Non-Transfusion-Dependent Thalassemia: A Panoramic Review.

Non-transfusion-dependent thalassemia (NTDT) has been considered less severe than its transfusion-dependent variants. The most common forms of NTDT include ß-thalassemia intermedia, hemoglobin E/beta thalassemia, and hemoglobin H disease. Patients with NTDT develop several clinical complications, despite their regular transfusion independence. Ineffective erythropoiesis, iron overload, and hypercoagulability are pathophysiological factors that lead to morbidities in these patients. Therefore, an early and accurate diagnosis of NTDT is essential to ascertaining early interventions. Currently, several conventional management options are available, with guidelines suggested by the Thalassemia International Federation, and novel therapies are being developed in light of the advancement of the understanding of this disease. This review aimed to increase clinicians' awareness of NTDT, from its basic medical definition and genetics to its pathophysiology. Specific complications to NTDT were reviewed, along with the risk factors for its development. The indications of different therapeutic options were outlined, and recent advancements were reviewed.

Luspatercept for the treatment of anaemia in non-transfusion-dependent ß-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.

BACKGROUND: In patients with non-transfusion-dependent ß-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent ß-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent ß-thalassaemia. METHODS: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of ß-thalassaemia or haemoglobin E/ß-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent ß-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing. FINDINGS: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study. INTERPRETATION: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent ß-thalassaemia, for whom effective approved treatment options are scarce. FUNDING: Celgene and Acceleron Pharma.

Ruxolitinib Treatment in an Adolescent With Chronic Graft-Versus-Host Disease Mimicking Eosinophilic Gastrointestinal Disorders: A Case Report.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGIDs) are well-documented entities in pediatric solid organ transplantation. However, the diseases are rare after bone marrow transplantation (BMT). CASE PRESENTATION: We present an adolescent male with hemoglobin E-ß-thalassemia who underwent BMT and developed chronic graft-versus-host disease (GVHD) mimicking EGIDs. Initially, the patient presented with a presumed diagnosis of eosinophilic gastroenteritis (subserosal type) and received corticosteroids for 12 weeks. Six months after corticosteroids cessation, he again developed abdominal pain, treated with corticosteroids, azathioprine, and a six-food elimination diet. Still, he later had similar symptoms with persistent hypereosinophilia. The patient was subsequently diagnosed with chronic GVHD after excluding various potential causes. Ruxolitinib also led to significant clinical improvement and the disappearance of eosinophilia. CONCLUSION: The differential diagnosis of chronic GVHD should be a concern in BMT recipients with persistent gastrointestinal symptoms and eosinophilia. Ruxolitinib may be a treatment option in children with a steroid-refractory disease.

Haemoglobin-E in the presence of oxidative substances from fava bean may be protective against Plasmodium falciparum malaria.

A case-control study was carried out at a community hospital in eastern Thailand in order to study the association between haemoglobin E and Plasmodium falciparum malaria; 271 P. falciparum cases and 271 controls were enrolled. After adjusting for age, sex, time since last malaria attack, history of mosquito net use, and history of fava bean consumption in the previous month, neither heterozygous nor homozygous haemoglobin E provided significant protection against P. falciparum infection, with odds ratios (OR) = 0.91 (95% confidence limits = 0.61, 1.36) and 0.78 (0.34, 1.82) respectively when compared to persons with haemoglobin A who were not consumers of fava beans. However, haemoglobin E carriers who ate fava beans were significantly protected against P. falciparum malaria with OR = 0.26 (0.09, 0.76) and OR = 0.001 (0.00, 1120.59) for subjects with heterozygous and homozygous haemoglobin E, respectively. The study suggests a possible synergistic protective effect of haemoglobin E on the risk of P. falciparum malaria in subjects who have consumed fava beans.