ALBERT

Description: Introduction: The majority of published data about Deferasirox (DFX) are obtained on the dispersible formulation (DFX DT). A film-coated formulation (DFX FCT) with higher bioavailability is now approved and used in most countries, in tablets containing 30% less active principle. However, only few reports exist about long-term effects of DFX FCT and no independent comparison of the two formulations is available. Hypothesizing a bioavailability even higher than described, we conducted a study comparing PK/PD and safety of both formulations in a cohort of patients with congenital anemias. Methods: Clinical records of patients treated at our referral Centre in the period from 2011 to March 2019 were reviewed, identifying patients that performed a 24-hours PK profile for both DFX formulations and completed at least 1 year of continuous treatment for each one. Data about PK (drug dose, maximum plasma concentration (Cmax), Area Under Curve (AUC)), PD (serum ferritin (FTN), Liver Iron Concentration (LIC) by biosusceptometry) and safety (ALT, AST, creatinine, eGFR, protein/creatinine ratio) were collected. Acute Kidney Injury (AKI) was defined according to guidelines as previously described (Bird, 2018). Estimated compliance was also considered. Serum DFX concentrations were measured by HPLC (De Francia et al, 2012). For PD and safety analysis, study time was defined as the period between two subsequent LIC measures; timeframes closest to the beginning of the therapy were selected. Wilcoxon matched-pairs test, Chi-square test and Spearman r index were used to analyze differences and correlations between DFX DT and DFX FCT treatments, with a significance threshold of 0.01. Results: Seventy-four patients diagnosed of β-thalassemia major (61), β-thalassemia intermedia (11), Diamond-Blackfan anemia (1) and Stomatocytosis (1) met inclusion criteria for PK analysis. DFX was tested at a mean dose of 26.1 (DT) and 15.5 mg/kg (FCT; -41%), with a Cmax of 71.0 and 101.5 μMol/L (+43%) and an AUC of 855.0 and 1301.3 (+52%), respectively. Cmax and AUC correlated significantly with dose for both formulation, but highly for FCT (r(dose-Cmax) = 0.41 and 0.58, r(dose-AUC) = 0.37 and 0.52 for DT and FCT, respectively), suggesting a stronger association between administered dose and systemic bioavailability (Fig.1). Forty-nine out of 74 patients, with at least 1-year follow-up for each formulation, were further analyzed for PD and safety. Actual administered dose was adjusted if indicated, but no significant differences were observed from doses tested at PK. LIC and FTN levels did not change significantly during treatments; as expected, the rate of iron overload variation (ΔLIC) was proportional to the iron overload at baseline for both formulations, but this correlation was stronger for FCT (Tab.1). Mean compliance was high with both formulations but improved significantly with DFX FCT (DT=89.3%; FCT=91.6%; p=0.001). Liver enzymes, creatinine, eGFR and protein/creatinine ratio at the end of treatments did not differ from baseline. AKI episodes were experienced in both formulations at rates comparable or higher than described (Diaz-Garcia, 2014 and Bird, 2018), but significantly lower with DFX FCT (DT=1.47; FCT=0.49 episodes/patient/year; p=0.0083). Overall kidney function was maintained at the end of the study for both treatments. Discussion: This study presents a direct and extended comparison of DFX formulations from real-word experience. DFX FCT, even at doses lower than recommended (-41% instead of -30%) was superior to DT in terms of PK and comparable in overall PD after 1 year of observation. Here described for the first time, DFX FCT also resulted to be superior in terms of scalability, i.e. it showed better correspondence between administered dose and serum concentration and between the baseline iron burden and the rate of iron elimination during treatment. Acute renal impairment was confirmed to be a major complication of DFX treatment, however AKI prevalence was significantly lower for FCT and, consistently, a significant dose-dependent association was observed for FCT, but not DT. Altogether, our results suggest that FCT formulation is more bioavailable than expected and could improve chronic treatment with DFX, underlining the critical role of personalized dose tailoring and monitoring to maximize the delicate balance between effectiveness and safety . Disclosures Longo: Blue Bird Bio: Consultancy. Piga:Celgene Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Acceleron Pharma: Research Funding.

