Lower-risk Myelodysplastic Syndromes Patients Research Articles

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients: A proof-of-concept study.

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients. Data showed decreased glycolytic activity in red blood cells of 2/3 of patients with lower-risk MDS. These results highlight a potential effect of the PK activator in this setting.

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.

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.

Red Blood Cell Transfusion Dependence Is Associated with Greater Healthcare Resource Utilization, Higher Medical Cost, and Poorer Prognosis in Patients with Lower-Risk Myelodysplastic Syndromes: A 28-Year Retrospective Observation Study Result

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of myeloid neoplasms characterized by cytopenia due to inefficient hematopoiesis, with a considerable risk of progression to acute myeloid leukemia (AML) or early mortality. In lower-risk MDS (LR-MDS) patients, anemia and its associated complications have been the focus of clinical attention. A significant portion of these patients eventually develop red blood cell transfusion dependence (RBC TD), which has been linked to a poorer prognosis. Given the limited efficacy of available treatments in reducing RBC TD, most patients face increased risks of chronic anemia and various complications. Moreover, RBC TD is known to be associated with reduced overall survival (OS) and leukemia-free survival (LFS). This study aimed to assess the impact of RBC TD on the socioeconomic burden and clinical prognosis of LR-MDS patients, utilizing an electronic medical records (EMR) database spanning nearly 30 years of MDS patient data. This retrospective observational study examined adult MDS patients (≥ 18 years of age) treated at Samsung Medical Center in the Republic of Korea. Eligible patients were diagnosed with MDS between Sep 1, 1994, to Apr 1, 2022 (index period), with the observation period spanning from Sep 1, 1994, to Sep 1, 2022. Baseline assessments included estimation of revised international prognostic scoring system (IPSS-R) scores, categorizing patients with very low, low or intermediate risks as lower-risk MDS (LR-MDS). TD was defined as the occurrence of any 16-week period with RBC transfusion of ≥ 2 units per 8 weeks, without consecutive 56-day period without transfusion. Healthcare resource utilization (HCRU), medical costs, and prognosis indicators including overall survival (OS) and AML-free survival (AFS) were analyzed and compared between patients who experiencing TD and those not (non-TD). Out of 831 MDS patients, 349 (42.0%) were classified as lower-risk at baseline. Among LR-MDS patients, 29.5% (103/349) experienced TD while 23.3% (194/831) experienced TD in the entire study population. The median age at diagnosis of MDS was 63 (ranging from 18 to 89), and 65.3% (543/831) were male. In LR-MDS patients, there were no significant differences in either baseline age (61 vs 63, P=0.16) or gender (71.8% vs 61.0% males, P=0.053) between TD and non-TD groups. However, TD group exhibited significantly higher median erythropoietin (EPO) level than non-TD group (290.5U/L vs. 112U/L, P&amp;lt;0.001) among LR-MDS patients with available baseline serum EPO levels (76 TD and 178 non-TD). Among the 76 TD LR-MDS patients with baseline serum EPO levels, 51 (67.1%) exhibited &amp;gt; 200U/L, which is considered a clinical threshold for erythropoiesis-stimulating agent (ESA) treatment. As shown in Table 1, RBC TD was consistently associated with greater HCRU and higher medical costs, especially in LR-MDS patients. TD LR-MDS patients had higher rates of outpatient department and emergency room visits (15676 vs. 8303 visits and 587 vs. 328 visits per 1000 person-years [PY], respectively), and increased hospitalizations (709 vs. 456 per 1000 PY), with longer hospital stays (13343 vs. 8272 days per 1000 PY). Furthermore, TD LR-MDS patients required over four-times of packed RBC units than non-TD patients (31107 vs. 7073 units per 1000 PY). Consequently, TD LR-MDS patients incurred higher total medical cost than their non-TD counterpart (13.5 million vs. 6.1 million USD per 1000 PY). Median OS (58.4 months vs. 103.1 months) and AFS (52.7 months vs. 102.7 months) were both significantly shorter in the TD group compared to the non-TD group among LR-MDS patients, while the differences in OS and AFS did not reach the level of significance in the entire study population (Table 1 and Figure 1). Notably, median OS after the first documented RBC TD event was 33.8 months (95% confidence interval: 24.7-58.5 months) in LR-MDS patients. The findings of this study indicate that RBC TD can be a strong predictor of increased HCRU and medical costs, as well as decreased OS and AFS over a 20-year period following the initial diagnosis of LR-MDS. Given that a majority of LR-MDS patients experiencing TD may not be eligible for ESA treatment due to elevated EPO levels exceeding 200U/L, and the use of cytotoxic agents is not usually recommended for these patients, these results highlight a substantial unmet need for alternative treatment options to address RBC TD in LR-MDS patients.

