ALBERT

Description: Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses 〉25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leuko-reduced, double RBC units. One unit was autologously transfused “fresh” (3-7 days of storage), and the other “older” unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. Compared with fresh RBCs, mean serum total bilirubin increased by 0.55 mg/dL at 4 hours after transfusion of older RBCs (P = .0003), without significant changes in haptoglobin or lactate dehydrogenase. In addition, only after the older transfusion, transferrin saturation increased progressively over 4 hours to a mean of 64%, and non–transferrin-bound iron appeared, reaching a mean of 3.2μM. The increased concentrations of non–transferrin-bound iron correlated with enhanced proliferation in vitro of a pathogenic strain of Escherichia coli (r = 0.94, P = .002). Therefore, circulating non–transferrin-bound iron derived from rapid clearance of transfused, older stored RBCs may enhance transfusion-related complications, such as infection. The trial was registered with www.clinicaltrials.gov as #NCT01319552.

Description: Abstract 1029 Purpose of study: Transfusion dependent thalassemia (TM) patients are routinely supplemented with vitamin D due to their increased risk of developing osteoporosis. Recent studies from North America have found that these patients have high rates of vitamin D “deficiency” and “insufficiency,” despite supplementation. The amount of vitamin D supplementation required to raise serum 25 hydroxy-vitamin D (25-OHD) to optimal levels is not known in these patients. Recent studies have linked 25-OHD levels to hypercalciuria and nephrolithiasis in patients with TM. The purpose of this study is to determine the effect of various doses of vitamin D supplementation on vitamin D stores and calcium excretion in TM patients. Description of project: Prospective, single-blind, placebo-controlled study of TM patients followed in the transfusion center at Weill Cornell/New York Presbyterian Hospital. Patients with 25-OHD concentrations between 15–29 ng/mL were eligible for this 3-month study. Subjects were assigned in a block type of enrollment to the “high dose” equivalent of 2,000 IU of vitamin D per day versus placebo. Results: 14 subjects were enrolled, with 8 assigned to the “high dose” group and 6 assigned to the placebo group. The “high dose” group consisted of 6 females, aged 15.2–45.5 years with an average baseline 25-OHD level of 22.4 ng/mL (15–26). The “placebo” group consisted of 4 females, aged 22.5–45.7 years with an average baseline 25-OHD level of 19.8 ng/mL (16–24). After the 3 month study period, hypercalciuria developed more frequently in those treated in the “high dose” group. In the placebo group, hypercalciuria was noted in 1/6 (16.7%) spot urine calcium/creatinine tests and 0/3 (0%) 24 hour urine calcium estimations. In the “high dose” group, the corresponding number of patients based on the same methods of testing were 5/8 (62.5%) and 2/5 (40%). No episodes of hypocalcemia, hypercalcemia or nephrolithiasis occurred in either group. Conclusion: Our findings suggest that “high dose” vitamin D supplementation results in higher rates of hypercalciuria in TM patients. Further studies are necessary to determine the optimal dose of vitamin D supplementation to minimize the risk of osteoporosis while preventing nephrolithiasis in TM patients. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points PK deficiency manifests a broad spectrum in anemia severity that moderately improves after splenectomy. Close attention to monitoring for iron overload, gallstones, and other complications is recommended in all patients with PK deficiency.

