decrease in LIC of ≥30%. Median SF decreased to 2035 ng/mL (range 158–10520 ng/mL) with median absolute change from baseline of –630 ng/mL. There was a significant correlation between BL LIC and SF (R=0.548; P<0.0001). Change in LIC significantly correlated with change in serum ferritin (R=0.336; P=0.0042, Figure A). Mean ALT decreased from 55.9 to 38.9 U/L (absolute change –17.0). The change in LIC correlated with the change in ALT (R=0.397, P=0.0006, Figure B). Conclusions: This pooled analysis in a large cohort of transfusion-dependent MDS patients with LIC assessment shows significantly elevated LIC, with a high proportion of patients (55%) having severely elevated LIC of >15 mg Fe/g dw, a level known to markedly increase liver dysfunction and other iron overload-related complications. One year of treatment with deferasirox produced relevant reductions in LIC, an outcome possibly indicative of a clinical benefit. SF and ALT (an important indicator of liver function) also decreased, with reductions correlating with those of LIC. These findings indicate that correction of moderate-to-severe iron overload in MDS patients is associated with a parallel improvement in liver function. Disclosures: Gattermann: Novartis Pharma: Honoraria, Research Funding. Greenberg:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharma: Employment. Kpamegan:Novartis Pharma: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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 ◽  
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.

Serum Ferritin, Labile Plasma Iron and Transferrin Saturation: Comparison Between Underlying Anemias with Transfusional Iron Overload Before and After Treatment with Deferasirox.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2126-2126 ◽  
Author(s):  
John B Porter ◽  
Mohsen Elalfy ◽  
Vip Viprakasit ◽  
Stephane Giraudier ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Full Range ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Serum Markers ◽  
Advisory Committees ◽  
The Relationship

Abstract Abstract 2126 Background: In patients with transfusion-dependent anemias, monitoring the efficacy of iron chelation therapy (ICT) using serum ferritin (SF) alone can sometimes be challenging; therefore, additional serum markers would be helpful. Furthermore, any differences between different anemias for the relationship between SF and other serum markers both before and in response to ICT may be useful to predict relative risk of iron-mediated toxicity between these conditions. Data from the 1-yr EPIC (Evaluation of Patients' Iron Chelation with Exjade®) trial allows assessment of iron parameters in a large cohort of patients with thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Here we evaluate trends in liver iron concentration (LIC), transferrin saturation (TfSat) and labile plasma iron (LPI) in their relation to SF levels and assess systematic differences between underlying anemias. Relationships were assessed at baseline (BL), reflecting iron accumulation at study entry, and also at end of study (EOS), with changes reflecting iron excretion after 1 yr treatment with deferasirox. Methods: LIC, TfSat and LPI were measured at BL and at EOS for each underlying disease. Changes in these parameters as well as relationships between these parameters and SF were assessed by SF categories at BL and at EOS. For EOS measurements, last observation carried forward was used for all parameters (last post-BL available value), except for LPI, for which 1-yr visit was used. Pre-deferasirox dose LPI levels are reported. Results: Data from 1114 thalassemia patients, 336 MDS patients and 80 SCD patients were available for analysis. For all underlying anemias, LIC was higher at higher SF categories; in thalassemia patients for eg, with BL SF categories <1000, 1000–2000, 2000–3000, 3000–4000, 4000–5000, >5000 ng/mL, the mean LIC values at BL were 4.9, 9.0, 15.3, 22.1, 27.2, 32.5 mg Fe/g dw, respectively. Overall, mean TfSat was 89.6% (n=755) in thalassemia patients at BL and 96.1% (n=955) at EOS, compared with 82.5% (n=116) and 83.8% (n=171) in MDS patients, respectively. In SCD patients, TfSat was 61.3% (n=71) at BL and 64.1% (n=74) at EOS. TfSat was lowest in SCD patients across the full range of SF categories examined (Figure). At BL, TfSat was higher at higher SF categories in all diseases, with a similar trend at EOS, although at EOS this trend was more evident in MDS and SCD (Figure). Overall, mean LPI levels at BL and EOS were 1.25 μmol/L (n=472) and 0.59 μmol/L (n=818) in thalassemia patients, 0.53 μmol/L (n=221) and 0.14 μmol/L (n=147) in MDS patients, and 0.11 μmol/L (n=55) and 0.10 μmol/L (n=46) in SCD patients, respectively. LPI levels were highest in patients with thalassemia and lowest in SCD patients across SF categories (Figure). After 1 yr treatment with deferasirox, LPI levels were reduced in thalassemia and MDS patients, but there was no difference in patients with SCD. LPI was higher at higher SF categories in MDS patients at both BL and EOS, with a similar trend in SCD patients at EOS, although there was little relationship in thalassemia patients (Figure). Discussion: At matched SF levels and across a wide range of SF values, TfSat was lower in SCD patients, in comparison to thalassemia and MDS patients, both at BL and EOS. Similar observations have been reported previously and may contribute to the lower propensity for extra-hepatic iron accumulation in SCD patients. The mechanisms for this difference remain unclear, but could be attributed to sequestering of iron due to chronic inflammation in SCD. TfSat did not appear to decrease after 1 yr treatment with deferasirox, in any underlying anemia. The relationship of LPI to SF categories differed between underlying anemias; both at BL and EOS. At BL, SCD patients had low LPI values across the full range of measured SF values, whereas higher LPI levels at higher SF categories were most evident in MDS patients. Overall, LPI was highest in thalassemia patients. After 1 yr treatment with deferasirox, LPI was decreased in thalassemia and to a lesser extent in MDS patients, but there was no change from the low level at BL in SCD patients. The decrease in LPI in MDS and thalassemia at EOS may reflect the effects of residual plasma chelator 1 day after the previous dose and/or the decrease in storage iron over 1 yr of treatment. With further evaluation, LPI could become a useful marker of iron overload and chelation response in patients with MDS and possibly thalassemia. Disclosures: Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

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 ◽  
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.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3542-3542 ◽  
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&lt;0.001) and for SF&lt;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&gt; 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 &lt; 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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