Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes

Abstract

During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and efficient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

“…Aconitine, a potent cardiotoxin, was previously reported to modify the amplitude and gating of I K(DR) in neurons and heart cells [39,46]. Shenfu injection, the composition of which contains aconitine, has been demonstrated to be beneficial for secondary aplastic anemia induced following chemotherapy via stimulation of bone marrow function [6,55,56]. Previous studies have demonstrated the ability of aconitine to depress I K(DR) amplitude and to fasten the inactivation rate of the current [39,46].…”

Roxadustat as treatment for a blood transfusion-dependent maintenance hemodialysis patient: A case report and review of literature

“…However, approximately 5%-10% of patients have a low response or show resistance to ESAs. Iron deficiency, inadequate dialysis, inflammation, malnutrition, chronic blood loss, secondary hyperparathyroidism, aluminum toxicity, and hypersplenism may be important reasons for resistance to ESAs[ 24 ]. Despite the efficacy of ESAs for treating anemia, high doses may increase the risk of vascular thrombosis, myocardial infarction, heart failure, tumor progression or recurrence, and mortality[ 25 ].…”

Annual banned‐substance review – Analytical approaches in human sports drug testing

“…The successful implementation of additional target analytes such as the transforming growth factor‐beta (TGF‐β) inhibitors sotatercept and luspatercept into different conventional ESA‐specific ITPs was reported by various research units. For instance, Martin et al described a strategy employing magnetic nanoparticles coated with monoclonal anti‐EPO‐, anti‐ActRIIA‐, and anti‐ActRIIB antibodies used to immunoextract 0.3–1.0 mL of serum or plasma .…”