Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review

Abstract

β-thalassemia is characterized by the faulty generation of hemoglobin resulting in an elevated α/β globin ratio; this led to several patients needing red blood cell (RBC) transfusions for the rest of their lives. Luspatercept is an erythroid maturation test for treating various types of anemia, including β-thalassemia. It inhibits the Smad2/3 cascade and treats β-thalassemia by downregulating the transforming growth factorbeta (TGF-β) pathway. Luspatercept was evaluated in randomized controlled trials (RCTs). However, there is still limited data. Therefore, the study aims to review the current literature to assess the efficacy of luspatercept in cure β-thalassemia and its safety. From 2015 to 2022, searches were undertaken in PubMed, Google Scholar, and Cochrane. Only RCTs published in English were eligible for inclusion. The Cochrane Collaboration tool for bias assessment was used to analyze the quality of the publications. Our search strategy revealed 94 publications, of which 12 full-text papers were read and five were chosen for this review. All five trials included 1161 participants. Of whom, 153 (13.18%) entered phase 2, and 1008 (86.82%) entered phase 3. Two articles included 153 participants, of whom 70 (45.75%) were transfusion-dependent beta-thalassemia (TD) and 83 (54.25%) were non-transfusion-dependent beta-thalassemia (NTD) of phase 2. Three articles included 1008 participants, of whom 672 (66.67%) were given luspatercept and 336 (33.33%) were given a placebo. All participants in RCTs were 18 years of age or older. In phase 2, 0.2 to 1.25 mg/kg of luspatercept was given, and in phase 3, 1.0 to 1.25 mg/kg of luspatercept was given once every three weeks. In beta-thalassemia patients, luspatercept was more effective than a placebo and well tolerated. The high dose has shown promising results in the erythroid response, measured by a drop in blood transfusions or an average rise in hemoglobin levels. Luspatercept might make patients less likely to need RBC transfusions, improve their clinical results, and improve their quality of life. Adverse events were hyperuricemia, arthralgia, dizziness, influenza hypertension, and bone pain, but they were manageable.

Luspatercept's use in a patient with transfusion‐dependent beta‐thalassemia and intrathoracic extramedullary hematopoiesis (EMH)

“…It decreased the mean transfusion rate by at least 33% or 50% from baseline, increasing the interval between subsequent transfusions and relieving the patients from the cumbersome recurrent transfusions. 15 After starting treatment, our patient didn't need any blood transfusion, while before that, she was on regular transfusion every 1-2 months.…”

“…The main advantage of luspatercept was decreasing the burden of transfusion dependency. It decreased the mean transfusion rate by at least 33% or 50% from baseline, increasing the interval between subsequent transfusions and relieving the patients from the cumbersome recurrent transfusions 15 …”

Kidney transplantation in an adult with transfusion-dependent beta thalassemia: A challenging case report and literature review

“…It intensifies latestage erythroid development in the bone marrow, lowers Smad 2/3 signaling, and ameliorates hematological parameters. It has been shown in thalassemia clinical studies that it causes a prolonged excess of hemoglobin and a decrease in transfusion requirements [23].…”

What Is the Relevance of Murburn Concept in Thalassemia and Respiratory Diseases?

“…The pathophysiology of thalassemia stems from mutation(s) in hemoglobin (alpha-beta gene(s), leading to poor assembly/function of functional hemoglobin (Hb) and underproduction or poor maturation of erythrocytes [62,63]. The currently adopted clinical approach centers around basic strategies involving: (a) the administration of small/large molecules such as hydroxyurea to enhance Hb production and erythrocyte osmolarity/turgor [64], folate to aid erythropoiesis [65], chelation agents to counter Fe-overload [66], growth hormones to alleviate the limited development of body [67], and recombinant proteins (e.g., luspatercept or Reblozyl) aiding better erythrocyte population [68]; (b) blood transfusion [69]; (c) bone marrow/stem cell transplantation [70,71]; (d) gene therapy (e.g., CRISPR-methodology and Zynteglo) [72,73], etc. Murburn concept is relevant in all of these contexts and also in a bevy of other redox/respiratory and mitochondrial diseases (which are also gene-based ailments) that are supposed to involve "oxidative stress".…”