Myelodysplastic Syndrome Anemia Research Articles

Rytelo: a novel option for transfusion-dependent anemia in myelodysplastic syndromes

Rytelo: a novel option for transfusion-dependent anemia in myelodysplastic syndromes

Treatment of Anemia in Lower-Risk Myelodysplastic Syndrome.

A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.

Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice.

Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Ncoa4 and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Mutant Srsf2 Diminishes Jak2V617F-Induced Erythrocytosis in Mice and Is Associated with Lower Hemoglobin in Patients with Chronic Phase JAK2-Mutant MPN

Polycythemia vera (PV) is characterized by marked erythrocytosis, most commonly managed with therapeutic phlebotomy or cytoreduction. Conversely, anemia is often a feature of myelofibrosis (MF), where it is associated with poor prognosis. The transition from PV to MF is associated with the acquisition of additional somatic mutations in several gene classes, including RNA splicing factors. Since mutations in the RNA splicing factor SRSF2 are associated with anemia in myelodysplastic syndrome (MDS), we set out to investigate how SRSF2 mutations impact erythropoiesis in multiple contexts, including at steady-state, stress-induced, and in the setting of MPN. We first studied the consequences of Srsf2P95H mutations on steady-state erythropoiesis. Primary Mx-Cre Srsf2P95H/+ mice had a reduced red blood cell count (RBC, P<0.001), increased mean corpuscular volume (MCV, P<0.001), and reduced percentage of early erythroid progenitors (pre-CFU-E) in the bone marrow (BM, P=0.04) compared to Mx-Cre mice, consistent with published data (Kim et al., 2015). Moreover, Srsf2P95H/+ mice had a reduced percentage of proliferating pre-CFU-E cells (P=0.03). We next studied the impact of Srsf2P95H mutations on stress-induced erythropoiesis, using a phenylhydrazine (PHZ)-induced hemolysis model. We treated primary Mx-Cre and Mx-Cre Srsf2P95H/+ mice with 30 mg/kg PHZ on days 0 and 1. As expected, RBCs were reduced by ~40% confirming effective hemolysis on day 3. On day 6, PHZ-treated control mice had higher reticulocyte counts compared to Srsf2P95H/+ mice (P=0.005), while the inverse was true on day 9 (P=0.03). Consistently, the frequency of BM pre-CFU-E cells was increased in Srsf2P95H/+ mice vs controls on day 9 (P=0.04). In aggregate, these data indicate that Srsf2P95H/+ mice have a slower recovery to PHZ-induced anemia. Moreover, late erythroid progenitors (CFU-E) were reduced in PHZ-treated Mx-Cre Srsf2P95H/+ vs control mice on day 4 post PHZ (P=0.04). Also, the percentage of BM erythroblasts was 24% reduced (P=0.04), mostly due to a reduction in stage III erythroblasts, and spleen weights were 19% lower in Srsf2P95H/+ vs controls on day 4 (P=0.01). These data suggest defects at the stage III erythroblast, and erythroid progenitor levels due to Srsf2P95H. Our next goal was to understand how Srsf2 mutations affect Jak2-mutant MPN. In line with the data outlined above, primary Mx-Cre Jak2V617F/+Srsf2P95H/+ mice had lower RBC (Fig. A, P=0.002) and higher MCV values (P<0.001) compared to Mx-Cre Jak2V617F/+ mice. These data were recapitulated in a BM transplant model confirming that impaired erythropoiesis is cell intrinsic. Moreover, pre-CFU-E and CFU-E levels were lower in the BM and spleen of Jak2V617F/+Srsf2P95H/+ vs Jak2V617F/+ transplant mice ~30 weeks post pIpC (BM P=0.003 and 0.01, spleen 0.02 and 0.005, respectively). Compared to wild-type mice, mice transplanted with Jak2V617F/+ cells had an elevated fraction of stage II and reduced fraction of stage III erythroblasts, which was partially normalized in Jak2V617F/+Srsf2P95H/+ mice. Finally, spleen weights were >50% lower in Jak2V617F/+Srsf2P95H/+ vs Jak2V617F/+ transplant mice (P<0.001). These data show that Srsf2P95H diminishes Jak2V617F-driven erythropoiesis at the progenitor level and at erythroblast stages II and III. Finally, we interrogated a clinical dataset of 301 JAK2-mutant MPN patients (PV n=157; ET n=129; pre-fibrotic MF n=15) with comprehensive molecular profiling and laboratory results. Eight patients carried both, an SRSF2 mutation (VAF>5%) and a JAK2 mutation. JAK2-SRSF2 co-mutant patients had significantly reduced hemoglobin values compared to JAK2-mutant patients (Fig. B, P=0.01), in agreement with our mouse models. Together, our study shows that Srsf2P95H impairs erythropoiesis in the BM and spleen at multiple differentiation levels. These data contribute to a better understanding of phenotypic differences between JAK2-mutant MPN patients. Since several genes implicated in erythropoiesis and heme metabolism have been shown to be misspliced in SRSF2-mutant MDS, we are currently analyzing RNA-sequencing data from wild-type and Srsf2P95H/+ CFU-E cells, with the expectation that these data will provide insights into the underlying mechanisms driving anemia. These data may ultimately help identify novel therapeutic targets to alleviate anemia in SRSF2-mutant MPN and MDS, which is an area of unmet clinical need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First Single-Center Experience with Luspatercept Therapy in Low-Risk Myelodysplastic Syndrome (LR-MDS) Patients with Transfusion Dependence Refractory to Erythropoietin Therapy

