ALBERT

Description: Introduction. Despite the increasing of number of patients with Sickle Cell Disease (SCD) in Italy, due to multi-ethnic migratory phenomena, a large percentage of Caucasian sickle population is already present in Italy mainly with b-thal/HbS genotype. Red cell transfusion is one effective treatment for both acute and chronic complications of SCD, while hydroxycarbamide (HC) is used to reduce the frequency of painful vaso-occlusive crises (VOCs) and decrease the need for blood transfusion. Through the National Comprehensive Reference Centers for SCD, the Italian Society of Thalassemia and Hemoglobinopathies (SITE), in collaboration with the Society Italian Transfusion Medicine and Immunohematology (SIMTI) and the Italian Association of Hematology and Pediatric Oncology (AIEOP) conducted a national survey to collect information on different therapeutic approaches used for SCD patients. Aim. To assess therapeutic approaches used a large Italian cohort of patients with SCD, accounting for age, genotype and ethnicity. Patients and Methods. Observational Longitudinal Systemic Multicentre Study (https://clinicaltrials.gov/ct2/show/NCT03397017). Data were collected from 2015 to 2018 through a standard web-based application (www.SITE-italia.org) encrypted by the Central Server. All the SCD patients, treated or not treated, were included in order to identify the overall number and all gave written informed consent. The study was approved by Ethics Committee of Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy. Results. Thirty-four centers were involved from 14 Italian regions and 1,579 patients were enrolled (802 male and 777 female; median age 23 years - IQR, 25th-75th 10-41 yrs). Genotype, age and ethnicity distribution are shown in Table 1A. As expected, the median age of non-Caucasian patients, mainly HbSS, is significantly lower than Caucasian ones (p

Description: 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*

Description: Key Points DFX-DFO combination followed by DFX monotherapy led to a meaningful decrease in myocardial and liver iron in severe siderosis patients. Substantial liver iron reduction may be helpful in patients needing rapid control of liver iron (eg, pretransplant or planned pregnancy).

Description: Iron loading in patients with thalassemia intermedia occurs slowly and is mainly due to increased gastrointestinal iron absorption secondary to chronic anemia, while in patients with thalassemia major iron overload is faster and secondary to the chronic transfusion therapy. Moreover, iron accumulation in thalassemia intermedia is prevalent in parenchymal cells, while in thalassemia major iron derived from red cell breakdown firstly accumulates in the reticulo-endothelial cells and subsequently in the parenchymal cells. Although heart disease represents the main determinant of survival in beta thalassemias, the cardiac complications are different in the two clinical forms, that are thalassemia major and thalassemia intermedia. In this study we evaluated liver and iron overload in patients with thalassemia intermedia. We have studied 8 patients with thalassemia intermedia with a mean age of 36 ± 12 years. All these patients were homozygotes for the beta zero 39 non-sense mutation (C→T) and were never transfused or had received only sporadic transfusions (less than 10 blood units throughout their life). Myocardial iron (heart T2*, Anderson et al 2001), echocardiographic left ventricular ejection fraction, serum ferritin (mean of the last 5 years) and hemoglobin (mean of the last 2 years) have been evaluated in each patient. Hepatic iron content was determined in 5 patients with atomic absorption after liver biopsy. Six patients were on chelation therapy with subcutaneous desferrioxamine (mean 2 ± 1 grams/week). Mean ferritin was 637 ± 497 ng/ml and mean hemoglobin 8.0 ± 1.0 g/dl. Heart T2* was normal in all patients (mean 46 ± 11 msec, range 36 – 62 msec). The mean left ventricle ejection fraction was 61 ± 6 % (range 51 – 70 %). Echocardiogram showed in all the patients a mild enlargement of both ventricles. Three patients had pulmonary hypertension and two had an extrasystolic arrhythmia. To our knowledge this is the first study reporting the results of heart T2* in thalassemia intermedia. As a consequence of the mechanism and rate of accumulation patients with thalassemia intermedia do not have heart iron overload, while liver iron concentration is quite relevant. Cardiac complications in thalassemia intermedia are mainly due to the hyperdynamic circulation associated with chronic anemia and to pulmonary hypertension.

Description: Background and Aim: Direct-acting antiviral drugs (DAAs) have a very high efficacy in patients with hepatitis C virus (HCV) infection, but they have not been extensively used in patients with haemoglobinophaties. To evaluate the safety and efficacy of DAA regimens in this subset we used the ITHACA-SITE dataset, which includes patients with haemoglobinophaties and chronic HCV liver disease treated in Italy. Patients and methods: Between March 2015 and June 2016, 121 patients included in the ITHACA-SITE dataset started DAA regimens. Cirrhosis was defined by FibroScan®showing≥12 kPa performed within 6 months before the treatment. Regimen choice and use of ribavirin were based on viral genotype and stage of disease, according to guidelines. Negative HCV RNA at week 12 of post-treatment follow up was considered as Sustained Virological Response (SVR). Results: The mean age of 121 patients was 42 years, 75 (62%) were males, 101 (83.5%) had β-thalassemia major, 9(7.5%) had β-thalassemia intermedia and 10 (8.3%) had sickle cell disease. Sixty-six patients (54%) had the diagnosis of chronic hepatitis and 55 (46%) hadthe diagnosis of cirrhosis. The prevalence of HCV genotypes (G) was: G1a 6 (5%), G1b 70 (57.8%), G2 31 (25.6%), G3 6 (5%), G4 8 (6.6%). Fifty-six patients (46.3%) were Peg-interferon (P) and Ribavirin (R) naïve and 65 (53.7%) were P/R experienced, 20 patients (16.5%) had diabetes and 29 (24%) had heart disease. By June 2016 63 patients (52%) had concluded the treatment and 33 (27.3%) had concluded the post-treatment follow-up. By ITT, the rate of response at the end of treatment (ETR) was 100% (63/63) and 94% (31/33) of patients achieved a SVR. No patients stopped treatment because of adverse events. No interference with chelation therapy was observed. Conclusions: Use of DAAs regimens in practice is safe and effective in patients with haemoglobinophaties and cirrhosis or chronic hepatitis due to HCV. The therapy is indicated also in patients with co-morbidity. The lifetime utility of HCV eradication in terms of reduction of events and overall survival needs evaluation in long-term observational cohorts. Disclosures Piga: Novartis: Research Funding; Apopharma: Honoraria. Di Marco:Gilead: Research Funding. Forni:Novartis, Celgene: Research Funding.

