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Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations., (© 2024 Wiley Periodicals LLC.)

Anemia and hyperferritinemia are frequent findings at diagnosis of Gaucher disease (GD). Macrophage-independent dyserythropoiesis and abnormal iron metabolism have been shown. We evaluated hematological and iron status at diagnosis (T0) and the effect of enzyme replacement therapy (ERT) on erythropoiesis and iron utilization over 5-year follow-up in type 1 GD patients and in an ex vivo model of erythropoiesis from CD34 + peripheral blood cells. At T0, 41% of patients had anemia and 51% hyperferritinemia. Hemoglobin increased from 12.6 (T0) to 13.9 g/dL (T6), GFD15, a marker of ineffective erythropoiesis, decreased from 5401 to 710 pg/ml, and serum ferritin decreased from 614 to 140 mcg/L (p < 0.001). In parallel, transferrin saturation (TSAT) increased. Hepcidin, although in the normal range, decreased from T0 to T6. Ex vivo studies showed that ERT restores the erythroid cells derived from CD34 + impaired ability to differentiate. During ERT, an increase in TFRC expression, consistent with the ability of erythroid precursors to uptake iron, and a reduction in HAMP and concomitant increase in SLC40A1 were observed. This is the largest study with a longitudinal follow-up evaluating erythropoiesis and iron metabolism, combining clinical and ex vivo data in GD. Iron dysregulation likely contributes to anemia, and ERT, by improving iron distribution, improves erythropoiesis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/Objectives: Anemia during acute inflammation is not well described in the literature. We aimed to study whether patients develop a transient hemoglobin decrease during an acute attack of recurrent pericarditis. Methods: We retrospectively analyzed patients with recurrent pericarditis. The primary endpoint was the difference in hemoglobin levels during an acute attack and in the following remission. As secondary endpoints, we correlated this variation with laboratory and clinical features; we also evaluated the available baseline hemoglobin values. Results: Sixty-two patients, including thirty females (48.4%), with a median age of 39 years, were observed during an acute attack and remission. The attack indexed was the first in 21 patients and the second or the third in 41, with pre-attack hemoglobin levels available for the latter group. Median hemoglobin levels (IQR) were 13.8 (12.8-15.1) g/dL at baseline, 12.0 (11.2-13.4) during attacks and 13.6 (13.1-14.0) during remission ( p < 0.001). The median hemoglobin reduction between an acute attack and remission was 1.4 g/dL. Their mean corpuscular volume remained in the normal range. Hb reduction significantly correlated with C-reactive protein (CRP) elevation, neutrophilia and the neutrophil-to-lymphocyte ratio, but not serosal involvement. Only CRP elevation remained associated with the variation of Hb in a multivariate analysis ( p = 0.007). Conclusions: This study is a proof of concept: hemoglobin levels may decline rapidly during acute inflammation in correlation with CRP elevation, with transient normocytic anemia, followed by a rapid rebound. In this regard, idiopathic pericarditis may represent a pathogenetic model of this type of anemia.

In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding β-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Introduction: Ineffective erythropoiesis and subsequent anemia as well as primary and secondary (transfusional) iron overload are key drivers for morbidity and mortality outcomes in patients with β-thalassemia., Areas Covered: In this review, we highlight evidence from observational studies evaluating the association between measures of anemia and iron overload versus outcomes in both non-transfusion-dependent and transfusion-dependent forms of β-thalassemia., Expert Opinion: Several prognostic thresholds have been identified with implications for patient management. These have also formed the basis for the design of novel therapy clinical trials by informing eligibility and target endpoints. Still, several data gaps persist in view of the challenge of assessing prospective long-term outcomes in a chronic disease. Pooling insights on the prognostic value of different measures of disease mechanism will be key to design future scoring systems that can help optimize patient management.

