ABSTRACT:Iron overload is a significant cause of transfusion-related morbidity and mortality. Deferiprone (DFP) is an established oral iron chelator approved for the treatment of transfusional iron overload in patients with thalassemia, sickle cell disease (SCD), or other anemias. Although DFP was initially approved as a thrice daily formulation, a twice daily formulation was developed to improve patients' treatment adherence. Here, we assess the safety of DFP twice daily in patients with thalassemia, SCD, or other anemias in real-world clinical practice in the United States. Data for patients referred for DFP twice daily between 1 July 2020 and 31 August 2023 were obtained from the Ferriprox Total Care Registry. The frequencies of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and fatal outcomes were assessed. Of the 425 patients referred to the registry, 348 received ≥1 DFP shipment, and was designated the safety analysis group. The primary diagnosis was a thalassemia syndrome in 129, SCD in 189, and other anemia in 30 patients. Mean (standard deviation) DFP exposure was 343.0 (281.9) days. In total, 1021 AEs and 369 SAEs were reported. As seen with the thrice daily formulation, the most common AEs associated with DFP twice daily were predominantly gastrointestinal or related to underlying disease. Cases of neutropenia and agranulocytosis were rare, reported in 1.7% and 0.6% of patients, respectively, and all cases recovered. None of the 26 fatal outcomes reported were assessed as related to DFP treatment. DFP twice daily was well tolerated in real-world clinical practice, and its safety profile was consistent with DFP thrice daily. No new safety concerns were observed.

Background Treatments to reduce red blood cell (RBC) transfusion burden among patients with transfusion-dependent f3-thalassaemia remain limited. Here, we report long-term follow-up data from the phase 3 BELIEVE trial of luspatercept for transfusion-dependent f3-thalassaemia. Methods BELIEVE was a phase 3, randomised, double-blind, placebo-controlled study performed at 65 sites in 15 countries. The trial included adults with transfusion-dependent f3-thalassaemia or haemoglobin E/f3-thalassaemia and Eastern Cooperative Oncology Group score of 0-1. Patients were randomly assigned (2:1) using integrated response technology stratified by region to luspatercept (10-125 mg/kg) or placebo administered subcutaneously once every 21 days. After study unblinding, patients could receive luspatercept in the open-label extension phase (crossover allowed). The primary endpoint results (proportion of patients with reduction in transfusion burden of >= 33% and >= 2 RBC units during weeks 13-24) are described elsewhere; herein we present an update to the primary endpoint analysis consequent to late-reported transfusion events. We also report long-term efficacy (intention-to-treat population) and safety data (safety population) for patients followed up for approximately 3 years. This trial is registered on ClinicalTrials.gov (NCT02604433) and is completed. Findings Between May 2, 2016, and May 16, 2017, 336 patients were randomly assigned to luspatercept (n=224) or placebo (n=112). The median age of patients was 30 years (IQR 23-40); 195 (58%) were female and 141 (42%) male. As of Jan 5, 2021, the median duration of treatment in the luspatercept group was 1536 weeks (IQR 810-1710) and median study follow-up was 1631 weeks (1405-1762). Due to the difference in treatment duration between the luspatercept and placebo groups, no comparative analyses between the two groups were performed after week 96. Patients in the luspatercept group showed a sustained reduction in RBC transfusion burden from baseline through week 192, with mean decreases of 62 RBC units (SD 57) during weeks 97-144 and 64 RBC units (43) during weeks 145-192. In the luspatercept group, a 33% or greater reduction in transfusion burden from baseline was observed in 173 (77%) patients over any 12-week interval and in 116 (52%) patients over any 24-week interval. The median total duration of 33% or greater transfusion burden reduction response during any period of at least 12 weeks was 5860 days (IQR 2640-10100). The most common grade 3 or worse treatment- emergent adverse events (TEAEs) among all patients who received luspatercept (n=315, including 92 patients who crossed over after study unblinding) were anaemia (nine [3%]), increased liver iron concentration (seven [2%]), and bone pain (seven [2%]); serious TEAEs occurred in 71 (23%) patients. No treatment-related deaths occurred in any group during the study. Interpretation These long-term results affirm luspatercept's efficacy in addressing key unmet needs of patients with transfusion-dependent f3-thalassaemia with a manageable safety profile. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

