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Introduction: Patients with transfusion-dependent-thalassemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions following vaccination have been reported, with severe ones being extremely rare. TDT patients may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. The safety profile of vaccination in chronically transfused patients with thalassemia has not been reported. AIM: To evaluate the safety profile of COVID-19 vaccines in TDT patients. Patients and Methods: This is a single institution's, retrospective analysis evaluating all TDT patients, older than 18 years old, who had completed the vaccination protocol at least 30 days before data cut-off time (July 20 th 2021). Adverse events were reported by patients up to 30 days post each dose. Demographic data and hematological data, including mean hemoglobin levels before and up to 30 days after each dose, were recorded. T-test was performed to investigate changes in hematological profile and transfusion burden post vaccination. Results:186 patients (median age:45; range:18-61 years old; male/female:87/99) were included for data analysis corresponding to 53% of all TDT patients followed in our Thalassemia Unit. Distribution of vaccine types were: Comirnaty -BNT162b2 (Pfizer Inc. and BioNTech)90.86% (n =168), Vaxzevria (previously COVID-19 vaccine, AstraZeneca)1.61% (n=3), Moderna (Moderna TX Inc.)6.99% (n =13) and JNJ-78436735 (Janssen Pharmaceuticals Companies of Johnson & Johnson)0.54% (n =2). No patients had confirmed or suspected previous COVID-19 infection. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The incidence of adverse events after 1 st and 2 nd dose were 43.5% (81/186) and 54.8% (102/186), respectively. Adverse events after 1 st dose included pain at injection site 26.3%( n=49), fatigue 9.7%(n=18), fever 5.4% (n=10),headaches 4.3% (n=8), arthralgia and myalgia 2.2% (n=4), and lymphadenopathy 0.5% (n=1). Adverse events after 2 nd dose included fever 28.5% (n=53), fatigue 17.7% (n=33), pain at injection site 15.6%(n=29), arthralgia and myalgia 11.3% (n=21), headaches 9.1% (n=17), lymphadenopathy 3.2% (n=6), dizziness 0,5% (n=1), tachycardia 0.5% (n=1), diarrhea/ vomiting 0.05% (n=1) and amaurosis fugax 0.5%: (n=1). No grade 4-5 events or anaphylaxis were observed. Two patients (both males, 51 years and 45 years old, respectively) presented with acute hemolytic crisis with hemoglobinuria in 3 rd and 20 th day after the second dose with Pfizer/BioNTech, respectively. They are receiving treatment with corticosteroids without partial response. Both patients had a history of acute hemolysis crisis within the last 3 years. A decrease in Hb levels after either the first or second dose compared to pre-vaccination mean Hb levels was observed (mean=9.9 /sd=0.63 vs mean=9.44 /sd=0.76), (p < 0.001). Conclusions: Compared to the vaccine trials, we observed some lower incidence of vaccine-related adverse events in our cohort of TDT patients, which may be related to the less stringent reporting methods outside official trials. A temporary drop in hemoglobin levels may be noted in chronically transfusion patients, which parallels what is observed when patients are developing infection or inflammation. Of interest, two patients with previous history of alloimmunization, developed hemolysis. Close hematological follow up may be required in TDT patients post vaccination. The risk/benefit of the vaccination is strongly positive for this vulnerable population. Disclosures Kattamis: Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy.