Description: Background: The prevalence of thalassemia in the US is rising due to migration, new births, and improved survival. Advances in monitoring and treatment have significantly reduced morbidity and mortality in transfusion-dependent thalassemia (TDT), the most severe form of this inherited disease. Thalassemia Treatment Centers (TTCs) utilize a comprehensive care model to provide expert-recommended and evidence-informed treatment, but a majority of the patients with TDT are not managed at such centers owing to long travel distance and lack of insurance portability. The resulting lack of access to specialized care increases the risk of complications and reduces health-related quality of life. To address this challenge, a national project was launched to develop Thalassemia Management Checklists (TMCs), a set of quick reference guides that provide decision support to physicians for blood transfusion, iron overload and chelation therapy. Methods: Three TTC's (New York, NY, Philadelphia, PA, and Oakland, CA) collaborated on the development of the following TMCs: (1) Guidelines for Managing Transfusion therapy for Thalassemia, (2) Monitoring of Iron Overload, and (3) Monitoring Deferasirox Therapy. A comprehensive review of literature including over 600 published studies and case reports, as well as the existing expert guidelines was conducted. Utilizing relevant references, the clinical guidelines were developed and a consensus on content and design of the Checklists was achieved. Subsequently, feedback obtained from national experts and patients with thalassemia was incorporated into the final Checklists. Results: Each Checklist was divided into three sections and formatted as a quick reference guide. Part 1 was a summary table having essential information printed on one side of letter-sized paper. For transfusion therapy, the table contained actions to be triggered by the pre-transfusion hemoglobin level. For iron overload, the optimal and elevated liver and cardiac iron concentration were defined along with the frequency of iron measurement using MRI. For monitoring of deferasirox, the monitoring guidelines for adverse effects and the response to abnormal laboratory tests were presented. Part 2 consisted of a literature review and rationale for the recommendations presented in the table, which was printed on the opposite face of the page. Part 3 was a bibliography of publications cited in the literature review that was made available online with a link provided in the TMC. The final product was three separate pages each covering a single topic, allowing easy access to the summary information while displaying detailed information on demand. The TMCs were distributed as printed copies to hematologists and can be downloaded from thalassemia-related websites. Discussion: The TTC's involved with this effort recognized that physicians providing care to only a few patients with TDT within general hematology (or more commonly oncology) -focused practices are far more likely to consult a desktop quick reference guide instead of a textbook, journal or handbook of comprehensive guidelines. TMCs are expected to cover most of the routine management of TDT while encouraging consultation with TTC's for complex decisions. TMCs will form the backbone of the first national attempt to standardize the management of TDT and reduce disparities in access to and quality of care. Over the next 3 years, the adoption of TMCs and their impact on patient care will be formally evaluated in selected regions. Patient access to TMCs through online publication will increase knowledge and promote self-advocacy. We are grateful to Craig Butler and Cooley's Anemia Foundation for coordinating this project. This project is/was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number U1AMC28548: Cooperative Agreements to Support Comprehensive Medical Care for Thalassemia with no funds from non-governmental sources. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. Disclosures Lal: Insight Magnetics: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Terumo Corporation: Research Funding; Celgene Corporation: Research Funding. Sheth:Terumo Corporation: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Celgene Corporation: Consultancy, Research Funding; Bluebird Bio: Consultancy. Kwiatkowski:Novartis: Research Funding; Apopharma: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding.

Description: Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having 〉4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064]) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Description: Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children 〈 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was 〉1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) 〉3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values

Description: Abstract 637 Transfusion therapy is hampered by the development of alloantibodies to transfused red blood cells (RBCs). A recent mathematical model for RBC alloimmunization predicted that approximately 13% of the general population are antibody producers (responders) (Higgins and Sloan, 2008). However, immune molecular markers which may predict these transfusion responders have not been clearly demonstrated. We recently reported in a mouse model that key immune response regulators, CD4+ regulatory T cells (Tregs) have reduced activity in alloantibody responders compared to non-responders (Bao, 2009). (Bao, 2009). Here, we designed a study to determine whether alloimmunized humans have an altered immune response to red cell transfusions, similar to that seen in the mouse model. Peripheral Treg frequency and activity was studied in a cohort of 18 chronically transfused patients with sickle cell disease (SS), receiving either exchange transfusions (n=7) or simple transfusions (n=11). All had been receiving leukoreduced units, matched for Kell and Rh antigens on a roughly 4 weekly intervals for at least 2 years prior to the study. Nine patients were identified as having had a positive history of alloimmunization (responders), 6 on simple transfusions and 3 on exchange transfusions responders. We found no statistically significant differences in the Treg frequencies (Foxp3+CD25hi in the CD4+ population) between alloimmunized and non-alloimmunized SS patients (p〉0.1). However, Treg activity as measured by suppression of proliferation of autologous CD4+CD25–cells at 1:4 and 1:16 ratios of Tregs: CD4+CD25–cells was significantly lower in responders compared to non-responders (at 1:4 ratio, 38±5% alloimmunized versus 54±3% non-alloimmunized, p=0.02 and at 1:16 ratio, 10±6% versus 28±4%, p=0.03). To determine if there was a skewing of the T helper (Th) responses as a result of reduced Treg activity in responders, we analyzed the functional phenotype of peripheral CD4+ T cells by single-cell measurement of intracellular cytokines using flow cytometry. CD4+ T cells were classified as Th1, Th2 or Th17 by assessing their intracellular cytokine profile of IFN- γ, IL-4 and IL-17, respectively. Expression of secreted cytokines was also measured in stimulated cultured supernatants by ELISA. Following stimulation with PMA and ionomycin, we found higher proportion of IL-4 single positive Th2 cells as well as higher levels of secreted IL-4 in sorted populations of CD4+CD25−T cells from responders compared to non-responders receiving either simple or exchange transfusions (p=0.01), indicating that responder status is skewed towards a Th2 response. Although we did not find statistically significant differences in either secreted IL-17 or IFN- γ or in IL-17- or IFN- γ -expressing Th cells between alloimmunized and non-alloimmunized patients, our transfused SS cohort had significantly higher levels of secreted proinflammatory IL-17 and IFN- γ compared with normal healthy race-matched controls (n=7, p=0.03). These latter data are consistent with an underlying Th cytokine imbalance in chronically transfused SS patients, although it remains to be determined if the perturbations in cytokine balance is the result of chronic transfusions, or specific to SS patients. In summary, our data indicate that in chronically transfused SS patients, responders have compromised Treg activity. This may be responsible for the observed increase in Th2 responses, known to be associated with induction of antibody production. The mechanisms responsible for these differences in responders are under further study. Our findings suggest that Treg associated molecular markers may be used to predict in advance antibody producers to reduce alloimmunization-associated morbidity and mortality. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p