ABSTRACT:Before the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major, and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, noninvasive monitoring of organ-specific iron loading in humans, and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron, which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

Our understanding of the molecular pathways and associated clinical presentations characterizing various thalassemia phenotypes has substantially improved over the years. Non-transfusion-dependent thalassemia (NTDT) refers to patients who present with mild–moderate anemia, which does not necessitate lifelong, regular transfusion therapy. This typically includes patients with β-thalassemia intermedia, mild–moderate hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease) (Figure 1) [1-7]. The underlying α/non-α globin chain imbalance and subsequent ineffective erythropoiesis and peripheral hemolysis lead to chronic anemia, primary iron overload, and a hypercoagulable state. These, in turn, are associated with a range of clinical morbidities that can impact quality of life and lead to premature death (Figure 2) [2, 8-22]. In view of the growing evidence on the negative impact of untreated anemia in these patients, long-term management becomes key. However, the only options that have been available so far include transfusions which can worsen iron overload and introduce transfusion-dependence burden, off-label use of hydroxyurea based on data from small trials or observational studies, and splenectomy which is associated with increased risks of infections and thrombosis (Figure 3) [6, 9, 23, 24]. Beyond anemia, cumulative iron overload due to increased intestinal iron absorption needs to be regularly monitored and managed with iron chelation therapy. Multimorbidity in NTDT also requires close monitoring and early intervention through a multidisciplinary team approach (Figure 4) [2, 6, 25-27]. In the last decade, we have witnessed several novel agents being developed to manage anemia in NTDT. Agents targeting hepcidin dysregulation have not been successful in clinical trials, despite encouraging data in animal models. Luspatercept, an erythroid maturation agent, showed efficacy in improving hemoglobin level in adults with β-NTDT and is now approved in Europe (but not the United States). Mitapivat, a pyruvate kinase activator, has also shown efficacy in improving hemoglobin level and functional status in a recent phase 3 trials in adult patients with both α- and β-NTDT (Figure 5) [24, 28-30]. Clinical management guidelines are now available, but awareness of the various morbidities and treatment options in NTDT, especially among patients remains essential (a patient friendly summary is provided in the Appendix S1). All authors contributed to conceptualization and manuscript drafting or critical review. K.M.M. was also involved in the creation of visualizations. All authors validated the manuscript and gave final approval for submission. The authors thank Dr. Yuva Oz of Art 4 Science, Amsterdam, the Netherlands for providing creative support, which was funded by Agios Pharmaceuticals Inc., Cambridge (MA), USA. Ethics approval not applicable as no patients were involved in this work. K.M.M. reports consultancy fees from Novartis, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, Novo Nordisk, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. S.S. reports consultancy fees from Agios Pharmaceuticals, Bristol Myers Squibb, and Novo Nordisk; being a member of a clinical trial steering committee for Vertex Pharmaceuticals; and research funding (for clinical trials) from Agios Pharmaceuticals, Bristol Myers Squibb, Novo Nordisk, and Regeneron. T.D.C. reports advisory support to Agios Pharmaceuticals, Bristol Myers Squibb, and Chiesi. H.A.-S. reports consultancy fees from Agios Pharmaceuticals, Alnylam, Alpine, Amgen, argenx, Novartis, Pharmacosmos, and Sobi; and research funding to institution from Agios Pharmaceuticals, Amgen, Novartis, Sobi, and Vaderis. M.D.C. reports consultancy fees from Novartis, Bristol Myers Squibb (Celgene Corp), Vifor Pharma, and Vertex Pharmaceuticals; and research funding from Novartis, Bristol Myers Squibb (Celgene Corp), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. K.H.M.K. reports grants from Agios Pharmaceuticals and Pfizer; consulting fees from Agios Pharmaceuticals, Alexion Pharmaceuticals, Biossil, Bristol Myers Squibb, Forma, Novo Nordisk, Pfizer, and Vertex Therapeutics; honoraria from Agios Pharmaceuticals and Bristol Myers Squibb; and being on a data safety monitoring board/advisory board for Sangamo. V.V. reports grants from Agios Pharmaceuticals, Bristol Myers Squibb (Celgene Corp), DisperSol Technologies, IONIS Pharmaceuticals, Novartis, Pharmacosmos, The Government Pharmaceutical Organisation, and Vifor; and consulting fees from Agios Pharmaceuticals, Bristol Myers Squibb (Celgene Corp), DisperSol Technologies, IONIS Pharmaceuticals, Novartis, Pharmacosmos, and Vifor. A.T.T. reports consultancy fees from Novo Nordisk, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, Pharmacosmos, and Roche; and research funding from Novo Nordisk, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, Pharmacosmos, and Roche. Data S1 Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Introduction: β-thalassemia is characterized by ineffective erythropoiesis leading to chronic anemia. Although patients with non-transfusion-dependent (NTD) β-thalassemia usually require fewer red blood cell (RBC) transfusions than patients who are transfusion-dependent (TD), the underlying ineffective erythropoiesis and related anemia, bone marrow expansion, and iron overload lead to multiple complications. In pediatric patients who are NTD, RBC transfusions are typically needed only during specific circumstances, such as infections and to support growth. There remains an unmet need among pediatric patients with NTD β-thalassemia for treatments that maintain hemoglobin levels in order to optimize early treatment and prevent or reduce the risk of subsequent serious or irreversible morbidities as patients enter adulthood. Luspatercept has been shown to durably increase hemoglobin levels and reduce transfusion burden in adult patients with NTD and TD β-thalassemia, respectively. Results from a phase 2a study of the safety and pharmacokinetics of luspatercept in pediatric patients with β-thalassemia (NCT04143724; EudraCT 2022-502499-22-00) showed that the safety profile in pediatric patients who are TD is consistent with that observed in adults (Kattamis A., et al. HemaSphere 2024;8[S1]:2804–2805). Here we present safety data from the NTD dose-confirmation cohort of the study. Methods: This ongoing phase 2a study has a staggered design conducted in 2 parts for patients 12 to <18 years of age (part A) and 6 to <12 years of age (part B); both parts include separate NTD and TD cohorts. This analysis focused on the NTD dose-confirmation cohort of part A. The treatment of pediatric patients with NTD β-thalassemia is evaluated at sites outside of the United States; study locations include China, Germany, Greece, India, Italy, Thailand, and Türkiye. Patients eligible for inclusion in this cohort were 12 to <18 years of age with NTD β-thalassemia, defined as receiving <4 RBC transfusions in the 24 weeks pre-enrollment, not on a regular transfusion program, being RBC transfusion-free for ≥8 weeks pre-enrollment, and having a mean baseline hemoglobin level of ≤10 g/dL. Patients received luspatercept at 1.0 mg/kg subcutaneously once every 3 weeks for 4 cycles to confirm that the dose is safe and well tolerated in adolescent patients with NTD β-thalassemia. Results: As of June 9, 2025, 3 patients from Italy, China, and Thailand had been enrolled in the dose-confirmation cohort. Patients had a median age of 13 years (range, 12–17); 1 patient (33.3%) was female and 2 (66.7%) were male; and 1 patient (33.3%) was White and 2 (66.7%) were Asian. One patient (33.3%) had hemoglobin E/β-thalassemia combined with α-thalassemia and 2 had β-thalassemia (1 with an α-gene triplication). Median baseline hemoglobin level was 7.8 g/dL (range, 6.7–8.6); 2 patients had liver iron concentration (LIC) <3 mg/g dry weight (dw) and 1 had LIC >7 to ≤15 mg/g dw. No patients had received iron chelation therapy or had a splenectomy. Baseline performance status was evaluated using the Karnofsky (1 patient) and Lansky (2 patients) performance scales; performance status scores were 100, 90, and 100, respectively. Two patients had ≥1 comorbidity: 1 had splenomegaly and osteopenia and 1 had splenomegaly, iron overload, and growth retardation. Median treatment duration was 184 days (range, 127–237) and patients had received a median of 7 doses (range, 6–9) of luspatercept. One patient experienced a dose delay at day 84 due to a hemoglobin level of ≥11.5 g/dL. All 3 patients experienced at least 1 treatment-emergent adverse event (TEAE); reported TEAEs were upper respiratory tract infection, gastroenteritis, abdominal pain, toothache, oropharyngeal pain, influenza-like illness, hyperuricemia, and headache (each reported by 1 patient). One patient experienced a grade 3/4 TEAE of gastroenteritis. No serious TEAEs, grade 5 TEAEs, TEAEs leading to dose delay, or TEAEs suspected to be related to treatment were reported. Conclusions: Safety data from pediatric patients with NTD β-thalassemia who have received luspatercept 1.0 mg/kg indicate no new safety signals and no patients experiencing serious TEAEs or dose-limiting toxicities, consistent with previous results from the pediatric TD cohort at the same dose. TEAEs were generally non-hematologic in nature and considered not related to luspatercept treatment. Recruitment is ongoing for the part A NTD dose-expansion cohort.

