Lower-risk Myelodysplastic Syndromes Research Articles

Efficacy and safety analysis of hypoxia-inducible factor prolyl hydroxylase inhibitors for anemia in low-risk myelodysplastic syndromes patients

Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.

Imetelstat: Finally a disease-modifying treatment for lower-risk myelodysplastic syndromes?

Favorable results were achieved in a phase 3 clinical trial (IMerge) with the telomerase inhibitor imetelstat in transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDSs) who relapsed or were refractory to erythropoiesis-stimulating agents.1 Imetelstat is likely to become a useful addition to our limited therapeutic options for patients with MDS.

Clinical Outcomes, Survival, and Predictors in Lower-Risk Myelodysplastic Syndrome Patients Treated with Cyclosporine A

Plain Language SummaryTherapeutic options to improve myelodysplastic syndrome (MDS)-related cytopenias in patients with lower-risk MDS are limited, and cyclosporin A (CSA) is an available option. We retrospectively assessed the effects of CSA on patients with lower-risk MDS at Shuguang Hospital affiliated with Shanghai University of Traditional Chinese Medicine. After statistical analysis, we found that more patients treated with CSA improved cytopenias than those treated without CSA. Patients with hypocellular marrow were more likely to get responses to CSA. Hypocellular marrow was defined as marrow cellularity of <30%. However, CSA did not delay disease progression and prolong survival span. The results of this study suggest that CSA is a safe treatment and can significantly improve cytopenias of a substantial proportion of patients with lower-risk MDS, especially in individuals with hypocellular bone marrow.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

The Role of Hepcidin in Myelodysplastic Syndromes (MDS): A Systematic Review of Observational Studies.

Iron overload emerges as a serious complication in myelodysplastic syndromes (MDS), particularly associated with frequent transfusions during the course of the disease. The discovery and description of hepcidin's mechanisms of action have contributed to a deeper understanding of iron metabolism. The existing literature reports a potential role of hepcidin in MDS, yet these data are fragmented and presented in an unstructured, somewhat chaotic manner. Hence, to address the existing data, we performed a systematic review of observational studies examining hepcidin levels in MDS. An extensive review of three bibliographic databases (Pubmed, Web of Science, and Scopus) enabled us to identify 12 observational studies. These studies focused primarily on adult patients with low-risk MDS who underwent transfusions and chelation therapy. An in-depth analysis of these manuscripts led to four main conclusions: (1) although high serum hepcidin levels are associated with MDS, most studies generally have not found a significant difference in these levels between patients and healthy individuals; (2) serum hepcidin levels are specific to MDS type; (3) serum hepcidin levels in MDS are strongly associated with transfusions and the genetic status of patients; and (4) high-risk MDS is associated with high serum hepcidin levels. While we have furnished a comprehensive summary of the significance of hepcidin in MDS, there are still gaps that future research should address. This pertains primarily to the capacity of hepcidin in predicting adverse outcomes for MDS patients and evaluating the efficacy of chelation therapy or the need for transfusion.

Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦsin regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age-paired patients with lower-risk MDS (N = 15), higher-risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro-inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher-risk MDS compared to lower-risk MDS. BM MФs from patients with higher-risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower-risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower-risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher-risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower-risk MDS. Gene Ontology enrichment comparing BM MΦs from lower-risk MDS and higher-risk MDS for genes was involved in hematopoiesis- and immunity-related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS.

Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes.

Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients. The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients. Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis. ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders. ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45; p = 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7 versus 3.1 years in patients receiving BSC (p < 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes versus 22.2% in ⩾3; p = 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p = 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes versus <3 (33.3% and 10.7%, respectively; p < 0.001). This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.

Hematopoietic Stem Cell Transplantation in the Management of Myelodysplastic Syndrome: A Retrospective, Current, and Future Perspective.

