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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2257-2257 ◽  
Author(s):  
Yesim Aydinok ◽  
Antonis Kattamis ◽  
M Domenica Cappellini ◽  
Amal El-Beshlawy ◽  
Raffaella Origa ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Iron Removal ◽  
Advisory Committees ◽  
Liver Iron ◽  
Off Label ◽  
Cardiac Iron ◽  
Cardiac Siderosis

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

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.

Initial Liver Iron Predicts Cardiac Chelation Efficacy of Deferasirox (Exjade®) Monotherapy in Chronically Transfused β-Thalassemia (β-Thal) Patients: 18- and 24-Month Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4069-4069
Author(s):  
John C. Wood ◽  
Alexis A. Thompson ◽  
Carole Paley ◽  
Tara Glynos ◽  
Barinder Kang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Employment Equity ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Equity Ownership

Abstract Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Deferasirox was administered at 30–40 mg/kg/day for 18 months. Following core study completion (18 months), patients could continue treatment for an additional 6 months if their 18-month cardiac T2* was <20 ms and they demonstrated ≥25% improvement in cardiac T2* or LIC from baseline. Serum ferritin (SF) was assessed monthly. Liver iron concentration (LIC), cardiac T2* and LVEF were assessed by MRI every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean ± SE (range) unless otherwise stated. Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change <10%) and five worsening. Baseline LIC was a powerful predictor of response (Figure); cardiac T2* in 14 patients with LIC <18.5 mg Fe/g dw improved 2.2% per month, with 13/14 patients showing large improvements and one patient remaining stable. In contrast, in eight patients with LIC >18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P<0.0001); three patients remained stable and five worsened significantly. Improvements in cardiac iron were correlated with changes in LIC (r2 = 0.27, P=0.013). In general, initial T2* did not predict therapeutic response, although all three patients with T2* <6 ms increased their cardiac iron. LIC decreased 4.1 mg Fe/g dw over the study interval (P=0.003). LVEF remained stable. 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC <18.5 mg Fe/g dw was a strong predictor of favorable response. LVEF remained stable during the study. Patients in the extension (18–24 months) improved their cardiac T2* without further improvements in LIC or SF. Deferasirox monotherapy at 30–40 mg/kg/day provides good cardiac chelation in patients with moderate cardiac and liver iron burdens. More aggressive therapy is warranted for more severe iron overload. Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

A Study of Magnetic Resonance Imaging Assessment of Cardiac and Liver Iron Load in Patients with Haemoglobinopathies, Myelodysplastic Syndromes or Other Anaemias Treated with Deferasirox (the MILE study CICL670AAU01) – Results of An Interim Analysis At a Planned Sample Size Reassessment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3181-3181
Author(s):  
P. Joy Ho ◽  
Lay Tay ◽  
Juliana Teo ◽  
Paula Marlton ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Sample Size ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Thalassaemia Major ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Cardiac Siderosis

Abstract Abstract 3181 Background: Cardiac failure is the leading cause of death in patients with thalassaemia major. However, the introduction of new monitoring techniques, such as cardiac iron Magnetic Resonance Imaging (MRI), may lead to the improvement of patient care and prolong survival. Although the impact of cardiac siderosis in patients with thalassaemia major has been extensively studied, further examination of the effect of specific iron chelators such as deferasirox are important in the development of treatment protocols, while the clinical consequences of cardiac iron accumulation in patients with myelodysplastic syndromes (MDS) is still controversial. Aim: The primary objective of this study is to investigate the effect of single agent deferasirox on cardiac iron levels and cardiac function, in a cohort of patients receiving regular red blood cell transfusions. Methods: Patients with transfusional siderosis were enrolled in this study and received deferasirox for 53 weeks. Doses up to 40 mg/kg/day were allowed according to transfusional requirement, response to chelation therapy and safety markers. Cardiac siderosis (cardiac T2* measured by linear fitting to the decay of logarithmic magnetic resonance signal) and left ventricular ejection fraction (LVEF) were measured at baseline and at 53 weeks. The sample size was originally calculated based on the standard deviation (SD) of the change in log(T2*) (0.47), according to previously published reports. A planned sample size reassessment as per protocol was undertaken when 42 patients had follow-up data. For the sample size reassessment, log(T2*) was calculated for each result and the change in log(T2*) estimated for each patient. Results from the interim sample size reassessment and the analysis of cardiac iron and function are described below. Results: Results were available for 36 patients with haemoglobinopathies (mainly represented by thalassaemia major), 5 patients with MDS and one post-bone marrow transplant patient. The SD observed for change in log(T2*) with the current data was 0.26 (original assumption 0.47). Assuming the SD for the final data does not increase above 0.34 the current cohort should be sufficient to detect a change in log(T2*) of the pre-specified 0.14. Safety assessments were consistent with previous studies on deferasirox. An overall increase in cardiac T2* from 23.0 to 26.1 ms was observed (p<0.001). Further analysis was performed based on the T2* baseline values: 5–10 ms, no significant change (n=6; 8.5 to 7.9 ms; p=0.6; non-significant); 10–20 ms, improvement of 26% (n=8; from 14.8 to 18.7 ms; p=0.001); >20 ms, increase of 10% (n=28; 32.3 to 35.6 ms; p=0.04). Overall, an increase in LVEF of 2.1% was observed, just below statistical significance (from 60.9% to 63.0%, p=0.076). The largest increase in LVEF was observed in patients with moderate cardiac siderosis (baseline T2* 10–20 ms; statistically significant increase in LVEF of 5.7%, from 56.8% to 62.5%, p=0.045). Descriptive preliminary analyses of the MDS subgroup showed that all 5 patients had baseline cardiac T2* >20 ms (median 32 ms; range: 29.7 to 34 ms). Similarly to the overall patient pool, deferasirox induced a 12% increase in cardiac T2* although not statistically significant (32.2 to 35.9 ms, p=0.13). In this subgroup of MDS patients, a statistically significant increase in LVEF was also observed (56.4% to 63.6%, p=0.04). Results on liver iron concentration will also be presented. Conclusion: The interim results from this study showed for the first time that once-daily deferasirox induced a simultaneous and statistically significant increase in both cardiac T2* levels and cardiac function in patients with moderate cardiac siderosis. Although the small number of patients in the MDS subgroup had cardiac T2* levels above 20 ms, chelation therapy induced an increase in LVEF in all 5 patients enrolled to date. Taken together, these results also confirm previous reports showing that single agent deferasirox is an effective therapy for maintenance and reduction of cardiac iron levels, especially for patients with cardiac T2* >10 ms. Recruitment has been halted based on the recommendations of the interim sample size re-estimation in consultation with the Data Monitoring Committee. Six patients are ongoing, and will be included in the final analysis of the study. Disclosures: Ho: Novartis: Honoraria, Invited speaker, Membership on an entity's Board of Directors or advisory committees. Tay:Novartis: Membership on an entity's Board of Directors or advisory committees. Teo:Novartis: Research Funding. Marlton:Novartis: Membership on an entity's Board of Directors or advisory committees. Grigg:Novartis: Invited speaker, Membership on an entity's Board of Directors or advisory committees. Pierre:Resonance Health: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Brown:Novartis: Consultancy, Invited speaker. Gervasio:Novartis: Employment. Bowden:Novartis: Honoraria, Research Funding, 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.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 618-618
Author(s):  
Janet L. Kwiatkowski ◽  
Mohsen Saleh Elalfy ◽  
Caroline Fradette ◽  
Mona Hamdy ◽  
Amal El-Beshlawy ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Concentration ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Upper Limit ◽  
Iron Load ◽  
The Difference

Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation. Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage. Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment. Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints. With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs. Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias. Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study. Disclosures Kwiatkowski: Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment. OffLabel Disclosure: Deferiprone is an oral iron chelator.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5106-5106
Author(s):  
Gillian Smith ◽  
Dudley J. Pennell ◽  
John B. Porter ◽  
M. Domenica Cappellini ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Left Ventricular ◽  
Myocardial Iron ◽  
Advisory Committees ◽  
Off Label ◽  
Cardiac Siderosis ◽  
Rv Function

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

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4062-4062 ◽  
Author(s):  
Dudley J. Pennell ◽  
John B. Porter ◽  
M. Domenica Cappellini ◽  
Lee Lee Chan ◽  
Amal El-Beshlawy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Extension Phase ◽  
Left Ventricular Ejection ◽  
Advisory Committees ◽  
Off Label ◽  
The Core ◽  
Cardiac Siderosis

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

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2430-2430
Author(s):  
Eduard J van Beers ◽  
Wilma Barcellini ◽  
Stefan W. Eber ◽  
Janet L Kwiatkowski ◽  
Jennifer A Rothman ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Disease Severity ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Status ◽  
Compound Heterozygous ◽  
Advisory Committees ◽  
Cardiac Iron ◽  
Significant Difference

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

Safety and Efficacy of Combination Therapy of Interferon-Alpha2 + JAK1-2 Inhibitor in the Philadelphia-Negative Chronic Myeloproliferative Neoplasms. Preliminary Results from the Danish Combi-Trial - an Open Label, Single Arm, Non-Randomized Multicenter Phase II Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 824-824 ◽  
Author(s):  
Stine Ulrik Mikkelsen ◽  
Lasse Kjær ◽  
Vibe Skov ◽  
Mads Emil Bjørn ◽  
Christen Lykkegaard Andersen ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Advisory Committees ◽  
Off Label ◽  
Chronic Myeloproliferative Neoplasms ◽  
Major Response ◽  
Travel Grant ◽  
Grade 3

Abstract Background: The Philadelphia-negative, chronic myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) (PMF). Chronic inflammation and a deregulated immune system are considered important for clonal evolution and disease progression. Ruxolitinib is a potent anti-inflammatory agent and has shown great benefit in MPN patients (pts), reducing spleen size and inflammation-mediated symptoms, thereby improving quality of life (QoL). Interferon-alpha2 (IFNa2) has been used successfully for decades in the treatment of MPN. However, 10-20% of pts are intolerant to IFNa2, yet others show limited response. Since concurrent inflammation might attenuate the efficacy of IFNa2 therapy, a combination therapy (CT) with the two agents may be more efficacious than monotherapy, likely reducing the inflammation-mediated adverse effects of IFNa2 as well. The purpose of this COMBI-trial is to evaluate the safety and efficacy of CT with IFNa2 and ruxolitinib. Patients and Methods: At the time of data cutoff, a total of 30 pts ≥18 years with prefibrotic or hyperproliferative PMF (n=7), PV (n=20) or post-PV MF (PPV-MF) (n=3) with or without prior treatment with IFNa2 and without serious comorbidity were enrolled. Evidence of active disease was required. Initial therapy was IFNa2 45 μg x 1 sc/week (Pegasys®) or 35 μg x 1 sc/week (PegIntron®) + ruxolitinib (Jakavi®) 20 mg x 2/day. Efficacy was evaluated by internationally accepted clinicohematological response criteria, with the modification that splenomegaly was assessed by palpation instead of imaging, by week 2 and 1, 3, 6 and 9 months. In addition, JAK2V617F-allele burden was monitored. Adverse events (AE) including serious AE (SAE) were recorded. Results: Median treatment duration was 24.4 weeks (range, 3.4 weeks-43.3 weeks). Twenty-seven pts were previously treated with IFNa2 (n=18 intolerant, n=5 unresponsive, n=4 both). Three pts were treatment-naïve. Twenty-seven pts (90%) remained on CT; 3 pts discontinued treatment due to an AE. One patient died from transformation to AML shortly after initiation of CT and was not included in this interim analysis. Marked improvements in pruritus, night sweats, and fatigue were recorded within the first 2-3 days in the large majority of pts and in all within 4 weeks. Palpable splenomegaly in 7 pts at baseline was significantly reduced by week 2. Hct control without phlebotomy was achieved by week 4 in 78 % of pts (7 of 9), who at baseline had an elevated hct. Only 3 pts required a total of 3 phlebotomies after initiation of CT. In Figure 1 median hct levels at 0, 1, 3, 6 months are shown. Overall, complete response (CR) was achieved as best response in 19 pts (63.3%) and partial response (PR) or major response in 8 pts (26.7%). Only 3 pts (10%) had no response (NR) to treatment. Among PV pts, 15 (75%) achieved CR (week 2, n=6; 1 month, n=6; 3 months, n=3). The other 5 PV pts achieved PR (week 2, n=3; 1 month, n=2). In PMF pts, CR (n=2) or major response (n=2) was achieved in 4 pts (57.1%) by week 2 or 1 month, and NR in 3 pts (42.8%). Among PPV-MF pts, 2 pts (66.7%) achieved CR and 1 patient (33,3%) PR by week 2. Furthermore, JAK2V617F% declined significantly as depicted in Figure 2 (JAK2V617F% over time for each patient) and 3 (median JAK2V617F% at 0, 3, 6 months). Anemia (n=15, 2 grade 3), granulocytopenia (n=13, 2 grade 3) or thrombocytopenia (n=6, 1 grade 3) were the most common AEs and were managed by dose reduction. One patient with PPV-MF (leuko- and thrombocytosis) developed pancytopenia within the first 2 weeks on CT, necessitating pausing medication for > 2 weeks. Eleven SAEs requiring hospitalization were recorded in 9 pts: pneumonia (n=3), fever (n=2), lipotymia, hematemesis, phlebitis, herpes zoster, angina pectoris and arterial hypertension, 1 patient each. Conclusion: CT with IFNa2 and ruxolitinib is highly efficacious and safein pts with PV or hyperproliferative MF,who were unresponsive or intolerant to monotherapy with IFNa2. Complete clinicohematological responses were achieved in the majority of pts in concert with a reduction in the JAK2V617F-allele burden. In general, the treatment was well tolerated. The preliminary results from this study are highly promising, encouraging a prospective study with CT in newly diagnosed pts. Additional follow-up data will be presented including QoL assessment and the impact of concurrent treatment with statins. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Off Label Use: The combination therapy with ruxolitinib (JAK1-2 inhibitor) and interferon-alpha is off-label in MPNs. The concept is dual myelosuppressive action and dual clonal suppression in addition to the anti-inflammatory properties of ruxolitinib.. Bjørn:Novartis Oncology: Research Funding. Bjerrum:Bristoll Myers Squibb, Novartis and Pfizer: Other: educational activities. El Fassi:Novartis Denmark: Honoraria, Other: Have conducted an educational session for Novartis Denmark, regarding MPNs and ruxolitinib, for this a honorarium was received.. Nielsen:Novartis: Research Funding. Pallisgaard:Roche: Other: travel grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau; Novartis: Other: travel grant, Research Funding, Speakers Bureau; Qiagen: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Speakers Bureau. Hasselbalch:Novartis: Research Funding.

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