Introduction: Luspatercept inhibits select ligands of the TGF-β superfamily implicated in thalassemic erythropoiesis and promotes late-stage erythroid maturation (Suragani RN, et al. Nat Med 2014;20:408-414). This leads to greater red blood cell (RBC) output from thalassemic marrow and reduces transfusion dependence in TDT (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231). The underlying mechanisms for this clinical outcome are not well understood in a syndrome involving significant iron overload and cyclical stimulation of erythropoiesis between transfusions. Here we report novel physiological and clinical insights from a BELIEVE trial (NCT02604433) biomarker analysis, which demonstrate that hepcidin and erythropoietic changes in TDT lead to iron redistribution from macrophages to hepatocytes on luspatercept. Methods: 336 TDT patients ≥ 18 years of age who took part in the BELIEVE study, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (Cappellini et al. 2020), were randomized 2:1 to receive luspatercept or placebo subcutaneously every 21 days for 48 weeks. This ethically approved study was conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent. Transfusion iron loading rate (ILR) was calculated assuming 1 unit = 200 mg Fe. Liver iron content (LIC) was measured by R2 MRI and R2* MRI, and total body iron stores by Angelucci formula. Serum was assayed for ferritin (SF) nephelometrically (Covance lab), and hepcidin, erythroferrone (ERFE), growth differentiation factor (GDF)15, and transferrin receptor (sTfR1) by ELISA at Intertek (San Diego, CA). Median and interquartile ranges are shown; P value < 0.05 was deemed significant. Results: Within 48 weeks on luspatercept, transfusion iron loading fell by 1.6 g (8 RBC units, ILR difference −0.08 mg Fe/kg/d ± 0.07, range −0.4 to 0.2). Regardless of thalassemic genotype, SF fell by 269.3 ± 963.7 and earliest at 12 weeks by 103.6 ± 690.3 µg/L (both P < 0.0001), with no change on placebo, indicating reduced macrophage iron. However, despite unchanged chelation exposure, no reduction in LIC (5.7 to 6.7 mg/g dw) or calculated body iron stores (3.6 to 4.2 g, not significant) occurred on luspatercept, even though saved iron loading from transfusion was 44% (1.6 g/3.6 g) of baseline body iron stores. On luspatercept, but not placebo, hepcidin fell by 53%, while erythropoietin (EPO), ERFE, GDF15, sTfR1, and reticulocytes rose by 93%, 51%, 59%, 66%, and 112%, respectively (all P < 0.0001). 71% (120/169) patients with and 47% without (17/36) ILR reduction had negative SF trends (P < 0.0001). In patients with SF reduction on luspatercept, bilirubin and LDH rose 50% and 67% (P < 0.0001) indicating increased RBC hemolysis from residual (effective and ineffective) erythropoiesis. ILR change correlated with changes in EPO, hepcidin, sTfR1, and bilirubin, but not with changes in ERFE, GDF15, reticulocytes, or LDH (Figure A). Hepcidin reduction was related to LIC increase post splenectomy (Figure B), suggesting a role for the spleen in preventing hemolytic iron redistribution to the liver. Decrease in SF thus associates with erythroid iron incorporation (sTfR1), hence RBC production that reduces transfusion needs (falling ILR) but enhances hemolytic rerouting of iron to the liver. In a mixed-effect linear regression analysis, transfusion, LIC, baseline SF, time, and treatment predicted SF changes in a benchmark model. We found high baseline LIC lessens the SF outcome, and hepcidin, EPO, and bilirubin jointly explained 66% of the treatment effect of luspatercept on SF. Conclusions: Luspatercept-increased ERFE, likely as a result of increased production or higher frequency of late-stage erythroblasts, partially reduces hepcidin production. Lower hepcidin mobilizes iron stores to facilitate bulk hemoglobinization, erythropoietic response, and transfusion burden reduction. Luspatercept leads to SF reduction that marks hepcidin-dependent iron egress from macrophage compartment to plasma. This relocated iron, variably utilized by thalassemic erythron, refluxes back to plasma for hepatocyte and extrahepatic iron uptake, or as heme iron shunts into the liver through hemolytic pathways from intramarrow ineffective erythropoiesis or peripheral breakdown of newly made thalassemic RBC. Macrophage to hepatocyte iron redistribution in TDT appears to be a mechanism of luspatercept. Figure 1 Figure 1. Disclosures Garbowski: Imara: Consultancy; Vifor: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Suragani: Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Shetty: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Vodala: BMS: Current Employment, Other: stock options. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Schwickart: BMS (Celgene): Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other, Patents & Royalties; Exelixis: Current Employment, Current equity holder in publicly-traded company. Porter: Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Thalassemia is one of the most common hemoglobinopathies, with around 5% of world's population expected to have some degree and type of thalassemia. Beta thalassemia (BT) occurs due to a deficient production of the beta-globin chain of hemoglobin. BT is classified into minor, intermedia, and major, defined by their clinical and laboratory findings. Extramedullary hematopoiesis is one of the complications of BT, primarily seen in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta thalassemia major (BTM). However, there are multiple case reports of EMH in BTM. The incidence of EMH in BTM is thought to be Methods: This is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO: CRD42021242943. Results: Data from 253 cases of EMH in BTM patients were extracted from 2 retrospective studies and 71 case reports (some of the descriptive data from case reports and most of the descriptive data from retrospective studies was missing). The mean age at presentation was 35.3 +/- 0.5 years. Males constituted 57.7% of the total population. Mean hemoglobin at presentation with EMH was 8.2 +/- 2.1 mg/dL. Lower limb weakness was the most common presenting feature (N=23). Other features included localized pain, urinary incontinence, and an incidental finding of EMH. Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (N=226). However, computed tomography scans, positron emission tomography scans, tissue biopsy, myelograms, and X-rays were also used to diagnose EMH. Various treatments were reported either alone or in combination. Overall, blood transfusion was the commonest reported treatment (N=30), followed by radiotherapy (N=20), surgery (N=15), hydroxyurea (N=12), steroids (N=6), and exchange transfusion (N=2). An outcome was reported in 20% of patients, all recovered, with no reported mortality. Conclusion: EMH is considered a rare phenomenon in BTM patients. However, there are many cases reported in which EMH occurred in BTM despite chronic blood transfusions. EMH can occur in any organ system and can present with a varied clinical feature. MRI can effectively diagnose EMH, and conservative management is reported to have similar results compared to invasive treatments. More extensive studies, focusing especially on outcomes, are required to enhance the guidelines on managing EMH in patients with BTM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Cardiac failure is one of the leading causes of death in sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT). For this reason, early detection of silent cardiac dysfunction is crucial for treatment and prevention of heart failure. Speckle-tracking echocardiography (STE) is an easily accessible tool for analyzing myocardial function and this modality has increased sensitivity in detecting asymptomatic disease. Attenuation in cardiac strain has been correlated to early systolic dysfunction among patients with cardiomyopathies. This technique has not been consistently evaluated in children with SCD and TDT. Due to the role of anemia and siderosis in the pathology of cardiac dysfunction, we hypothesized that early myocardial dysfunction correlates with the degree of anemia and hyperferritinemia in SCD. We analyzed the clinical, echocardiographic, STE and laboratory parameters in SCD and compared them to children with TDT and normal controls. We retrospectively analyzed date from consecutive patients with SCD and TDT who received treatment at our institution from 2008 to 2018. Echocardiographic data from children with benign murmurs served as normal controls (NC). Data was independently verified by a pediatric cardiologist. Descriptive and correlation analysis were used; a p-value < 0.05 was considered significant. Echocardiographic data were available for 77 SCD (HbSS and HbS/ ß 0 Thal), 25 TDT (ß 0/ ß 0 and ß +/ ß + Thal)and 138 NC. Mean hemoglobin (Hg) and ferritin values were 9.8 g/dl (6.8-14.6 g/dl); 392 ng/ml (19.3-8,3437.67 ng/ml), respectively for SCD patients and 9.3 g/dl (7-17.03 ng/dl); 2,960 ng/ml (13-13,831 ng/ml), respectively for TDT. Standard echocardiographic parameters left ventricular ejection fraction (LVEF), right VEF and LV shortening fraction (LVSF) were within the normal limits in SCD, TDT, and NC children. Significant differences were observed in the steady-state global circumferential strain (GCS) between the three groups SCD, TDT and NC [-26.5 (mean), 3.6 (SD); -27.6 (mean), 4.8(SD); -25.0 (mean), 3.6 (SD), respectively; p = 0.002] (Table 1). Subset analysis based on ferritin levels (> or < 1000 ng/ml), revealed no significant difference in GCS between the SCD or TDT groups (Table 2). However, global longitudinal strain (GLS) was significantly lower among SCD compared to TDT with ferritin levels greater than 1,000 ng/ml (Table 2). A positive correlation (r = 0.25, p = 0.046) was found between GLS and Hg in SCD patients (n=63) (Figure 1). No significant correlation was found between Hg and GLS in the TDT group (Figure 2). No significant correlation was found between GCS and Hg (r = 0.1, p = 0.42); GLS and GCS and ferritin in the SCD group. LVEF was found to be normal in patients with abnormal strain indices. Cardiac strain indices are abnormal in children with SCD and TDT compared to normal children. Significantly abnormal GLS was noted in hyperferritinemic SCD patients compared to TDT patients. A positive correlation between severity of anemia and GLS was observed in this study in SCD children. Based on these results, we speculate that therapies aimed at ameliorating anemia can potentially improve GLS and thus, early cardiac dysfunction in SCD patients. However, further studies are warranted to understand the contributory role of anemia and hyperferritinemia and its therapeutic implications on early myocardial dysfunction in SCD. Figure 1 Figure 1. Disclosures Sathi: Vertex Pharmaceuticals: Consultancy.