Myelodysplastic syndrome (MDS) is a clonal disorder that affects hematopoietic stem cells (HSCs), primarily occurring in the elderly population. Lower-risk MDS is characterized by a decrease in blood cells, whereas higher-risk MDS is associated with an increased risk of transformation to acute myeloid leukemia (AML). Currently, the treatment of MDS is still unsatisfactory, although demethylating agents, azacitidine (AZA), and decitabine (Dec) have been successfully used to treat MDS and improve survival rates. However, hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for MDS patients, effectively increasing patient survival and quality of life. Nevertheless, treatment-related toxicity, graft-versus-host disease, infectious complications, and relapse are still major post-transplant issues. In this review, through a retrospective analysis of past and present HSCT for the treatment of MDS, we provide insights for the future.

Novel therapies for MDS and future prospects

Myelodysplastic syndromes (MDS) are clonal diseases resulting from the accumulation of genetic mutations. In general, MDS is categorized into two risk groups, with management and treatment varying significantly based on this classification. Over the past two decades, allogeneic transplantation and hypomethylating agents (HMAs) have become the standard of care and remain crucial for higher-risk MDS. Unfortunately, no new drugs have emerged to replace HMAs as the standard of care. However, the landscape of practice and research in MDS has evolved. In 2022, the focus of diagnostic classification of MDS shifted significantly from morphology to genetic alterations. As a result, treatment strategies centered on genetic mutations are now already used internationally. Revisions made to the International Working Group (IWG) criteria for assessing treatment response in 2023 are expected to further improve accuracy. Meanwhile, interest has increased in understanding the relationship between inflammation and the development and progression of lower-risk MDS. This year, luspatercept, an anti-anemic agent targeting the TGFβ pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1β, CD33, TLR, IRAK4, and p38MAPK.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group

Background: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. Methods: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. Results: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1–2. Conclusions: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

Next-generation therapy for lower-risk MDS.

Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

Lower-Risk Myelodysplastic Syndrome (MDS) Patients Exhibit Diminished Proteasome Proteolytic Activity and High Intracellular Reactive Oxygen Species (ROS) Levels.

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and an elevated risk of transformation to acute myeloid leukemia (AML). Available disease-modifying treatment approaches are limited. The ineffectiveness of proteasome inhibitors (PIs) in MDS patients is currently investigated, although it is unclear whether they rapidly develop resistance to PIs or whether proteasome proteolytic activity (PPA) is constitutively lower in the hematopoietic cells of these patients, thus limiting treatment effectiveness. We investigated 20 patients with MDS, categorized according to the International Prognostic Scoring System (IPSS) into a lower- or a higher-risk group. Peripheral blood mononuclear cells, bone marrow mononuclear cells, and cluster of differentiation 34-positive (CD34+) cells were isolated and assessed for the chymotrypsin-like activity of the proteasome and β5 subunit accumulation. Additionally, intracellular reactive oxygen species (ROS) generation was screened. The lower-risk patient group (n=10) exhibited significantly lower proteasome activity (p<0.001) compared to both the higher-risk group (n=10) and healthy subjects (n=10). Furthermore, the lower-risk group had elevated oxidative stress levels (p<0.0001) and reduced β5 subunit expression (p=0.0286). Both parameters were shown to be associated with transfusion dependency, since transfusion-dependent patients (n=5 in each subgroup) had decreased proteasome activity and simultaneously exhibited higher ROS levels. Our results indicate that reduced β5 expression might potentially explain PIs' ineffectiveness in lower-risk MDS, elucidating the importance of the risk group in the selection of the proper treatment algorithm.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial

Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Hematological Response to Frontline Treatment in Lower Risk Myelodysplastic Syndromes (LRMDS) Is Associated with Better Overall Survival