Iron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruating individuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replaced through dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the most common cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the most common consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body iron stores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increased needs as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, the developing fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with ID and IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis, treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic., Competing Interests: Patricia Aguilar Martinez: Nothing to Disclose. Dorine Swinkels: Nothing to Disclose. Sule Unal: Nothing to Disclose. Fabiana Busti: Nothing to Disclose. Myka Sanchez: Co‐Founder of SME BLOODGENETICS SL (a genetic company www.bloodgenetics.com); Participation in 2 clinical trials one for IRIDA (KEROS THERAPEUTICS), one for atransferrinemia (SanquinBlood Netherland). Achille Iolascon: Nothing to Disclose. Ali Taher—Outside Work: Novartis Pharmaceuticals: Consultancy, Research funding; Bristol‐Myers Squibb (Celgene): Consultancy, Research funding; Ionis Pharmaceuticals: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Agios: Consultancy. Rayan Bou Fakhredin: Nothing to Disclose. Graça Porto: Nothing to Disclose. Immacolata Andolfo: Nothing to Disclose. Roberta Russo: Nothing to Disclose. Martina Muckenthaler Silence Therapeutics PLC, Editorial Board/Blood Journal/HemaSphere. Malcolm. G. Munro: Consultancies Pharmacosmos, Vifor, Daichi‐Sankyo, Shield Therapeutics, Myovant, Abbvie; Immediate Past Chair, FIGO Menstrual Disorders Committee. Tomas Ganz: shareholder and scientific advisor of Intrinsic LifeSciences, and consultant for Ionis Pharmaceuticals, Disc Medicine, Silence Therapeutics, Chugai, Vifor, Akebia, Dexcel, and Avidity Bio., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs)., Methods: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β 0 /β 0 , β 0 /β 0 -like, or non-β 0 /β 0 -like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed., Results: A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred., Conclusions: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.)., (Copyright © 2024 Massachusetts Medical Society.)

Background & Aims: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION., Methods: Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (n = 48) or placebo (n = 46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted., Results: During givosiran treatment, the median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item short-form health survey physical and mental component summary scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lower urinary delta-aminolevulinic acid and porphobilinogen levels were sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran., Conclusions: Long-term monthly givosiran treatment provides sustained and continued improvement in clinical manifestations of AHP., Gov Identifier: NCT03338816., Eudract Number: 2017-002432-17., Impact and Implications: Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders associated with overproduction and accumulation of neurotoxic heme intermediates (delta-aminolevulinic acid and porphobilinogen), sometimes resulting in recurrent acute attacks and long-term complications. Givosiran, a small-interfering RNA that prevents accumulation of delta-aminolevulinic acid and porphobilinogen, is approved for the treatment of AHP. These final 36-month results of ENVISION, a phase III study of givosiran in patients with AHP and recurrent attacks, show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in annualized attack rate and use of hemin over time, as well as improved quality of life, with an acceptable safety profile. These results are important for physicians, patients, families, and caregivers who are grappling with this debilitating and potentially life-threatening disease with few effective and tolerable treatment options., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified heterozygous loss-of-function mutations in SUPT5H, which encodes SPT5, in individuals with β-thalassemia. During erythropoiesis in healthy human cells, cell cycle genes were highly paused as cells transition from progenitors to precursors. When the pathogenic mutations were recapitulated by SUPT5H editing, RNA Pol II pause release was globally disrupted, and as cells began transitioning from progenitors to precursors, differentiation was delayed, accompanied by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, identifying a role for RNA Pol II pausing in temporally coordinating the cell cycle and erythroid differentiation., Competing Interests: Declaration of interests V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, Sana Biotechnology, and Cellarity, all unrelated to the present work. J.C.U. is an employee of Illumina, Inc., unrelated to the present work. R.I. is a founder, board member, and shareholder of Cellforma, unrelated to the present work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Blood transfusion is one of the most overused procedures, especially in elderly patients. Despite the current transfusion guidelines recommending a restrictive transfusion strategy in stable patients, the clinical practice varies according to physicians' experience and implementation of patient blood management. This study aimed to evaluate the anemia management and transfusion strategy in anemic elderly hospitalized and the impact of an educational program. We enrolled ≥ 65-year-old patients who presented or developed anemia during admission to a tertiary hospital's internal medicine and geriatric units. Patients with onco-hematological disorders, hemoglobinopathies and active bleeding were excluded. In the first phase, anemia management was monitored. In the second phase, the six participating units were divided into two groups and two arms: Educational (Edu) and non-educational (NE). During this phase, physicians in the Edu arm underwent an educational program for the appropriate use of transfusion and anemia management. In the third phase, anemia management was monitored. Comorbidities, demographic and hematological characteristics were similar in all phases and arms. The percentages of transfused patients during phase 1 were 27.7% in NE and 18.5% in the Edu arm. During phase 3, it decreased to 21.4% in the NE and 13.6% in the Edu arm. Hemoglobin levels at discharge and after 30 days were higher in the Edu group despite reduced use of blood transfusion. In conclusion, a more restrictive strategy was comparable or superior to the more liberal one in terms of clinical outcomes, with the advantage of saving red blood cell units and reducing related side effects., Competing Interests: Declaration of Competing Interest MDC has been or is a current consultant for Vifor Pharma. The other authors have no conflict of interest related to this research., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Patients with transfusion-dependent (TD) β-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL)., Methods: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD β-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders., Results: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019)., Conclusions: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years.    Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non β0/β0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old)., (© 2023. The Author(s).)

Patients with transfusion-dependent β-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent β-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with β-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Clinical evidence highlights a relationship between the blood and the bone, but the underlying mechanism linking these two tissues is not fully elucidated. Here, we used β-thalassemia as a model of congenital anemia with bone and bone marrow (BM) niche defects. We demonstrate that fibroblast growth factor 23 (FGF23) is increased in patients and mice with β-thalassemia because erythropoietin induces FGF23 overproduction in bone and BM erythroid cells via ERK1/2 and STAT5 pathways. We show that in vivo inhibition of FGF23 signaling by carboxyl-terminal FGF23 peptide is a safe and efficacious therapeutic strategy to rescue bone mineralization and deposition in mice with β-thalassemia, normalizing the expression of niche factors and restoring hematopoietic stem cell (HSC) function. FGF23 may thus represent a molecular link connecting anemia, bone, and the HSC niche. This study provides a translational approach to targeting bone defects and rescuing HSC niche interactions, with potential clinical relevance for improving HSC transplantation and gene therapy for hematopoietic disorders.

Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤10 g/dL. These data led to luspatercept's approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population., Competing Interests: K.M.M. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. A.T.T. reports consultancy fees Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, Silence Therapeutics and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and Agios Pharmaceuticals. A.K. reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene/Bristol Myers Squibb, Forma, Pfizer, Novo Nordisk, Vertex, and Novartis; honoraria from Alexion and Novartis; membership on an advisory committee for Agios Pharmaceuticals and Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. S.S. reports consultancy fees from Agios Pharmaceuticals, Bluebird bio, Bristol Myers Squibb, Forma, and Chiesi; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. The authors report no other conflicts of interest in this work., (© 2023 Musallam et al.)

The hematologic disorders myelodysplastic syndromes and beta-thalassemia are characterized by ineffective erythropoiesis and anemia, often managed with regular blood transfusions. Erythropoiesis, the process by which sufficient numbers of functional erythrocytes are produced from hematopoietic stem cells, is highly regulated, and defects can negatively affect the proliferation, differentiation, and survival of erythroid precursors. Treatments that directly target the underlying mechanisms of ineffective erythropoiesis are limited, and management of anemia with regular blood transfusions imposes a significant burden on patients, caregivers, and health care systems. There is therefore a strong unmet need for treatments that can restore effective erythropoiesis. Novel therapies are beginning to address this need by targeting a variety of mechanisms underlying erythropoiesis. Herein, we provide an overview of the role of ineffective erythropoiesis in myelodysplastic syndromes and beta-thalassemia, discuss unmet needs in targeting ineffective erythropoiesis, and describe current management strategies and emerging treatments for these disorders., Competing Interests: Declaration of Competing Interest MDC has received advisory board fees from Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Sanofi Genzyme, and Vifor Pharma. ATT has received consulting fees from Agios Pharmaceuticals; and research funding and consulting fees from Celgene/Bristol Myers Squibb, Imara, Ionis Pharmaceuticals, Novartis, and Vifor Pharma. AV has received grants from Bristol Myers Squibb, Curis, Eli Lilly, Glaxo Smith Kline, Incyte, MedPacto, and Prelude; advisory board fees from Acceleron Pharma, Celgene, and Novartis; consulting fees from Janssen; holds