How I treat non-transfusion-dependent ß-thalassemia.

The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent ß-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.

Iron chelation therapy for children with transfusion-dependent ß-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

Management of luspatercept therapy in patients with transfusion-dependent ß-thalassaemia.

Patients with transfusion-dependent ß-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 ß-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with ß-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit.

Thalassaemia-A global view.

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Development of a Thalassemia International Prognostic Scoring System (TIPSS).

A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.

Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.

CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.

Patient preference for deferasirox film-coated versus dispersible tablet formulation: a sequential-design phase 2 study in patients with thalassemia.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.

Health-related quality of life in patients with ß-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept.

BACKGROUND: Patients with transfusion-dependent (TD) ß-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 ß-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.

Epidemiology of clinically significant forms of alpha- and beta-thalassemia: A global map of evidence and gaps.

This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE, and the Cochrane Library were searched for observational studies published January 1, 2000, to September 21, 2021. Of 2093 unique records identified, 69 studies reported across 70 publications met eligibility criteria, including 6 records identified from bibliography searches. Thalassemia prevalence estimates varied across countries and even within countries. Across 23 population-based studies reporting clinically significant alpha-thalassemia (e.g., hemoglobin H disease and hemoglobin Bart's hydrops fetalis) and/or beta-thalassemia (beta-thalassemia intermedia, major, and/or hemoglobin E/beta-thalassemia), prevalence estimates per 100 000 people ranged from 0.2 in Spain (over 2014-2017) to 27.2 in Greece (2010-2015) for combined beta- plus alpha-thalassemia; from 0.03 in Spain (2014-2017) to 4.5 in Malaysia (2007-2018) for alpha-thalassemia; and from 0.2 in Spain (2014-2017) to 35.7 to 49.6 in Iraq (2003-2018) for beta-thalassemia. Overall, the estimated prevalence of thalassemia followed the predicted pattern of being higher in the Middle East, Asia, and Mediterranean than in Europe or North America. However, population-based prevalence estimates were not found for many countries, and there was heterogeneity in case definitions, diagnostic methodology, type of thalassemia reported, and details on transfusion requirements. Limited population-based birth prevalence data were found. Twenty-seven studies reported thalassemia prevalence from non-population-based samples. Results from such studies likely do not have countrywide generalizability as they tended to be from highly specific groups. To fully understand the global prevalence of thalassemia, up-to-date, population-based epidemiological data are needed for many countries.

Primary HBB gene mutation severity and long-term outcomes in a global cohort of ß-thalassaemia.

In ß-thalassaemia, the severity of inherited ß-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 ß-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as ß0 /ß0 , ß0 /ß+ , ß+ /ß+ , ß0 /ß++ , ß+ /ß++ , and ß++ /ß++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, ß0 and ß+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with ß0 /ß0 , ß0 /ß+ , or ß+ /ß+ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with ß-thalassaemia and suggests inclusion of both ß+ and ß0 mutations in strata of greatest severity.

COVID-19 pandemic and transfusion medicine: the worldwide challenge and its implications.

COVID-19 pandemic has imposed worldwide challenge and has significantly affected transfusion medicine. Shortage in blood products along with concerns regarding the safety of blood products have emerged. Measures to overcome these challenges have been implemented in order to decrease the demand on blood products and to encourage blood donations while taking full precautions to minimize risk of COVID-19 transmission mainly at blood banks and medical centers. Several countries have been successful in facing these new challenges. In addition, the role of plasma therapy in the treatment of COVID-19 patients, especially in severe cases, has been proposed and current studies are being conducted to determine its efficacy. Other therapeutic options are currently being explored. So far, the use of convalescent plasma is considered a promising rescue treatment to be looked at.

Temporal trends and outcome of splenectomy in adults with immune thrombocytopenia in the USA.

Splenectomy is one of the treatments of immune thrombocytopenia (ITP) with a high response rate. However, it is an irreversible procedure that can be associated with morbidity in this setting. Our aim was to study the trends of splenectomy in adults with ITP, and the factors associated with splenectomy and resource utilization during these hospitalizations. We used the National (Nationwide) Inpatient Sample (NIS) to identify hospitalizations for adult patients with a principal diagnosis of ITP between 2007 and 2017. The primary outcome was the splenectomy trend. Secondary outcomes were (1) incidence of ITP trend, (2) in-hospital mortality, length of stay, and total hospitalization costs after splenectomy trend, and (3) independent predictors of splenectomy, length of stay, and total hospitalization costs. A total of 36,141 hospitalizations for ITP were included in the study. The splenectomy rate declined over time (16% in 2007 to 8% in 2017, trend p < 0.01) and so did the in-hospital mortality after splenectomy. Of the independent predictors of splenectomy, the strongest was elective admissions (adjusted odds ratio [aOR]: 22.1, 95% confidence interval [CI]:17.8-27.3, P < 0.01), while recent hospitalization year, older age, and Black (compared to Caucasian) race were associated with lower odds of splenectomy. Splenectomy tends to occur during elective admissions in urban medical centers for patients with private insurance. Despite a stable ITP hospitalization rate over the past decade and despite listing splenectomy as a second-line option for management of ITP in major guidelines, splenectomy rates consistently declined over time.

Digital thermography and vascular involvement in ß-thalassemia intermedia.

Beta-thalassemia intermedia (ß-TI) is associated with vascular dysfunction. We used digital thermal monitoring (DTM), a non-invasive tool that evaluates vascular function based on changes in fingertip temperature during and after cuff occlusion on ß-TI patients. Thirty-three patients (18 years and older) were recruited in this study and divided into 3 groups: thalassemia, anemic controls, and healthy controls. Exclusion criteria included factors that are known to be associated with vascular damage. Patients underwent DTM and results were extracted as vascular reactivity index (VRI), a measure of how well the circulatory system responds to stimuli that require adjustments of blood flow. One-way analysis of variance (ANOVA) was used to test the mean difference in VRI between the 3 groups. A multiple linear regression was also carried out with VRI as the outcome of interest and a function of covariates that were thought to be of clinical relevance to VRI. The frequency, mean VRI ± standard error (SE) for the thalassemic group were (N = 16), mean = 2.243 ± 0.111; for anemic controls (N = 9), mean = 2.374 ± 0.162; and for the controls (N = 8), mean = 2.338 ± 0.092. ANOVA test indicated a non-significant difference in mean VRI between the three groups (P value = 0.731). Multiple linear regression couldn't detect any significant association between VRI and any of the predictors including the groups. Our study did not show a significant difference in VRI between the 3 study groups. Prospective studies of larger sample size are warranted to establish DTM as a possible non-invasive tool used to evaluate vascular function in ß-TI patients.

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.

Could Preoperative Unintended Weight Loss Predispose to Postoperative Thrombosis in Patients Undergoing Colorectal Cancer Surgery? An Analysis of the NSQIP Data.

Objective: A significant portion of colorectal cancer patients lose weight preoperatively. Here we examine the influence of pre-operative significant weight loss on venous thromboembolism (VTE) risk and determine whether pre-operative BMI and albumin could influence VTE outcomes in patients who have lost significant weight prior to surgery.Methods: We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and identified 103,455 colorectal cancer patients undergoing major surgery from 2008 to 2012. Patients were assigned to one of two groups based on whether they lost significant weight preoperatively or not. Simple and stepwise multiple logistic regressions were used to evaluate the association between pre-operative unintended weight loss and 30-days postoperative outcomes. The association between weight loss and postoperative thrombosis was further assessed across several strata.Results: The overall prevalence of pre-operative significant weight loss was 6.8%. Significant weight loss prior to surgery was significantly and independently associated with a higher risk of VTE (adjusted OR 1.23, 95% CI 1.06-1.44), mortality (adjusted OR 1.55, 95% CI 1.35-1.78), composite morbidity (adjusted OR 1.52, 95% CI 1.42-1.62), bleeding (adjusted OR 1.78, 95% CI 1.67-1.91) and return to operation room (adjusted OR 1.29, 95% CI 1.16-1.42). The effect of pre-operative significant weight loss on thromboembolic outcome was evident across patients with a BMI <18.5 kg/m2, 18.5 < BMI < 24.99 and BMI >40kg/m2.Conclusions: Significant weight loss and BMI both need to be measured preoperatively to stratify patients who are at a higher risk of VTE.

2021 update on clinical trials in ß-thalassemia.

The treatment landscape for patients with ß-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusion-dependent ß-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost. Patients with non-transfusion-dependent ß-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in ß-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation.

Recommendations for diagnosis and treatment of methemoglobinemia.

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions.

Henoch-Schönlein purpura: Another COVID-19 complication.

Whether affecting children or adults, SARS-CoV-2 infection (COVID-19) can have multi-organ involvement mediated by an inflammatory cascade. Immunoglobulin A (IgA) is one of the key components of the inflammatory cascade that can lead to endothelial injury and inflammation. IgA vasculitis or Henoch-Schönlein purpura (HSP) has been rarely reported in the context of COVID-19. In this report, we highlight a case of HSP occurring 2 days after diagnosis of COVID-19 in a 16-year-old boy, who presented with palpable purpura of the lower extremities and buttocks, diffuse abdominal pain, hemoptysis, and hematochezia. He was treated with oral prednisolone with rapid clinical improvement.

CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of ß-Thalassemia through an Increase in 20-HETE Activity.

Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbbth3/+ mice, a mouse model for ß-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbbth3/+ mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbbth3/+ mice through an NADPH-dependent pathway.