Introduction: In the treatment of low-risk myelodysplastic syndromes (MDS) patients, anemia is the predominant problem. A recent breakthrough in the therapy of anemia in low-risk MDS patients are drugs involved in TGFβ pathway blockade. Luspatercept is a recombinant fusion protein derived from human activin receptor type IIB. It binds TGFβ superfamily ligands and inhibits the SMAD2/3 pathway leading to potentiation of red cell line differentiation and proliferation. Luspatercept was approved last year by the FDA and EMEA in the treatment of anemic low-risk MDS patients with ring sideroblasts (MDS-RS-MLD, MDS-RS-SLD) and/or SF3B1 mutated patients who are not eligible for erythropoiesis-stimulating agents (ESA) or for patients who failed on this therapy. Luspatercept showed high clinical activity for the treatment of anemia in the phase 2 trial (PACE-MDS) and subsequently in the phase 3 trial (MEDALIST). It has led to transfusion independence (TI) in about 40 % of patients. Methods: From January 2021 to July 2022, 27 patients were treated with luspatercept at the hematology department of Charles University Hospital in Prague, Czech Republic. The median age of the patients was 77 years (range 57-89) with a male to female ratio 17:10. WHO 2016 diagnosis were: MDS-RS-MLD (N = 23) and MDS/MPN-RS-T (N = 4). Median of IPSS-R was 2.5 (range 1-4). Median of IPSS-R cytogenetic score scaled from 0-2 with the median of 1. Median follow-up was 7.8 months (range 1-38). Luspatercept was administered in subcutaneous injections once every 3 weeks with an initial dose of 1 mg/kg. Dose escalation was done according to the level of response to 1.33 and 1.75 mg/kg. The median number of cycles administered was 7 (2-17). Transfusion dependency before luspatercept initiation ranged from 2 transfusion units (TU)/8 weeks to 12 TU/8 weeks, 11 patients had low transfusion burden (LTB), 16 high transfusion burden (HTB). Baseline erythropoietin (EPO) level was 374 IU/l in average (range 150-770) and ferritin level was 1307 μg/l in average (range 234-3832). 9 patients received chelation therapy. 22 patients were tested for SF3B1 mutation with 21 positive results (95.5 %) using Sanger sequencing (N = 3) or NGS approach (N = 18). Isolated mutation of SF3B1 was present in 8 patients (44 %). The most frequent mutations besides SF3B1 were TET2 (N = 8; 44 %), ASXL1 (N = 3; 17 %), DNMT3A and RUNX1 (N = 2; 11 %). Average mutations count per one patient was 1.7 (range 0-5). We did not observe any TP53 mutation. Results: There were 24 evaluable patients in terms of response. Thus far 11 (45 %) patients have responded by achieving TI, 5 (20 %) patients have had a reduction in transfusion dependence (HI, according to IWG criteria 2006), 8 (33 %) patients have not responded. One patient progressed to the higher risk MDS, and one transformed to acute myeloid leukemia. Median duration of response was 7.4 months (range: 0.7-31.8). Median number of cycles to achieve response was 4. Eleven patients responded to the basic dose 1 mg/kg, 2 additional patients on the dose 1.33 mg/kg and 2 more on the dose 1.75 mg/kg. There were differences in response according to transfusion burden, in LTB group achieved TI 8 patients and HI 1 patient, in HTB group we observed TI in 3 patients and HI in 4 patients. In 9 patients, we added ESA to luspatercept therapy, as they act both at different levels of erythropoiesis, which led to the improvement of response in 5 cases. In general, patients with lower initial baseline EPO level were better responders. We did not observe decrease in ferritin level during therapy. There was no significant effect of mutation burden on patient's OS, although patients with single mutated SF3B1 achieved better ORR (75 %), than patients bearing mutations in multiple genes (ORR = 40 %). There were no adverse effects of Grade II or more. Conclusion: In conclusion, luspatercept is certainly the next major step in the treatment of anemia in MDS patients. The advantage of the drug is very good tolerance and easy administration. We observed better responses in patients bearing single mutation in SF3B1, patients with LTB and lower initial baseline EPO levels. The higher response rate in our follow-up may be influenced by the combination with ESA and rapid dose escalation. This work was supported by the following grants: grant AZV 2021-2024 NU21-08-00312, Grant AZV 2019-2023 NV19-08-00144, UNCE/MED/016

