Editorial: MDS: New Scientific and Clinical Developments

Sabine Blum ^1* Argiris Symeonidis ² Ulrich Germing ³

• ¹ Hematology Service and Central Laboratory of Hematology, Lausanne University Hospital and University of Lausanne, Switzerland, Lausanne, Switzerland
• ² Hematology Division, Department of Internal Medicine, University of Patras-School of Medicine & Olympion General Clinic, Patras Greece, Patras, Greece
• ³ Department of Hematology, Oncology and Clinical Immunology, Faculty of Medicine, Heinrich Heine University, Düsseldorf, Germany

dedicated to the new scientific and clinical developments of the field of MDS and aspires to become a useful source of information for all scientists working in this field.The original work from Kathrin Nachtkamp and colleagues explains the deviation and concordance of results between cytology and histomorphology, and demonstrated for which type of information, cytology, and for which other type, histology is preferable and reliable. The review paper from Howard Oster and Moshe Mittelman explains how to approach the diagnosis of this complex group of neoplasms with less interventional ways, and in line with this approach, Evgenia Verigou and colleagues explain the role of multiparametric flow cytometry in their review, in the light of the molecular era in detail here. Next to classical cytogenetic analyses and NGS, the role of microRNA dysregulation is analyzed in the review by Ilina Dimitrova-Micheva and her colleagues.Over the decades, different prognostic scores for MDS have been developed, such as the IPSS; the WPSS; the IPSS-R and more recently the IPSS-M, to help estimate survival and transformation rates to acute myeloid leukemia (1)(2)(3)(4). In their original work, Irene Zamanillo and colleagues demonstrate a retrospective validation of the M-IPSS in their MDS patient cohort here.We still do not exactly know, nor understood in detail, how and why MDS develops, but the role of an intact immune system in preventing the development of MDS or delaying its evolution appears to be crucial and is backed up by a higher incidence of MDS in patients suffering from autoimmune or over-immune diseases (5). Luca L-G. Janssen and colleagues explain the role of monocytes and thrombomodulin expression on monocytes in the pathogenesis of MDS here. An established risk factor for the development of MDS is the preexistence of clonal hematopoiesis of indeterminate potential (CHIP) (6). With a comprehensive review Anna Maria Cacic and coworkers explain all the relevant aspects for giving medical advice to patients diagnosed with CHIP, given that besides avoiding chemotherapy whenever possible, not much can be done to avoid the progression to the MDS status. Despite the fact that in the last version of the WHO classification, published in 2022, several new MDS subtypes have been defined in a more granular way, many patients cannot be precisely classified according to this classification (7). In her original work, Blanca Xicoy and colleagues describe the hybrid entity of chronic myelomonocytic leukemia with ring sideroblasts and SF3B1 mutation, which strikingly resembles the entity of MDS with low blasts and SF3B1 mutation.Many patients suffering from MDS are still treated with best supportive care only, even though in the latest decades new treatment approaches for higher-risk MDS and specific, targeted treatments for some forms of lower -risk MDS, especially for MDS with low marrow blasts (LB) and SF3B1 mutation and for MDS with LB and 5q deletion are available. However, for most MDS subtypes, no specific treatment is available, and patients only receive supportive red blood cell and platelet transfusions (8,9). In these patients, very often iatrogenic iron overload occurs, with need for iron chelation therapy. The iron homeostasis and its regulation is complex, and new regulators such as the "master regulator" hepcidin and its regulator erythroferrone have been discovered in the last decades (10). This mini review of Mohammed L Abba and colleagues focuses on the role of erythroferrone in MDS.subgroups, as it is for example the case of SF3B1 mutated MDS with low blasts. In this subgroup, which has the best prognosis of all MDS subtypes, erythropoietin and luspatercept are both approved as treatment options (8,11). These drugs are normally used sequentially, but in this original article, Anna Jonasova and colleagues describe their real-world experience with the combination of both drugs in lower-risk MDS.In patients not undergoing allogeneic stem cell transplantation, we know that intensive chemotherapy does not lead to a prolonged overall survival in the majority of cases (12). Since the publication of the phase 3 study of 5-azacytidine (AZA), compared to conventional care regimen (intensive chemotherapy, low-dose cytarabine or best supportive care), known as AZA-001 study, the treatment of higher risk MDS with AZA considered the gold standard (13). Even though response rates and survival proved to be better with AZA, more than half of the treated patients do not respond to this treatment, and on the contrary may suffer from side effects of the drug, mainly due to aggravating preexisting cytopenias. To date, we do not have tools available, which would allow us to predict response and spare the non-responders a treatment trial. For this issue, Mónica del Rey González and colleagues provide data of molecular profiling, that may help to predict future responders to AZA treatment in this original paper. In elderly patients progressing from MDS to AML, the combination of AZA with Venetoclax (VEN+ AZA) is nowadays the standard therapy (14). However, most patients will experience a relapse and will ultimately die from their disease. Deciphering resistance mechanisms leading to relapse will help to further prolong survival of this patient group in the future. Finally, Petra Bašovà and her colleagues created a mouse model for VEN+ AZA resistance and are describing this model in their original paper they also tested drug combinations to overcome this resistance. This edition touches on major clinical problems with regard to diagnostics, prognostication, and treatment of patients with MDS and hopefully will inspire both clinicians as well as scientists. We hope that the readers will enjoy reading this gallery of manuscripts and will enrich their knowledge on both, basic research and clinical practice.