Description: Introduction: Transfusion dependent thalassemia (TDT) requires regular transfusion of red cell concentrates (RBCC) to prevent the complications of anemia and excessive erythroid expansion. Despite donor testing, long-term transfusion has a substantial cumulative risk of transfusion-transmitted infection (TTI) due to undetected viruses, bacteria, and protozoa. Splenectomized (-S) TDT patients may have greater TTI morbidity than patients with spleens (+S); but may benefit from reduced use of red blood cell concentrates (RBCC) and reduced transfusion iron (Fe) loading. Pathogen reduction (PR) of RBCC with amustaline-glutathione (A-GSH) offers potential to reduce the risk of TTI. Objectives: To determine, the impact of PR-RBCC on hemoglobin (Hb) use, transfused Fe burden, incidence of RBC antibodies, and safety in -S and +S TDT patients. Methods: TDT patients at 3 sites, not stratified by spleen status, were prospectively enrolled in a two- period cross-over study randomized by sequence for RBCC preparation. Leukocyte reduced PR-RBCC (Test) were treated with 0.2mM amustaline and 20 mM GSH, re-suspended in saline-adenine-glucose mannitol (SAGM), and stored up to 35 days at 4°C. Leukocyte reduced conventional RBCC (Control) were suspended in SAGM and stored for up to 35 days at 4°C. Patients received 6 transfusions in each treatment sequence of Test or Control RBCC over ~ 5 months. Clinicians, blinded to RBCC Hb content and treatment sequence, ordered RBCC to maintain targeted pre-transfusion Hb thresholds of ~ 9-10 g/dL. Transfusion intervals or number of RBCC transfused were adjusted for clinical management. The primary efficacy outcome was assessed by non-inferiority (NI) analysis for Hb use (expressed as g/kg body weight/ day) using a pre-specified NI margin (≤ 15% of the observed Control mean). Results : Overall, mean (SD) Hb content (g) of 1024 Test RBCC = 54.6±5.9 (range: 39-73) and of 1008 Control RBCC = 55.6 ± 5.9 (range: 35-74) and varied widely. By intent-to-treat (ITT), 80 patients (40 +S and 40 -S) were transfused. For ITT patients (Table), the baseline Hb level (BL-Hb, g/dL) at first transfusion of Control periods was significantly lower than at Test periods; but the mean number of RBCC transfused, RBCC storage days, total Hb dose (g), and transfusion intervals were not significantly different for Test and Control. ITT analysis for all transfusion episodes showed Hb use for Test RBCC (0.110 g/kg/d) was not different from Control RBCC (0.112 g/kg/day). Non-inferiority was demonstrated (T-C = - 0.002 g/kg/d: 95% CI: -0.005, 0.001). ITT Test patients received a slightly lower mean total Hb dose (- 14g), and mean pre-transfusion Hb levels declined after 6 transfusions (9.4 to 8.8 g/dL). -S patients had lower BL-Hb levels (g/dL) than S+ patients in Test (9.2 vs 9.7) and Control (8.8 vs 9.2) periods (Table). -S patients received a lower mean total Hb dose of Test than Control RBCC (p=0.019); and had a decline in mean pre-transfusion Hb levels during Test periods (from 9.2 to 8.7 g/dL). Transfusion intervals were significantly longer for -S patients than +S patients with both Test and Control RBCC (p〈 0.001 by 2-sample t test, respectively); and -S patients had lower Hb use than +S patients. However, Hb use of Test and Control RBCC was comparable within -S and + S cohorts (Table). Transfused Fe was less for -S patients for Test and Control RBCC. During 6 Test and 3 Control treatment periods, 8 patients (6 -S, 2 +S) had worsening anemia with pre-transfusion Hb levels (6.0-7.8 g/dL) substantially below the targeted transfusion threshold, but without evidence of hemolysis. Each of these patients received one or more Hb doses below the average RBCC transfusion episode dose (Test: 114.5 g) or (Control: 116.7 g); and 3 patients had concurrent infections. None of 80 patients had evidence of increased RBC clearance, developed antibodies to PR-RBCC, or had treatment emergent RBC alloantibodies in either treatment period. There were no differences in the overall safety profiles for Test and Control RBCC. Conclusions: Amustaline-GSH PR treatment of RBCCs offers the potential to reduce TTI risk without impacting Hb use or Fe burden in TDT. However, Hb content of Test and Control RBCC varies widely and may contribute to unexpected changes in pre-transfusion Hb levels. Spleen status affected Hb use comparably for PR-RBCC and Control RBCC, and remains an important factor in assessing transfusion requirements and Fe loading. Table. Table. Disclosures Aydinok: TERUMO: Research Funding; Cerus: Honoraria, Research Funding; CRISPR Tech: Other: DMC; Protagonist: Other: SSC; La Jolla Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau. Piga:Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Acceleron: Research Funding; Novartis: Research Funding. Origa:Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding; Apopharma: Honoraria. Mufti:Cerus Corporation: Employment, Equity Ownership. Erikson:Cerus Corporation: Employment, Equity Ownership. North:Cerus Corporation: Employment, Equity Ownership. Waldhaus:Cerus Corporation: Employment, Equity Ownership. Ernst:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Huang:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

Description: Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P 〈 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P 〈 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P 〈 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P 〈 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Description: Background The hemoglobin (Hb) response to the activin receptor type IIA ligand trap ACE-011 (Sotatercept) in non-transfusion-dependent thalassemia (NTDT), and the transfusion requirement response in TDT are described, but the mechanisms of action, clinical predictors and markers of response, are unclear. In principle, ACE-011 may act on early and/or late erythroblasts to decrease ineffective erythropoiesis (IE), both in healthy subjects and in thalassemia. As erythropoiesis intimately links to iron metabolism, changes in markers of iron metabolism relative to those of erythropoiesis may inform the mechanisms and developmental stage at which ACE-011 acts. Methods Markers of IE and iron metabolism in 46 thalassemia patients (30 NTDT, 16 TDT) were taken before and during a median follow up of 722.5 days, (IQR 830.5, range 152-1427) of escalating doses of ACE-011 (3-weekly 0.1 to 1.0 mg/kg s.c. injections), depending on the protocol, as part of the approved study (Cappellini, et al. 2018 under review). Markers of erythropoiesis included Hb, Reticulocytes (Ret), soluble transferrin receptor 1 (sTfR), growth differentiation factor 11 and 15 (GDF11, GDF15), erythroferrone (ERFE). Markers of iron metabolism included plasma hepcidin, serum ferritin (SF), transferrin saturation (TSAT), and non-transferrin-bound iron (NTBI). Data were analyzed using longitudinal multilevel model for change (LMMC) on STATA (Version 14) as generalized linear mixed model with random and fixed effects to account for repeated measures and highly complex temporal data structure. Final LMMCs were built to explain the change in Hb from baseline and the behavior of key biomarkers. Independent variables were entered into the models based on the study design (predictors from design) and theoretical background (predictors of interest and control variables). P value