U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes

AbstractHemolysis is a well-recognized but poorly characterized phenomenon in a subset of patients with myelodysplastic syndromes (MDS). Its pathobiological basis seems to underpin a nonimmune etiology whose clinical significance has not been adequately characterized. Hemolysis in MDS is often attributed to either ineffective intramedullary erythropoiesis or acquired hemoglobinopathies and red blood cell (RBC) membrane defects. These heterogeneous processes have not been associated with specific genetic subsets of the disease. We aimed to describe the prevalence of hemolysis among patients with MDS, their baseline characteristics, molecular features, and resulting impact on outcomes. We considered baseline serum haptoglobin <10 mg/dL a surrogate marker for intravascular hemolysis. Among 519 patients, 10% had hemolysis. The baseline characteristics were similar among both groups. Only 13% of patients with hemolysis were Coombs-positive, suggesting that hemolysis in MDS is largely not immune-mediated. Inferior survival trends were observed among lower-risk patients with MDS undergoing hemolysis. Decreased response rates to erythropoiesis-stimulating agents (ESA) and higher responses to hypomethylating agents (HMA) were also observed in the hemolysis group. U2AF1 and EZH2 hotspot mutations were more prevalent among those undergoing hemolysis (P < .05). U2AF1 mutations were observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hotspot. Somatic mutations encoding splicing factors may affect erythrocyte membrane components, biochemical properties, and RBC metabolic function, which underpin the development of atypical clones from erythroid precursors in MDS presenting with hemolysis. Future studies will explore the contribution of altered splicing to the development of acquired hemoglobinopathies.

Evolution of severe (transfusion-dependent) anaemia in myelodysplastic syndromes with 5q deletion is characterized by a macrophage-associated failure of the eythropoietic niche.

Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34+ CD71+ precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14-dependent intrinsic (S100A8+ ) and extrinsic [tumour necrosis factor α (TNF-α)-overproduction] alterations of (CD169+ ) marrow macrophages (p<0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71high Ter119- immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro-erythroblasts. Marked Ery-Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p=0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage-associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC-TD in MDS.del(5q).

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.

Integrated traditional Chinese and conventional medicine in the treatment of anemia due to lower-risk myelodysplastic syndrome: study protocol for a randomized placebo-controlled trial

BackgroundErythropoiesis and iron homeostasis are closely related; anemia due to lower-risk myelodysplastic syndromes (MDS) remains difficult to treat. In the last decade, we have been committed to improving the regulation of iron metabolism using traditional Chinese medicine (TCM). Previous studies have found that the TCM Yi Gong San (YGS) can reduce the expression of transferrin by inhibiting hepcidin overexpression caused by inflammation, promote the outward transfer of intracellular iron, and improve the symptoms of anemia. Here, our study aimed to compare the efficacy of a conventional drug with YGS with that of conventional medicine with placebo to provide a scientific basis for making clinical decisions.MethodsA prospective, multicenter, double-blinded, randomized controlled clinical trial will be conducted to evaluate the therapeutic efficacy of conventional medicine combined with YGS with that of conventional medicine alone in the treatment of MDS. A total of 60 patients would be enrolled in this study, with each treatment group (conventional medicine + YGS and conventional medicine + placebo) comprising 30 patients. Oral medication would be administered twice daily for 3 months. All patients would be followed up throughout the 3-month period. The primary outcome was measured by assessing blood hemoglobin level. The secondary outcome was measured by assessing TCM symptom score, iron metabolism, hepcidin levels, and inflammatory factors.DiscussionThis trial would aim to demonstrate the effectiveness and feasibility of YGS in the treatment of lower-risk MDS anemia, as well as its impact on inflammatory factors and iron metabolism in patients with lower-risk MDS.Trial registrationChinese Clinical Trials Registry (http://www.chictr.org.cn/) ChiCTR1900026774. Registered on October 21, 2019.

Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients.

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

U2AF1 and EZH2 Mutations Are Associated with Non-Immune Hemolytic Anemia in Myelodysplastic Syndromes

Introduction Hemolysis is a well-recognized clinical observation in a subset of myelodysplastic syndromes (MDS) patients (pts). However, the clinical consequence of hemolysis and the associated molecular phenotype in MDS is not well described in the literature. Nonimmune hemolysis in MDS is often attributed to ineffective intramedullary erythropoiesis or acquired hemoglobinopathies that have been described in rare cases of MDS. In this study, we report the prevalence of hemolysis among MDS pts, their clinical and genomic characteristics and its impact on outcomes. Methods We identified all pts in our institutional MDS database who had serum haptoglobin measured at time of diagnosis or referral. We considered serum haptoglobin &amp;lt; 10 mg/dl as a surrogate marker for intravascular hemolysis. We compared the baseline characteristics, response to treatment, and overall survival (OS) in those with hemolysis (haptoglobin &amp;lt; 10 mg/dl) to those in the non-hemolysis group. Further, we explored the mutational landscape among pts with hemolysis compared to the non-hemolysis group. Results Among 519 pts in our database with a known serum haptoglobin at first referral or diagnosis, 54 pts (10%) had serum haptoglobin &amp;lt; 10 mg/dl (the hemolysis group). The baseline characteristics were similar among the two groups except for a slightly younger age and lower platelets count in the hemolysis group. Other laboratory markers associated with hemolysis such as total bilirubin and LDH were significantly increased in the hemolysis groups. However, no difference was seen in coombs test results. Only 13% versus 9% were Coombs positive suggesting that hemolysis in MDS is typically not immune mediated (table 1). The median OS was 31 months versus 39 months among pts with hemolysis and no hemolysis respectively, (p=.98). There was a trend of inferior survival among pts with hemolysis in the low and intermediate risk revised IPSS (R-IPSS) risk groups. The median OS was 44 months with hemolysis compared to 89 months with no hemolysis in low risk R-IPSS (p=.2) and 19 months versus 34 months in intermediate risk group. (p=.7) The hematological improvement (HI) rate using erythroid stimulating agents (ESA) was 16% (3/19 pts) in the hemolysis group compared to 30% (39/130 pts) in the non-hemolysis group. (p=.2) The HI+ best response with hypomethylating agent (HMA) was 70% (22/31) compared to 45% (127/280) among hemolysis and non-hemolysis groups respectively, (p=.05). Table-2 summarizes the somatic mutations landscape between the hemolysis and non-hemolysis groups. U2AF1 and EZH2 hotspot mutations were statistically significantly more common among hemolysis group. Out of the 16 pts with U2AF1 mutations, 15 (94%) harbored a mutation at serine 34 (S34) in the hemolysis group while only 22 of 55 (40%) cases with U2AF1 mutation had an S34 hot spot mutation in the non-hemolysis group suggesting that the association between U2AF1 and hemolysis is allele specific. (p .0001) Conclusion Non immune hemolysis was observed in 10% of MDS patients. Inferior survival trends were observed among lower risk MDS patients with hemolysis. A decreased response rate to ESA and higher responses to HMA were also observed in the hemolysis group. U2AF1 mutation was observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hot spot. Our data suggest that nonimmune hemolysis is associated with allele specific somatic mutations and associated with key clinical outcomes. Future work will explore the contribution of altered splicing to these acquired hemoglobinopathies. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding.

New Approaches for Anemia in MDS

The heterogeneous nature of myelodysplastic syndromes (MDS) demands a complex and personalized variety of therapeutic approaches. Within this multifaceted setting, the treatment of anemia represents one of the major challenges as the erythroid line is affected in the majority of (especially lower-risk) MDS patients. 1 Platzbecker U Treatment of MDS. Blood. 2019; 133: 1096-1107 Crossref PubMed Scopus (66) Google Scholar The aim of therapy in this population is to improve anemia, decrease transfusion needs, enhance quality of life, attempt to prolong overall survival, and to reduce the risk of progression. 2 Scalzulli E Pepe S Colafigli G Breccia M Therapeutic strategies in low and high-risk MDS: What does the future have to offer?. Blood Rev. 2020; Crossref Scopus (4) Google Scholar Over the past decade, the understanding of MDS pathophysiology has significantly improved and thereby opened new opportunities for more targeted research approaches, biomarkers, and individualized treatment options. 3 Bewersdorf JP Zeidan AM Evolving therapies for lower-risk myelodysplastic syndromes. Ann Hematol. 2020; Crossref PubMed Scopus (12) Google Scholar This abstract provides a short overview of the current therapeutic landscape in MDS-based anemia and some of the emerging therapies.

Editorial introductions

Current Opinion in Oncology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of psychiatry is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Céleste LebbeCéleste LebbeProfessor Lebbe has particular interest in the field of melanoma, merkel cell carcinoma and Kaposi's sarcoma where she conducts clinical and translational research. She has been Principal Investigator in more than 50 clinical trials in the field of dermato-oncology. She coordinates Melbase, a national biobank dedicated to advanced melanoma. She works on therapeutic targets in melanoma (EMMPRIN, PDE4, KINDLIN, cKIT) and biomarkers of resistance to targeted or immunologic treatment in melanoma. Professor Lebbe is co-author and/or senior author of more than 100 publications in international peer-reviews. Pierre HainautPierre HainautPierre Hainaut is PhD in Biology (Zoology), University of Liège, Belgium, 1987. After postdocs in France and in the UK (1988–1994), he joined the International Agency for Research on Cancer (IARC, World Health Organization) in 1994, where he held the post of head of Molecular Carcinogenesis from 1999 to 2011. In 2013, he was awarded a Chair of Excellence in Translational Research at University Grenoble-Alpes and since 2014, he is Director of the Institute for Advanced Biosciences, a research center dedicated to Epigenetics, Chronic Diseases and Cancer. His research focuses on TP53 mutations and p53 protein regulation in cancer and chronic diseases. From 1994 to 2011, he led the development of the international IARC database of TP53 mutations, a worldwide source of information on the causes and consequences of mutations affecting the p53 suppressor protein in cancer. His work addresses mechanisms of mutagenesis and prognostic/predictive significance of TP53 mutations in several cancers including liver, lung and oesophagus. Hi mechanistic studies on p53 focus on the biochemistry of p53 conformational control by metalloregulation and oxidation-reduction and on the identification of p53 isoforms as factors acting as dominant inhibitors of p53 function. His current research address the diversity of TP53 mutations and genetic and non-genetic factors that modulate the penetrance of the Li-Fraumeni Syndrome, a familial cancer predisposition caused by germline TP53 mutation. Pierre Hainaut is author of over 450 publications and 50 book chapters. He has co-edited two books on p53 (25 Years of p53 Research 2005, 2007, p53 in the Clinics, Springer) and a textbook of molecular epidemiology (Molecular Epidemiology: Principle and Practice, IARC Press, 2011), a two-volume textbook on Human Biobanking (Human Biobanking, Principle and Practice, 2017, 2018) and is currently co-editing with Paolo Boffetta the 3rd edition of Elsevier's Encyclopedia of Cancer (2018). Sophie ParkSophie ParkProfessor Sophie Park, is MD and PhD from Paris V University, Cochin Hospital, France. She has done a postdoc in the UK at Cancer Research UK in the laboratory of Dominique Bonnet. Since 2014, she has been appointed as Professor of Hematology at University and Hospital Grenoble Alpes, France. She is the Head of the Hematology Department of Hospital Grenoble Alpes since 2019. Her specialty is myelodysplastic syndromes. She holds fundamental research in the niche and exosomes field, and on the iron metabolism in myelodysplastic syndromes. She has organized the 11th Congress of Myelodyplastic Syndromes of the French Group of Myelodysplastic syndromes (GFM) in 2016 in Grenoble. She has authored more than 90 publications and more than 10 book chapters. She is a member of the editorial committee of “Innovations Thérapeutiques en Oncologie”, a member of the scientific board of the GFM and a member of the French, European and American Society of Hematology. She was awarded the Zittoun Price of the French Society of Hematology in 2013 for her work on anemia in myelodysplastic syndromes.

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

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.

The fraction of CD117/c-KIT-expressing erythroid precursors predicts ESA response in low-risk myelodysplastic syndromes.

Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context. Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients. We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation. The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.

The impact of sex on disease phenotype and prognostic thresholds of anemia in myelodysplastic syndromes

The impact of sex on disease phenotype and prognostic thresholds of anemia in myelodysplastic syndromes

Management of anemia in low-risk myelodysplastic syndromes treated with erythropoiesis-stimulating agents newer and older agents.

The myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders. The International Prognostic Score System (IPSS) groups MDS in lower-risk (IPSS low and intermediate-1) and higher-risk disease (IPSS intermediate-2 and high). AML transformation is the main concern in higher-risk MDS, while anemia and transfusion dependency represent the major issues for low-risk MDS patients. Improving erythropoiesis, and eliminating fatigue and symptoms, is the main therapeutic goal for low-risk MDS patients. Around 50% of MDS patients present with anemia with an Hb level < 100g/L. Severe anemia increases the negative effects of comorbidities, such as heart and lung failure. Erythropoiesis-stimulating agents (ESAs), with or without granulocyte colony-stimulating factor, induce erythroid response rates in 40-50% of lower-risk anemic MDS patients. The median response duration of 24months. Apoptosis of erythroid cells is inhibited by ESAs leading to erythrocyte production. Our paper considers the state of the art of treatment of anemia in low-risk MDS patients and the treatment options in MDS resistant or refractory to ESAs.

Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS

Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.

Epoetin \u03b2 pegol (continuous erythropoietin receptor activator, CERA) is another choice for the treatment of anemia in myelodysplastic syndrome: a case report

BackgroundIn most patients, anemia is present when myelodysplastic syndrome is diagnosed. Although darbepoetin α is the first-choice supportive therapy for low-risk myelodysplastic syndrome, half of all patients develop a loss of response to darbepoetin α within 12 months. However, few reports have described supportive therapy after the loss of response to darbepoetin α.Case presentationWe herein present a case involving a 65-year-old Japanese woman with low-risk myelodysplastic syndrome whose erythropoiesis-stimulating agent treatment was switched from darbepoetin α to epoetin β pegol (continuous erythropoietin receptor activator) to treat transfusion-dependent anemia. The frequent transfusions required to treat the anemia resulted in transfusion-associated circulatory overload. The transfusion-dependent anemia was initially treated with darbepoetin α, which negated the requirement for transfusion. However, after 12 months of darbepoetin α therapy, the hemoglobin concentration sharply declined. We switched her therapy from darbepoetin α to continuous erythropoietin receptor activator to avoid transfusion. After initiation of continuous erythropoietin receptor activator therapy, the hemoglobin concentration gradually increased and transfusion was not required. At the time of writing, no progression of the anemia had occurred.ConclusionsAlthough darbepoetin α is the first-choice supportive therapy for low-risk myelodysplastic syndrome, continuous erythropoietin receptor activator might be considered the second-choice therapy.