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.

The Pyruvate Kinase (PK) Activator AG-946 Improves PK Properties and Red Blood Cell (RBC) Characteristics upon Ex Vivo treatment of RBCs from Patients with Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) consist of a heterogenous group of clonal myeloid malignancies, characterized by dysplasia, ineffective hematopoiesis and cytopenias. MDS patients frequently suffer from anemia, directly affecting quality of life. The limited therapeutic options often do not result in the desired clinical improvement. Interestingly, in MDS the activity of the red blood cell (RBC) enzyme pyruvate kinase (PK), a key regulatory enzyme of glycolysis, may be decreased. The activation of PK via small molecules is hypothesized to be beneficial in a wide range of anemias. Currently, a phase 2a, open-label, proof of concept trial is running on the use of the PK activator AG-946 in low-risk MDS patients (NCT05490446). In light of these developments, we investigated the effect of ex vivo treatment of MDS RBCs with AG-946. Objectives: To evaluate RBC PK and cellular properties of patients with MDS, and to determine the effect of ex vivo treatment with the PK activator AG-946. Methods: Eleven low-risk non-transfusion dependent MDS patients and six healthy controls (HCs) were studied. Baseline PK activity and PK thermostability were measured in RBC lysates of purified RBCs, under V max conditions (phosphoenolpyruvate (PEP) 5mM final concentration). Hexokinase (HK) activity was included to relate PK activity to mean RBC age. Ex vivo treatment was performed by incubating MDS RBCs for 16 hours at 37 °C in presence or absence of the PK activator AG-946 (10μM or 5μM) using dimethylsulfoxide (DMSO) as a blank. Effect was assessed by measuring PK activity (using a final concentration of PEP 0.5mM) and levels of adenosine triphosphate (ATP) (LC-MS/MS). Functional RBC analysis was performed by osmotic gradient ektacytometry (Lorrca MaxSis). To investigate the effect on PK thermostability, RBC lysates were incubated with AG-946 (2μM or 1μM) or DMSO, after which residual PK activity was measured (PEP 0.5mM). The effect of AG-946 on erythroid development was studied using peripheral blood mononuclear cells, cultured in MethoCult TM H4434 medium for 14 days in the presence or absence of AG-946 (10μM or 625nM, DMSO as blank). Differences between conditions were determined using Unpaired T-test, ANOVA with Dunnett's test or Kruskal-Wallis with Dunn's test via GraphPad Prism. Results: Mean PK/HK ratio was significantly lower in RBCs from MDS patients compared to HCs (6.1 (SD 1.8) versus 10.5 (SD 1.5), p&amp;lt;0.001). Upon ex vivo treatment, PK activity significantly increased (independent of dosage) when compared to DMSO (10μM AG-946, mean increase 30% ( p&amp;lt;0.001); 5μM, 28% ( p&amp;lt;0.0001)) (Figure 1A). MDS RBCs displayed decreased PK thermostability at baseline under V max conditions (HCs 79% residual activity versus 68% in MDS, p&amp;lt;0.01). This was restored by ex vivo treatment with AG-946 (DMSO, 33% residual activity, 2μM AG-946, 85% ( p&amp;lt;0.0001); 1μM, 87% ( p&amp;lt;0.0001)). The increase in PK activity was accompanied by significantly increased ATP levels (N=10, DMSO, mean ATP 14.9 μg/mL RBC; 10μM AG-946, 21.0 μg/mL RBC ( p&amp;lt;0.01); 5μM, 21.1 μg/mL RBC ( p&amp;lt;0.01)) (Figure 1B). Functionally, RBC properties improved upon ex vivo treatment with AG-946 as reflected by the modest yet significant increase in O hyper, indicating improved hydration status (10μM AG-946, mean increase 2.3% ( p&amp;lt;0.001); 5μM, 2.9% ( p&amp;lt;0.0001)). To date, culture assays were performed in 8 patients; 3/8 showed an increase in the number of burst forming units-erythroid (BFU-Es) upon treatment with AG-946 when compared to DMSO. The percentual increases differed per patient: increase of 25% with 10μM AG946 and 150% with 625nM, increase of 40% (10μM) and 39% (625nM), and for the third an increase of 22% (10μM) and 39% (625nM). Conclusion: Our findings show that RBCs from MDS patients have decreased PK activity and thermostability. We demonstrate that ex vivo treatment with AG-946 increases PK activity and ATP levels and restores PK thermostability. Moreover, ex vivo treatment with AG-946 improves RBC hydration, suggesting that improved energy status directly improves RBC functional properties. The preliminary results of the culture assay could indicate that in certain patients, dyserythropoiesis may be ameliorated upon PK activation. To better understand the effects on erythropoiesis additional experiments are required. In conclusion, our data might support a rationale for the use of PK activators as a novel therapeutic option for MDS.

