Lower-risk Myelodysplastic Syndromes Research Articles

HSR24-142: Real-World Clinical Benefit Among Patients (pts) With Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated With Luspatercept.

HSR24-142: Real-World Clinical Benefit Among Patients (pts) With Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated With Luspatercept.

HSR24-159: Relationship Between Durable Transfusion Independence (TI) and Survival Outcomes in Patients (Pts) With Lower-Risk Myelodysplastic Syndrome (LR-MDS): An Analysis From US Health Insurance Claims Data.

HSR24-159: Relationship Between Durable Transfusion Independence (TI) and Survival Outcomes in Patients (Pts) With Lower-Risk Myelodysplastic Syndrome (LR-MDS): An Analysis From US Health Insurance Claims Data.

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.

Therapeutic 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 analysed the clinical data of 153 consecutive patients with lower-risk MDS at our institution from July 1997 to October 2017. Propensity score matching method was used to balance the influence of confounding factors between patients with MDS treated with CSA and other conventional treatments (excluding CSA), and 50 pairs of cases were successfully identified for the final analysis. We assessed response rates, progression-free survival (PFS), overall survival (OS), and factors affecting response and survival. Haematological improvement (HI) was observed in 35 (70%) patients treated with CSA and in 25 (50%) patients treated with conventional therapies (P < 0.05), respectively. Treatment with CSA was a favourable prognostic factor for HI in lower-risk MDS patients of both cohorts in univariate analysis [odds ratio (OR) 2.333, P < 0.05], but not in multivariate analysis. In the multivariate analysis, hypocellular marrow was the only independent prognostic factor for HI in the CSA group (OR 6.259, P < 0.05), and in the overall cohort (OR 3.102, P < 0.05).CSA treatment did not improve PFS or OS (P > 0.05). CSA is a safe treatment and can significantly improve cytopenias in a substantial proportion of patients with MDS, especially in individuals with hypocellular bone marrow. However, CSA is not associated with PFS or OS.

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 are not well described. We divided our low risk (LR) MDS patients (n=1914) into 4 cohorts: 1) Patients who remained LR-MDS (LR-LR; n=1300; 68%), 2) Patients who progressed from LR to HR MDS (LR-HR) without AML transformation (n=317; 16.5%), 3) Patients who progressed from LR to HR MDS and then AML (LR-HR-AML; n=124; 6.5%), 4) Patients who progressed from LR MDS to AML directly (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.

Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

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.

An accessible patient-derived xenograft model of low-risk myelodysplastic syndromes.

Not available.

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

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Adult lower risk MDS patients with a cumulative transfusion burden of &amp;gt;20 red blood cell units and evidence of iron overload (serum ferritin &amp;gt;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 &lt;i&gt;t&lt;/i&gt; test was applied for statistical analyses. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; 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 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 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% (&lt;i&gt;p&lt;/i&gt; &amp;lt; 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 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1–2. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; 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.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin &amp;lt; 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

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.

Durable Transfusion Independence in Lower-Risk Myelodysplastic Syndrome (LR-MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database

