ALBERT

Description: Abstract 2125 Background: Young children typically receive more blood transfusions per kg body weight compared with adults, increasing the risk of iron overload. Iron overload may lead to endocrine abnormalities that can affect growth and development. Data from clinical trials of the iron chelator deferasirox (Exjade®) have demonstrated tolerability and efficacy in transfused patients with a range of underlying anemias. The registration clinical trials included 52 patients aged 2–33% increase from baseline on two consecutive measurements (baseline range 20–39 μmol/L); none of these five patients discontinued. Increased ALT 〉5 × ULN was confirmed in 11/247 patients (4.5%); most abnormalities were transient, five of these patients discontinued (increased ALT [n=3], protocol deviation [n=1] and vomiting [n=1]). The most common (≥4 patients) investigator-reported drug-related AEs were investigations and GI disorders; these are shown in the Table as investigator-reported preferred terms. The majority of investigations were mild-to-moderate in severity. Overall, 178/247 patients (72.1%) are continuing the study. Main reasons for discontinuation were protocol deviation (n=12, 4.9%) and AEs (n=7, 2.8%: increased ALT; proteinuria; hepatic AE [increased ALT/AST for second time after drug administration]; abdominal pain/vomiting/hypokalemia/transaminase elevation; vomiting; reversible increase of ALT of 239 U/L reported as hepatic cytolysis; transaminase elevation/lack of efficacy; all n=1). One patient with DBA died (severe pancytopenia and sepsis following bone marrow transplantation). Conclusions: The safety profile of deferasirox in very young pediatric patients was consistent with the available evidence in adult patients, including the rate of creatinine and liver enzyme changes which did not appear to be progressive. Many patients did not have appropriate dose adjustments during the study, despite substantial increases in weight. In addition to safety and efficacy parameters, weight change in pediatric patients should be considered during dose adjustments to optimize efficacy and safety. Disclosures: Vichinsky: Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding. Bernaudin:Novartis: Research Funding. El-Ali:Novartis: Employment. Arrowsmith:Novartis: Employment. Martin:Novartis: Employment.

Description: Abstract 4280 Beta thalassemia intermedia syndromes are serious conditions for which there is no satisfactory therapy to correct the underlying globin chain imbalance. Some agents that induce fetal globin gene expression have ameliorated anemia in thalassemia patients by reducing the imbalance in alpha: non-alpha globin synthesis, but none have been broadly accepted or are currently approved by regulatory authorities. HQK-1001 is an oral agent that targets the fetal globin gene promoter, thereby increasing fetal hemoglobin (HbF) expression. It has been well tolerated in single dose and multiple dose escalation clinical studies in healthy volunteers. We now report the results of a randomized, double blind, placebo-controlled, multiple ascending dose Phase I/II trial in 21 adult patients with beta thalassemia intermedia (BTI), including 14 with HbE/ß0 thalassemia and 7 with ß+/ß0 thalassemia (including 12 different beta globin gene mutations). Study medication was taken as a single daily dose for 8 weeks. Four ascending dose levels (10, 20, 30, and 40 mg/kg/day) were sequentially evaluated in 4 dose level cohorts after the preceding dose and schedule were determined safe by an independent and unblinded Safety Monitoring Committee. HQK-1001 was well-tolerated. Adverse events in treated subjects included headache, upper respiratory infection and nausea, but the rates of such events were not markedly different than those observed in the placebo-treated subjects. The 20 mg/kg dose was associated with a 10% mean increase above baseline in HbF, (p〈 0.001). Total hemoglobin (Hgb) increased by a mean of 1.1 gram/dL in 3 of 6 treated BTI patients with Mediterranean mutations. F-cells increased over the study period with maximal increases often observed 2 weeks following therapy. Doses higher than 20 mg/kg were not associated with the same magnitude of pharmacodynamic effects. These observations indicate that HQK-1001 is well-tolerated at doses associated with favorable pharmacodynamic effects on Hgb and HbF. These findings with brief treatment provide a rationale for conducting larger and longer studies in BTI patients. Disclosures: Fuchareon: HemaQuest Pharmaceuticals, Inc: Honoraria, Research Funding. Inati:HemaQuest Pharmaceuticals, Inc: Honoraria, Research Funding. Boosalis:HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thein:HemaQuest Pharmaceuticals, Inc: Research Funding. Wallis:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Bobbitt:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Description: Abstract 904 Background: As a result of previous transfusions, β-thalassemia major (TM) patients who have undergone curative hematopoietic stem cell transplantation (HSCT) are at increased risk of iron overload. There are, however, limited data on iron removal in such patients with either phlebotomy (PHL) or iron chelation. The aim of this study was to compare the efficacy, safety and convenience of the oral iron chelator deferasirox (DFX; Exjade®) with PHL for the treatment of iron overload in children with TM following HSCT, over a 1-year period. Methods: LB03T is a prospective, randomized trial enrolling children with TM aged 2-3 mg Fe/g dry weight [dw]). Eligible patients were randomized to PHL (6 mL/kg blood/2 weeks) or DFX (10 mg/kg/day starting dose; 5 mg adjustments up to 20 mg/kg/day were permitted). One of the primary endpoints was change in LIC assessed using magnetic resonance imaging techniques. Changes in serum ferritin levels, hemoglobin (Hb), total iron binding capacity (TIBC), non-transferrin-bound iron (NTBI), adverse events (AEs) and compliance with study treatment (PHL: ratio of performed:planned; DFX: tablet count) were also assessed. Convenience of treatment was evaluated using parents' responses to pre-prepared questions. Results: 27 patients were randomized to DFX or PHL; one patient randomized to PHL refused treatment, hence 12 patients received DFX and 14 received PHL. Mean age was 12.4 yrs and 53.8% were male. Patients were followed up for a mean of 12.0 months. 2 and 5 patients had DFX dose increases to 15 and 20 mg/kg/day, respectively. Mean DFX dose at last visit was 11.0 and 18.1 ng/mL in the LIC≤7 and LIC〉7 groups, respectively. Median serum ferritin was significantly reduced from baseline over 12 months with DFX (–497.5 ng/mL, P=0.004 vs baseline) and PHL (–901.8 ng/mL, P

Description: Introduction:Regular supportive transfusion therapy from an early age is common practice in young children with β thalassemia major (βTM), sickle-cell disease (SCD) and Diamond-Blackfan anemia (DBA). Patients consequently accumulate iron that can affect organ function and delay growth/development. As such, iron chelation therapy is often necessary from an early age, with lifelong requirements for patients who cannot be cured with hematopoietic stem cell transplantation. Deferasirox, a once-daily oral iron chelator, has demonstrated efficacy and safety in adult and pediatric patients with chronic iron overload. Long-term evaluation of deferasirox in young pediatric patients with transfusional hemosiderosis is valuable, as conducted in the 5-yr multinational, observational ENTRUST study. Here, we report safety and efficacy outcomes in pediatric patients with transfusional hemosiderosis receiving up to 5 yrs of continuous deferasirox treatment in clinical practice. Methods :Patients aged 2-

Description: Treatment of β-thalassemia is still largely dependent on supportive care, including blood transfusions and iron chelation. No oral drugs have been shown to consistently improve the severe anemia in thalassemia. Hematopoietic stem cell transplantation is potentially curative, but only a fraction of patients are eligible. Reactivation of fetal globin gene expression and increased γ-globin chain production is an attractive therapeutic approach, because it can compensate for defective β-globin chain production and the consequent α/β-chain imbalance that is a hallmark of β-thalassaemia. HQK-1001 (2,2-dimethylbutyrate, sodium salt), a new butyrate derivative with moderate potency but greater bioavailability, no cytotoxicity, and no HDAC-inhibitory activity compared to earlier butyrates, was shown to stimulate γ-globin production and erythropoiesis in animal models and in vitro. HQK-1001 reactivates γ-globin gene expression by inducing targeted dissociation of the inhibitory complex HDAC3 and its adaptor protein NCoR from the γ-globin gene promoter. HQK-1001 also enhances erythropoiesis by prolonging phosphorylation and activation of STAT-5, and enhancing Bcl-xL expression. In a multicenter dose-escalation study, HQK-1001 administered orally at 10, 20, 30 and 40 mg/kg once daily for 8 weeks in 21 subjects with non-transfusion-dependent β-thalassemia (NTDT) was well-tolerated and increased fetal hemoglobin (Hb F) in most subjects, with best results observed at 20 mg/kg. This single-center study (NCT01642758) evaluated HQK-1001 administered at 20 mg/kg/day for a longer duration than previously studied. Patients 18-50 years old with NTDT of Mediterranean phenotypes were eligible if their hemoglobin (Hb) was between 6.0 and 9.0 g/dL within the prior 30 days and had no transfusions within the prior 3 months. HQK-1001 was administered at 20 mg/kg once daily for 24 weeks. Folic acid was administered daily and oral iron supplementation was prescribed if serum ferritin was

Description: Abstract 5300 Background: Patients with thalassemia major (TM) who have undergone hematopoietic stem cell transplantation (HSCT) often demonstrate iron overload due to their previous requirement for regular blood transfusions, and are therefore at risk of associated toxicities. Efficient iron removal in such patients is therefore essential to prevent complications. For patients post-HSCT who undergo iron removal with phlebotomy, analysis of liver volume in combination with measurement of liver iron concentration (LIC) by MRI enables a calculation of total liver iron content (TLIC) in units of g Fe (in contrast to LIC in units of mg Fe/g tissue) both before and after phlebotomy. The aim of the study was to determine the average fraction of the Hb iron removed represented by the reduction in TLIC. Methods: LB03T is a prospective, randomized trial enrolling children aged 2-3 mg Fe/g dry weight [dw]). Eligible patients were randomized to phlebotomy (6 mL/kg blood/2 weeks) or deferasirox (10 mg/kg/day starting dose; 5 mg/kg/day adjustments up to 20 mg/kg/day were permitted). A primary study endpoint was change in LIC assessed using spin-density projection assisted R2-MRI (FerriScan®). For the patients undergoing phlebotomy, liver iron content was calculated as [liver volume] × [LIC]. A wet to dry weight conversion factor (3.8) was then applied, to transform the LIC into units of mg Fe/g wet tissue. The density of liver tissue was assumed as 1.051 g/mL, from which the TLIC was estimated. TLIC was calculated before and after phlebotomy to reduce iron overload, which enabled the total iron reduction in the liver to be calculated. Results: A total of 27 patients were randomized to deferasirox (n=12) or phlebotomy (n=14). One patient randomized to phlebotomy refused treatment. The results presented here refer to the patients in the phlebotomy arm only. The median time between MRI scans was 405 days (range: 254–632). The initial median LIC and TLIC were 7.4 (range: 3.1–24.0) mg/g dw and 2.6 (range: 0.6–7.4) g. Thirteen of the 14 subjects showed a response to phlebotomy therapy with LIC and TLIC decreasing with phlebotomy therapy. One subject (LIC 24.0 mg/g dw and TLIC 7.4 g) did not respond to phlebotomy therapy and showed an increase in both LIC and TLIC to 33.5 mg/g dw and 10.95 g respectively over a period of 425 days. For the 13 subjects who responded to phlebotomy therapy, there were significant correlations between reduction in LIC and grams of Hb iron phlebotomized (r2=0.41; P=0.02) and between reduction in TLIC and grams of Hb iron phlebotomized (r2=0.79; P

Description: Abstract 2082 Introduction: Stem cell transplantation (SCT) is the only available cure for patients with thalassemia major (TM). Transfusional iron overload is a common complication with SCT. Data defining the natural history of iron overload, its impact on morbidity and mortality, and its treatment in transplant recipients is limited. There are currently no randomized trials addressing post SCT iron removal in children with TM. This prospective randomized trial will compare the efficacy, safety, and convenience of phlebotomy versus deferasirox for the treatment of iron overload in children with TM who have undergone allogeneic SCT. Patients and methods: Chelation naïve patients between 2 – 3 mg Fe/g dry liver weight (dw) as determined by R2 MRI will be randomized to two groups: phlebotomy or deferasirox. The starting dose of deferasirox will be 10 mg/kg/day adjusted every 3 months in increments of 5 mg/kg to a maximum dose of 20 mg/kg/day according to monthly SF and its trend. For phlebotomy, 6 ml/kg of blood will be withdrawn every 2 weeks. The amount of blood removed during each phlebotomy session will be recorded, and the hemoglobin and iron concentrations will be calculated. Correlation between total body iron stores (TBISs) and LIC will be undertaken. Patients will undergo monthly SF, quarterly serum/urine iron, and yearly cardiac echo, liver R2 and cardiac T2* MRI measurement. Continuous adverse event monitoring will be made. Total liver iron content will be determined by R2 MRI and liver volume measurement. Quality of life (QoL) will be measured by the PEDSQL questionnaire. Treatment duration will be one year but interrupted if SF drops below 300 ng/ml and/or with major adverse events. We herein describe baseline characteristics of 27 chelation naïve, hepatitits C and B negative children with TM (16 males, 11 females) cured by SCT from an HLA-identical family member (unrelated donor in 1 patient) who are enrolled in the above trial. Result: Patients’ characteristics at enrollment are outlined in Table 1. Ten patients (37.0%) had SF 2500 ng/ml. Twelve patients (44.4%) had LIC 3-15 mg Fe/g dw. Five (18.5%) patients had cardiac T2* 2500 ng/ml, or LIC 〉15 mg Fe/g dw, or T2*

Description: BACKGROUND: Treatment of thalassemia patients with HCV using combination interferon and ribavirin is limited to few case series. DESIGN: Multicenter randomized single-blinded trial comparing PEG-IFN a-2a +/− ribavirin in thalassemia major patients with chronic HCV. METHODS: 20 patients with HCV genotypes 1 and 4 were randomized into Group A (PEG-IFN 180 mg SC once weekly) and B [PEG-IFN and ribavirin (≥10.6 mg/kg/d)] for 48 weeks. Baseline studies included liver biopsy (histology and iron concentration), quantitative PCR, and HCV genotyping. The primary end point was a SVR 24 weeks post-treatment. Secondary end points were transfusion requirements, EVR, ETR, and biochemical response. RESULTS: Baseline characteristics of both groups were comparable. The mean age was 21.6 ± 11 years in group A and 16.5 ± 3.9 in group B. Fibrosis grade 〉1 was present in 42% in group A and 50 % in group B. Mean viral load was 137,570 IU/ml and 178,087 IU/ml respectively. Genotype 1 was found in 66% in group A and 87% in group B. EVR occurred in 8/12 in group A and 6/8 in group B (67 and 75% respectively). ETR was observed in 7/12 in group A and 6/8 in group B (59.3% and 75% respectively). Transfusion requirements increased by 55% in group B versus 21% in group A (p=0.08). Adverse events were not significantly different between treatment groups. CONCLUSIONS: This interim report suggests that combination PEG-IFN and ribavirin is effective at achieving ETR in thalassemics, is associated with an increase in transfusion requirements but no other significant side effects. Additional follow up and patient recruitment is needed to evaluate long term safety and sustained viral response.

Description: Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon. Acute stroke, defined as an acute neurological syndrome secondary to arterial occlusion or hemorrhage with resultant neurological symptoms and signs lasting for more than 24 hours, is the most catastrophic brain injury seen in this disorder and has a prevalence of around 10% by 50 years of age. Silent cerebral infarcts (SCI), defined as an abnormal magnetic resonance image (MRI) of the brain and no history of neurologic deficit, are seen in 20–44% of children with sickle cell anemia (SCA) and represent a major risk factor for overt stroke. Identifying asymptomatic patients at high risk of developing sickle-related brain injury helps physicians implement preventive therapies. Aims: Determine prevalence of brain imaging abnormalities in a group of Lebanese patients with SCD and Identify predictive factors for these abnormalities. Methods: A review of brain MRI for 53 SCD patients followed in 2 centers specialized in inherited hemoglobin disorders was undergone. Of those, 42 asymptomatic patients had surveillance brain MRI and 20 had imaging at least twice. T1- and T2- weighted MR imaging at 1.0 T plus FLAIR at 5-mm section thickness were used. All images were read independently by two radiologists with a 10 years experience in neuroradiology. Brain images considered abnormal included atrophy, lacunar infarction, leukoencephalopathy and encephalomalacia. Fisher’s Exact test (Wilcoxon two sample rank-sum test) was employed to study the association of binary data (continuous data) with the 2 groups. The SAS v8.2 (Cary, N.C.) was used to analyze the data. A p-value less than 0.05 was considered significant. Results: Overall stroke prevalence in this group was 34% (18/53). 11 patients (21%), median age 14 years and 6 months, had overt strokes. Of those, 91% had SCA and 9% sickle beta thalassemia (ST). Of the remaining 42 patients, 6 (14%), median age 13 years and 5 months, all having SCA, had MRI findings compatible with SCI. 3 had brain atrophy and 3 encephalomalacia. None of the overt stroke patients had ever received hydroxyurea. As for SCI patients, 5 were on hydroxyurea at imaging time. No one of these 5 had undergone brain imaging prior to hydroxyurea treatment, and it is possible that these SCI are old ones. Bivariate analysis showed an association between the occurrence of overt stroke and premature death (p=0.006), regular blood transfusions (p=0.006), and osteomyelitis (p=0.009). Bivariate analysis showed an association between the occurrence of SCI and presentation of disease before 2 years of age (p=0.053, borderline) and acute chest syndrome (p=0.035). The small number of patients in this group did not allow for multivariate analysis. Conclusion: Stroke prevalence rate in Lebanese SCD patients is lower than reports from others. This may be attributed to the small sample size and to the imaging technology utilized being less sensitive than newer MRI technology. A multicenter Lebanese SCD trial is warranted to assess the true stroke prevalence, the importance of modifying genes and gene-gene interaction in predicting stroke risk, and the efficacy of hydroxyurea for primary stroke prevention.