Introduction: Allogeneic stem cell transplantation (HSCT) is a potential curative treatment for TDT. BuCy based regimen has been used widely as a standard myeloablative chemotherapy. However, the use of treosulfan based conditioning regimen has increased over the last decade (Choudhary D et al BBMT 2013). We analysed the safety and efficacy of BuCy based vs Treosulfan/Thiotepa/Fludrabine (Treo/Thio/Flu) regimens in TDT between September 2013 and March 2021. Method: This is an observational retrospective hospital record-based study approved by Institutional Review Board. Regimen used: Treo/Thio/ Flu : Thiotepa 8 mg/kg , treosulfan 14 g/m2/day for 3 days, and fludarabine 40 mg/m2/day for 4 days . Flu/Bu/Cy/ATG : Fludrabine 30mg/ m2/ day for 6 days ,Antithymocytoglobulin 4.5mg/kg in 3 days , Busulfan (per oral) 14mg/kg ( boys) and 12mg/kg (girls) in 4 days, Cyclophosphamide 40mg/kg/day ( boys)and 50mg/kg/day ( girls) for 4 days. Statistical Analysis: Fisher's exact test was used for discrete variables and t-test was used for continuous variables. Log-rank test was used for the difference in survival between the groups. P value < .05 was considered statistically significant. Cox regression for survival analysis was also used for time to event data of the predicted variables. Results: As shown in Table 1, 74 patients were enrolled, out of which 35 (47.2%) patients received BuCy based regimen whereas 39(52.7%) patients received Treo/Thio/Flu. All were fully HLA matched. Median age was 5.5 (1-12) years and 9 (1-15) years respectively. According to Lucarelli classification, number of patients with Class I, II, III were 17, 12, 6 in BuCy group vs 2, 14,18 in Treo/Thio/Flu group respectively. When stratified according to Matthew classification, 06 (17.1%) and 11 (28.2%) patients were in class IIIB respectively (Mathews V et al, BBMT 2007). Source of graft was bone marrow in BuCy group vs peripheral blood stem cell (PBSC) in Treo/Thio/Flu group. Mean CD34 cell dose was 3.82(2.2-9.1) vs 5(1.65-8.01) 106/kg in BuCy vs Treo/ Thio/Flu group respectively. Neutrophils and platelets engrafted at median of 16 days (14-21) and 16 days (9-47 ) in BuCy and 15 days (10-20) and 13 days (9-41) in Treo/ Thio/ Flu. Median duration of follow-up was 28 (23-32.9) months. Two (5.7%) patients had rejection (primary=1, secondary=1) in BuCy group whereas none in Treo/Thio/Flu. Five (14.3%) vs 10 (25.6%) patients developed grade ¾ oral mucositis respectively where 1 patient in each group belonged to Class III. Sinusoidal obstruction Syndrome (SOS) was observed in 02 (5.7%) vs 04 (10.3%) patients (p=0.047) respectively, with no patients affected in Class III. BuCy group had 04(11.4%) patients with acute GVHD, including one patient with grade 3. Treo/Thio/Flu group had 15(38.5%) patients with acute GVHD including 4 patients with grade 3 which had significant impact on survival (p=0.038). We also observed chronic GVHD in 04(11.4%) and 11(28.2%) patients respectively which was mainly limited stage in former and extensive in later which impacted the survival (p=0.031). CMV viremia was observed in 14 (40%) vs 8 (20.5%) patients respectively. We also encountered significant infections in both groups {21 (60%) vs 17 (43.6%)}, however, difference was not statistically significant. Four (5.1%) patients had transplant related mortality (TRM) in Treo/Thio/Flu group, in contrast to none in BuCy group. Commonest cause of death was sepsis. Mixed chimerism was commonly seen in BuCy group {20 (57.1%)} vs Treo/Thio/Flu group {12(30.1%)}.(Table 2) At last follow up, all alive patients except two patients with rejection are transfusion independent. Five-year Thalassemia-free survival (TFS) and overall survival (OS) of entire cohort was 94%+3% and 93%+4% respectively. Estimated OS and Event free survival (EFS) of BuCy vs Treo/Thio/ Flu was 100% vs 89.7% (p=0.060) and 93.9% vs 89.7% (p=0.472) respectively.(Figure 1) Discussion: We observed significant difference in TRM, acute and chronic GvHD and SOS favoring the BuCy group even in class III. On the contrary, we encountered rejections(n=2) and increased number of mixed chimerism in BuCy group which corroborates with previous literature (Fouzia N et al, BMT 2018). Conclusion: In our experience BuCy based conditioning regimen is a safe and effective regimen even in high risk class III TDT, with less TRM in comparison to Thio/Treo/Flu regimen. However, one needs to be vigilant for rejections and mixed chimerism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: An assessment of morbidity and mortality caused by transfusion dependent thalassemia in India has never really been done despite thalassemia being the most prevalent life threatening non-communicable disorder of childhood. There is little structured understanding identifying the key risk factors feeding into research and policy making for effective management of thalassemia. With an estimated 10,000-12,000 children born with thalassemia each year in India, in addition to increasing focus on early pregnancy targeted screening, it seems critical to increase our understanding of risk factors associated with early mortality and morbidity. This is also relevant to family counselling about management options. Methodology: A retrospective analysis of mortality key risk factors in patients suffering from thalassemia major from 5 thalassemia day care centres in India was carried out. This included a total of 1,087 patients (656 males and 431 females with a median age of 8.6 years) enrolled for care between 1 Jan 2010 - 31 Oct 2018 at these centres. These centres were set up by a non-profit organization in collaboration with blood banks and /hospital facilities with the objective to provide comprehensive thalassemia care; A common web-based application was employed (ThalCare™). This system was used to track information associated with treatment including disease history at enrolment, demographic data and follow-up information. All analyses were performed with R Statistical software (3.5.2). Survival analysis was done from the age at presentation to the centre till October 2018. The reasons for mortality were categorized. Overall survival was also separately analyzed for patients in their 1st,2nd, 3rd or subsequent decades of life. The Cnaan and Ryan approach was used as patients entered and left the study cohort (left censored and right truncated data) and observation began only at enrolment and not at disease onset Results: The median age at enrolment was 5.4 years and the median follow up at the centre was 2.5 years. A total of 86 patients were cured by bone marrow transplantation (BMT), 13 of them moved to other centres for care and 41 patients died during the study period (28 males and 13 females). The median age at death was 15.4 years. Actuarial survival at 26.9 years of age was 50% (Figure 1) and under-five mortality was 7 times higher than the general population. Patients with transfusion-transmitted infections (TTI) had 3.4 times higher risk of death (p=0.031). Serum ferritin >4,000 ng/dL was associated with 4.6 times higher risk of mortality compared to ferritin 2 gm/dL/week had 7.7 times higher mortality risk compared to 2 gm/week (hazard ratio 5.58 ,p=0.0007) and lack of attention towards care for possible prevention from TTI (hazard ratio 2.86, p=0.0004) are factors independently associated with high mortality. Table 2 shows that in patients born after the year 2,000 overall survival is 85.2% compared to 29.4% for patients born earlier. Main causes of death were infection, iron overload, TTIs, and alloimmunization; In a quarter of patients the cause of death was unknown (Figure 2). Patients who received more than 4 years of adequate care had more than 66% mortality risk reduction (p Conclusion: Comprehensive care right from an early age at dedicated management centres is key to improving life expectancy of thalassemia patients in India. Optimizing blood transfusion, intensifying chelation and preventing TTIs seem particularly important. Sustained efforts in these areas coupled with increased prevention and access to safe BMT will ease the burden for both families and public healthcare. Disclosures No relevant conflicts of interest to declare.

Introduction One of the treatment modalities in transfusion dependent thalassemia (TDT) patient is splenectomy which aims to ameliorate red cell transfusion. However, not all thalassemia patients respond to splenectomy. Moreover, splenectomy may increase many unfavorable consequences. The study about the efficacy and complications after splenectomy is limited and the effect of splenectomy on iron overload is still unclear. This study aims to investigate the long-term efficacy of splenectomy, factor predicting a response to splenectomy, the consequences of splenectomy complications, CBC parameter changes and the effect on iron overload parameters after splenectomy. Methods All TDT patients (PRC transfusion ≥3 units/year), aged >15 years who had splenectomy were recruited from our hematology division data base. Clinical characteristics including age, sex, age at splenectomy, operation date, hemoglobin (Hb) typing were collected. PRC transfusion requirement (unit/year) and CBC were collected 1 year before splenectomy, 1 year and 5 year post splenectomy. In the complication cohort, TDT patients with intact spleen were recruited into control group. The sample size was calculated that at least 33 patients (66.6% from splenectomy group and 33.3% from non-splenectomy group) needed to be recruited to have 80% power to detect a difference in complication at an alpha level of 0.05. The diagnosis of pulmonary hypertension (PHT) was based on the echocardiogram performed by the cardiologist and using definition from the 2015 ESC guideline. The thrombosis events were collected from medical record. The iron overload was compared by serum ferritin, liver iron concentration (LIC) and cardiac iron concentration were assessed by MRI of liver and cardiac T2*. The associated factors of efficacy and complication for splenectomy were compared using Chi-squared test or Fisher exact test for categorical variables and T-test or Mann-Whitney test and repeated measure mixed model for continuous variables. Multivariate regression analysis was used to identify relationships between variables with the level of significance was defined as P value Results Fifty TDT patients were included from the data base. In term of splenectomy efficacy, 21 patients (42%) has been changed from TDT to non-transfusion dependent thalassemia (NTDT) patients after splenectomy and 25 patients (50%) had 50% reduction in PRC transfusion. The significant factors associated with changing from TDT to NTDT were genotype of thalassemia (P=0.001). HbH disease and beta thalassemia/HbE (β/E) patients were the group who had higher response (28.57% and 52.38%, respectively) compared to HbH with CS (9.52%) and homozygous beta-thalassemia (9.51%). Lower percentage of neutrophils (10 year old) was associated with higher response after splenectomy (P = 0.005). CBC before splenectomy, 1 and 5 years after splenectomy were compared. Mean Hb level was increased from 6.0 to 8.2 and 7.7 g/dL (P Sixty-four patients were included in the complication cohort, (44 patients in splenectomy group and 20 patients in non-splenectomy group). The baseline characteristics including age, sex, Hb, ferritin were similar between 2 groups. The splenectomy group had significant higher tricuspid valve regurgitation velocity (TRV) compared to non-splenectomy group (2.54 m/s vs. 2.31 m/s, P=0.029). The prevalence of PHT and thrombosis were higher in splenectomy group (27.3% vs. 15% and 9.1% vs. 0%, respectively). Serum ferritin, LIC and cardiac T2* were not different between the 2 groups. From multivariable analysis, the only significant factor for predicting PHT was the longer duration after splenectomy (p=0.045). Conclusion Splenectomy had benefit in some TDT patients. Factors that predict a higher response to splenectomy were thalassemia type (HbH and β/E), higher neutrophil percentage and older age at the time at splenectomy. Hb and platelet was significantly increased after splenectomy. In term of complication, splenectomy group had significant higher TRV and tended to have more prevalence of PHT and thrombosis. The longer time post splenectomy was the only significant factor for developing PHT. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Transfusion dependent thalassemia (TDT) patients is a group of thalassemia patients who require regular blood transfusion. Red blood cell transfusion and increased intestinal iron absorption leads to iron overload. The cellular damage associated with iron overload is mainly mediated by the state of oxidative stress and the effect of free oxygen radicals on various cell components. Telomeres are terminal protein-DNA complexes that stabilize chromosome and prevent DNA from double-stranded breaks. Chronic oxidative stress from iron overload and ineffective erythropoiesis in thalassemia may lead to shortening of telomere length. METHOD We conducted a cross-sectional study in TDT patients aged more than 18 years old who attended the adult hematology clinic at Maharaj Nakorn Chiang Mai hospital, Chiang Mai University, Thailand from 1 January 2016 to 30 April 2016. TDT was defined as thalassemia who requiring a red cell transfusion at least 3 times per year, included both beta-thalassemia and alpha-thalassemia patients. Telomere length was measured by real-time quantitative PCR and compared with matched healthy controls by age and sex. We used Pearson's correlation coefficient to test whether telomere length was associated with any factors. The threshold for statistical significance for all comparisons was chosen as P RESULT Thirty TDT patients and 30 matched healthy control were included in this study. For TDT group, there were 19 female patients (63.3%). The median age was 29.2 (18-48) years. Baseline hemoglobin pre-transfusion 6.4 g/dL (5.3-7.4). Of these, there were 18 beta-thalassemia/Hb E disease (60%) who was the majority population. There were 11 beta-thalassemia major patients (36.4%) and 1 HbH with Constant spring patient (3.3%). The median telomeric terminal restriction fragment (TRF) length of TDT thalassemia group was 5.76 (4.94-7.13) kb. The median TRF length of control group was 6.79 (5.52-9.02) kb. TDT patients had significant shorter TRF length compared to control group (age and sex match), (p CONCLUSION TDT patients had shorter telomere length compared to control group. Telomere shortening in TDT thalassemia is aging-dependent process. Chronic oxidative stress from iron overload and ineffective erythropoiesis in thalassemia may play the significant role in this accelerated telomere shortening process. Table The median telomeric terminal restriction fragment length of TDT patients compared with control group Table. The median telomeric terminal restriction fragment length of TDT patients compared with control group Disclosures No relevant conflicts of interest to declare.

Introduction: Although routine tissue iron monitoring using magnetic resonance imaging (MRI) has become a standard clinical management of both transfusion dependent and non-transfusion dependent thalassemias (TDT & NTDT) in several developed countries since this module can provide a better organ-directed iron measurement and related to clinical outcome including morbidity and mortality secondary to iron overload (IOL). However, accessibility of this monitoring remains limited in several developing countries including Thailand, where thalassemia and hemoglobinopathies are highly prevalent. Earlier in 2016, we have demonstrated that although not so perfectly crafted, a cross-sectional measurement of serum ferritin (SF) can be used for determination of IOL as a predictive marker; in NTDT, MRI for liver iron concentration (LIC) should be performed in those with SF >300 ug/L and for TDT, the SF cut off of >2,500 and >3,500 ug/L are useful to predict patients with severe LIC (>15 mgFe/g dw) and cardiac siderosis (T2*< 20 ms) (Ekwattanakit S. et.al., EHA 2016). In this study, we performed a further analysis to evaluate whether a serial measurement of SF and its trend can provide a better prediction. Objectives: To evaluate the clinical utility of serial SF trend compared with a cross-sectional SF cut-off for early detection of IOL in a real-life practice in thalassemic patients in order to select the most vulnerable patients for further MRI evaluation in a resource limited setting. Methods: In this prospective study, total 968 standard MRI for LIC and cardiac T2*were performed at Siriraj hospital during 2009-2014 and paired clinical data including serial SF measurements were collected from 301 thalassemia patients; NTDT (N=76; 109 LIC and 95 cardiac T2* results) and TDT (N=155; 478 LIC and 474 cardiac T2*). In addition, 71 patients were NTDT with regular blood transfusion later on in their life, mainly Hb E/β thalassemia (218 LIC and 210 cardiac T2*). These patients were evaluated for IOL using SF every 4-12 weeks during their follow up. Median follow up time was 96 months. Receiver operating characteristic (ROC) analysis was performed using different SF cut-off levels (1000, 1500 and 2000ug/L) and percentage of serial SF measurements that above each these cut-off levels (50 and 75%) during