Erythropoiesis stimulation agents represent a novel class of therapeutic agents acting on the differentiation and maturation pathways of erythroid precursors. Unlike erythropoietin, which primarily stimulates early stages of erythropoiesis, these agents target the later stages of red cell development. Their principal therapeutic effect is mediated through modulation of Smad signaling, a pathway that regulates late erythroid maturation.

Luspatercept (trade name: Reblozyl) is a recombinant fusion protein consisting of the Fc portion of IgG linked to a modified receptor for members of the transforming growth factor-beta (TGF-β) superfamily. It functions as a ligand “trap” for specific molecules (e.g., growth differentiation factor 11, activins) involved in the late stages of erythropoiesis. By inhibiting Smad2/3 signaling, luspatercept effectively “releases the brake” on terminal erythroid maturation and promotes the differentiation of erythroid precursors in the bone marrow, thereby reducing ineffective erythropoiesis.^[1-3] Clinically, this results in decreased transfusion requirements in β-thalassemia: in transfusion-dependent thalassemia (TDT) patients, transfusion burden is reduced, while in non-transfusion-dependent thalassemia (NTDT) patients, hemoglobin levels increase. Following positive preclinical findings, the drug was evaluated in clinical trials that led to its regulatory approval. The BELIEVE study, conducted in patients with transfusion-dependent β-thalassemia, demonstrated a ≥33% reduction in transfusion requirements by week 24 of treatment.^[4] Moreover, long-term follow-up (over 3 years) confirmed sustained efficacy together with a favorable safety profile.^[5] Most adverse effects were mild to moderate, supporting the suitability of luspatercept as a long-term treatment option for patients with β-thalassemia.^[6] The drug has also been evaluated in NTDT β-thalassemia in the BEYOND trial, where it demonstrated a sustained increase in hemoglobin levels.‌^[7] Since November 2019, Reblozyl has been approved for the treatment of patients with TDT beta-thalassemia.‌^[8] In addition, in 2023 its indication was expanded to patients with NTDT. Importantly, luspatercept also addresses disease-related complications, particularly those associated with iron overload. Treated patients not only experience hemoglobin improvement but also a reduction in iron burden while maintaining a favorable safety profile. ^[9,10] Beyond monotherapy, ongoing studies are assessing the safety and efficacy of combination regimens that include luspatercept and erythropoietin (EPO). Biologically, these agents may act synergistically: EPO stimulates earlier stages of erythropoiesis, whereas luspatercept enhances late-stage maturation, together yielding a more robust erythropoietic response.^[9,11] This combination therapy has shown promising results in preclinical models and early-phase clinical trials. Studies in cohorts of patients with myelodysplastic syndrome (MDS) demonstrate that the concurrent administration of luspatercept and EPO redirects erythropoiesis from the proliferation of early precursors toward enhanced late-stage maturation, resulting in more substantial hemoglobin improvements compared with EPO alone.^[12-14] These findings highlight the value of a combined therapeutic strategy aimed at optimizing erythropoiesis and improving the quality of life of patients with anemia.^[3,15] Extrapolating these data from MDS, the rationale for such a combination can be logically extended to the field of thalassemia. In a study using mouse models of β-thalassemia, luspatercept was shown to enhance the sensitivity of early erythroid precursors to endogenous EPO, suggesting that combining EPO with luspatercept may yield superior therapeutic outcomes.^[16] However, their concurrent use still requires validation in clinical settings. At present, a clear scientific gap persists in this area, as no dedicated clinical trial has systematically evaluated the impact of this combination therapy in β-thalassemia cohorts.