Background The majority of LRMDS patients (pts) (70%) do not progress but unfortunately succumb to complications related to cytopenia, namely anemia and red blood cell transfusion dependency (RBC-TD) or their interplay with co-morbidities. RBC-TD is associated with worse outcome reflecting bone marrow failure and long-term sequela of RBC-TD. There is growing evidence that response to treatment and RBC transfusion independence (TI) are associated with favorable outcome. In lieu of 2 recent randomized clinical trials demonstrating efficacy of luspatercept &amp; imetelstat in LRMDS, we assessed the impact of response to sequential lines of treatment in LR-MDS on overall survival (OS) to guide our treatment choices and to determine whether erythroid stimulating agents (ESA) should still be our 1 st line of therapy. Methods We included LRMDS pts (IPSS-R very low &amp; low) from Moffitt Database who received ESA as frontline therapy (FL) and assessed subsequently outcomes with second line (SL) therapy (SOC or clinical trial). We excluded MDS/MPN and del5q pts. We also excluded all pts who eventually progressed to either higher risk MDS or AML to better reflect the majority LRMDS in that disease state. We assessed details of FL and SL. Pts who received FL &amp; SL were then divided into 4 groups based on response to FL and SL therapy: group 1 (no/no), group 2 (no/yes) with response only to SL, group 3 (yes/no) response to FL only, and group 4 (yes/yes) with response to both lines of therapy. Response was defined as hematological improvement (HI) with ≥1.5 g/dl Hgb increase in non-TD pts and RBC-TI in TD pts at baseline for at least for 8 weeks. We compared median OS (mOS) among those groups. Results There were 603 LRMDS pts who met eligibility criteria and received ESA as FL (Table-1); 43% were RBC-TD, mean serum EPO was 132 (n=211 pts), 69% received epoetin, 17% darbepoetin and 14% with G-CSF. HI was observed in 42% of pts with no difference among ring sideroblasts (RS) +/- (46% vs 40%, p =.12). Response was higher among non-RBC-TD (52% vs 31%, p&amp;lt; .001). The median time to start ESA was 1.2 mo (0-249). The median time on ESA therapy was 11 mo (.4-213). 331 pts (55%) received SL which included HMA 43% (n= 142), lenalidomide 39% (n=130), luspatercept 7% (n=24), ATG 2% (n=8), investigational agent 4% (n=14), and other 4% (n=13) . The HI rate was 27% (91/331). No difference in HI based on RS nor RBC-TD was observed. The median duration on SL treatment was 6 mo (.1-93). 170 pts (28%) received 3 rd line of therapy with 7% HI, 88 pts (15%) received 4 th line of therapy with 3% HI and 39 pts (7%) had 5 th line of therapy with 2% HI. Among the 331 pts who received at least FL and SL, pts were divided into 4 groups based on response to (methods, table-2), the mOS was 114 mo among Yes/Yes response group, 103 mo among yes/no group, 97 mo no/yes and 64 mo among no/no ( P=.007; Figure-1). Response to FL was significantly associated with better OS after adjusting for RS (HR .74 ,95% CI .55-.99, p=.043). Conclusions Only half of patients who receive ESA as FL therapy for LRMDS received any subsequent therapies. Response rates were highest with ESA as FL than any SL therapy. HI with FL and/or SL is associated with improved OS. Lack of response to first line of therapy is associated with worse OS. Responses beyond SL were rarely observed. Identifying and moving agents with high HI rate as FL therapy and or selecting option based on predictors of best chance of response to a specific treatment as FL may lead to better overall survival.

Ker-050 Treatment Reduced Iron Overload and Increased Bone Specific Alkaline Phosphatase in Participants with Lower-Risk MDS Supporting Potential to Restore Balance to the Osteohematopoietic Niche

Background: Iron overload (IO) in myelodysplastic syndromes (MDS) contributes to the deterioration of the osteohematopoietic niche (OHN), where hematopoietic and osteogenic precursors interact to regulate hematopoiesis and bone metabolism. Excess iron exacerbates ineffective hematopoiesis, inflammation, and bone loss via direct effects on resident hematopoietic and osteogenic precursors. Iron chelation therapy (ICT) is associated with improved event-free survival in patients with MDS but does not address the underlying cause of IO and introduces patient burden due to tolerability and cost. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) and promote differentiation and maturation of erythroid and megakaryocytic precursors. KER-050 has potential to reduce dependence on red blood cell transfusions and increase iron utilization via erythropoiesis, possibly mitigating IO at its source. As previously reported from an ongoing Phase 2 study (NCT04419649), KER-050 treatment in participants with lower-risk (LR) MDS resulted in rates of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) of 51.4% and 42.3%, respectively, with a mean decrease in ferritin (322 ng/mL at Week 24) among HI-E and/or TI responders. KER-050 treatment also demonstrated effects on osteogenic precursors, including prevention of bone loss in a mouse model of MDS and dose-dependent increases in bone specific alkaline phosphatase (BSAP), a marker of bone formation, observed in healthy postmenopausal women. Thus, KER-050 has potential to address the multifaceted pathogenesis of MDS, including IO. Here, we present new data from the ongoing Phase 2 study in MDS, exploring the potential of KER-050 to provide benefit beyond hematologic responses and to ameliorate IO in MDS. Methods: This ongoing Phase 2 study is evaluating KER-050 in participants with LR MDS. Data from exploratory assessments of markers of IO, hematopoiesis, and bone turnover are presented as of a cutoff date of April 3, 2023, for all participants who had received the recommended Part 2 dose (RP2D; 3.75-5 mg/kg q4wks). Results: Baseline ferritin levels in RP2D participants (N=59) were generally elevated, while levels of mean corpuscular hemoglobin and reticulocyte hemoglobin were in the normal range (Table 1). After KER-050 treatment, sustained decreases in serum ferritin were observed among participants with baseline levels ≥1000 ng/mL (Figure 1), likely driven in part by reduced transfusion burden in responders. Concomitant increases observed in soluble transferrin receptor (sTfR; Figure 1) suggest that increased erythropoiesis may also have contributed. Mean decreases in ferritin observed in non-transfused (NT) participants (-228 ng/mL at Week 24, n=7) indicate potential for KER-050 to affect iron homeostasis by mechanisms other than transfusion reduction. In 1 NT participant receiving ICT, the baseline ferritin of 1632 ng/mL decreased to &amp;lt;500 ng/mL over 32 weeks, leading to ICT discontinuation and coinciding with an increase in hemoglobin (Hgb) from 9.2 g/dL at baseline to 11.3 g/dL over the same period. In another NT participant not receiving ICT, ferritin decreased from 1094 ng/mL at baseline to 884 ng/mL and 583 ng/mL at Weeks 24 and 68, respectively, while Hgb gradually increased from 9.94 g/dL at baseline to 10.7 and 12.2 g/dL at Weeks 24 and 68. KER-050 treatment was also associated with increases in BSAP, a new finding in this MDS population that is consistent with prior observations in preclinical and healthy volunteer studies. Despite some heterogeneity, mean increases of 8.47% (n=23) and 10.4% (n=13) were observed at Weeks 24 and 48, respectively; 3 participants with erythroid responses had increases in BSAP of ≥30% at these time points. Summary: Exploratory data indicate potential for KER-050 to drive meaningful decreases in ferritin in participants with LR MDS, particularly among those with IO. While transfusion reduction likely contributes, observations in NT participants highlight the potential for enhancement of erythropoiesis to improve IO, irrespective of transfusions. Observed changes in BSAP suggest that KER-050 is also acting on osteogenic precursors, with the potential to provide functional improvements within the OHN. Updated results will be provided at the presentation.

Efficacy of Luspatercept in Low-Risk Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes (MDS) in whom erythropoiesis-stimulating agent therapy is not effective, inevitably become RBC-transfusion dependent, unless other lines of therapy are offered. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, has been FDA approved for use in MDS with ring sideroblasts (RS) and/or detection of an SF3B1 mutation. The efficacy of luspatercept in lower risk (LR) MDS (regardless of RS) patients has been evaluated in clinical and real-world (RWD) studies, suggesting conflicting data. OBJECTIVES This study aimed to conduct a systematic review and meta-analysis of clinical trials and RWD evidence to evaluate the efficacy of luspatercept among lower risk MDS patients. METHODS Prospective randomized controlled trials (RCTs) and phase II trials, retrospective cohort studies and case series of patients with MDS treated with single agent luspatercept were retrieved from PubMed, EMBASE and conference proceedings. References were screened until June 30 th 2023. Two reviewers appraised the quality of the studies and extracted data. Primary outcome was the rate of transfusion independence (for at least 8 weeks). Secondary outcomes included erythroid hematologic improvement (HI-e) rate and safety. Subgroup analysis was conducted for MDS-RS and SF3B1 mutation. Studies were critically appraised using Joanna-Briggs Institute checklists. All studies were included in the meta-analysis. RESULTS We screened 244 titles and eventually included 9 studies, conducted between 2013-2022, and including 839 MDS patients who were treated with luspatercept. Of them: 2 RCTs, one single arm phase 2, and 6 retrospective “real-world” (RWD) studies. Six were published in peer reviewed journals and three RWD studies published as abstracts. Median age of patients ranged between 68-75 years and 707/839 patients had MDS-RS. Three studies were of moderate-high quality (N= 389) and 6 were deemed moderate quality (N=450). Rates of transfusion independence for at least 8 weeks were highly variable ranged between 8-87% among all patients and between 42-87% among MDS-RS subgroup. The median duration of longest response ranged between 23.9-42 weeks. Rates of erythroid hematologic improvement (HI-e), ranged between 25-100%. Pooled estimate of achieving independence from red-cell transfusion for &amp;gt;= 8 weeks was 39.5% (95% CI 0.24, 0.55; I²=96.6%, p&amp;lt;0.001) by meta-analysis. Pooled estimate of HI-e was 54.4% (95% CI 0.44,0.65; I²=87.8%, p&amp;lt;0.001). The most common cause for drug discontinuation was lack or loss of response and disease progression. CONCLUSION The response rate to luspatercept is highly heterogenous among different studies. Overall, the response rate and duration in the RWD setting did not compare favorably with clinical trials. Of note, the vast majority of patients had MDS-RS and the role of luspatercept in the management of patients with MDS without RS is still unclear, even when data from several studies are pooled together. This study has many limitations arising from heterogeneity of patient characteristics and outcomes ascertainment. This highlights the need for standardized post-marketing studies of new drugs and the heterogeneity in RWD patient population.

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial

CONCLUSIONS Transfusion-dependent anemia and related fatigue are commonly associated with lower-risk myelodysplastic syndromes (LR-MDS) and frequently not improved with therapy. Patients with symptoms associated with anemia have an impaired quality of life and inferior overall survival. In IMerge (NCT02598661), the phase 3, randomized, global trial of patients with LR-MDS and a red blood cell transfusion burden of ≥4 U, imetelstat-treated patients had a significantly higher transfusion independence rate than those treated with placebo and showed sustained improvement in patient-reported fatigue via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Sekeres et al. EHA 2023. P732). Here, we assess the impact of imetelstat on several patient-reported outcomes (PROs) relevant to LR-MDS. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Analyses included symptom-specific derived scores for the following parameters: dyspnea, measured by 1 FACT-An and 1 QUALMS item; physical function and systemic symptoms, by 3 FACT-An items each; pain, by 2 FACT-An items; and bleeding, by 1 QUALMS item. Higher scores indicated improvement. QUALMS total score and physical burden score were also analyzed. Psychometric analyses were conducted using blinded interim data to document the measurement properties of these item sets and define the scores that would be used to specify PRO end points in IMerge; all analyses were exploratory and were conducted in the intention-to-treat (ITT) population. The overall effect of imetelstat on each score was evaluated from the repeated measurement mixed model (RMMM) comparing the least-squares means (LSMs) of change in score estimated in the 2 treatment groups using all available data while on treatment up to cycle 30. A positive mean change in the dyspnea score was observed throughout the treatment, up to cycle 24, in the imetelstat group but not in the placebo group (Figure). The RMMM analysis showed an overall change in dyspnea score from baseline of 0.53 (by LSM with 95% CI, 0.241-0.825) with imetelstat versus −0.40 (by LSM with 95% CI, −0.794 to 0.003) with placebo, with a significant difference between the treatment groups (LSM difference, 0.93; 95% CI, 0.446-1.411; P &amp;lt; .001; Table). The model-based mean change estimates for each score showed that, despite having high transfusion burden at baseline, patients in the imetelstat group did not experience more deterioration in any of the other outcomes than those in the placebo group (Table). In addition, the QUALMS composite scores suggested significantly improved health outcomes with imetelstat versus placebo based on RMMM. LSM difference was 4.66 (95%CI, 0.862-8.461; P = .016) and 6.34 (95% CI, 1.771-10.913; P = .007) for QUALMS total and QUALMS physical burden, respectively (Table). Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Reclassification of Ascertain (ASTX727-02) Myelodysplastic Syndrome (MDS) Patients: Outcomes Including Clinical Response, Overall Survival (OS), and Leukemia Free Survival (LFS) Based on IPSS-R and IPSS-M Scoring Systems

Background: Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) given once daily X 5 days on a 28-day cycle producing pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m 2 daily X 5 days on a 28-day cycle. This was demonstrated in the pivotal ASCERTAIN study (Garcia-Manero, et al, ASH 2019) as it provided a PK bridge to existing decitabine data and demonstrated median OS was 31.7 mo. (Savona,et al. Intl. MDSF International Congress on MDS, 2021). Subjects were initially classified by the International Prognosis Scoring System (IPSS) for historical reasons, however IPSS-R and IPSS-M are enhancements to IPSS that provide dynamic risk assessment for predicting clinical outcomes in MDS. Here, the objective was to re-classify the MDS subjects enrolled on the ASCERTAIN study by IPSS-R and IPSS-M and measure the impact of informing patient outcomes based on re-calculated risk assessment. Methods: One hundred thirty-three subjects with MDS/CMML (chronic myelomonocytic leukemia) were enrolled in ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient's decision, or HSCT. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next-generation sequencing (NGS) hematologic malignancy panel of 179 genes including all genes commonly mutated in MDS. In the initial analysis of clinical outcomes, subjects were classified by IPSS with response assessment by IWG 2006 IPSS low and Int-1 risk levels were categorized as lower-risk MDS (LR-MDS), whereas IPSS Int-2 and high-risk categories were categorized as higher-risk MDS (HR-MDS). Subjects with sufficient data based on (e.g., available heme parameters, cytogenetics, NGS etc.) were reclassified by IPSS-R and IPSS-M. Subjects with IPSS-R score of ≤3.5 or IPSS-M of either very low, low, or moderate low were categorized as LR-MDS. Similarly subjects with IPSS-R score of &amp;gt;3.5 or an IPSS-M categorization of either moderate high, high, or very high were categorized as HR-MDS. Reclassified subjects were reassessed for CR (Complete Response), OS, and LFS and Harrell's concordance index (c-index) was used to describe the level of agreement between each scale and outcomes. Results: Based on the available data, the number of MDS subjects in the different risk classifications were the following: IPSS: 117, IPSS-R: 104, and IPSS-M: 105. Thirteen and 12 subjects on the IPSS could not be reclassified in the IPSS-R and IPSS-M, respectively, including 5 Int-1 and 2 low-risk MDS cases. CMML subjects were excluded from these analyses. Re-classification generally resulted in the upgrade of the subjects from LR-MDS to HR-MDS (Fig. 1). Thirty-one (26.5%) subjects from IPSS were reallocated in the IPSS-R to different risk categories; 3 (9.7%) were downgraded and 28 (90.3%) were upgraded. Similarly on reclassification with IPSS-M 34 (32.4%) of the patients reclassified; 5 (14.8%) were downgraded and 29 (85.3%) were upgraded. For IPSS LR-MDS, 23.2% of patients achieved CR, and 22.9% in the IPSS HR-MDS. Similarly, 21.6% patients achieved CR in the IPSS-R LR-MDS, and 23.9% in the IPSS-R HR-MDS; 26.3% patients achieved CR in the IPSS-M LR-MDS, and 20.9% in the IPSS-M HR-MDS. The c-index for the IPSS was .64 (OS) and .67 (LFS), IPSS-R was .70 (OS) and .71 (LFS), and .75 (OS) and .78 (LFS) for the IPSS-M (Table1). Conclusion: Reclassification from IPSS to IPSS-R or IPSS-M upgraded multiple subjects from a LR to a HR category, describing the ASCERTAIN patient population as a majority higher risk population with worse prognosis than previously assumed based on the IPSS. The efficacy as measured by the CR rates did not change when the LR and HR categories were defined by the different risk stratification systems. In contrast, the c-index improves with migration from IPSS to IPSS-R to IPSS-M, indicating an increased discriminatory ability of IPSS-M score in comparison to IPSS and IPSS-R, to predict patient outcomes.