stock options in and received advisory board fees from Bakx and Stelexis; and holds stock options in Throws Exception. FS has received consulting fees from Bristol Myers Squibb, Silence Therapeutics, and Vertex Pharmaceuticals Inc.; consulting fees and support for attending meetings from bluebird bio Inc.; honoraria and support for attending meetings from Novartis; honoraria from Biologix Pharma and Chiesi Ltd.; has participated in the data safety monitoring board for Agios Pharmaceuticals; and serves as the chair of the UK Forum on Haemoglobin Disorders and the National Haemoglobinopathy Registry. OH holds equity in AB Science; and has received research funding from Celgene/Bristol Myers Squibb and Mnemo Therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare disease, and several gaps of knowledge on various issues remain, particularly at a regional/national level. Expert opinions collected through well-defined consensus methodologies are increasingly used to make available reliable information in the context of rare/ultra-rare diseases. With the aim to provide indications on infantile neurovisceral ASMD (also formerly known as Niemann-Pick disease type A), chronic neurovisceral ASMD (formerly known as Niemann-Pick disease type A/B) and chronic visceral ASMD (formerly known as Niemann-Pick disease type B) in Italy, we conducted a Delphi consensus of experts focused on five main areas: (i) patients and disease characteristics; (ii) unmet needs and quality of life; (iii) diagnostic issues; (iv) treatment-related aspects; and (v) patient journey. Pre-specified, objective criteria were used to outline the multidisciplinary panel, based on 19 Italian experts in ASMD in paediatric and adult patients from different Italian Regions, including both clinicians (n = 16) and ASMD patients' advocacy or payors with expertise in rare diseases (n = 3). During two Delphi rounds, a high ratio of agreement was found on several topics related to ASMD characteristics, diagnosis, management and disease burden. Our findings may provide valuable indications for management of ASMD at a public health level in Italy., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The diversity of disease-related complications among patients with β-thalassemia is complicated by the wide spectrum of genotypes and clinical risk factors. The authors herein present the different complications seen in patients with β-thalassemia, the pathophysiology underlying these complications and their management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Erythropoiesis is the physiological process that results in the production of red blood cells (RBCs). In conditions of pathologically altered erythropoiesis or ineffective erythropoiesis, as in the case of β-thalassemia, the reduced ability of erythrocytes to differentiate, survive and deliver oxygen stimulates a state of stress that leads to the ineffective production of RBCs. We herein describe the main features of erythropoiesis and its regulation in addition to the mechanisms behind ineffective erythropoiesis development in β-thalassemia. Finally, we review the pathophysiology of hypercoagulability and vascular disease development in β-thalassemia and the currently available prevention and treatment modalities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: The non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404)., Design: Analysis of a phase 2, double-blind, randomised, placebo-controlled trial., Setting: USA, Greece, Italy, Lebanon, Thailand and the UK., Participants: Adults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L., Measures: NTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S)., Results: Cronbach's alpha at weeks 13-24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test-retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13-24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs., Conclusions: The NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials., Competing Interests: Competing interests: ATT—consulting