Sotatercept (ACE-011) is a ligand trap for activins and related ligands of the TGF-β superfamily, utilizing the extracellular domain of the activin receptor IIA fused to an IgG1 Fc fragment.^[17] Its mechanism of action suggests that by reducing inhibitory signaling in late erythropoiesis, it promotes the maturation of erythroid precursors.^[18] In a phase II study by Cappellini and colleagues, sotatercept was assessed for its efficacy in patients with β-thalassemia and related conditions. The results demonstrated significant hemoglobin increases and a reduction in transfusion requirements.^[17] Despite these encouraging phase II data, no large randomized phase III trials of sotatercept in β-thalassemia have been conducted to date.^[19] A 2023 review by Zehao et al. reports that a planned phase III study had been discontinued in favor of advancing the luspatercept development program.^[20] Potential off-target effects, including bleeding and hypertension, may also have contributed to redirecting resources away from sotatercept. Its future inclusion in treatment regimens would require robust phase III randomized studies with long-term safety data, as well as a clearer definition of target patient subgroups (e.g., specific genotypes, TDT vs. NTDT) and a formal risk-benefit assessment.

Mitapivat (AG-348) is the first therapeutic agent designed to target the underlying metabolic defect rather than erythropoiesis itself. It functions as an activator of pyruvate kinase (PK), specifically its erythrocyte isoforms (PKR/PYK-R).^[21] In contrast to pyruvate kinase deficiency, where mitapivat directly restores pyruvate kinase activity, in thalassemia the drug enhances erythroid energy metabolism without correcting an underlying enzymatic defect. Evidence confirms markedly reduced ATP levels and increased oxidative stress in β-thalassemia, contributing to shortened red blood cell survival. Mitapivat stabilizes the active conformation of PKR, thereby enhancing ATP synthesis in red blood cells. The expected therapeutic outcomes include reduced hemolysis and improved red blood cell survival.^[22-25] Preclinical data shows that mitapivat not only reduces transfusion dependence but is also well tolerated, supporting its potential for long-term use.‌^[21] In addition, evidence suggests complementary activity when mitapivat is used in combination with luspatercept, offering a potentially innovative therapeutic strategy for beta-thalassemia.^[26] Early-phase clinical trials (phase II) show that mitapivat improves hematological parameters.‌^[27] Several active clinical studies are currently underway, with preliminary but as yet unpublished data. The ENERGIZE-T trial (NCT04770779), a phase II study, reports a ≥30% reduction in transfusion burden with sustained transfusion independence at 36 weeks and a rate of serious adverse events comparable to placebo. Another study, NCT04770753, evaluates mitapivat in NTDT patients. Initial data show a significant increase in hemoglobin level and reduced fatigue in NTDT (α-/β-thalassemia), alongside an acceptable safety profile.‌^[28] The phase II open-label study NCT03692052 in NTDT enrolled 15 patients with β-thalassemia and demonstrated a substantial hemoglobin response rate.^[29] Overall, phase III clinical trials are essential to fully assess the long-term safety, durability of response, and broader clinical utility of mitapivat.

Studies of small molecules capable of inducing fetal hemoglobin (HbF) production have yielded promising early results, offering the possibility of an accessible therapeutic strategy without the risks related to stem cell transplantation. The well-established effect of hydroxyurea on HbF levels is widely recognized, particularly in patients with NTDT, and in TDT there is evidence supporting a reduction in transfusion requirements.^[30-32] More recently, additional molecules with HbF-inducing potential have been identified. Most of these agents remain in the preclinical or early clinical trial phase in β-thalassemia.

Histone deacetylase inhibitors (e.g. trichostatin A and butyrate), induce HbF synthesis by activating the γ-globin gene through modulation of the p38 mitogen-activated protein kinase (MAPK) pathway.^[33] Resveratrol and its analogues have also demonstrated HbF-inducing potential, as shown in a study by Theodorou et al.^[34] Another emerging class of agents includes newly synthesized isoxazole derivatives.^[35] This represents a promising direction for the development of oral, affordable HbF inducers that could potentially replace hydroxyurea in the future.