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P &amp;lt;0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P&amp;lt;0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Real-World Impact of Luspatercept on Patients with Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions and with Prior Exposure to Erythropoietin-Stimulating Agents: A United States Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are among the most common hematologic cancers in older US adults. MDS are characterized by abnormal bone marrow function leading to impaired production of blood cells, persistent cytopenia, and variable risk of progression to acute myeloid leukemia (AML). Since anemia is a common complication of MDS, many patients (pts) become dependent on red blood cell transfusions (RBCTs) and erythropoiesis-stimulating agents (ESAs) are the standard of care for patients with lower-risk MDS. In a randomized, double-blind, placebo-controlled phase 3 MEDALIST clinical trial, luspatercept, a first-in-class erythroid maturation agent, was shown to reduce the severity of anemia among transfusion-dependent (TD) pts with lower-risk MDS with ring sideroblasts (RS) status and who were refractory to prior ESA treatment (Fenaux P, et al. N Engl J Med 2020; 382:140-151). However, real-world evidence regarding the effect of luspatercept on transfusion burden among pts with MDS requiring RBCTs and with prior ESA exposure is currently limited. Aim: To describe clinical outcomes and MDS-related treatment patterns before and after the initiation of luspatercept among real-world pts with lower-risk MDS in the USA who required RBCTs before luspatercept initiation and were previously exposed to ESAs. Methods:In this retrospective claims-based cohort study, data from Symphony Health, a nationally representative database, (Jan 1, 2010 to June 30, 2022) were used to identify adults with ≥1 claim with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Pts were considered TD at luspatercept initiation if they had ≥1 claim for RBCT in the 8 weeks before index date, and ESA-exposed if they had ≥1 ESA claim at any point before or at luspatercept initiation. Pts with chemotherapy treatments, with a diagnosis for refractory anemia with excess blasts, or with AML during the study period were excluded as they were presumed to have higher-risk MDS. Pts were also excluded if they had prior use of hypomethylating agents (HMAs) or a diagnosis for β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months prior to index date (baseline period). Pt demographics and clinical characteristics were assessed during the baseline period. Pts' RBCT status (transfusion independent [TI] or TD) was measured in the 6 months after index date. A pt was considered 8-week TI if they had 0 RBCT in ≥1 rolling 8-week period in the 6 months after index date. 12-week, 16-week, and 24-week TI pts were defined similarly, using increasingly longer periods without RBCT. Pts' use of MDS-related treatment classes (ie, chemotherapy, ESAs, granulocyte-colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD] agent) was measured before and after index date until end of data availability or clinical activity (follow-up). Results:The population comprisedof240 pts with MDS who were TD and had ESA exposure before luspatercept initiation. The mean (standard deviation [SD]) age was 75.4 (5.4) years and 56.7% were male. About one fifth of pts received ≥2 treatment classes before luspatercept initiation (2: 17.5%; 3+: 1.7%). Most pts (64.2%) achieved 8-week TI in the 6 months after luspatercept initiation. Similarly, 53.8%, 43.3%, and 29.6% of pts achieved 12-, 16-, and 24-week TI in the 6 months after luspatercept initiation, respectively (Figure 1). The percentage of pts achieving 8-, 12-, 16-, and 24-week TI was numerically higher among pts with positive RS status than those with negative/unknown RS status (Figure 1). Most pts (64.2%) did not require any additional MDS-related treatments during the study follow-up period (mean (SD) 15.6 (7.3) months). The most common treatment classes used after luspatercept initiation were ESA (22.5%) and HMA (16.3%; Figure 2). Conclusions:The findings of this real-world study strongly corroborate clinical trial results, showing that luspatercept is highly effective in reducing transfusion dependence among ESA-exposed pts with lower-risk MDS who were TD before luspatercept initiation. In this study, over half of pts achieved 8-week and 12-week TI status during the follow-up period, and more than a quarter did not require any RBCT over a 24-week period. Further, most pts treated with luspatercept did not require any additional MDS-related treatments during the follow-up period.