ABSTRACT:Chronic anemia due to non-transfusion-dependent β-thalassemia (NTDT) can result in clinical morbidities, particularly with inadequate management. Luspatercept was previously shown to improve hemoglobin levels in patients with NTDT in the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (ClinicalTrials.gov identifier: NCT03342404). Here, we report long-term efficacy and safety results from the final analysis of BEYOND spanning an additional 26 months (∼2.2 years) of follow-up. Median treatment duration was 202.8 weeks for luspatercept and 61.1 weeks for placebo. Overall, 94.8% and 22.4% of patients in the luspatercept and placebo arms, respectively, achieved a mean hemoglobin increase from baseline ≥1.0 g/dL during any 12-week interval, with mean durations of response of 1136.0 and 203.3 days, respectively. Patient-reported tiredness and weakness showed sustained improvement with luspatercept treatment. The most common treatment-emergent adverse events in the luspatercept group were headache (45.8% vs 20.4% with placebo), bone pain (43.8% vs 6.1%), back pain (39.6% vs 12.2%), and arthralgia (38.5% vs 16.3%). Treatment-emergent extramedullary hematopoiesis events were reported in 12 (9.0%) and 2 (4.1%) patients receiving luspatercept and placebo, respectively, although differences in treatment exposures prevented informative comparisons. Of the 4 patients receiving luspatercept who reported thromboembolic events, all had >1 risk factor. These results show that luspatercept led to a sustained increase in hemoglobin levels in patients with NTDT for up to ∼4.6 years of treatment, with a consistent safety profile and no new safety findings. Luspatercept is a valuable treatment option for patients with NTDT, addressing the need for effective long-term treatment of anemia. This trial was registered at www.clinicaltrials.gov as #NCT03342404.

BACKGROUND:Chronically transfused patients with sickle cell disease (SCD) and beta thalassemia major (TM) develop iron overload. OBJECTIVE:Determine the impact of iron overload on glucose regulation in SCD. METHODS:Prospective study of 28 patients with SCD and 38 patients with TM who underwent liver and pancreas R2* measurements and oral glucose tolerance tests. RESULTS:Impaired fasting glucose (2 vs. 9, p = 0.27) and impaired glucose tolerance (1 vs. 11, p = 0.019) were less common in patients with SCD compared with patients with TM. No SCD patient had diabetes. CONCLUSION:Iron-mediated glucose dysregulation is present but less common in SCD patients.

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.

Severe aplastic anemia (SAA) is characterized by pancytopenia and is either inherited or acquired (idiopathic). Accurate diagnosis is critical for proper treatment; however, the frequent overlap in clinical presentation between idiopathic SAA and inherited bone marrow failure syndromes (IBMFS) presents diagnostic and management challenges. For patients with idiopathic SAA, immunosuppressive therapy (IST) is considered the standard of care, when there is no available matched related donor. While 70-75% of pediatric patients with SAA respond to IST, patients with IBMFS do not. To our knowledge, there are no published data on a specific age cut-off that predicts a higher likelihood of an inherited disease, to guide treatment with IST or hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate response to IST in children with SAA who are less than 3 years of age and to gain insight into the age below which response to IST is unlikely, suggesting an IBMFS. In a retrospective cohort study, we extracted data of patients diagnosed with SAA between 2002 and 2021 from 3 ethics board-approved multicenter databases: (1) North American Pediatric Aplastic Anemia Consortium (NAPAAC; 2002-2014), (2) Canadian Aplastic Anemia and Myelodysplasia Study (CAMS) and (3) Canadian Inherited Marrow Failure Registry (CIMFR). Patient characteristics, treatment and outcomes were collected. Patients were included if diagnosed with acquired SAA before the age of 3 years and received IST as a first line treatment for at least 3 months. Patients were excluded if they had physical malformations suggestive of an IBMFS, a first-degree relative with a history of bone marrow failure, or insufficient available data. Response rate was compared with published literature on pediatric patients with SAA over the age of 3 years. Descriptive statistics were utilized (SPSS V25). Among 31 patients aged 1.3-2.9 years (median 2.25) treated with IST as a first line therapy for SAA, 13 (42%) were male, 10 (32%) had hepatitis associated SAA, 3 (10%) had mild physical abnormalities (vesicoureteral reflux, patent ductus arteriosus, mild hearing impairment), none had short stature, and 7 (23%) had a family history of cancer (n=4), polycythemia vera (n=1), hyper-eosinophilic syndrome (n=1) or consanguinity (n=1). Twenty-nine patients (93%) were treated with horse anti-thymocyte globulin (ATG) and cyclosporine A (CSA), while 2 (7%) were treated with cyclophosphamide (CTX). Of the 31 patients, 24 (77%) had a complete response (CR) to IST (including the 2 patients post CTX). Twelve (50%), 22 (92%) and 24 (100%) were transfusion independent by 3, 6 and 12 months from the start of IST, respectively. CSA was discontinued after a median time of 20.4 months (range 5.6-55). No relapse was reported during long-term follow up (median 79 months, range 29-233). Seven patients (23%, age 1.95-2.83 years, median 2.44), had no response to a first IST course, 5 of whom received a second IST course with rabbit ATG. Of these 5 patients, 3 (age 1.95, 2.44 and 2.45 years) did not respond to the second IST and underwent HSCT, 1 (age 2.8 years) had a partial response and became transfusion-independent, 1 (age 2.83 years, who had a second IST with tacrolimus) achieved partial response and then switched to danazol with a CR. Two of the 7 patients who did not respond to the first IST did not receive a second IST before transplant; 1 of them (age 2.25 years) had an unsuccessful response to danazol and 1 (age 2.04 years) had no interim treatment. Complications during the first 3 months post IST included infections (bacteremia/sepsis, n=5; cellulitis, n=2; viral gastroenteritis, n=1), gross hematuria (n=1), hypertension (n=4) and gum hyperplasia (n=1). In the 3-6 months post-IST interval, 2 patients had bleeding events (gross hematuria, oral bleed) and 1 had a bacteremia episode. In the 6-12 months post-IST interval, 1 patient had bacteremia, 2 had hypertension and 1 developed a chronic kidney injury secondary to CSA. In conclusion, our study indicates for the first time a high complete response rate of 77% in SAA patients under 3 years of age who were treated with IST, a response rate comparable to what is reported in the literature for IST response in older pediatric patients. Although our study is limited by its retrospective nature and a relatively small cohort, due to the lack of previously published data, this research provides critical insight to help in managing this age group.

Introduction: Transfusions and iron chelators have improved survival and outcomes in transfusion-dependent (TD)-thalassemia. However, they are associated with adverse effects, such as end organ complications and high healthcare resource utilization, and can become a burden for patients (pts), limiting adherence and negatively impacting quality of life. These limitations highlight a need for new agents targeting disease pathophysiology. There are no approved oral disease-modifying therapies for β-thalassemia, and no therapies are approved for α-thalassemia. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase that increases adenosine triphosphate production, which may improve thalassemic red blood cell (RBC) health by addressing their increased cellular energy demands. In a phase 3 trial in non-transfusion-dependent (NTD)-α- or β-thalassemia (ENERGIZE [NCT04770753]), mitapivat significantly improved hemoglobin levels and fatigue vs placebo. Aim: To assess the efficacy and safety of mitapivat vs placebo in adults with TD-α- or β-thalassemia in ENERGIZE-T (NCT04770779). Methods: Adults (≥18 years) with TD-α- or β-thalassemia from 19 countries were randomized 2:1 to mitapivat 100 mg or placebo twice daily for 48 weeks. TD was defined as 6-20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization. Randomization was stratified by thalassemia genotype (β0/β0 and non-β0/β0, including HbE/β-thalassemia and α-thalassemia/HbH) and geographic region. The primary endpoint was transfusion reduction response (TRR, a ≥50% reduction in transfused RBC units and a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline [BL]). Key secondary endpoints were: TRR2, a ≥50% reduction from BL in transfused RBC units in any consecutive 24-week period through Week 48; TRR3, a ≥33% reduction from BL in transfused RBC units in Weeks 13-48; and TRR4, a ≥50% reduction from BL in transfused RBC units in Weeks 13-48. Transfusion independence (TI, transfusion-free for ≥8 consecutive weeks through Week 48) and safety were among the secondary endpoints. Results: A total of 258 pts were randomized (mitapivat: N=171; placebo: N=87); 155 (90.6%) and 83 (95.4%) pts in the mitapivat and placebo arms, respectively, completed the 48-week double-blind period. Overall, mean age was 35.5 years; 70.9% of pts had a 24-week BL transfusion burden of >12 RBC units; and 44.2% had β0/β0 genotype. There was no imbalance in BL characteristics between treatment arms deemed to impact the interpretation of the results. A TRR was achieved in 30.4% of pts in the mitapivat arm vs 12.6% in the placebo arm (2-sided p=0.0003). Statistically significant reductions in transfusion burden for mitapivat vs placebo were also demonstrated by all key secondary endpoints: 13.5% vs 2.3% (2-sided p=0.0003) achieved TRR2; 14.6% vs 1.1% (2-sided p<0.0001) achieved TRR3; and 7.6% vs 1.1% (2-sided p=0.0056) achieved TRR4. Overall results for these endpoints were not driven by any of the individual prespecified subgroups, including genotype and BL transfusion burden. A higher proportion of pts in the mitapivat arm achieved TI (9.9%) vs the placebo arm (1.1%). The proportion of pts with any treatment-emergent adverse events (TEAEs) was similar across treatment arms (mitapivat: 90.1%; placebo: 83.5%). TEAEs occurring in ≥10% of pts on mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhea, and fatigue. Serious TEAEs were reported in 11.0% and 15.3% of pts on mitapivat and placebo, respectively; 2.3% and 1.2%, respectively, were considered treatment-related. Discontinuation due to TEAEs occurred in 5.8% of pts on mitapivat and 1.2% on placebo. Conclusions: In a globally representative population with TD-α- or β-thalassemia, mitapivat vs placebo significantly reduced transfusion burden and demonstrated a durable reduction of up to 36 weeks (Weeks 13-48). Mitapivat was generally safe and well tolerated with a low treatment discontinuation rate. These data, alongside data in NTD-α- or β-thalassemia from ENERGIZE, demonstrate the efficacy of mitapivat across the full range of thalassemia, supporting it as a potential oral disease-modifying therapy.

OBJECTIVE To assess nationally endorsed claims-based quality measures in pediatric sickle cell anemia (SCA). METHODS Using data from the Sickle Cell Data Collection programs in California and Georgia from 2010 to 2019, we evaluated 2 quality measures in individuals with hemoglobin S/S or S/β-zero thalassemia: (1) the proportion of patients aged 3 months to 5 years who were dispensed antibiotic prophylaxis for at least 300 days within each measurement year and (2) the proportion of patients aged 2 to 15 years who received at least 1 transcranial Doppler ultrasound (TCD) within each measurement year. We then evaluated differences by year and tested whether performance on quality measures differed according to demographic and clinical factors. RESULTS Only 22.2% of those in California and 15.5% in Georgia met or exceeded the quality measure for antibiotic prophylaxis, with increased odds associated with rural residence in Georgia (odds ratio 1.61; 95% confidence interval 1.21–2.14) compared with urban residence and a trend toward increased odds associated with a pediatric hematologist prescriber (odds ratio 1.28; 95% confidence interval 0.97, 1.69) compared with a general pediatrician. Approximately one-half of the sample received an annual assessment of stroke risk using TCD (47.4% in California and 52.7% in Georgia), with increased odds each additional year in both states and among younger children. CONCLUSIONS The rates of receipt of recommended antibiotic prophylaxis and annual TCD were low in this sample of children with SCA. These evidence-based quality measures can be tracked over time to help identify policies and practices that maximize survival in SCA.

Objectives:Vaso-occlusive crises (VOCs) are a hallmark symptom of sickle cell disease (SCD). Physical stressors can trigger decreased microvascular blood flow and increase the risk for VOCs. However, the effect of mental and psychological stressors on vascular physiology in SCD is not well-established. We hereby examined fluctuations in continuous blood pressure (BP) to evaluate hemodynamic changes in SCD patients during mental and psychological stress. Methods:Thirteen SCD (HbSS) subjects from the Children's Hospital Los Angeles and 11 healthy (HbAA) volunteers were recruited. Continuous BP was recorded as subjects participated in two mental and one psychological stress tasks. Systolic beat-to-beat BP variability (BPV) measurements were calculated for each subject. Three very short-term BPV metrics served as outcome measures: standard deviation, coefficient of variation, and average real variability. Linear mixed effects models evaluated associations between patient factors and outcome measures. Results:SCD patients were associated with increased systolic BPV and exhibited a distinct increase in BPV in response to psychological stress. All subjects exhibited a decrease in systolic BPV in response to mental stress tasks. During mental stress, both groups displayed increased augmentation index, reflective of stress-induced vasoconstriction, while psychological stress in SCD patients led to both decreased mean arterial pressure and increased AI, suggestive of uncompensated vasoconstriction. Conclusion:These findings emphasize the impact of mental and psychological stressors on vascular function in SCD, the potential for monitoring physiological signals to predict VOC events, and the importance of counseling SCD patients on lifestyle practices to reduce their stress to prevent pain.

Germline variants of the RUNX1 gene are associated with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (RUNX1-FPDMM), which is characterized by an increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. Patients with FPDMM have also been described to develop B- or T-cell acute lymphoblastic leukemia. We present a pediatric patient with RUNX1-FPDMM that evolved into concurrent MDS and T-cell acute lymphoblastic leukemia after a decade of monitoring with serial blood counts. We aim to highlight the treatment challenges and clinical decision-making that may be anticipated in this unique disorder, as well as the potentially curative role for allogenic hematopoietic stem cell transplant in the first complete remission.

Background In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. Methods We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. Results Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. Conclusions Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. Impact Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

In this issue of Blood, Musallam, Forni, and colleagues show that survival in transfusion dependent beta-thalassemia (TDT) is measurably better in patients whose pretransfusion hemoglobin levels are maintained >10.5 g/dL, at the upper end of the currently recommended treatment range.(1) In this landmark study, the 10-year survival of a group of 779 patients with TDT of median age 33.1 years (range 18.1-61 years) increased monotonically from 91% to 100% in 5 categories marked by median pretransfusion hemoglobin levels that increased from <9.0 to >= 10.5 g/dL in 0.5-g/dL increments. Of note, 88% of the thalassemia-related deaths were in groups with a median hemoglobin <10 g/dL and 70% were from cardiovascular disease. When the data were stratified by ferritin, the association with hemoglobin level groups was only significant for ferritin <1000 ng/mL, consistent with an effect of anemia on survival separate from that of iron overload.

AbstractA recent evidence gaps assessment of the clinical, health‐related quality of life, and economic burden associated with α‐thalassemia is lacking. We conducted a systematic literature review (SLR) following the methodological and reporting requirements of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and the Cochrane Handbook for Systematic Reviews, using available literature over the past decade. This SLR identified a considerable evidence gap with regard to understanding the current burden of α‐thalassemia as evident from paucity of studies published in the past 10 years. The limited data available still indicate that patients with α‐thalassemia experience substantial morbidity and quality of life/economic burden that is generally comparable to patients with β‐thalassemia.