Description: Background: As pediatric patients with β-thalassemia will require lifelong iron chelation therapy, it is important to evaluate the long-term efficacy, safety and growth during treatment with any iron chelator. This analysis presents cumulative efficacy and safety data from a cohort of pediatric patients treated with the once-daily, oral chelator deferasirox during two 1-year core and 4-year extension trials. Methods: β-thalassemia patients aged 2–

Description: Abstract 3257 Background: In previous studies with deferasirox (Exjade®), some patients experienced dose-dependent, non-progressive increases in serum creatinine, mostly within normal limits and mostly reversible with dose reduction/interruption. Although the cause of these increases is not fully understood, the most likely mechanism is hypothesized to be a reduction in glomerular filtration rate (GFR) as a result of a pharmacological effect of deferasirox on the kidney, specifically on its intraglomerular hemodynamics (Schetz et al. 2005). This study was initiated to test this hypothesis and estimate the long-term effect of deferasirox 30 mg/kg/day on renal hemodynamics by measuring changes in renal function markers, specifically GFR, renal plasma flow (RPF) and filtration fraction (FF), in β-thalassemia patients with transfusional iron overload. Methods: This study enrolled deferasirox-naïve β-thalassemia patients aged ≥18 yrs receiving transfusions every 2–5 wks (iron intake ≥0.25 mg/kg/day), transfusion history ≥20 units packed red blood cells and serum ferritin ≥500 ng/mL or liver iron concentration (LIC) ≥2 mg Fe/g dry weight (dw). Patients were excluded if they had serum creatinine 〉upper limit of normal (ULN), estimated creatinine clearance (CrCl) 0.5 mg/mg, ALT 〉5 × ULN, history of nephrotic syndrome, or treatment with drugs known to affect renal parameters. As per the initial protocol, patients received deferasirox 30 mg/kg/day for 8 weeks, followed by a 2-week washout. In order to provide long-term data the study was amended: following the initial 10-week period, patients could receive deferasirox for an additional 94 weeks (up to Week 104) followed by a 4-week washout. GFR and RPF were measured using chromium-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) and 123ortho-iodohippurate (123I-OIH). Parameters were assessed at baseline, 2, 8, 10, 104 and 108 weeks. Results: Eleven patients were enrolled (mean age 35.2 yrs; 7:4 male:female). For these 11 patients at baseline, median serum ferritin was 2110 ng/mL (range 840–3131 ng/mL); mean LIC 7.3 ± 4.0 mg Fe/g dw. Mean GFR (111.5 ± 17.5 mL/min), RPF (603.5 ± 94.3 mL/min) and FF (0.2 ± 0.03) were normal. Ten patients completed 10 weeks of treatment (one discontinued due to voluntary withdrawal). Five of these patients did not enter the extension trial as they had completed the initial trial prior to the protocol amendment extending the study duration (no patient discontinued due to adverse events [AEs]) and five patients completed the 108-week study. For the five patients completing the 108-week study, mean GFR decreased from 108.5 ± 18.1 mL/min at baseline to 90.2 ± 17.8 mL/min at Week 104; mean RPF decreased from 595.4 ± 43.1 mL/min at baseline to 479.5 ± 87.6 mL/min at Week 104 (a mean relative decrease of 19.6%; Figure). After 4 weeks' washout following the 104-week period, both mean GFR and RPF recovered to near baseline values: from 90.2 ± 17.8 mL/min at Week 104 to 103.5 ± 17.1 mL/min at Week 108 and from 479.5 ± 87.6 mL/min at Week 104 to 553.5 ± 91.8 mL/min at Week 108, respectively. Mean percentage change for GFR from baseline was –9.5% at Week 8, +2.1% at Week 10, –17.2% at Week 104, and –4.5% at Week 108. For RPF, mean percentage change from baseline was –17.8% at Week 8, –9.0% at Week 10, –19.6% at Week 104 and –7.3% at Week 108. Mean FF showed only mild fluctuations (0.18–0.21) during the study. Serum