CONCLUSIONS Red blood cell (RBC) transfusions are commonly used to treat patients with LR-MDS and anemia. RBC transfusion dependence (TD) is an impairment on patients' quality of life and associated with worsened survival (Lemos et al. Sci Rep. 2021). The few approved therapeutic options for LR-MDS have limited efficacy and durability. In this study, the baseline RBC-TD before first-line (1L) and second-line (2L) of therapy, durability of transfusion independence (TI), and associated survival among patients with LR-MDS treated with current standard-of-care therapies were assessed in a large US health insurance claims database. Optum Clinformatics ®, a large single-payer database of administrative health claims for members of large commercial and Medicare Advantage health plans, includes approximately 17-19 million annual covered lives, for a total of &amp;gt;76 million unique lives over a 9-year period. Patients with LR-MDS were identified through 5 relevant International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes (D46.0, D46.1, D46.9, D46.A, and D46.B) between Oct 2015 and Jun 2022 and were required to have no MDS/acute myeloid leukemia (AML) diagnosis and no use of higher-risk MDS or AML medication before their respective index diagnosis dates. As revised International Prognostic Scoring System or other risk score classification information was not available in the database, ICD-10 diagnosis codes were used as a proxy for the identification of LR-MDS; these codes have been used previously in published studies (Zeidan et al. Leuk Lymphoma. 2019). Lines of treatment were determined based on claims for MDS treatments contained in the database: erythropoietin stimulating agents (ESAs; darbepoetin, epoetin alfa), hypomethylating agents (HMAs; azacitidine, decitabine, decitabine-cedazuridine), lenalidomide, luspatercept, eltrombopag, and cyclosporine. Outcomes of interest included transfusion burden (RBC units [U] in 8 weeks), proportion of patients who were transfusion independent before and after different lines of treatment, time to 8- and 16-week continuous TI, Kaplan-Meier analysis of real-world progression-free survival (starting a next line of treatment, progression to higher-risk MDS or AML, and death were considered events), and overall survival. The analysis included 5662 patients with LR-MDS (median age, 79 years; 57% male; 76% non-Hispanic White, primarily covered by Medicare Advantage) who received ≥1 line of treatment. Overall, 66% and 17% of patients received frontline monotherapy with ESAs and HMAs, respectively. In the 16 weeks before 1L treatment initiation, 35% of patients received ≥1 RBC transfusion. During 1L treatment, 45% of patients received ≥1 RBC transfusion, of whom 49% received &amp;gt;3 U and 24% received &amp;gt;6 U during any 8-week period. 2L treatment consisted of ESA monotherapy (40%), HMA monotherapy (21%), luspatercept (9%), or a combination thereof (19%). In the 16 weeks before 2L treatment initiation, 49% of patients received ≥1 RBC transfusion, and 55% received transfusions during 2L treatment (Table). Among patients receiving ≥1 transfusion during 2L treatment, 61% and 31% had &amp;gt;3 and &amp;gt;6 U/8 weeks, respectively. Transfusion burden was greater for patients with ring sideroblast-positive disease and increased with subsequent lines of therapy. Among 612 patients who received ≥1 transfusion in the 16-week period before 2L, 33% achieved 16-week TI with subsequent therapies. Median real-world progression-free survival from start of 2L was 20.0 months in patients who achieved 16-week TI and 4.1 months in patients who did not ( P &amp;lt; .0001). The median overall survival from start of 2L was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming RBC-TI vs nonresponders, respectively ( P &amp;lt; .0001; Figure). Among patients with LR-MDS, 35% and 49% were RBC-TD before 1L and 2L of therapy, respectively. Achievement of TI was associated with improved survival, suggesting that RBC-TD is a modifiable predictor of clinical outcomes in LR-MDS. Despite the currently available therapies, RBC-TD after any line of therapy is associated with poorer outcomes. Our study results show that novel therapies that provide durable TI are expected to yield decreased progression and improved survival.

Biochemical and Metabolomic Analysis of Glycolytic Activity in Red Blood Cells from Low-Risk Myelodysplastic Syndromes (LR-MDS) Patients and in-Vitro Effect of the Pyruvate Kinase Activator AG-946

Background: Anemia is the most common cytopenia occurring in 80%-85% of patients (pts) with LR-MDS and therapeutic strategies remain limited. Beyond defective maturation, preliminary data has shown decreased glycolytic activity in MDS-RBCs. Glycolytic pathway is the prominent metabolic cascade in RBCs and is currently targeted with PK activators in clinical trials of congenital anaemias which are also marked by ineffective erythropoiesis like MDS. AG946 is an investigational, potent activator of PK with potential to enhance RBC functionality and survival by increasing glycolysis. Aim: Evaluate enzymatic activity of the glycolytic pathway in pts with anemia due to LR-MDS and in-vitro effect of pyruvate kinase (PK) activator (AG946) in RBCs cultures of LR-MDS pts. Methods In part A, 66 anemic pts (i.e., Hb&amp;lt;11 g/dL) diagnosed with MDS according to WHO 2022 were enrolled in the study and sampled for peripheral blood &amp;gt;4 weeks after the last RBC unit to reduce blood donor contamination. The determination of activities of RBC enzymes hexokinase (HK) and PK (the initial and terminal steps of glycolytic pathway), and of ATP levels was performed by standard spectrophotometric method according to Beutler et al, 1984. 2,3DPG levels were tested by (2,3-BPG) ELISA kit (ElisaGenie, IE). In part B, purified RBC or whole blood of 10 LRMDS pts and 5 healthy controls (HC) were incubated for 6 and 24 h at 37°C in presence or absence of AG946 in phosphate-buffered saline containing 1% glucose, 170 mg/L adenine, and 5.25 g/L mannitol (AGAM, pH 7.40). RBC were incubated with 1, 5 and 50 uM of AG946 for up to 24 h, at 37°C. After 6 and 24 h, enzymatic activities (HK, PK) and ATP levels were measured. Additionally, metabolomic analysis was performed by LC-MS on extracts from blood samples for each condition. Results Part A: Pts were mainly elderly males (median age 80yr, range 58-92), and mostly belonged to IPSS-R low (78%) and very low/low groups (85%). PK activity (median 13.7 IU/gHb, 7.5-35.9) was reduced in 35% of cases and HK activity (median 2.3 IU/gHb, 0.8-8.1) was increased in 91%, resulting in an abnormally reduced PK/HK ratio in majority of pts (95%). Notably, ATP levels (median 3.4 umol/gHb, 1.3-6.5) were also reduced in 33/56 tested patients (59%), whilst 2,3DPG levels were close to the upper limit of the normal range (median 389 nmol/gHb, 318-639). Conclusions: Our data demonstrates decreased glycolytic activity in a large cohort of anemic pts with LR-MDS versus HC, with reduced PK activity in 1/3 of cases, decreased PK/HK ratio in nearly all subjects, and reduced ATP in 2/3 of pts. Furthermore, in vitro incubation with AG946 led to an increase in PK activity and PK/HK ratio and stable ATP levels in RBCs of LR-MDS pts across all WHO classifications. Metabolomic analysis confirmed an altered RBC-metabolic status of MDS versus HC at baseline with possible modulation of glycolysis by AG946, further supporting a potential therapeutic role of PK Activation with AG946 in LR-MDS.