The treatment of beta-thalassemia also encompasses strategies aimed at managing complications arising from chronic transfusion therapy. Iron overload necessitates effective chelation approaches. Novel agents targeting the transferrin receptor (TFRII) are currently under evaluation for their capacity to reduce iron accumulation.^[36] In addition, ongoing research on Janus Kinase 2 (JAK2) inhibitors and hepcidin agonists offers promising avenues for correcting the dysregulated iron metabolism in beta-thalassemia.^[37] Chronic ineffective erythropoiesis leads to sustained activation of the JAK2/STAT signaling pathway, promoting excessive proliferation of erythroid precursors and contributing to massive extramedullary erythropoiesis and splenomegaly. This mechanism plays a role in multiple pathological processes, including accelerated atherosclerosis requiring interventional treatment.^[38,39]

This makes JAK2 a plausible therapeutic target that theoretically may decrease pathological hyperplasia, limit extramedullary erythropoiesis, and improve the efficiency of erythroid maturation.^[40] Studies of JAK2 inhibitors in β-thalassemia models have shown reductions in splenomegaly, decreased extramedullary erythropoiesis, and partial restoration of erythroid cell morphology and function.‌^[41] Early phase IIa clinical data in humans demonstrate symptomatic improvement and spleen size reduction. However, the effect on anemia remains limited.^[42] The modest impact of JAK2 inhibition on anemia in thalassemia is explained by its primary action on inflammatory and proliferative signaling pathways, while the fundamental imbalance between globin synthesis and ineffective erythropoiesis remains uncorrected. To the present, JAK2 inhibitors have not received regulatory approval for use in patients with beta-thalassemia, and their application remains limited to scientific and early clinical research.

Gene therapy represents one of the most significant advances in the treatment of beta-thalassemia over the past decade. It marks a shift from supportive care to potentially curative strategies by addressing the underlying genetic defect. Through the development of viral vectors, genome-editing technologies, and ex vivo modification of hematopoietic stem cells (HSCs), gene therapy aims to restore endogenous production of functional hemoglobin, thereby eliminating or substantially reducing the need for transfusions.

At present, two main gene therapy approaches predominate:

1. Gene supplementation using lentiviral vectors, and

2. Genome editing techniques such as CRISPR/Cas9

Allogeneic HSCT remains a potential curative treatment option for beta-thalassemia, but its applicability is often constrained by the limited availability of compatible donors and by the risks inherent to the procedure. Traditionally, HSCT is performed using a myeloablative conditioning regimen that includes busulfan and cyclophosphamide.^[58] Although HSCT carries risks such as graft rejection and graft-versus-host disease, advances in conditioning protocols and immunosuppressive strategies have contributed to reducing these complications.^[59] Allogeneic transplantation from unrelated donors is increasingly considered for patients without a suitable related donor.^[60] Studies indicate that, with rigorous donor selection, such transplants can be successful, though survival rates remain lower than those achieved with related donors.^[61] Efforts to improve the success of allogeneic HSCT include the use of haploidentical donors, which expands donor availability and has been associated with improved outcomes in recent protocols.^[62,63]

Contemporary advances in the treatment of beta-thalassemia are transforming the traditional therapeutic approach, shifting it toward a fundamentally new model that directly targets ineffective erythropoiesis, iron dysregulation, and β-globin synthesis. The emergence of novel therapeutic classes focusing on erythroid maturation, modulation of HbF production, correction of iron overload, and genome editing has enabled more effective and often durable correction of hemoglobin deficiency, while simultaneously mitigating many complications associated with chronic transfusion therapy. Despite these major breakthroughs, the need remains for rigorous safety monitoring, optimization of treatment protocols, and clearer definition of the role of combination strategies in the management of patients with beta-thalassemia.

The authors have declared that no competing interests exist.

The graphical elements of the figures were created using AI tools and Excel, and the author prepared the textual content and final formatting.

The authors have no funding to report.

KS did the literature search, data extraction and critical evaluation of the evidence; developed the concept, structured the manuscript, and wrote the full text of the manuscript.