creatinine was 61.5 ± 15.1 μmol/L at baseline, 65.4 ± 15.1 μmol/L at Week 104 and 62.9 ± 10.7 μmol/L at Week 108; CrCl was 115.0 ± 21.3 mL/min at baseline, 107.4 ± 13.8 mL/min at Week 104 and 109.9 ± 8.8 mL/min at Week 108. For the 11 patients enrolled, AEs regardless of study drug relationship were mainly gastrointestinal (diarrhea and upper abdominal pain n=3 each, abdominal pain n=2), pyrexia (n=3), rhinitis (n=3), back pain (n=2), headache (n=2), cough (n=3), oropharyngeal pain (n=3), rash (n=2). There were no deaths or serious AEs. Discussion: Deferasirox appears to produce a mild effect on renal hemodynamics, reflected by a decrease in RPF, leading to a decrease in GFR; these effects were reversible after drug interruption over the short and long term. Both mean GFR and RPF recovered to near baseline values after washout, suggesting that renal function is stable with up to 2 years' treatment with deferasirox. Disclosures: Piga: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cappellini:Novartis: Speakers Bureau. Habr:Novartis: Employment. Wegener:Novartis: Employment. Bouillaud:Novartis: Employment.

Description: Background Cardiac iron removal is relatively slow and patients with cardiac siderosis can take years to normalize cardiac T2* to 〉20 ms. Prospective comparison of iron chelators are mostly limited to studies of 1-yr duration. CORDELIA is a large randomized trial comparing deferasirox (DFX) with deferoxamine (DFO) in patients with β-thalassemia major (TM), which demonstrated the non-inferiority of DFX vs DFO for cardiac iron removal at 1 yr, with a trend for superiority of DFX (P=0.057). This 1-yr extension was planned to collect additional data on efficacy and safety of DFX and DFO in patients with cardiac siderosis when treated for up to 2 yr. Methods Study design has been reported previously (Pennell Blood 2012; abst 2124). Patients enrolled had cardiovascular magnetic resonance-measured cardiac T2* 6–20 ms, left ventricular ejection fraction (LVEF) ≥56%, and R2-magnetic resonance imaging liver iron concentration (LIC) ≥3 mg Fe/g dw. Patients completing 1 yr were eligible to continue on DFX or DFO as assigned, or to switch treatment on entering the extension if judged by the investigator to be of therapeutic benefit. Target doses were an intensified DFO regimen of 50–60 mg/kg/d sc for 8–12 h, 5–7 d/wk, or DFX at 40 mg/kg/d. Efficacy is reported for changes from core baseline (BL). Safety was monitored continuously. Results for patients continuing with DFX or DFO are reported here. Results In total, 160/197 patients completed 1 yr; 74 patients continued into the extension on DFX (mean age 20.1 ± 6.9 yr; 59.5% male) and 29 patients on DFO (17.0 ± 5.4 yr; 58.6%). At core BL, 29.7% DFX patients had cardiac T2* 33% from BL and 〉 upper limit of normal (ULN) at 2 consecutive values occurred in 2.7% of DFX and 3.4% of DFO patients. Frequency of ALT elevations 〉5 x ULN and 2 x BL were comparable between groups. Discussion Cardiac T2* increased substantially during 2-yr treatment with DFX or DFO. Improvement with DFX was comparable with DFO, although DFO patient numbers were low. The magnitude of cardiac T2* improvement with DFX was consistent with previous long-term studies (Pennell Blood 2010). Mean LVEF was stable and remained within normal limits in both groups. LIC continued to decrease from very high BL levels with DFX and DFO. The reduction in CIC in the extension was similar or possibly greater than in the core, which might relate to the falling LIC. Long-term safety profiles of DFX and DFO were consistent with previous reports. Disclosures: Pennell: Shire: Consultancy, Honoraria; ApoPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Piga:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wegener:Novartis: Employment. Habr:Novartis: Employment. Shen:Novartis: Employment. 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.

