What Predicts Adrenal Insufficiency in Patients with Thalassemia Major?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5299-5299
Author(s):  
Karen E Huang ◽  
Steven D Mittelman ◽  
Thomas D. Coates ◽  
Mitchell Geffner ◽  
John C Wood
Keyword(s):  
Iron Overload ◽  
Adrenal Insufficiency ◽  
Board Of Directors ◽  
Cortisol Level ◽  
Research Funding ◽  
Thalassemia Major ◽  
Stimulation Test ◽  
Glucagon Stimulation Test ◽  
Advisory Committees ◽  
Research Contract

Abstract Abstract 5299 Background: Thalassemia is one of the most common genetic blood disorders worldwide. With recent improvements in medical therapy, patients with transfusion-dependent thalassemia, i.e., thalassemia major, are living longer. As a result, there is a greater need to address endocrine complications related to chronic iron overload. Adrenal insufficiency (AI), in particular, is important to identify because therapies are available and can be life-saving. Objectives: The objectives of this study are to determine the prevalence of AI in our population of subjects with thalassemia major; to identify risk factors that predict AI in these individuals; and to localize the origin of the AI within the hypothalamic-pituitary-adrenal (HPA) axis. Methods: This is a prospective study of individuals with thalassemia major with an enrollment goal of 30 subjects. All subjects enrolled were initially tested for AI using a glucagon stimulation test. Those found to have AI (stimulated cortisol <18 mcg/dL) subsequently underwent an ovine corticotrophin-releasing hormone (oCRH) stimulation test for confirmatory purposes and to define the physiological basis for the AI. Results: Eleven subjects (8 - 29 years old, 6 female) have been enrolled to date. In our population of patients with TM, the prevalence of AI was 55%. There was no correlation between age, number of years transfused, or ferritin levels and AI. All male patients failed the glucagon stimulation test, whereas 5 of 6 females passed the glucagon stimulation test, p = 0.0024. There was no correlation between 8 AM ACTH levels and 8 AM cortisol levels. There was a significant correlation (p = 0.025) between 8 AM cortisol level and peak cortisol level following glucagon stimulation testing. Of the six subjects with AI, two subjects subsequently failed the oCRH stimulation test (peak cortisol < 21.9 mcg/dL). In these two subjects, peak oCRH ACTH levels were elevated, 144 and 164 pg/mL, respectively, suggesting primary adrenal insufficiency. Conclusions: We conclude that 8 AM cortisol level is a good predictor of adrenal insufficiency in our population, and can potentially be used as a simple screening test for AI with a strong negative predictive value. There appears to be a male predominance of AI in our population. This may indicate a protective role of female sex in this population. Two subjects had classic primary AI with robust ACTH levels in the face of inadequate cortisol production following oCRH testing. Four subjects (all males) who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol response to oCRH, indicating a possible hypothalamic origin to their AI. This dysfunction is likely independent of iron overload and warrants further investigation. Alternatively, these subjects may have impaired sympathetic nervous system function leading to hypoglycemic unawareness. Both outcomes are novel to the field and of medical significance. Disclosures: Geffner: Daiichi- Sankyo: Steering Committee for Clinical Trial; Eli Lilly, Inc.: Research Contract; Endo Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Data Safety Monitoring Board and Research Contract; Novo Nordisk: Research Funding; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

A Multicenter, Randomized, Open-Label Trial Evaluating Deferasirox Compared with Deferoxamine for the Removal of Cardiac Iron in Patients with β-Thalassemia Major and Iron Overload (CORDELIA).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2124-2124 ◽  
Author(s):  
Dudley J Pennell ◽  
John B Porter ◽  
Antonio Piga ◽  
Yongrong Lai ◽  
Amal El-Beshlawy ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Lower Limit ◽  
Research Funding ◽  
Thalassemia Major ◽  
Iron Removal ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Cardiac Iron ◽  
Randomized Controlled

Abstract Abstract 2124 Background: Without effective iron chelation therapy (ICT), patients with transfusional iron overload are at risk of excess iron-related cardiac complications. Cardiac iron accumulation can be measured using T2* magnetic resonance (normal >20 ms, high risk <10 ms). There are few randomized controlled trials assessing ICT for cardiac iron removal. CORDELIA is a Phase II, multinational, randomized comparison of efficacy and safety of 1-yr treatment with deferasirox or deferoxamine (DFO). Primary objective was non-inferiority of deferasirox vs DFO for cardiac iron removal after 1 yr. Methods: Patients with β-thalassemia major, cardiac T2* 6–20 ms, no clinical symptoms of cardiac dysfunction, aged ≥10 yrs, history of ≥50 transfusions, left ventricular ejection fraction (LVEF) ≥56% and liver iron concentration (LIC) ≥3 mg Fe/g dry weight (dw) were recruited. Patients were randomized to an intensified DFO regimen with a target dose of 50–60 mg/kg/d sc for 8–12 hrs, 5–7 d/wk, or deferasirox with a target daily oral dose of 40 mg/kg/d. Dose adjustment recommendations were based on continuous assessment of efficacy and safety markers. Efficacy was assessed in the per-protocol analysis population. Primary efficacy endpoint was change after 1-yr treatment (using last available value ≥150 d after randomization) in cardiac T2* expressed as the ratio of geometric means (Gmean) at end of study (EOS) over baseline (BL) for deferasirox divided by the ratio of Gmeans for DFO. Non-inferiority was pre-defined if the lower limit of the 2-sided repeated 95% confidence interval (CI) for ratio of Gmeans was >0.9. Results: From 925 screened patients, 197 patients (mean age 19.8 ± 6.4 yrs) were randomized. Mean time since start of transfusions was 19.3 and 18.4 yrs in deferasirox and DFO patients, respectively. All patients had received previous ICT. At BL, Gmean cardiac T2* was 11.4 ms; mean ± SD LIC was 29.8 ± 17.5 mg Fe/g dw in deferasirox patients and 30.3 ± 17.9 mg Fe/g dw in DFO patients; median (range) serum ferritin level was 5062 (613–15331) and 4684 (677–13342) ng/mL, respectively. 160 (81.2%) patients completed 1 yr. Mean actual dose of deferasirox was 36.7 ± 4.2 mg/kg/d and DFO was 41.5 ± 8.7 mg/kg/d for 7 d/wk. Overall, Gmean cardiac T2* increased by 12% with deferasirox and 7% with DFO after 1 yr (Fig A). The Gmean ratio between the two arms was 1.0557 (95% CI 0.9981, 1.1331). Lower limit of the 95% CI was >0.9, demonstrating non-inferiority of deferasirox vs DFO, with a trend towards superiority (P=0.0567). Trends toward increases were observed in patients with severe or mild/moderate cardiac iron (Fig B, C). In patients with BL LIC <7 mg Fe/g dw, increase in cardiac T2* was 30% for deferasirox (n=11) and 10% for DFO (n=8), for BL LIC 7–<15 mg Fe/g dw increase was 19% (n=14) for deferasirox and 13% (n=14) for DFO, and in patients with BL LIC ≥15 mg Fe/g dw increase was 9% (n=66) and 5% (n=59), respectively. LVEF was stable with deferasirox (BL 66.9 ± 5.61%; EOS 66.3 ± 5.8%) and DFO (BL 66.4 ± 5.2%; EOS 66.4 ± 5.8%). LIC absolute change from BL was –8.9 ± 11.4 (95% CI –11.5, –6.4) mg Fe/g dw for deferasirox and –12.7 ± 11.4 (–15.3, –10.1) mg Fe/g dw for DFO. Overall adverse event (AE) rates were 67.7% in deferasirox patients and 75.8% in DFO patients. In deferasirox patients, most common AEs were diarrhea (12.5%), proteinuria (11.5%) and influenza (10.4%). Most common AEs in DFO patients were proteinuria (8.8%), upper respiratory tract infection (8.8%) and influenza (6.6%). Serious AEs occurred in 10.7% patients overall (10.4% deferasirox; 11.0% DFO), with many related to the underlying disease. 3 deferasirox patients and 1 DFO patient had 2 consecutive serum creatinine increases >33% above BL and >upper limit of normal (ULN). Overall, 14.6% of deferasirox patients and 3.3% of DFO patients had ALT levels >5xULN and >2xBL. One death (arrhythmia) in the deferasirox arm was considered unrelated to study drug. One death (meningitis) in a DFO patient was suspected to be related to DFO. Discussion: CORDELIA, the first randomized controlled trial comparing deferasirox with DFO for cardiac iron removal, met its primary endpoint in demonstrating non-inferiority of deferasirox vs DFO, with a trend for superiority. There was a trend toward more pronounced improvements in cardiac T2* with deferasirox vs DFO in patients with BL LIC <15 mg Fe/g dw. The frequency of AEs was similar between treatment groups and the deferasirox safety profile was comparable to previous reports. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CVIS: Equity Ownership. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Piga:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lawniczek:Novartis: Employment. Habr:Novartis: Employment. Weisskopf:Novartis: Employment. Zhang:Novartis: Employment. Aydinok:Ferrokin: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4058-4058
Author(s):  
Ali Taher ◽  
Mohsen Saleh Elalfy ◽  
Amal El-Beshlawy ◽  
Dunhua Zhou ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Advisory Committees ◽  
Liver Iron ◽  
Transfusion Requirements

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

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.

Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4071-4071
Author(s):  
Patrick B Walter ◽  
Paul R Harmatz ◽  
Annie Higa ◽  
David Killilea ◽  
Nancy Sweeters ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Iron Overload ◽  
Board Of Directors ◽  
Innate Immune Response ◽  
Research Funding ◽  
Innate Immune ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5111-5111 ◽  
Author(s):  
Ali Taher ◽  
John B. Porter ◽  
Antonis Kattamis ◽  
Vip Viprakasit ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. 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. Kattamis:Novartis: Consultancy, Honoraria, 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. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4269-4269 ◽  
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.

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1016-1016 ◽  
Author(s):  
John Porter ◽  
Ali T Taher ◽  
Yesim Aydinok ◽  
Maria D Cappellini ◽  
Antonis Kattamis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Iron Removal ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Significant Difference ◽  
Liver Iron Overload ◽  
The Impact

Abstract Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al., 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC <7, 7–≤15 and >15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p-values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (LIC >15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p=0.0016) and 46% (7.3 ±7.3 ms, p<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those with LIC >15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC <7, LIC 7-≤15 and LIC >15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase (p <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher:Novartis Pharma: Honoraria, Research Funding. Aydinok:Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini:Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali:Novartis Pharma: Employment. Martin:Novartis Pharma: Employment. Pennell:Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria.

Prospective, Multinational/Regional, Non-Interventional Study to Assess Treatment Practices in Anemia Patients Prone to Iron Overload: Results from the 3-Year Transfusional Hemosiderosis Registry (TORS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2152-2152
Author(s):  
Noppadol Siritanaratkul ◽  
Jong Wook Lee ◽  
Jun Ma ◽  
Mustafa Pehlivan ◽  
Elena Volodicheva ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Final Visit ◽  
Common Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Transfusion Therapy ◽  
Geographical Regions ◽  
Median Change

Abstract Background: Diseases whose treatment requires chronic transfusion therapy are relatively rare, and many have higher prevalence among certain ethnic groups and geographic regions. In these geographical regions, the patterns of care for these diseases and the epidemiology of iron overload (IOL) and other complications of treatment are currently undefined. To improve patient (pt) outcomes, it is important to understand how to diagnose, monitor, and manage these diseases. The TORS study aimed to collect information on a large number of newly diagnosed pts with various types of anemia and hemoglobinopathies to assess pt management considering diagnostic criteria and treatment pattern with iron chelation therapy (ICT) across various geographical regions. Methods: Inclusion and exclusion criteria were defined earlier by Siritanaratkul et al, EHA. 2015. Pts aged >2 years requiring chronic transfusion therapy with newly diagnosed anemias (<12 months from diagnosis), including low and intermediate-1 myelodysplastic syndromes (MDS), aplastic anemia (AA), and other transfusion-dependent (TD) anemias were enrolled. Pts were recruited from various geographical regions and were classified according to pt numbers, ethnicity and health care system as geo-1: Hong Kong, South Korea, Taiwan, Thailand; geo-2: China; geo-3: Tunisia, Morocco, Algeria, South Africa, Russia; geo- 4: Turkey. Pts were evaluated at baseline (BL) and at follow-up visits according to the standard practice for up to 3 years or until death. Results: Of the 564 pts (including 57 pts aged ≤18 years), 58.5% (n=330) were diagnosed with MDS, 31.2% (n=176) with AA, 10.1% (n=57) with other TD anemias. Diagnosis of 1 pt was missing. The mean age (±SD) was 51.9±23.87 years (range, 2-92); 49.5% of pts (n=279) were male. 97.2% (321/330) of MDS pts were classified using the WHO classification. In 89.0% of MDS pts, a risk assessment according to IPSS score was performed. Pts known to have received transfusions during the study include 92.6% (163/176) of AA, 68.4% (226/330) of MDS, and 93% (53/57) of other TD anemias. If analyzed by geographical region, 72.4% (126/174) of geo-1, 49.7% (99/119) of geo-2, 92% (115/125) of geo-3, and 70.5% (103/146) of geo-4 pts received transfusions during the study. At BL, serum ferritin (SF) was only available in 34.5% (195/564) of overall pts (50.9% [82/161] of chelated; 28% [113/403] of non-chelated pts) (Table 1). If analyzed by disease, among chelated pts, 38.4% (15/39) of AA, 57.1% (52/91) of MDS, and 48.3% (15/31) of other TD anemias had BL SF values. SF was available in 35% (20/57) of pediatric pts at BL (39.2% [11/28] of chelated; 31% [9/29] of non-chelated pts). In the overall pt population, data on ICT were available in 26% (13/50) of geo-1, 63.6% (7/11) of geo-2, 51.2% (20/39) of geo-3, and 68.8% (42/61) of geo-4 pts. At the final visit, the overall median change in SF from BL was -67.0 ng/mL. Among the pts receiving ICT (n=161), median change in SF from BL was -325.6 ng/mL (-433.5 in AA, +483.5 in MDS, and -1113.0 in TD anemias) at final visit. Among the pts without ICT (n=403), the median change in SF from BL was +116.7 ng/mL (+116.2 in AA, +163.2 in MDS and -306.5 in TD anemias). Among the pts with ICT (n=161), median change in SF from BL was +395 in geo-1, +113.5 in geo-3, and -433.5 in geo-4 at the final visit (pt data not available for geo-2). Among the pts without ICT (n=403), median change in SF from BL was +70.1 in geo-1, -170.6 in geo-2, -71.7 in geo-3, and +348.7 in geo-4 pts. Conclusions: In this large observational study, MDS was the most common disease type. This was potentially biased by site selection. Although the majority of pts received transfusion therapy leading to IOL, the awareness of IOL was low if measured by the availability of SF at BL and at each of the following visits. Consequently, many pts did not receive ICT. Interestingly, the majority of the MDS pts were classified according to WHO and stratified according to the recommended IPSS risk score, confirming that these guidelines are part of the standards of care in the clinical practice regardless of the geographic zone or the healthcare system. Overall, these results suggest that diagnosis and management practices of IOL and the underlying anemias may still be suboptimal in many parts of the world. Therefore, there is a need to improve local or regional understanding of IOL and its clinical consequences based on feasible therapeutic options in those regions. Disclosures Siritanaratkul: Janssen-Cilag: Research Funding; Novartis: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Volodicheva:CELLTRION, Inc.: Research Funding. Wong:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Louw:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Han:Novartis: Employment. Losco:Novartis: Employment.

Role of T1 Mapping As a Complementary Tool to T2* for Cardiac Iron Overload Assessment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3624-3624
Author(s):  
Camilla Torlasco ◽  
Elena Cassinerio ◽  
Patrizia Pedrotti ◽  
Andrea Faini ◽  
Marco Capecchi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
T1 Mapping ◽  
Short Axis Slice ◽  
Strong Relationship ◽  
Thalassemia Major ◽  
Advisory Committees ◽  
Mean Values ◽  
End Diastolic Volume ◽  
Log Linear

Abstract Introduction. Iron overload-related heart failure is the principal cause of death in transfused Thalassemia Major (TM) (Modell B, Cardiovasc Magn Reson 2008;10:42-48). Iron toxicity is dose dependent so a strategy of chelation therapy titration (Kirk P, Circ 2009;120:1961-1968) before the onset of left ventricle (LV) impairment changes outcomes (AlpenduradaF, Eur Heart J. 2010; 31:1648-54). The presence of iron in tissue detectably changes the magnetic properties of water, T1, T2 and T2*, as validated against tissue in animal and human models (Carpenter JP, Circ 2011;14:1519-28). T2*, the most used technique, is susceptible to non-iron influence (susceptibility artefact) and has low accuracy for high and low iron levels (Carpenter JP, J Cardiovasc Magn Reson. 2014;12:16-62). T1 mapping could complement T2* as it appears to have superior reproducibility and to detect mild iron missed by T2* (Abdel-Gadir A. J Cardiovasc Magn Reson. 2015;17(Suppl1):P312. Sado DM, J Magn Reson Imaging. 2015;41:1505-11), but studies to date have been small and not using state-of-the-art sequences. Methods. In a prospectively single centre study of 138 TM patients and 32 healthy volunteers (HV) (no known medical conditions, normal CMR scan), we compared T1 mapping (Modifier Lock Locker Inversion sequence - MOLLI - Siemens Works in progress 448B) to the gold-standard dark (DB) and bright (BB) blood T2*, acquired on an Avanto 1.5T (Siemens Healthcare, Erlangen, Germany). For both T2* sequences, a single 10mm mid-ventricular short axis slice was imaged at 8 echo-times (2.58ms to 18.19ms, increment 2.23ms), flip angle=20¡, FOV read/phase=400mm/56,3%. The same slice was used for T1 images (thickness 6mm, distance factor=67%, FOV read/phase=360/75%, TR=740, TE=1.13, with motion correction for the in-line map generation). Results and discussion.All participants provided informed consent. Table1 illustrates patients' and HV's details. T2* was defined normal under the cutpoint value of 20ms. T1 normal range, defined by the HV cohort was 918-1015ms (the 2.5-97.5 quantiles with CI 95%). For DBT2*<20ms, both BBT2* and T1 mapping were broadly indistinguishable from DBT2* (DBT2* vs BBT2* R2=0.95; DBT2* vs T1 R2=0.92; all p<0.001). All subjects with low DBT2* (n=24, 17.4%) had low T1; 52 patients had normal DBT2* but low T1 mapping, i.e. 38% patients were reclassified from normal to iron loaded by T1. The relationship between DBT2* and MOLLI was described by a log-log linear regression (R2=0.80, p<0.001). Upper panel of Fig1 shows T1 vs DBT2* correlation over a 20ms window as the window moves by 1ms at a time on X-axis (so at X-axis point 'n', the Y-value is the R2 of the correlation of DBT2* vs T1 over the range n-to-n+20ms). As shown by lower panel of Fig1, three domains can be observed: strong relationship in the T2*=0-20ms range (R2=0.92, p<0.001); good relationship in the 21-28ms range, where the curve depicts a plateau (R2=0.80-0.77, p<0.001) and no relationship above 28ms. Given the conservative approach used to set T2* normality as above 20ms (Carpenter JP, Circ 2011;14:1519-28), the evidence that T2* SD values increase even for borderline T2* mean values (~20ms) (Anderson LJ, Eur Heart J. 2001;22:2171-9), and that 39% of normal T2* subjects have a low T1, we support prior suggestions that T1 is detecting mild iron in most of the subjects with DBT2*=20-28ms, missed by T2* as the threshold has had to be set too low for sensitivity reasons (Sado DM, J Magn Reson Imaging. 2015;41:1505-11). T1 mapping is thus a useful complementary tool to T2* both for clinical and research purposes. The reported reproducibilities of T1 square for power calculations and would translate into 6.25 to 49 times more power in studies to detect iron change (Alam MH, J Cardiovasc Magn Reson. 2015;24:17-102). Colour maps make iron instantly visible and add a confirmation step. Whether mild iron missed by T2* is important is unclear. In our cohort, 24-months follow-up was available for 9 patients with normal DBT2* and low T1. Although no statistical consideration is possible due to the small number, in those patients an increase in LV end diastolic volume was observed (from 78±18ml to 84±15ml), suggesting possible cardiotoxicity of even mild amount of iron. Further work is needed, especially in frail cohorts like children starting chelation and around pregnancy. Table 1 Table 1. Figure 1 Figure 1. Disclosures Moon: gsk: Consultancy; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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