Overall Survival in Patients with Ccus Depends on Presence of Anemia

Introduction Clonal cytopenia of undetermined significance (CCUS) is a recently recognized hematological disorder characterized by the presence of one or more cytopenias, evidence of clonal hematopoiesis and not fulfilling the criteria for a myeloid neoplasm. In contrast to myelodysplastic syndromes (MDS) where 95% of the patients are anemic at time of diagnosis, that is only the case for around 60% of patients with CCUS (Weeks et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid. 2023). Furthermore, as recent studies on survival in CCUS primarily included younger patients (Weeks et al. NEJM Evid. 2023) or population-based cohorts not specifically referred for diagnostic work up of unexplained cytopenia (UC) (Rossi et al. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years, Blood 2021) additional survival data on patients with CCUS are warranted. In this study, we investigated survival outcomes in patients with CCUS referred for primary work up of UC. Methods We included 241 patients with CCUS and compared them to 144 patients with low-risk MDS, defined as having less than 5% blasts in the bone marrow. Bone marrow biopsies and next-generation sequencing (NGS) were performed in all patients and cytogenetic analyses using G-band karyotyping was done in 362 (94%) of cases. For NGS, we used a gene panel with the most commonly mutated genes in MDS. The patients were included at 6 different institutions in Denmark from 2013 and onwards. A cut-point of 5 years follow-up was chosen for more robust survival data, and patients were censored at this time point if followed for more than 5 years. Patients with CCUS were stratified into 3 groups dependent on the type of cytopenia present at diagnosis. CCUS patients with pancytopenia (n = 35), and CCUS patients without pancytopenia were split based on whether they were anemic (n = 143) or not (n =63). We compared overall survival between the CCUS groups and low-risk MDS in a Cox proportional hazards model adjusted for age, sex, number of variants and presence of high-risk variants. Results Of the 241 CCUS patients, 178 (74%) were anemic (hemoglobin &amp;lt; 12 and 13 g/dL for women and men, respectively), while this was the case for 130 (90%) of the patients with MDS. A total of 772 variants were identified in the entire cohort with a median of 2 (IQR: 1-3) per patient for both CCUS and MDS patients. The overall survival at 5 years was 45% for low-risk MDS patients and 62% for CCUS patients. For CCUS patients without anemia, CCUS patients with anemia and CCUS patients with pancytopenia overall survival at 5 years was 85%, 52% and 55%, respectively (p &amp;lt; 0.0001). In the adjusted Cox proportional hazards model, we found a significantly superior overall survival for CCUS patients without anemia compared to those with anemia (HR: 0.28, 95%-CI: 0.13-0.58, p = 0.001) and pancytopenia (HR: 0.22, 95%-CI: 0.09-0.53, p = 0.001) and patients with low-risk MDS (HR: 0.18, 95%-CI: 0.09-0.38, p &amp;lt; 0.001). There was no significant survival difference between CCUS patients with pancytopenia and low-risk MDS patients (HR: 0.67, 95%-CI: 0.46-1.50, p = 0.5). Of the remaining variables, age was the strongest prognostic factor with hazard ratio increasing with a factor 1.05 (95%-CI: 1.03-1.07, p &amp;lt; 0.001) per year aged. Predicted survival probabilities for a 65-year-old and 80-year-old person demonstrate a substantial difference in overall survival across all 3 categories of CCUS (figure 1). Discussion Here we show that the presence of anemia impacts overall survival among CCUS patients. We observe that CCUS patients without anemia, representing 26% of CCUS patients in our cohort, have a superior overall survival compared to those with anemia, even with a comparable mutational profile. Our findings indicate that other factors than mutational signatures impact overall survival. Moreover, the prevalence of CCUS increases with age, and our findings demonstrate a considerable difference in survival between a 65-year-old and 80-year-old person diagnosed with CCUS. This raises the concern that prediction models can overestimate the survival rates if the elderly group of CCUS patients is not well represented in these models. In conclusion, we show that age and hemoglobin levels are important factors in overall survival for CCUS patients, and that patients with CCUS without anemia have a superior overall survival and should be considered as a separate group within the CCUS category.

Utilization Patterns and Outcomes from Iron Chelation in Elderly Patients with Low-Risk Myelodysplastic Syndrome

Introduction: Iron overload from red blood cell (RBC) transfusions is a source of morbidity and mortality in patients with myelodysplastic syndromes (MDS). Evidence supporting iron chelation therapy (ICT) in Low-Risk MDS (LR-MDS) is controversial on account of studies conducted in highly selected patients and limited clinical trial data. We conducted a large population analysis aimed at defining real-world ICT utilization in LR-MDS and associated outcomes. Methods: We included patients diagnosed with MDS from 2007 to 2017 in SEER-Medicare using ICD-O-3 codes, aged 66 or older, with continuous Medicare parts A, B, and D. Exclusion criteria included patients with high-risk histology (MDS with excess blasts), less than 2-year survival, without complete follow-up, or enrolled in HMO. ICT eligibility was defined as ICD-9/10 codes for transfusion-related iron overload and/or cumulative ≥20 RBC units within ≤2 years of MDS diagnosis. ICT was identified from HCPCS codes for deferoxamine or prescription records for deferasirox or deferiprone. Explanatory variables included age, sex, race, rurality, socioeconomic quintile, marital status, geographic region, MDS histologic subtype, year of diagnosis, Charlson comorbidity index (CCI), and MDS therapies, including erythropoietin-stimulating agents (ESA), hypomethylating agents (HMA), and lenalidomide, identified from HCPCS codes and prescription records. Outcomes were identified through validated algorithms using ICD-9/10 codes and included overall survival (OS), progression to acute myeloid leukemia (AML), and complications related to iron overload, comprising heart failure, non-ischemic heart disease, atrial fibrillation/flutter, and liver disease/cirrhosis. To control for confounding, we implemented 3 approaches: multivariable Cox-proportional hazards regression, propensity score matching (PSM) by conditional probability of receiving ICT, and cause-specific regression with competing risk of death. Results: We analyzed 2,564 LR-MDS patients who were eligible for ICT. The mean ± SD age was 81 ± 6 years and 56.2% were male. Only 393 (15.3%) of these patients received ICT. The initial agent of choice was deferasirox in 203 (51.7%), deferoxamine in 188 (47.8%), and deferiprone in 2 (0.5%). Median ICT duration was 7 months (IQR 1-20). Chelated patients were younger (median age 79 vs 81, p&amp;lt;0.01), more likely to have histology with ringed sideroblasts [RS] (17.8% vs 7%, p&amp;lt;0.01), had less comorbid burden (median CCI 1 vs 2, p&amp;lt;0.01), and were more frequently treated with ESA (42.8% vs 33%, p&amp;lt;0.01), HMA (59% vs 49.8%), and lenalidomide (27% vs 11.1%, p&amp;lt;0.01), than those not treated with ICT. Their median monthly RBC transfusion density was 4 (IQR 2-6). Factors predicting ICT use were histology with RS (OR=1.9, 95%CI 1.4 - 3.8), RBC transfusion density (OR=1.1 per 4 units/month, 95%CI 1.1-1.2), and therapy with ESA (OR=1.5, 95%CI 1.2-1.9), HMA (OR=1.3, 95%CI 1.1-1.8), or lenalidomide (OR=2.6, 95%CI 1.9-3.5). Among patients who received ICT, 352 (89.6%) were considered transfusion dependent (≥2 RBC units within 8 weeks before starting ICT). Of them, 278 (78.9%) achieved hematologic response (≥50% decrease in RBC units following ICT). ICT was associated with decreased risk of death (HR=0.52, 95%CI 0.46-0.59) in the multivariable model adjusting for all listed covariates. The PSM matched 379 chelated (96.4% case rate) with 729 non-chelated patients and yielded similar results for OS benefit from ICT (HR=0.53, 95%CI 0.46-0.61). Table 1 shows results for other outcomes. Across models, ICT was associated with 43-49% decreased risk of AML transformation and 23-32% reduced risk of adverse cardiac outcomes. Cardiac benefit was predominantly driven by a lower risk of heart failure. No significant association was observed between ICT and hepatic outcomes. Conclusions: Our results suggest that ICT is associated with fewer transfusions, improved OS, lower risk of AML, and less adverse cardiac outcomes in LR-MDS. Our older, unselected cohort better reflects real-world LR-MDS patients and builds upon OS benefit reported in more restricting settings. Given the link between clonal hematopoiesis, cardiovascular disease and LR-MDS, defining ICT's effect on molecular and clonal dynamics could clarify the mechanism behind improved cardiac outcomes.

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.

Combination Therapy with Luspatercept and the Ferroportin Inhibitor Vamifeport Is Superior to Either Drug Alone in Improving Anemia and Reducing Myeloid Skewing in MDS

Background: Patients with myelodysplastic syndromes (MDS) are prone to develop iron overload as a consequence of ineffective erythropoiesis and chronic transfusion therapy. Although iron overload is a common feature in MDS, it has remained unclear whether and how iron excess is detrimental for MDS pathophysiology. Recently, we have shown that iron restriction by the oral ferroportin (FPN) inhibitor vamifeport improves anemia and reduces myeloid skewing, being of benefit for MDS as single treatment. Luspatercept is a recombinant fusion protein acting as TGF-β superfamily ligands trap which has recently gained FDA approval for the treatment of anemia in transfusion-dependent low-risk MDS patients. Luspatercept promotes erythropoietin (EPO)-independent maturation of late-stage erythroid cells, resulting in increased hemoglobin and red blood cells (RBCs) count. However, this drug - due to a lack of improvement in myeloid skewing and AML evolution - is considered a non-disease-modifying therapy. Aims: In this study we investigated the effect of a combined therapy using luspatercept and the FPN inhibitor vamifeport in a preclinical MDS mouse model, with the hypothesis that both drugs could have additive effects with further benefit for the disease. Methods: To this end, we administered the FPN inhibitor vamifeport in NUP98-HOXD13 MDS mice for 3 months (0.5 mg/ml into drinking water), combined with luspatercept for the last 2 months (5 mg/kg twice a week, subcutaneous injection), starting at 3 months of age. Mice receiving the combined treatment were compared to those untreated or receiving single treatments. Results: At steady-state MDS mice develop anemia, neutropenia and lymphopenia, together with an iron overload phenotype, hallmarked by inappropriately low hepcidin levels, elevated serum iron and transferrin saturation, non-transferrin-bound iron (NTBI) formation and tissue iron deposition. Vamifeport administration in MDS mice reduced serum iron and NTBI formation and prevented tissue iron loading, either as a single or combined treatment with luspatercept. Luspatercept and vamifeport, as single-agent treatment, ameliorated anemia and the maturation of bone marrow and splenic RBCs in MDS mice. The combined therapy further improved anemia compared to the treatments with either drugs alone, as suggested by the higher hemoglobin levels, hematocrit and RBC count, and the decreased number of early erythroid precursors, sign of more effective erythropoiesis. Importantly, vamifeport, but not luspatercept, significantly altered myeloid skewing in MDS, revealing a major role of the iron status in myeloid expansion. Myeloid bias, monitored as percentage of CD11b + Gr1 + myeloid cells in the bone marrow was attenuated by iron restriction in vamifeport-treated MDS mice compared to control and luspatercept-treated MDS animals. The combined treatment merkedly reduced myeloid skewing in MDS mice, similarly to the single vamifeport treatment. Furthermore, the number of immature cKit + myeloid blasts in the peripheral blood of MDS animals were decreased by vamifeport alone and in combination with luspatercept, but not by luspatercept alone. Finally, splenomegaly was reduced in MDS mice treated with vamifeport alone or in combination with luspatercept, confirming that iron restriction improves ineffective erythropoiesis and limits myeloid skewing. Overall, the combination therapy with vamifeport and luspatercept showed superior effects in improving anemia and myeloid bias as compared to single treatments. Conclusion: In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action of luspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore, vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as single agent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and provide pre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as more effective therapeutic strategies for the treatment of MDS.

Clinical Application of the IPSS-M Prognostic Score in Myelodysplastic Syndrome

Objectives: Patients with myelodysplastic syndrome (MDS) currently get therapy in accordance with their prognosis scores. The newest MDS risk-stratified score, the IPSS-M, isn't still being extensively used in clinical practice and is based on clinical and molecular data. Comparing the IPSS-M score to the current IPSS-R score will enable us to assess the clinical relevance of the IPSS-M score, especially for low-risk MDS patients. Methods: In order to determine the IPSS-R and IPSS-M scores, we gathered clinical, cytogenetic, and molecular information from 210 MDS patients who were diagnosed between 2016 and 2023 and followed up until April 2023. Harrell's c index and Kaplan-Meier survival analysis were used to examine the impact of the two scores on overall survival (OS).The lower-risk group included patients with IPSS-R≤3.5 and IPSS-M≤0, whereas the higher-risk group included the remaining patients. Analysis was done on the differences in gene mutations between the two risk groups based on the two scoring standards, as well as the impact of IPSS-M reclassification on the choice of therapeutic treatments. Results: At least one genetic mutation was identified in 77.1% of patients. The genes ASXL1 (21.4%), TET2 (19.0%), TP53 (14.8%), and DNMT3A (13.3%) have the highest frequency of mutations. According to IPSS-R score, the higher-risk group's TP53 gene mutation rate was significantly higher than that of the lower-risk group; According to IPSS-M score, the higher-risk group had more instances of TP53 and ASXL1 gene mutations than the lower-risk group did, while the lower-risk group had a relatively higher incidence of SF3B1 gene mutations than the higher-risk group did. The difference in survival between IPSS-M groups was more prominent than that between IPSS-R groups under Kaplan-Meier survival analysis, which was used to assess the prognostic prediction power of IPSS-R and IPSS-M. When t 50 months, the Harrell's c index of OS predicted by IPSS-M exceeded that of IPSS-R (IPSS-R vs IPSS-M c-index: 0.710vs0.747, 0.692vs0.707, 0.705vs0.726, 0.752vs0.759, 0.743vs0.773, t=10, 20, 30, 40, 50 months), demonstrating that IPSS-M enhanced the outcome prediction.87 patients (41.4%) were re-stratified by IPSS-M, with 65 (30.9%) being upgraded and 22 (10.5%) being degraded. 64 patients (30.5%) who had changes in their IPSS-M scores qualified for reduced therapy, whereas 48 (22.9%) qualified for intensive treatment, including 32 patients who were reclassified as being in the lower risk category based on their IPSS-R scores. Conclusions: The research shows that IPSS-M offers a more thorough prognostic evaluation than IPSS-R. Certain patients' treatment modalities may need to be changed as a result of modifying IPSS-M in clinical settings, especially those who were previously classified as low-risk.