fees from Agios Pharmaceuticals; research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals and Vifor Pharma. KMM—consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, Pharmacosmos and Vifor Pharma. VV—research funding from Bristol Myers Squibb. AK—advisory board fees and consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex Pharmaceuticals, Ionis Pharmaceuticals, Novartis and Vifor Pharma; research support from Celgene/Bristol Myers Squibb and Novartis. JL-B, AY, JKS and LMB—employment by and stock/equity holder of Bristol Myers Squibb. SG—employment by Evidera; consultancy fees from Bristol Myers Squibb, Gilead and Janssen. CP—employment by Evidera. ALS—employment by Adelphi Values. DM—employment by Bristol Myers Squibb. MDC—advisory board fees from Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Sanofi Genzyme and Vifor Pharma., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report data on survival and complications for a longitudinal cohort of 709 transfusion-dependent β-thalassemia major patients (51.1% males) born between 1970 and 1997 and followed through 2020 at seven major centers in Italy. Overall survival probability at 30 years was 83.6% (95%CI: 78.5-89.1) in the oldest birth cohort (1970-1974) compared with 93.3% (95%CI: 88.6-98.3) in the youngest birth cohort (1985-1997) (p = 0.073). Females showed better survival than males (p = 0.022). There were a total of 93 deaths at a median age of 23.2 years with the most frequent disease-related causes being heart disease (n = 53), bone marrow transplant (BMT) complication (n = 10), infection (n = 8), liver disease (n = 4), cancer (n = 3), thromboembolism (n = 2) and severe anemia (n = 1). There was a steady decline in the number of deaths due to heart disease from the year 2000 onwards and no death from BMT was observed after the year 2010. A progressive decrease in the median age of BMT was observed in younger birth cohorts (p < 0.001). A total of 480 (67.7%) patients developed ≥1 complication. Patients in younger birth cohorts demonstrated better complication-free survival (p < 0.001) which was comparable between sexes (p = 0.230). Independent risk factors for death in multivariate analysis included heart disease (HR: 4.63, 95%CI: 1.78-12.1, p = 0.002), serum ferritin >1000 ng/mL (HR: 15.5, 95%CI: 3.52-68.2, p < 0.001), male sex (HR: 2.75, 95%CI: 0.89-8.45, p = 0.078), and splenectomy (HR: 6.97, 95%CI: 0.90-54.0, p < 0.063). Survival in patients with β-thalassemia major continues to improve with adequate access to care, best practice sharing, continued research, and collaboration between centers., (© 2023 Wiley Periodicals LLC.)

In heart failure, the biological and clinical connection between abnormal iron homeostasis, myocardial function, and prognosis is known; however, the expression profiles of iron-linked genes both at myocardial tissue and single-cell level are not well defined. Through publicly available bulk and single-nucleus RNA sequencing (RNA-seq) datasets of left ventricle samples from adult non-failed (NF) and dilated cardiomyopathy (DCM) subjects, we aim to evaluate the altered iron metabolism in a diseased condition, at the whole cardiac tissue and single-cell level. From the bulk RNA-seq data, we found 223 iron-linked genes expressed at the myocardial tissue level and 44 differentially expressed between DCM and NF subjects. At the single-cell level, at least 18 iron-linked expressed genes were significantly regulated in DCM when compared to NF subjects. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels, including: (1) imbalance of Fe 3+ internalization ( SCARA5 down-regulation) and reduction of internal conversion from Fe 3+ to Fe 2+ ( STEAP3 down-regulation), (2) increase of iron consumption to produce hemoglobin ( HBA1/2 up-regulation), (3) higher heme synthesis and externalization ( ALAS2 and ABCG2 up-regulation), (4) lower cleavage of heme to Fe 2+ , biliverdin and carbon monoxide ( HMOX2 down-regulation), and (5) positive regulation of hepcidin ( BMP6 up-regulation).

Lysosomal storage disorders are a group of inborn errors of metabolism due to defects in proteins crucial for lysosomal function. Gaucher disease is the most common autosomal recessive lysosomal storage disorder due to mutations in the GBA1 gene, resulting in the lysosomal deficiency of glucocerebrosidase activity. Gaucher disease is characterized by the toxic accumulation of glucosylceramide in the reticuloendothelial system. Acid sphingomyelinase deficiency (ASMD), previously known as Niemann Pick A/B disease, is also an autosomal recessive lysosomal storage disorder due to mutations in the SMPD1 gene, which result in acid sphingomyelinase deficiency and the accumulation of sphingomyelin in mononuclear phagocytic system and hepatocytes. The phenotypic expression of Gaucher disease type 1 (GD1), the most common type, and chronic visceral ASMD may overlap for several signs or symptoms. Splenomegaly is detectable in approximately 90% of the patients in both conditions; however, since GD1 is more frequent than ASMD, clinicians are more prone to suspect it, often neglecting the diagnosis of ASMD. Based on previous experience, a group of experts in the clinical and laboratory diagnosis, management, and treatment of lysosomal storage disorders developed an algorithm for both GD1 and ASMD to support physicians, including primary care providers, internists, and specialists (e.g., hepatologists, hematologists, and pulmonologists) to suspect and differentiate GD1 and ASMD and to provide the appropriate referral., Competing Interests: Declaration of Competing Interest MDC has been or is a current consultant for Sanofi-Genzyme, Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma and Ionis Pharmaceuticals, and has received research funding from Sanofi-Genzyme, Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. IM has been or is a current consultant for Bristol Myers Squibb, Sanofi-Genzyme, Amicus Therapeutics and has received honoraria for lectures and travel grants from Sanofi-Genzyme. AB received honoraria for lectures, advisory boards, meetings, and travel support from Sanofi Genzyme, and Takeda. FC has received travel grants and honoraria for lectures from Sanofi-Genzyme, Amgen, Amicus, Amryt, Daiichi-Sankyo, and Novartis. FG has received honoraria from Sanofi-Genzyme, Novartis, and Takeda., (Copyright © 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Gaucher disease (GD) is a lysosomal storage disorder. We evaluated the "real-world" effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry., Methods: Patients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated., Results: Data on bone manifestations were available for 73 of 229 patients (31.9 %). Bone crises frequency decreased significantly from baseline to the most recent follow-up (p < 0.001), with some improvement observed in bone pain prevalence. Bone pain and bone crises prevalence decreased significantly from baseline at 2 to <4 and 4 to <6 years (all p < 0.05). A low median (25th, 75th percentile) baseline imiglucerase dosage was identified in patients reporting bone pain or bone crises (15.0 [13.7, 30.0] and 22.8 [17.5, 36.0] U/kg once every 2 weeks, respectively)., Conclusion: Our study suggests that the management of GD in Italy, with regards to imiglucerase dosage, is suboptimal and confirms the need for clinicians to monitor and correctly treat bone disease according to best practice guidelines., Competing Interests: Declaration of competing interest MDC declares having served on advisory boards for Sanofi/Genzyme, BMS/Celgene, Vifor, Vertex/CRISPR, Novonordisk, Ionis, Agios, and Silence. FC declares funding from Sanofi, Amgen, and Amicus in the last 3 years. MDR declares having served on advisory boards for/received honoraria for lecturing or moderating meetings from Sanofi, Takeda, Orchad, Alnylan, and Ultragenix. FG declares funding from Sanofi, Novartis, and Takeda in the last 3 years. GG declares funding from Sanofi, Novartis, Amgen, Roche, Novo Nordisk, and Takeda in the last 3 years., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis., (© 2022 Wiley Periodicals LLC.)

In many countries, β-thalassemia (β-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for β-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of β-THAL; at the same time, and even though only one-fifth of β-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for β-THAL., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Kuo and colleagues 1 evaluated the safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion-dependent α-thalassemia or β-thalassemia. The high rate of hemoglobin response and good tolerability encourages further development in thalassemia., Competing Interests: Declaration of interests K.M.M. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos. M.D.C. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma, and Ionis Pharmaceuticals and research funding from Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. A.T.T. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma, Silence Therapeutics, and Ionis Pharmaceuticals and research funding from Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and Agios Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia., Methods: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing., Findings: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study., Interpretation: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests ATT reports receiving consulting fees from Agios Pharmaceuticals; and research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals, and Vifor Pharma. MDC reports receiving advisory board fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Novo Nordisk, Sanofi Genzyme, Silence Therapeutics, and Vifor Pharma. AK reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutuici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. SP reports receiving grant support, paid to his institution, from Novartis, and personal fees from bluebird bio and Celgene. AGP reports receiving grant support, paid to his institution, from Acceleron Pharma and Celgene, and advisory board fees from Celgene. AF reports advisory board fees from Celgene and grant support, paid to his institution, from bluebird bio and Novartis. JBP reports receiving advisory board fees from bluebird bio, Bristol Myers Squibb, Silence Therapeutics, and Vifor Pharma. TDC reports receiving consultancy fees from Agios Pharmaceuticals, bluebird bio, Bristol Myers Squibb/Celgene, Chiesi Farmaceutici, and Vifor Pharma. GLF reports receiving consulting fees and grant support, paid to his institution, from Agios Pharmaceuticals, Bristol Myers Squibb, and Novartis; and advisory board fees from Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb and Novartis. AA Thompson reports receiving grant support from Baxalta, Biomarin, bluebird bio, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Editas Medicine, and Novartis; and consulting fees from bluebird bio, Celgene/Bristol Myers Squibb, and CRISPR Therapeutics/Vertex; fees for leadership of fiduciary role in a committee or advocacy group from Global Blood Therapeutics; previous employment (last 12 months) at Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; and current employment at Children's Hospital of Philadelphia, Philadelphia, PA, USA. IT reports receiving honoraria from Celgene. KMM reports receiving consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, and Vifor Pharma. JTB reports ending employment at Acceleron Pharma in the last 12 months and owning stock in Acceleron Pharma, and Bristol Myers Squibb. OE, W-LK, and DM report being employed by Bristol Myers Squibb. ACG, JL-B, AY, and JKS report being employed by and owning stock in Bristol Myers Squibb. TZ reports ending employment at Bristol Myers Squibb in the last 24 months and owning stock in Bristol Myers Squibb. EV and VV report no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Iron deficiency (ID) and iron deficiency anemia (IDA) are highly prevalent among women across their reproductive age. An iron-deficient state has been associated with and causes a number of adverse health consequences, affecting all aspects of the physical and emotional well-being of women. Heavy menstrual bleeding, pregnancy, and the postpartum period are the major causes of ID and IDA. However, despite the high prevalence and the impact on quality of life, ID and IDA among women in their reproductive age is still underdiagnosed and undertreated. In this chapter we summarized the iron metabolism and the diagnosis and treatment of ID and IDA in women., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents.

β-thalassemia and sickle cell disease (SCD) are inherited hemoglobinopathies that result in both quantitative and qualitative variations in the β-globin chain. These in turn lead to instability in the generated hemoglobin (Hb) or to a globin chain imbalance that affects the oxidative environment both intracellularly and extracellularly. While oxidative stress is not among the primary etiologies of β-thalassemia and SCD, it plays a significant role in the pathogenesis of these diseases. Different mechanisms exist behind the development of oxidative stress; the result of which is cytotoxicity, causing the oxidation of cellular components that can eventually lead to cell death and organ damage. In this review, we summarize the mechanisms of oxidative stress development in β-thalassemia and SCD and describe the current and potential antioxidant therapeutic strategies. Finally, we discuss the role of targeted therapy in achieving an optimal redox balance.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The thalassemias are a group of inherited disorders of hemoglobin synthesis that continue to pause a global public health concern. The complex molecular and pathogenetic pathways involved in disease process lead to an array of comorbidities that require lifelong management. The disease and its treatment can also lead to alterations in immune function and a link to various autoimmune diseases has been frequently suggested. However, most data stem from single case reports and small studies that do not allow proper assessment of causal associations. Still, the high morbidity in thalassemia makes patients vulnerable to the added burden of coexisting autoimmune diseases, and special management considerations in this patient population are warranted. In this review, we explore insights and data from the literature on various autoimmune disease that have been observed in patients with thalassemia. The role of the thalassemia carrier state in modifying outcomes of patients with autoimmune diseases is also discussed., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited., Methods: To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels., Results: Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] μg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] μg/dL vs 109 [IQR: 63.25-154] μg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative., Conclusions: Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP., (© 2021 The Authors. Photodermatology, Photoimmunology & Photomedicine published by John Wiley & Sons Ltd.)

The β-thalassaemias are a group of inherited disorders of haemoglobin synthesis characterised by chronic anaemia of varying severity. Currently available conventional therapies in thalassaemia have many challenges and limitations. A better understanding of the pathology of β-thalassaemia has led to the development of new treatment options, most of which are currently in clinical trials. These could have the potential of reducing red blood cell transfusion burden, raising haemoglobin levels, and improving patients' overall quality of life. In this review, we will provide an overview of the novel therapeutic approaches that are currently under development to advance the care of β-thalassaemia patients.