different durations before MRI (1, 2, or 3 years priori) for predicting liver IOL (LIC >5 in NTDT and severe liver siderosis; LIC > 15 mgFe/g dw) and cardiac IOL (T2* Results: Baseline characteristics were shown in Table1. In NTDT, using ROC analysis, SF >1000 ug/L over 75% of serial measurements in 1-year period prior to MRI can predict LIC > 5 mgFe/g dw with the AUC of 0.59 with PPV 86.7% and NPV 51.1% and serial SF >1500 ug/l over 50% of measurement in a year prior predict LIC >15 mgFe/g dw (AUC of 0.72, PPV 75% and NPV 89.7%). Only 1 NTDT had cardiac IO. These newly identified criteria do not provide a more sensitive predictor of LIC results than our previous SF cut-off. In TDT population, the majority of patients were HbE/β thal (78%) and cardiac iron overload was detected mainly in patients older than 15 yrs (81/83; 97.6%). The best predictor for LIC>15 mgFe/g dw was SF >2000 ug/L over 75% of serial measurement durations in 3-year period (AUC 0.778, PPV 50.8%, NPV 95.5%). However this cut-off during 1 year priori also provided a similar prediction (AUC 0.769, PPV 51%, NPV 93.6%). This cut-off value also provided the best prediction for cardiac T2* < 20 ms in all age group (AUC 0.754, PPV 31.5%, NPV 97.4%) and a higher sensitivity and specificity when it was applied in patients >15 yrs of age (AUC 0.764, PPV 41.9%, NPV 96.3%). In NTDT with regular transfusion, all cardiac IOL (N=19) occurred after 15 years of age and again the same criteria was the good predictive cut-off for cardiac IO (AUC 0.788, PPV 19%, NPV 100%) and severe LIC >15 mgFe/g dw (AUC 0.728, PPV 52.8%, NPV 87.3%). Conclusions: In a resource limited setting for MRI evaluation, a serial measurement of SF and its values in thalassemic patients who received regular blood transfusion above the cut-off of 2000 ug/L over 75% of measurement in one year priori could be used as a predictive marker for selecting the most vulnerable TDT for MRI evaluation since this criteria is strongly associated with severe liver (LIC > 15 mgFe/g dw) and cardiac siderosis (T2* Disclosures Siritanaratkul: Novartis: Research Funding; Jansen-Cilag: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Wood:Celgene: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; World Care Clinical: Consultancy; AMAG: Consultancy; Celgene: Consultancy. Viprakasit:Agios: Consultancy; Mersanger: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Faculty of Medicine, Siriraj Hospital, Mahidol University: Employment; Shire: Research Funding.

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 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 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 15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC 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, p15 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 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 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 15mg/g group. At all-time points, in patients who achieved an LIC 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.

We read with interest Singer et al's report showing an increased alloimmunization and erythrocyte autoimmunization in a group of 64 transfusion-dependent thalassemia patients of predominantly Asian descent.[1][1] These patients have been receiving phenotypically different red blood cells from

Abstract 4261 Osteoporosis in thalassemia is extremely common and preventive approaches are required to avoid serious complications in adults. Vitamin D deficiency, which contributes to suboptimal bone mineralization, is frequently observed in thalassemia despite routine prescription for supplementation with 400–800 IU vitamin D per day. Screening for vitamin D status was conducted in 71 patients with thalassemia, of which 52 were transfusion-dependent and 19 were transfusion-independent (including 11 patients with hemoglobin H or H Constant Spring disease). Baseline assessment of plasma 25-OH vitamin D revealed 57 (80.3%) patients were either deficient (80 ng/mL) during the course of the study. These results show that vitamin D deficiency remains widespread despite daily low-dose supplementation. Non-transfused patients are at even greater risk of vitamin D deficiency, which may reflect less attention to nutrition in this group compared to the transfusion-dependent patients. We have found that supervised high-dose oral ergocalciferol supplementation is simple, safe, non-invasive and predictable method to improve vitamin D status in thalassemia. Disclosures: No relevant conflicts of interest to declare.