Performance of the Molecular International Prognostic Scoring System (IPSS-M) in Hypomethylating Agent-Treated Patients with Myelodysplastic Syndromes

Background: Patients with myelodysplastic syndromes (MDS) undergo risk stratification with various prognostication tools, such as the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). Recently, the Molecular IPSS (IPSS-M) was developed incorporating genomic data in addition to clinical and cytogenetic characteristics. Though IPSS-M has been shown to improve prognostication in all MDS patients at baseline, its utility in specifically patients undergoing hypomethylating agent (HMA) therapy remains unknown. Here, we assess the efficacy of IPSS-M in HMA-treated patients with MDS. Methods: We retrospectively evaluated all untreated patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who later received HMA therapy. Patient characteristics and bone marrow (BM) data, including morphology, cytogenetics, and mutations, were assessed at diagnosis. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in July 2023. Results: Out of 799 untreated MDS patients, 455 patients (57%) eventually underwent treatment with HMA. At diagnosis, the median age was 69 (range: 22-90) with 289 (64%) male patients. Patients were generally high risk, with therapy-related MDS in 160 (35%), complex cytogenetics in 167 (37%), and TP53 mutations in 168 (37%). By IPSS-R, 259 patients (58%) had high- or very high-risk disease, and 340 patients (75%) had higher-risk disease (moderate high-, high-, and very high-risk) by IPSS-M. A total of 291 patients (64%) were treated with HMA monotherapy, and lower-risk MDS patients received more cycles of HMA (p &amp;lt; 0.001). By IPSS-R, the median overall survival was 60.0 months (95% CI: 46.0, not estimable (NE)) in very low-, 87.4 months (95% CI: 59.9, NE) in low-, 36.2 months (95% CI: 30.0, 58.1) in intermediate-, 23.7 months (95% CI: 19.6, 34.8), in high-, and 12.8 months (95% CI: 11.0, 16.7) in very high-risk patients (p &amp;lt; 0.0001) with a concordance index of 0.669. Figure 1 depicts the reclassification of patients between IPSS-R and IPSS-M. Risk stratification by IPSS-M (Figure 2) provided similar results: not reached (95% CI: 56.8, NE) in very low-, 60.0 months (95% CI: 49.8, NE) in low-, 40.8 months (95% CI: 22.8, NE) in moderate low-, 44.2 months (95% CI: 27.8, NE) in moderate high-, 33.4 months (95% CI: 22.8, 44.5) in high-, and 16.6 months (95% CI: 13.8, 19.4) in very high-risk patients (p &amp;lt; 0.0001). The concordance index of IPSS-M in all HMA-treated MDS patients was 0.648. When analyzing patients with MDS who were more likely to undergo HMA as per standard-of-care treatment (those with IPSS-M moderate low-, moderate high-, high-, and very high-risk disease), the IPSS-M remained statistically significant (p &amp;lt; 0.0001) though less discerning in the patients with moderate-risk MDS, as seen by the concordance index of 0.620. Conclusions: In this group of MDS patients treated with HMA, the IPSS-M did not provide additional prognostic power over the IPSS-R though median overall survival remained inversely proportional to IPSS-M risk category. Concordance indices for survival remained below 0.7, likely due to the overlapping curves in moderate-risk patients by IPSS-M. Further development and validation of prognostic scoring systems in patients treated with HMA are warranted.

Use of steroids in the management of low-risk myelodysplastic syndromes with autoimmune features.

The boundaries between myelodysplastic syndromes (MDS) and immune-mediated cytopenias are often difficult to establish and both conditions may benefit from immunosuppressive therapy. The optimal timing and doses of immunosuppressants are largely unknown. We systematically evaluated a retrospective cohort of 79 patients with low-risk MDS tested for anti-erythrocyte or anti-platelet autoantibodies to assess their frequency and the efficacy of immunosuppression, particularly with steroids. We found autoantibody positivity in 43% of cases and overt autoimmune diseases in 18%, including autoimmune hemolytic anemia, immune thromboctyopenia, and Evans syndrome. Steroid treatment improved cytopenia in about half of patients, with 26% achieving a complete recovery lasting for a median of 12 months. Better responses were observed in anemic patients with anti-erythrocyte autoantibodies than in those with anti-platelet autoantibodies, and the combination with recombinant erythropoietin (7/10) had a possible synergistic effect. Steroid doses were heterogeneous depending on the clinical intent (i.e., anti-inflammatory, immunosuppressive, anabolizing). Patients treated with a dose of 1 mg/kg day of prednisone for overt autoimmune cytopenia showed high rates of complete responses (60%). This observation suggests a trial with a short course (2-3 weeks) of standard steroid doses to ascertain efficacy and properly silence the autoimmune pathogenic mechanism. Steroid-related adverse events (16% of cases) should be monitored carefully in this elderly, frail population. In conclusion, features of autoimmunity are present in more than two-thirds of low-risk MDS patients and a trial with prednisone 0.5-1 mg/kg day for 2-3 weeks, with proper monitoring of adverse events, may be useful to improve cytopenias in selected cases.

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

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

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

EE509 Burden of Disease in Low-Risk Myelodysplastic Syndromes in Spain

Myelodysplastic syndromes (MDS) are a group of hematological malignancies characterized by cytopenias and an increased risk of progression to acute myeloid leukemia (AML). Red blood cell transfusions constitute the main supportive care for patients with MDS after failure of Erythropoiesis-stimulating agents. The aim was to assess the disease burden in low-risk MDS (LR-MDS) patients from the Spanish National Health System (NHS) perspective.

The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high-risk clonal cytopenia of unknown significance.

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.

Current Cardiovascular Disease Risk Prediction Models Are Not Applicable in MDS Patients: Preliminary Results of a Prospective Observational Single-Centre Cohort Study

Background/aims Cardiovascular disease (CVD) is a leading cause of death in lower-risk Myelodysplastic syndrome (LR-MDS) patients and a shared pathobiology between MDS and CVD has been postulated. However, current evidence emanates only from retrospective cohorts suffering from crucial shortcomings. Prospective annotation can overcome these limitations and delineate the role of MDS as an independent risk factor for CVD. For this reason we conducted a prospective observational single-centre cohort study in LR-MDS patients. Methods Patients underwent thorough evaluation for CVD every 6 months. Cerebrovascular, peripheral and coronary vascular beds were assessed for atherosclerosis by ultrasound and coronary artery calcium (CAC), respectively. Cardiac structure and function was assessed by echocardiography. Multi-Ethnic Study of Atherosclerosis (MESA), Framingham (FRS) risk scores and serum markers of myocardial injury (Serum high-sensitivity troponin T, hsTnT), stress (N-terminal pro-B-type natriuretic peptide, NT-proBNP), and systemic inflammation (high-sensitivity C-reactive protein, hsCRP) were also estimated at each visit. Chi-square, Wilcoxon signed-ranks tests and Pearson's correlation coefficient were used as appropriate. Multiple linear regression was applied for modeling the relationship between a dependent and one or more independent variables. The level of statistical significance was set to P=0.05. Results Table 1 presents baseline characteristics of 26 patients included so far. There were no correlations of CAC, MESA and FRS with either MDS subtype or IPSS-R risk category after adjustment for preexisting CVD, age, sex, and transfusion dependence. In sharp contrast to the general population (Okwuosa, TM et al. JACC 2011), CAC score was not associated with FRS (p=0.7) and was disproportionately increased in low and very low FRS risk patients (Figure 1). Likewise, the number of affected vascular beds (AVB) did not correlate with FRS (p=0,51) (Figure 2), further suggesting that the current CVD risk prediction tools are inaccurate in MDS and arguing for an intrinsic tendency of MDS towards CVD development. A second and a third evaluation was available in 17 and 7 patients, respectively. All patients increased significantly the CAC score both at 6 months (p=0.04) and 1 year (p=0.003). The average increase from baseline was 26.2% at 6 months and 72.6% at 1 year, markedly higher than expected in the general population (McCullough PA et al. Arch Int Med 2009), and was marginally higher in transfusion dependent patients (p=0.049), but not associated with baseline MESA score, FRS, preexisting CVD, exposure to ESAS, statin therapy, sex. Finally, baseline NT-proBNP levels correlated strongly with CAC score P=0.001 (Figure 3) in line with numerous evidence showing that NT-proBNP can potentially serve as a predictor of CVD risk in both MDS and non-MDS individuals. Conclusion To our knowledge this is the first study in LR-MDS patients assessing longitudinally all critical parameters and providing objective measurements of subclinical atherosclerosis in all vascular beds. Our preliminary results indicate that the established CVD prediction models do not operate properly in LR-MDS patients and reinforce the notion of a pro-atherogenic role of MDS. Accurate assessment of CVD risk and prompt detection of subclinical cardiovascular disease in MDS patients will assist clinical decisions on the introduction of intensive monitoring and preventive use of CVD-specific interventions in these individuals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal