Novel Therapeutic Advances in β-Thalassemia

The main characteristic of the pathophysiology of β-thalassemia is reduced β-globin chain production. The inevitable imbalance in the α/β-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or “disease-modifying” therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of β-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or β-globin gene have entered the clinical trial setting. Agents such as TGF-β ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-β ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent β-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in β-thalassemia

Anti-CD20 Treatment of Autoimmune Hemolytic Anemia Refractory to Corticosteroids and Azathioprine: A Pediatric Case Report and Mini Review

Autoimmune hemolytic anemia (AIHA) is a relatively uncommon hematological entity in children and sometimes is characterized by a severe course requiring more than one line course therapy. Treatment decisions depend on the severity and chronicity of the anemia and the characteristics of the autoantibodies. Immunosuppression with corticosteroids is the first-line treatment, especially in warm-reactive AIHA. Refractory cases are treated with immunosuppressive drugs, cytotoxic agents, androgens, or splenectomy, with various side effects and questionable efficacy. Another second-line option is rituximab, an anti-CD20 monoclonal antibody, which has been used as an off-label agent with encouraging results from small limited studies or case reports. Herein, we add our experience on the safety and clinical efficacy of rituximab by presenting the case of a boy with warm-type AIHA resistant to corticosteroids and azathioprine, successfully treated with rituximab. We also offer a review of the relevant literature

Optimal Periodic Radio Sensing and Low Energy Reasoning for Cognitive Devices

Heterogeneous wireless access networks have emerged as a paradigm that offers the potential for increased flexibility, improved QoS and higher data rates. New, dedicated radio channels conveying context information from the network to the terminal as well as terminal observations back to the network have been proposed to facilitate terminal operation in such environments. On the other hand, low energy and “green” aspects are becoming increasingly important, not only for environmental reasons but also because low energy systems offer extended battery duration, reduced operational cost and improved long-term reliability. This work proposes a solution to the problem of low energy periodic sensing of available networks, focusing on the definition of optimal sensing period through markovian models. Moreover, low energy decision making utilizing a hierarchical fuzzy logic approach consisting of reasoners organized in tree form is introduced. The input parameters of the system are grouped taking into consideration their interrelation, in order to define the position of each reasoner in the structure. Such an approach facilitates utilization of previous knowledge and triggers a minimal number of reasoners, thus considerably reducing energy costs

Constraint Handling Techniques for Metaheuristics: A State-of-the-art Review and New Variants

Metaheuristic optimization algorithms (MOAs) are computational randomized search processes which draw inspiration from physical and biological phenomena, with an application spectrum that extends to numerous fields, ranging from engineering design to economics. MOAs were originally developed for solving unconstrained NP-complete problems, and hence their application to constrained optimization problems (COPs) requires the implementation of specialized techniques that facilitate the treatment of performance and bound constraints. While considerable research efforts have been oriented towards the development and subsequent enhancement of novel constraint handling techniques (CHTs) for MOAs, a systematic review of such techniques has not been conducted hitherto. This work presents a state-of-the-art review on CHTs used with MOAs and proposes eight novel variants based on the feasibility rules and ε-constrained techniques. The distinctive feature of the new variants is that they consider the level and number of constraint violations, besides the objective function value, for selection of individuals within a population. The novel variant performance is evaluated and compared with that of four well-known CHTs from the literature using the metaheuristic pity beetle algorithm, based upon 20 single-objective benchmark COPs. The computational results highlight the accuracy, effectiveness, and versatility of the novel variants, as well as their performance superiority in comparison with existing techniques, stemming from their distinctive formulation. The complete code can be downloaded from GitHub (https://github.com/nikoslagaros/MOAs-and-CHTs).ISSN:1389-4420ISSN:1573-292

Chelation Therapy with Oral Solution of Deferiprone in Transfusional Iron-Overloaded Children with Hemoglobinopathies

Iron overload in hemoglobinopathies is secondary to blood transfusions, chronic hemolysis, and increased iron absorption and leads to tissue injury requiring the early use of chelating agents. The available agents are parenteral deferoxamine and oral deferiprone and deferasirox. There are limited data on the safety and efficacy of deferiprone at a very young age. The aim of our study was the presentation of data regarding the use of oral solution of deferiprone in 9 children (mean age 6.5, range 2–10) with transfusion dependent hemoglobinopathies (6 beta thalassemia major, 1 thalassemia intermedia, and 2 sickle cell beta thalassemia). The mean duration of treatment was 21.5 months (range 15–31). All children received the oral solution without any problems of compliance. Adverse reactions were temporary abdominal discomfort and diarrhea (1 child), mild neutropenia (1 child) that resolved with no need of discontinuation of treatment, and transient arthralgia (1 child) that resolved spontaneously. The mean ferritin levels were significantly reduced at the end of 12 months (initial 2440 versus final 1420 μg/L, ). This small study shows that oral solution of deferiprone was well tolerated by young children and its use was not associated with major safety concerns. Furthermore, it was effective in decreasing serum ferritin

Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders