Alpha-Thalassemia: A Practical Overview (PDF)

Blood Reviews xxx (xxxx) xxx Contents lists available at ScienceDirect Blood Reviews journal homepage: www.elsevier.com/locate/issn/0268960X Review Аlpha-thalassemia: A practical overview Khaled M. Musallam a, M. Domenica Cappellini b, Thomas D. Coates c, Kevin H.M. Kuo d, Hanny Al-Samkari e, Sujit...

Blood Reviews xxx (xxxx) xxx Contents lists available at ScienceDirect Blood Reviews journal homepage: www.elsevier.com/locate/issn/0268960X Review Аlpha-thalassemia: A practical overview Khaled M. Musallam a, M. Domenica Cappellini b, Thomas D. Coates c, Kevin H.M. Kuo d, Hanny Al-Samkari e, Sujit Sheth f, Vip Viprakasit g, Ali T. Taher h, * a Center for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, United Arab Emirates Department of Clinical Sciences and Community, University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy c Hematology Section, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA d Division of Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada e Center for Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA f Division of Pediatric Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA g Department of Pediatrics & Thalassemia Center, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand h Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon b A R T I C L E I N F O A B S T R A C T Keywords: alpha-thalassemia Hemolysis anemia Diagnosis Management Transfusion α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency. 1. Introduction The thalassemias are inherited, autosomal recessive disorders of hemoglobin (Hb) synthesis characterized by a variety of molecular de­ fects and are among the most common genetic diseases worldwide [1–3]. The principal forms, α- and β-thalassemia, result from mutations in globin genes that lead to a deficit or qualitative change in the pro­ duction of the α-globin and β-globin chains of adult Hb, respectively. The global disease burden of thalassemia is substantial, with 5% to 20% of the world population carrying one or more α-thalassemia mu­ tations, and ≈1.5% carrying one or more β-thalassemia mutations [5–7]. Prevalence rates vary among regions but are highest in tropical and subtropical countries, particularly in Southeast Asia and the Mediter­ ranean. α-Thalassemia has almost reached fixation (frequency has reached 100% in the population) in some parts of southern Asia, with 80% to 90% of the population being carriers [9–11]. The thalassemias are more common in areas where falciparum malaria has been wide­ spread and endemic, possibly conferring a protective advantage in ma­ larial environments [12–16]. The total burden of thalassemia on economic and healthcare systems is not currently known but is under­ stood to be increasing, not only in countries with high prevalence where more patients are surviving and living longer lives , but also where prevalence is increasing due to immigration and demographic transi­ tions [3,18]. Although there are significant gaps in our knowledge of the prevalence and health burden of α-thalassemia, the increasing speed and decreasing cost of genetic testing and other screening methods may aid in the goal of treatment and future prevention. Of the hemoglobinopathies, α-thalassemia, with its complex muta­ tions, is particularly challenging to clinicians. Clinically diverse forms of the disease present across a wide spectrum of phenotypes, ranging from asymptomatic or mild carrier states to severe, transfusion-dependent or lethal types, with a broad range of clinical manifestations in between. * Corresponding author at: Medicine, Hematology & Oncology, Naef K. Basile Cancer Institute, Research, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 11-0236, Beirut 11072020, Lebanon. E-mail address: [email protected] (A.T. Taher). https://doi.org/10.1016/j.blre.2023.101165 Available online 3 January 2024 0268-960X/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/). Please cite this article as: Khaled M. Musallam et al., Blood Reviews, https://doi.org/10.1016/j.blre.2023.101165 K.M. Musallam et al. Blood Reviews xxx (xxxx) xxx This overview aims to describe the disease and its various manifestations to clinicians who practice in regions where it is relatively rare. We re­ view the molecular genetics and genotype/phenotype correlations to establish a firm knowledge base and promote the recognition, differ­ ential diagnosis, counseling, and clinical management of α-thalassemia. New information regarding emerging therapies and agents in develop­ ment is also provided. It is worth noting that overall, evidence-based observations in α-thalassemia are relatively limited, with several as­ pects of diagnosis and management extrapolated from studies of β-thalassemia. In this review, we use our experience in treating the disease over the past few decades to fill such evidence gaps. 2. Molecular understanding 2.1. Molecular genetics of normal hemoglobin Human Hb synthesis is directed by an α-globin gene cluster (con­ taining 1 embryonic ζ gene and a linked pair of fetal/adult α genes) located on chromosome 16 and a β-globin gene cluster containing 1 embryonic ε gene, 2 embryonic/fetal γ genes, and the adult δ and β genes (1 each) located on chromosome 11 (Fig. 1A) [19–22]. 2.2. Normal hemoglobin synthesis Hemoglobin is a tetrameric protein consisting of 2 homodimers of globin subunits, each comprising a globin chain conjugated with a heme moiety having a liganded iron atom at the center that binds one oxygen A B C Fig. 1. Human globin synthesis. (A) Chromosomal location and organization of the α- and β-globin gene clusters. The α- and β-globin gene clusters are located on chromosomes 16p13.3 and 11p15.4, respectively. The ζ-globin, α2-globin, and α1-globin genes are driven by 4 conserved enhancer elements (MCS-R1 through MCSR4), and the ε-globin, γ1-globin, γ2-globin, δ-globin, and β-globin genes are driven by an enhancer cluster, the locus control region (βLCR). Adapted from Farashi S, et al. Blood Cells Mol Dis 2018;70:43–53 with kind permission from Elsevier. (B) Hemoglobin switching at the α- and β-globin loci. During primitive erythropoiesis in the yolk sac, the embryonic ζ-globin (from the α-globin locus) and ε-globin (from the β-globin locus) genes are expressed until approximately 8 weeks’ gestation, when these genes are silenced and there is a maturational switch to α- and γ-globin expression during fetal life. A second switch from γ- to β-globin occurs at birth. Embryonic Hb (ζ2γ2 [Hb Portland], ζ2ε2 [Hb Gower 1], and α2ε2 [Hb Gower 2]) is produced through the yolk sac stage of development, when ζ- and ε-globin chain production stop, resulting in the formation of fetal Hb (α2γ2 [HbF]). As the fetus approaches birth, γ-globin production slowly decreases as β-globin production increases. Shortly after birth, β- and δ-globin production have replaced γ-globin production, resulting in the production of adult Hb (α2β2 [HbA1] and α2δ2 [HbA2]). This figure was first published in Bunn HF, et al. Human Hemoglobins. Philadelphia, PA: WB Saunders; 1977; adapted with kind permission from Elsevier. (C) Deletion or inactivation of one of the α-globin genes in a linked pair is designated α+-thalassemia. α+-Thalassemia is “heterozygous” when on only one of the two chromosome 16 and “homozygous” when on both. Deletion or inactivation of both α-globin genes in a linked pair on the same chromosome 16 is referred to as α0thalassemia. Abbreviations: βLCR, β-locus control region; Hb, hemoglobin; α1, fetal/adult α-gene 1; α2, fetal/adult α-gene 2; β, postnatal β-gene; δ, postnatal δ-gene; ε, embryonic ε-gene; γ1, embryonic/fetal γ-gene 1; γ2, embryonic/fetal γ-gene 2; ζ, embryonic ζ-gene; MCS, multispecies conserved sequence. 2 K.M. Musallam et al. Blood Reviews xxx (xxxx) xxx molecule [19,22,23]. Expression of human globin genes switches during transition from embryo to fetus to adult (Fig. 1B) [24,25]. Thus, the composition of Hb tetramers also changes from embryonic hemoglobins ζ2γ2 (Hb Portland), ζ2ε2 (Hb Gower 1), and α2ε2 (Hb Gower 2) embryonic Hb; to α2γ2 (HbF) fetal Hb; and then to α2β2 (HbA1) and α2δ2 (HbA2) adult Hb. The usual proportion of Hb types in normal adults is 95% to 98% HbA1 (α2β2), 2% to 3% HbA2 (α2δ2), and < 2% HbF (α2γ2) [17,26,27]. reduced red cell survival and a varying degree of hemolytic anemia [33,34]. The amount of α-globin produced impacts the amount of β-globin or γ-globin available to form HbH or Hb Barts. Newborns who inherit HbH disease (one functional α-globin gene) have 20% to 40% of Hb Barts at birth [32,35]. 3.2. Clinical forms and definitions α-Thalassemia presents in 3 carrier states (heterozygous or homo­ zygous α+- and α0-thalassemia) and 2 clinically relevant forms (HbH disease and Hb Barts hydrops fetalis syndrome; Fig. 2). Persons with heterozygous α+-thalassemia (silent carrier or α-thalassemia minima; 3 functional genes) are either clinically silent (asymptomatic, with normal red cell parameters, and normal HbA and HbF) or show normal HbA and HbF with mild hematological changes (eg, mild anemia with low mean corpuscular volume [MCV]) [27,36,37]. Persons with α0-thalassemia or homozygous α+-thalassemia (α-thalassemia trait or α-thalassemia minor; 2 functional genes) are usually asymptomatic but have a mild microcytic anemia with normal proportions of HbA and HbF, depending on the amount of α-globin produced [27,37]. Individuals with HbH disease (α-thalassemia intermedia; 1 func­ tional gene) have considerable variability in clinical severity that cor­ relates with the type of mutation and extent of α-globin deficit [36,38,39]. When the disease stems from α-globin gene deletions (termed deletional HbH), anemia is mild to moderate and may require intermittent blood transfusions during periods of stress-induced hemo­ lysis [38,40]. Studies in China, Canada, and California have shown that >50% of patients with HbH disease have deletional mutations [40–42]. When the genotype involves a nondeletional mutation, (termed non­ deletional HbH), the disease is often associated with an earlier and more serious phenotype, with profound microcytic anemia with hypochromia (often in utero); low absolute amounts of HbA and HbF; and transfusion dependence and the need for regular iron chelation [38,40–43]. The most common nondeletional HbH genotype is Hb Constant Spring (HbCS; − − / αCS α) due to a mutation in the termination codon of the α2globin gene that creates an unstable mRNA transcript. Any globin translated from this mRNA is unstable because of translation read­ through [44–46]. Recently, scoring systems have been proposed that may help eval­ uate HbH disease severity and support making treatment decisions in clinical practice [47,48]. In the first, the final validated scoring system comprised age at diagnosis 800 μg/L (and corresponding LIC >5 mg/g) have been associated with increased he­ patic, endocrine, and vascular morbidity and with increased mortality in NTD β-thalassemia and are used to flag the need for iron chelation therapy [106–109]. Similar associations between elevated serum ferritin and LIC and hepatic disease have also been observed in patients with HbH disease [97,110], though the prevalence of iron overload in NTD α-thalassemia is likely much lower than in NTD β-thalassemia because of the lower degree of ineffective erythropoiesis. Evaluating serial serum ferritin levels is the easiest and most widely available way to assess iron overload; however, results may be affected by factors beyond body iron stores, such as hemolysis, ascorbate defi­ ciency, inflammation, and liver disease. When available, assess­ ment of LIC and cardiac T* by noninvasive MRI techniques can provide valuable information on hepatic and cardiac iron overload and are strongly recommended to allow tailoring of iron chelation therapy. Recommendations for the monitoring (and management, see later sec­ tion [Iron Chelation]) of iron overload in patients with HbH disease are summarized in Fig. 4. 7.4. Specific morbidities Several complications linked to chronic anemia and ineffective erythropoiesis include hyperhemolysis, endocrinopathies (especially diabetes mellitus) and bone disease, cardiovascular disease, chronic leg ulcers, liver complications, gallstones, and EMH. 7.4.1. Hyperhemolysis Although most patients with HbH disease remain clinically healthy without regular transfusions, sporadic episodes of hyperhemolysis requiring RBC transfusions may occur. Hyperhemolysis leading to se­ vere anemia may be triggered by acute infection and high fever, or other stressors such as surgery. Hb levels may rapidly drop to as low as ≤3 g/dL , accompanied by hemoglobinemia and hemoglobinuria (intravascular hemolysis) and resulting in renal damage and insuffi­ ciency, and ultimately acute renal failure. Patients must therefore be continually monitored, especially during acute infections and py­ rexia, oxidative stress, hypersplenism, or pregnancy. 7.4.2. Endocrinopathies and bone disease The medullary expansion that follows from ineffective erythropoiesis leads to many of the bone complications observed in children and adults with thalassemia, including bone deformities and osteoporosis [75,76,113]. In addition, an association between iron overload and growth retardation, delayed sexual development, and endocrinopathies has been well established in patients with TD β-thalassemia [113–116]. A study of 361 TCRN patients with any thalassemia syndrome showed Fig. 4. Monitoring and management of anemia and iron overload in hemoglobin H disease. Common adverse events for iron chelators include: DFO, ocular and auditory symptoms, bone-growth retardation, local reactions, and allergy; DFP, gastrointestinal symptoms, arthralgia, agranulocytosis, and neutropenia; DFX, gastrointestinal symptoms, increased creatinine levels, and increased hepatic enzyme levels. Adherence should be regularly monitored in all patients on iron che­ lation. Abbreviations: AEs, adverse events; DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox; Hb, hemoglobin; LIC, liver iron concentration in mg/g; mo, months; SF, serum ferritin in μg/L; Q, every. 9 K.M. Musallam et al. Blood Reviews xxx (xxxx) xxx that 60% to 75% of adult patients showed reduced bone mass for their age. In addition, many patients aged 20 to 30 years who may not yet have attained peak bone mass, had early onset of osteopenia and osteoporosis, especially those dependent on transfusions. Estimated mean (95% confidence interval) spine bone mineral density (BMD) Zscores of a 20 year old with deletional and nondeletional HbH disease were − 1.64 (− 2.16,− 1.11) and − 2.00 (− 2.52,− 1.49), respectively, indicating suboptimal peak bone mass. High osteoporosis rates were also observed in a single-center, prospective study of patients with NTDT in Thailand (26.3%). Once again, most of the data are from patients with β-thalassemia and data specific to α-thalassemia are relatively sparse. An analysis in Guangxi Province, China of 200 children with HbH disease (deletional and nondeletional) aged 3 to 12 years showed that 68.5% of patients had growth retardation, 84.0% hypogonadism, 14.5% hypoparathyroidism, 13% hypothyroidism, and 7% diabetes mellitus, all significantly more prevalent compared with age-matched normal controls (p ≤ 0.001). A prospective study in Thailand of 57 adult patients with NTDT aged 18 to 74 years (59.6% β-thalassemia and 40.4% HbH disease) showed that in patients with HbH disease (n = 23), 13.0% had osteo­ porosis, 4.3% hypogonadism, and 4.3% diabetes mellitus. In Thailand, 40 children, adolescents, and young adults aged 10 to 25 years with HbH disease (nondeletional n = 17; deletional n = 23) were fol­ lowed for 2 years. There was a high prevalence of patients (52.5%) with an abnormal insulinogenic index, which indicated abnormal early-phase insulin secretion from β-cells, with no significant difference between nondeletional and deletional HbH disease. with thalassemia [52,53,97,110]. Moreover, hepatitis B or C are inde­ pendent risk factors, which together with iron overload can hasten progression, even leading to the development of hepatocellular carci­ noma. Liver disease is recently regarded as a major cause of mor­ tality in both NTDT and TDT patients, especially those not receiving adequate iron chelation therapy [122–124]. 7.4.5. Gallstones Approximately 38% to 52% of patients with HbH disease have “silent gallstones” [45,110]. These patients may develop acute and/or chronic cholecystitis (with or without known gallstones), which is very difficult to diagnose based on clinical symptoms alone. Gallstone formation is a factor of the degree of anemia and hemolysis. Patients with thalassemia (including those with HbH disease) who present with “peptic ulcer–like” symptoms should be referred for ultrasonography if symptoms do not dissipate with treatment [52,135]. Patients with HbH disease who are homozygotes or double heterozygotes for Gilbert alleles have a significantly increased risk of gallstones and jaundice. 7.4.6. Leg ulcers Leg ulcers are a painful and indolent complication of NTDT , which are attributed to chronic hypoxia, local iron overload deposits, and hypercoagulability-related ischemia; they may increase disability and disrupt quality of life. 7.4.7. Extramedullary hematopoiesis Extramedullary hematopoiesis is common in patients with thalas­ semia not requiring regular transfusions (NTDT]) [76,138]. It is thought that >80% of EMH cases may remain asymptomatic, with pseudotumors discovered only incidentally by radiologic techniques. A 3-year case-control study showed that of 17 patients with HbH disease enrolled and screened by computed tomography or MRI, 47% had EMH pseudotumors. In other observational studies, prevalence rates were lower than those reported in β-thalassemia and ranged between 0 and 8% [110,140,141]. Although different anatomical locations may be involved, paraspinal involvement is most concerning due to poten­ tially debilitating permanent clinical consequences secondary to spinal cord compression. EMH in the spleen and liver can lead to hep­ atosplenomegaly , which is more common in nondeletional HbH disease. 7.4.3. Cardiovascular disease Cardiomyopathy and arrhythmias are the main consequences of cardiac iron overload in patients with TDT, especially those reaching serum ferritin values >2500 μg/L and cardiac T2* values 5 mg/g considering iron-related morbidity and mortality above these thresholds (starting age of 10 years, or higher in HbH disease). In a small study of 17 patients with HbH disease who were not transfusion dependent, treatment with DFP significantly decreased serum ferritin levels after 6 months and 18 months of treat­ ment, and this decrease was maintained until 24 months. The first study to investigate a chelating agent in a large cohort of patients with NTDT was the THALASSA (Assessment of Exjade in NonTransfusionDependent Thalassemia) trial (2008–2011; reported in 2012). In this phase 2, prospective, randomized, double-blind, placebo-controlled trial, the efficacy and safety of DFX were evaluated in 166 patients ≥10 years of age with NTDT and iron overload, including 22 patients with α-thalassemia. At 1 year, both LIC and serum ferritin levels decreased significantly with DFX treatment compared with placebo, with re­ ductions notably seen in α-thalassemia patients receiving dispersible tablet doses as low 5 mg/kg/day. The frequency of adverse events (AEs) in patients receiving DFX was similar to placebo. The most com­ mon drug-related AEs were nausea (6.6%), rash (4.8%), and diarrhea (3.6%). The study also included a preplanned, 1-year, open-label extension phase. Here, LIC continued to decrease, and almost 40% of patients achieved LIC 60% of women carrying a fetus with Hb Barts hydrops fetalis syndrome develop hypertension during the pregnancy, 30% develop severe preeclampsia, and 11% develop antepartum hemorrhage [204,206]. Other serious complications may include worsening anemia, premature labor, placental abruption, oligohydramnios, potential miscarriage, renal failure, and congestive heart failure [205–208]. Postpartum complications can include retained placenta, hemorrhage, life-threatening hypertension, puerperal pyrexia, and anemia [209–211]. Thus, patients should be carefully monitored for these issues throughout the pregnancy and after delivery. 10.2. Intrauterine allogeneic stem cell transplantation Intrauterine allogeneic stem cell transplantation is currently an experimental approach that attempts to exploit the bidirectional maternal-fetal tolerance during pregnancy to correct the anemia before the baby is born. A single-center, non-randomized study (NCT02986698) enrolled fetuses with Hb Barts hydrops fetalis syn­ drome between 18 and 26 weeks’ gestation diagnosed by chorionic villus sampling, amniocentesis, cordocentesis, or by identification of parents as genetic carriers, and identification of fetal anemia or signs of impending hydrops without a second major anatomic anomaly (not related to thalassemia). Fetuses underwent a single intrauterine 9.4. Pregnancy in patients with HbH disease Key aspects of monitoring and management of pregnancy in patients with HbH disease are summarized in Table 1. 13 K.M. Musallam et al. Blood Reviews xxx (xxxx) xxx infusion of CD34+ cells from 300 mL of maternal marrow, followed by intrauterine red cell transfusion every 3 weeks. Two patients have un­ dergone this procedure thus far. Both had low levels of engraftment. One patient showed reactivity against maternal antigens, while the other was offered but declined booster transplant. Practice points In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic ane­ mia, iron overload, and associated short- and long-term complications. There is a direct correlation between a patient’s genotype (number of α-globin genes affected, with deletional or nondeletional mutations) and severity of clinical phenotype. Blood transfusion is the only available intervention for patients with symptomatic anemia, while iron chelation therapy is indicated in patients with evidence of iron overload (due to increased intestinal absorption or regular transfusion therapy). 10.3. Gene therapy Early clinical studies are evaluating the safety and efficacy of autologous HSCT using autologous CD34+ HSCs transduced with a lentiviral vector encoding the human α-globin gene for treating transfusion-dependent patients with α-thalassemia (HGI-002 [NCT05851105]; GMCN-508 A [NCT05757245]). Research agenda 10.3.1. Disease modifying agents Mitapivat is an oral, small-molecule allosteric activator of the RBCspecific form of pyruvate kinase (PK) that leads to increased adenosine triphosphate (ATP) production in RBCs and improves their survival in thalassemia mouse models [213–215]. Mitapivat is approved in the US for the treatment of hemolytic anemia in adults with PK deficiency and in the EU for the treatment of PK deficiency in adult patients. In an openlabel, multicenter phase 2 study, 20 patients with NTDT (α-thalassemia, n = 5; β-thalassemia, n = 15) and Hb levels ≤10 g/dL received mitapivat 50 mg twice daily for 6 weeks and then 100 mg twice daily for 18 weeks ; 80% (p < 0.0001) showed a Hb response, defined as Hb levels increasing ≥1.0 g/dL from baseline at ≥1 assessments between weeks 4 and 12, inclusive. An Hb response was observed in all 5 patients with α-thalassemia. Improvements in markers of hemolysis and inef­ fective erythropoiesis were also seen. Mitapivat was well tolerated in this study, and global phase 3 trials of mitapivat for treating adults with TD α-thalassemia and β-thalassemia (ENERGIZE-T; NCT04770779) and NTD α-thalassemia and β-thalassemia (ENERGIZE; NCT04770753) are ongoing. The efficacy and safety of another PK activator, etavopivat, is currently being studied in patients with α-thalassemia, β-thalassemia, or sickle cell disease in a phase 2 trial (NCT04987489). As a result of ineffective erythropoiesis, hepcidin expression is sup­ pressed through various erythroid factors, resulting in increased iron absorption and primary iron overload [216,217]. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6). Theoretically, inhibition of TMPRSS6 expression could increase hepci­ din production and reduce anemia and iron overload. A phase 1 single-dose study of a small interfering RNA (siRNA) conjugate (SLN124) optimized for hepatic targeting of TMPRSS6 is being con­ ducted in adults with NTD α-thalassemia and β-thalassemia (NCT04718844). Luspatercept, a recombinant fusion protein comprising a modified extracellular domain of activin receptor type IIB fused to the FC domain of human IgG1, is an erythroid maturation agent (ie, affects late-stage erythropoiesis) approved to treat anemia secondary to β-thalassemia in adult patients requiring regular RBC transfusions (US and EU) as well as those with NTD β-thalassemia (EU) [220–222]. The efficacy and safety of luspatercept in adult patients with HbH disease is presently being studied in a multinational phase 2 clinical trial (NCT05664737). Development of local disease registries to inform epidemiology. Establishment of collaborative longitudinal cohorts to evaluate dis­ ease outcomes, treatment patterns, and risk factors for morbidity and mortality. Development of novel therapies targeting the underlying genetic anomaly or the ineffective erythropoiesis. Author contributions All authors contributed to manuscript conceptualization, critical review of all drafts, and provision of suggestions on the scientific con­ tent. The authors retained full editorial control and provided final approval on all content. Role of funding source Medical writing and editorial support were provided by Symbiotix, LLC, and funded by Agios Pharmaceuticals. Data sharing and data availability Data sharing is not applicable to this article as no new data were created or analyzed in this review. Declaration of competing interest K.M.M. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Phar­ maceuticals and Pharmacosmos. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, and Ionis Phar­ maceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Thera­ peutics, and CRISPR Therapeutics. T.D.C. provides advisory support to Agios Pharma, Bristol Meyers Squibb, and Chiesi. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion Pharmaceuticals, Bristol Myers Squibb, Forma Therapeutics, Pfizer, NovoNordisk, and Vertex Pharmaceuticals; honoraria from Agios Pharmaceuticals and Bristol Myers Squibb; membership on an advisory committee for Bio­ verativ/Sanofi/Sangamo; and research funding from Agios Pharma­ ceuticals and Pfizer. H.A-S. reports consultancy fees from Novartis, Forma Therapeutics, Agios Pharmaceuticals, argenx, Moderna, Phar­ macosmos, and Sobi; and research funding from Agios Pharmaceuticals, Amgen, Sobi, Novartis, and Vaderis Therapeutics. S.S. reports consul­ tancy fees from Agios Pharmaceuticals, bluebird bio, Fulcrum Thera­ peutics, Chiesi, Celgene Corp (Bristol Myers Squibb), and Vertex; honoraria for CME activities from Plexus, CCO, and Physicians’ Educa­ tion Resource; advisory board travel from Agios Pharmaceuticals, Cel­ gene Corp (Bristol Myers Squibb), and bluebird bio; research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, and 11. Conclusion and future considerations α-Thalassemia is a genetic disorder with complex pathophysiology and multi-organ involvement. There is a need for heightened awareness of α-thalassemia in the medical community so that accurate diagnosis, early intervention to treat complications, and successful management of the condition is achieved. Beyond the treating hematologist or PCP, a multi-disciplinary team of experts is needed for monitoring and to deal with emerging complications in vital organs. Collaborative research efforts are also needed to establish the evidence-base on disease epide­ miology and unmet needs, to support the continued development of novel therapies and management approaches. 14 K.M. Musallam et al. Blood Reviews xxx (xxxx) xxx Forma Therapeutics; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. V.V. reports consultancy fees from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., and DisperSol Technologies, LLC; and research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., DisperSol Tech­ nologies, LLC, and The Government Pharmaceutical Organization (GPO). 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