Description: Introduction: β-thalassemia is a genetic blood disease characterized by ineffective erythropoiesis due to defective hemoglobin production that manifests as potentially fatal anemia. Patients with β-thalassemia rely on regular, lifelong red blood cell transfusions (RBCTs) for survival and suffer from multi-system complications, physical manifestations, and decreased health-related quality of life (HRQoL) due to iron overload and continual RBCTs. This literature review aims to describe the disease burden associated with β-thalassemia. Methods: Electronic databases (MEDLINE®, Embase®, Cochrane Library) were searched to identify articles in the English language assessing the clinical, economic, and humanistic burden of β-thalassemia in North America and Europe. Articles were selected based on predefined criteria including appropriate study design, disease state, country, and outcome measures. Results: Patients with β-thalassemia who received regular RBCTs were significantly more likely to develop ≥ 1 iron overload-related comorbidity than matched, non-thalassemia controls (P 〈 0.0001). Other iron-related issues included cardiac disease (observed in 13-30% of patients), hypogonadism (17-22%), diabetes (10-18%), osteoporosis (16%), hypothyroidism (12%), liver disease (4%), and hypoparathyroidism (2%). RBCTs also introduced the risk of transfusion reactions (48-50%), infections (24-65%), and development of alloantibodies (19-23%). Mortality rate for the US population was 1.9%. The direct annual cost per regularly transfused patient with β-thalassemia was significantly higher than in matched controls (USD 128,062 vs USD 5,438; P 〈 0.001; 2016 USD). The main annual cost drivers per patient were iron chelation therapy (48%; USD 61,974) and RBCTs (31%; USD 39,723). Indirect costs for β-thalassemia were impacted by unemployment, reported at 33% among patients with β-thalassemia versus 24% for the general US population. Patients scored significantly worse on 5 subdomains (physical functioning, role-physical, general health, social functioning, and role-emotional) of the Short Form-36 (SF-36) HRQoL questionnaire compared with the general US population (all P 〈 0.0001) with the greatest impairments seen in the general health subdomain (P 〈 0.0001). Clinically meaningful reductions in physical functioning, role-physical, and general health scores were observed for patients with β-thalassemia aged 〈 65 years with transfusion-related iron overload. Bodily pain was reported by 56-69% of patients with β-thalassemia, and pain interfered with patient physical and emotional functioning HRQoL outcomes. Increasing age correlated with higher numbers of pain responses (P 〈 0.001). Psychiatric comorbidities were found in 24% of patients with β-thalassemia, and mood disorders, including depression and anxiety, were associated with overall significantly poorer physical and mental HRQoL (P 〈 0.001). Conclusions: β-thalassemia is associated with a substantial clinical, economic, and humanistic burden in the USA. Patients with β-thalassemia experience reduced life expectancy, significant comorbidities, considerable direct healthcare costs, unemployment, and impaired HRQoL. There is a need for more effective management and therapeutic options for these patients. Disclosures Mearns: Celgene Corporation: Employment. Udeze:Celgene Corporation: Employment. Copher:Celgene Corporation: Employment. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy.