Innovative Treatments for Rare Anemias

Abstract

Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.

Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion‐independent a murine model of transfusion‐dependent β‐thalassemia

“…The therapy of TDT patients is still suboptimal. Recent advances in the elucidation of the pathophysiological mechanisms of the disease led to the design of novel therapeutic approaches 14,69 . However, none of these is fully effective in all patients, even when the genetic defect is corrected (i.e., by gene therapy), likely because different modifiers contribute to the complex phenotype of patients.…”

“…Recent advances in the elucidation of the pathophysiological mechanisms of the disease led to the design of novel therapeutic approaches. 14,69 However, none of these is fully effective in all patients, even when the genetic defect is corrected (i.e., by gene therapy), likely because different modifiers contribute to the complex phenotype of patients. For this reason, the identification of novel strategies to be eventually combined with available treatments, as occurs in hematological cancers, might offer new therapeutic perspectives.…”

“…Anemia severity can range from mild to severe and patients are classified as Non‐Transfusion Dependent (NTDT) or Transfusion Dependent (TDT) based on their blood transfusion requirement 12 . Patients affected by severe TDT require lifelong blood transfusions and iron chelation to control iron‐overload, symptomatic treatments that affect the quality of life 3,13,14 . For years, the only curative option was allogenic bone marrow (BM) transplantation, an approach effective in more than 90% of cases, but limited by the insufficient number of HLA‐matched donors and, in some cases, associated to severe post‐transplant complications 15–17 .…”

“…12 Patients affected by severe TDT require lifelong blood transfusions and iron chelation to control iron-overload, symptomatic treatments that affect the quality of life. 3,13,14 For years, the only curative option was allogenic bone marrow (BM) transplantation, an approach effective in more than 90% of cases, but limited by the insufficient number of HLA-matched donors and, in some cases, associated to severe post-transplant complications. [15][16][17] Two promising innovative treatments, Activin Receptor Ligand Trap Luspatercept-Reblozyl 18,19 and the gene therapy product Zynteglo, [20][21][22][23] received FDA and EMA approval and EMA conditional marketing authorization for TDT patients, respectively: however, these are not fully effective in all patients and/or suitable for selected individuals.…”

Rise of the planet of rare anemias: An update on emerging treatment strategies

“…Emerging therapies for beta-thalassemia aim to target α/β chain imbalance, ineffective erythropoiesis, and iron dysregulation and overload. In SCD the main targets are reducing the amount of Hb S (HbS), preventing red cell dehydration or sickling, endothelial adhesion, and oxidative stress ( 4 ) ( Figure 1 ).…”