Durable Clinical Benefit with Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants with Lower-Risk MDS

Background: In myelodysplastic syndromes (MDS), defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). 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) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS and myelofibrosis. Preclinical studies demonstrated that KER-050 increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, KER-050 has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB or non-ring sideroblast (RS) MDS. Methods: Analyses evaluating KER-050 at the recommended Part 2 dose (RP2D; 3.75 - 5 mg/kg q4wk) in participants with lower-risk (LR), RS+ or non-RS MDS from an ongoing Phase 2 study (NCT04419649) are presented as of a data cutoff date of April 3, 2023. The primary endpoint evaluates the safety and tolerability of KER-050. Secondary endpoints of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) ≥8 weeks are presented for participants who received ≥24 weeks of treatment or discontinued. DOR and changes in hematological parameters for participants with ongoing TI are presented for the first time. Results: At baseline, most participants receiving KER-050 at the RP2D (74.6%) required regular transfusions (≥2 RBC units/8 weeks); 52.5% of RP2D participants had HTB (≥4 RBC units/8 weeks) and 20.3% had ≥8 RBC units/8 weeks (Table 1). The median treatment duration was 166 days (range 6 to 649). Most participants (89.8%) had at least 1 treatment-emergent adverse event (TEAE), and 32.2% had TEAEs considered treatment-related (Table 1). The most frequently observed TEAEs in ≥15% of participants were fatigue (22.0%), nausea and diarrhea (18.6% each), epistaxis (16.9%), and COVID-19 and dyspnea (15.3% each). A minority of participants (10.2%) had TEAEs that led to treatment discontinuation. Consistent with prior data, rates of TI for ≥8 weeks were similar regardless of baseline transfusion burden or RS status (Table 1). Among TI responders, 72.7% maintained TI for ≥24 weeks (data not shown), and the median DOR was not yet evaluable as more than half (6/11) had ongoing TI as of the cutoff date (Figure 1). Five of the 6 (83.3%) participants with ongoing TI had HTB at baseline, including one participant with a baseline transfusion burden of 11 RBC units/8 weeks, and all 3 responders with ongoing TI for &amp;gt;60 weeks. One participant with HTB and non-RS MDS had ongoing TI for &amp;gt;72 weeks with a steady increase in hemoglobin from 8.4 to 11.8 g/dL. Erythroid responses were not at the expense of other cell lineages, as levels of platelets and neutrophils generally did not decrease (Figure 1). In fact, 44.1% of participants overall experienced a sustained (≥8 weeks) mean increase in platelet count of ≥30 x 10 9 within the first 24 weeks. Sustained decreases in ferritin were observed in parallel with increases in soluble transferrin receptor (Table 1), and for 3 participants, iron chelator therapy (ICT) was able to be discontinued. Investigation into changes in serum ferritin and ICT with KER-050 treatment will continue as cohorts of participants with MDS and iron overload are enrolled. Summary: Updated findings from this ongoing Phase 2 study in LR MDS continue to show that KER-050 is generally well-tolerated and has potential to elicit sustained hematological improvements in a broad population of participants with LR MDS, including those with HTB. New data reveal an encouraging DOR, with observed preservation or improvement of multilineage hematopoiesis and sustained decreases in ferritin manifesting clinically with discontinuation of ICT. The study is ongoing and an update with the latest data will be provided at the time of presentation.