Description: Prevalence of Left Ventricular Dysfunction (LVD), and Congestive Heart Failure (CHF) have been widely described in Thalassemia Major (TM) patients (pts), according to age, therapy, severity and coexisting diseases. However, so far no data are available in a large population adequately transfused and chelated. To determine the LV involvement in treated TM patients, we studied 524 pts from 5 Thalassemia Centers in Italy (49% males, mean age 30 yrs, range 16 to 56 yrs). In all pts clinical and echocardiographic data were recorded in WEBTHAL® database, a large co-operative Italian project among Thalassemia Centres based on an Internet-shared software for thalassemia. Data were evaluated blind by two independent researchers. Patients were considered having LVD if at least one cardioactive drug and/or history of cardiopathy (heart failure and/or clinically relevant arrhythmias) was recorded in their file (102/524 patients, 19,5%). Tables I and II summarize the echocardiographic results and cardiological treatment. Table I TM population without LV involvement (n°422 pts) and on cardiological treatment (n° 102 pts) Mean * Statistically significant between groups Pretrasfusional Hb (g/dl) 9,4 Ferritin (μg/dl) mean of last 10yrs 2027,7 LV end diastolic diameter index (mm/m2) 31,8 FS (%) 35,0 EF (%) 60,6 Duration of transfusion period (yrs) 24,5 Pretransfusional Hb (g/dl) 9,5 Ferritin (μg/dl) mean of last 10yrs * 2389,6 LV end diastolic diameter index (mm/m2)* 32,9 FS %* 31,3 EF % 54,4 Duration of transfusion period (yrs)* 26,2 Table 2 Cardiovascular Drugs N° % At least one drug 102 19,5 ACE Inhibitors 81 15,5 Diuretics 39 7,4 Beta-blockers 24 4,6 Antiarrhythmics 16 3,1 Digoxin 8 1,5 The majority of patients (422 subjects, 80.5%) did not take any cardioactive drugs and were considered without LV involvement. Systolic Pulmonary pressure was elevated (PH) (〉 25 mmHg) in 10% of pts. ACE-inhibitors were the most used cardiovascular drug (15.5% of the pts), mainly males (n°56 pts, p

Description: Background: The serum level of GDF15 has been recently indicated as a possible marker of erythropoiesis (Tanno et al., Nature 2007) suggesting a role of its over-expression in contributing to iron overload in thalassemia syndromes by inhibiting hepcidin expression. The aim of present study has been to evaluate GDF15 serum levels in a homogeneous series of thalassemia patients and the relationship with transfusional parameters and iron status markers. Methods: A group of consecutive patients with beta thalassemia major followed at our institution were included in the study. All patients were on regular transfusion and iron chelation treatment. Quantification of GDF15 on serum samples was performed with DuoSet ELISA for human GDF15 (R&D Systems) following the manufacturer’s protocol (Tanno et al., Nature 2007). Each patient had also a blood test for haemoglobin (Hb), serum iron, ferritin, transferrin, transferrin saturation and EPO levels. Liver Iron Concentration by SQUID and cardiac iron by MRI T2* have been assessed. The mean hemoglobin levels of the previous year (pre-transfusional, post-transfusional and mean) have been calculated for each individual. The presence of mild thalassemic mutations was used to classify mild or severe genotype. Clinical status has been assessed on the presence/absence of main complications (heart disease, liver disease, diabetes, hypothyroidism). Statistical analysis was performed using the software Statistica (StatSoft). Results: One hundred-forty patients (73 male, 67 females) were studied. The mean age was 27.9 ± 9.0 years (range: 3.5–42). One hundred (71%) were splenectomised. Betathalassemia major patients had elevated GDF15 serum levels (mean 6892 ± 6894 pg/mL; range 720–52521) in comparison with healthy volunteers (273 ± 104 pg/mL; range 129–401). GDF 15 levels were strongly related to EPO levels (r=0,81; p

Description: Iron accumulation and overload in beta thalassaemia patients are associated with significant morbidity and mortality. Iron chelators are used to manage iron accumulation but side effects and compliance issues restrict the use of available chelators. Deferitrin (Genzyme Corporation) is an orally available iron chelator intended for iron overload. Method: Patients were dosed in 4 cohorts, receiving 5, 10, 15 and 25 mg/kg/day of deferitrin. Deferitrin dosing in cohorts 1–3 was once daily for 12 weeks. Cohort 4 received deferitrin twice daily (BD) for 48 weeks (12.5mg/kg BD, 25 mg/kg/day). Pharmacokinetics (PK) were assessed in a subset of up to 5 patients in each cohort, pre-dose and 1, 2, 4 and 8 hours post dose. All patients had trough levels assessed at weeks 1, 6 and 12 (all Cohorts) and additionally at weeks 24, 36 and 48 for Cohort 4. PK parameters were determined by model independent (non-compartmental) analyses. Safety was assessed by collection of adverse events and laboratory assessments with renal parameters measured weekly due to observations of renal toxicity in preclinical testing. Efficacy (change in liver iron concentration (LIC)) was assessed by SQUID (superconducting quantum interference device) in Turin, Italy, between screening and end of study. Iron excretion and intake were estimated by calculation:Iron excretion due to deferitrin = Iron Intake (mg/kg/day) - TBI (mg/kg/day)Iron Intake (mg/kg/day) = [total mL pRBC (exclude last BT×) × 1.08] / [Weight (kg) × Days (Between 1st & last BT×)]TBI (mg/kg/day) = Change in LIC (mg Fe/g dry weight) × [10.6 (Angelucci Factor) / D (Days on deferitrin)] Key: pRBC = packed red blood cells, BT× = blood transfusion, TBI=Total Body Iron. Results: PK: PK for deferitrin dosed once daily was linear and dose proportional. The serum half-life was 1.3–1.8 hrs, clearance was 226–340 mL/min and mean residence time was 2.8–3.4 hrs for once daily dosing. PK data from BD dosing is not yet available. Safety: Deferitrin dosed once daily was generally well tolerated (Cohorts 1–3). Slight rises in transaminases were seen at 10 and 15 mg/kg/day. A large proportion of enrolled patients were hepatitis C positive (73%). When dosed BD (12.5 mg/kg BD in Cohort 4), 3 patients developed renal toxicity after 4–5 weeks of treatment. Two patients experienced increased proteinuria (max 3.73 g/L & 3.29 g/L) and one patient suffered acute renal failure (peak serum creatinine 4.1 mg/dL, lowest GFR 27 mmol/L). All patients recovered normal renal function after stopping treatment. No patients were re-challenged with deferitrin. Dosing was terminated in all patients because of safety concerns. Efficacy: Mean iron excretion in mg/kg/day (S.D) for Cohort 1 was 0.22 (0.22), Cohort 2 was 0.45 (0.14) and Cohort 3 was 0.33 (0.12). The reasons for the lack of dose proportionality in iron excretion are unclear. Efficacy could not be assessed in Cohort 4 due to early termination of the study. Conclusions: Deferitrin dosed once daily was generally well tolerated and associated with a mean iron excretion of 0.34 mg/kg/day. Deferitrin dosed BD (12.5mg/kg BD) was associated with unacceptable renal toxicity and led to study termination. Deferitrin does not appear to have an acceptable therapeutic margin to allow sufficient iron excretion for long-term administration.