Therapy For Myelodysplastic Syndrome Research Articles

Elesclomol-copper synergizes with imidazole ketone erastin by promoting cuproptosis and ferroptosis in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) encompass a collection of clonal hematopoietic malignancies distinguished by the depletion of peripheral blood cells. The treatment of MDS is hindered by the advanced age of patients, with a restricted repertoire of drugs currently accessible for therapeutic intervention. In this study, we found that ES-Cu strongly inhibited the viability of MDS cell lines and activated cuproptosis in a copper-dependent manner. Importantly, ferroptosis inducer IKE synergistically enhanced ES-Cu-mediated cytotoxicity both in vitro and in vivo. Of note, the combination of IKE and ES-Cu intensively impaired mitochondrial homeostasis with increased mitochondrial ROS, MMP hyperpolarized, down-regulated iron-sulfur proteins and declined oxygen consumption rate. Additionally, ES-Cu/IKE treatment could enhance the lipoylation-dependent oligomerization of the DLAT. To elucidate the specific order of events in the synergistic cell death, inhibitors of ferroptosis and cuproptosis were utilized to further characterize the basis of cell death. Cell viability assays showed that the glutathione and its precursor N-acetylcysteine could significantly rescue the cell death under either mono or combination treatment, demonstrating that GSH acts at the crossing point in the regulation network of cuproptosis and ferroptosis. Significantly, the reconstitution of xCT expression and knockdown of FDX1 cells have been found to contribute to the tolerance of mono treatment but have little recovery impact on the combined treatment. Collectively, these findings suggest that a synergistic interaction leading to the induction of multiple programmed cell death pathways could be a promising approach to enhance the effectiveness of therapy for MDS.

Enhanced ALOX12 Gene Expression Predicts Therapeutic Susceptibility to 5-Azacytidine in Patients with Myelodysplastic Syndromes.

5-azacytidine (AZA), a representative DNA-demethylating drug, has been widely used to treat myelodysplastic syndromes (MDS). However, it remains unclear whether AZA's DNA demethylation of any specific gene is correlated with clinical responses to AZA. In this study, we investigated genes that could contribute to the development of evidence-based epigenetic therapeutics with AZA. A DNA microarray identified that AZA specifically upregulated the expression of 438 genes in AZA-sensitive MDS-L cells but not in AZA-resistant counterpart MDS-L/CDA cells. Of these 438 genes, the ALOX12 gene was hypermethylated in MDS-L cells but not in MDS-L/CDA cells. In addition, we further found that (1) the ALOX12 gene was hypermethylated in patients with MDS compared to healthy controls; (2) MDS classes with excess blasts showed a relatively lower expression of ALOX12 than other classes; (3) a lower expression of ALOX12 correlated with higher bone marrow blasts and a shorter survival in patients with MDS; and (4) an increased ALOX12 expression after AZA treatment was associated with a favorable response to AZA treatment. Taking these factors together, an enhanced expression of the ALOX12 gene may predict favorable therapeutic responses to AZA therapy in MDS.

Eosinophilia During Lenalidomide Therapy in Myelodysplastic Syndrome

BackgroundLenalidomide is an immunomodulatory therapy used to treat multiple hematologic malignancies. The incidence of eosinophilia and hypereosinophilia during lenalidomide therapy, and the requirement for high-dose steroids are not well-defined Patients and MethodsWe retrospectively reviewed 44 patients with myelodysplastic syndromes who were treated with lenalidomide therapy from August 2006 and March 2023. ResultsEosinophilia (0.5-1.5 × 109/L) and hypereosinophilia (>1.5 × 109/L) were observed in 6 patients (14%) and 4 patients (9%), respectively. The median duration of lenalidomide therapy was 6.5 months. Backward multivariate ordinary logistic regression identified higher absolute eosinophil count (OR, 4759.986; 95% CI, 11.223-2018772.073; P = .006) and longer duration of lenalidomide therapy (OR, 1.148; 95% CI, 1.012-1.302; P = .032) as independent prognostic factors for the incidence of eosinophilia and hypereosinophilia. There was a trend for a higher use of high-dose steroids with hypereosinophilia. The median time to develop the first occurrence hypereosinophilia was 0.5 months. Steroids were used in 40% of patients with eosinophilia or hypereosinophilia. All events resolved with discontinuation of lenalidomide and/or use of steroids. No long-tern lasting adverse effects were recorded. ConclusionLenalidomide may induce or worsen existing eosinophilia which may lead to the need for steroids within a month of therapy.

Real-World Outcome and Prognostic Factors in MDS Patients Treated with Azacitidine-A Retrospective Analysis.

Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival and quality of life. Nevertheless, many patients fail to respond to AZA treatment, as prognostic factors still are not identified. The present retrospective analysis included 79 patients with MDS treated with AZA as first-line therapy in a real-life setting. The percentage of patients with good, intermediate, and poor cytogenetics was 46.8%, 11.4%, and 34.2%, respectively. The overall response rate (complete remission [CR], partial remission [PR], and hematological improvement [HI]) was 24%. The CR, PR, and HI rates were 13.9%, 2.5%, and 7.6%, respectively. Stable disease (SD) was documented in 40.5% of patients. The median overall survival (OS) and progression-free survival (PFS) were 17.6 and 14.96 months, respectively. Patients with ORR and SD had a significantly longer median OS (23.8 vs. 5.7 months, p = 0.0005) and PFS (19.8 vs. 3.5 months, p < 0.001) compared to patients who did not respond to AZA. In univariate analysis, only an unfavorable cytogenetic group was a prognostic factor of a lower response rate (p = 0.03). In a multivariate model, older age (p = 0.047), higher IPSS (International Prognostic Scoring System) risk (p = 0.014), and higher IPSS-R cytogenetic risk (p = 0.004) were independent factors of shorter OS. Independent prognostic factors for shorter PFS were age (p = 0.001), IPSS risk (p = 0.02), IPSS cytogenetic risk (p = 0.002), and serum ferritin level (p = 0.008). The safety profile of AZA was predictable and consistent with previous studies. In conclusion, our study confirms the efficacy and safety of AZA in a real-world population and identifies potential biomarkers for response and survival.

Community-Based Practice Patterns and Perceptions of Challenges Integrating New Therapies for High-Risk Myelodysplastic Syndrome

BACKGROUND : With a limited number of approved therapies for myelodysplastic syndrome (MDS), first-line treatment options for patients with high-risk MDS remain an unmet need. As many patients can become refractory to treatment or relapse, it is imperative that they receive the most suitable and effective therapy upfront based on their risk stratification. Several treatment strategies, including immunotherapy, are being investigated and have shown encouraging results with the potential to transform care for this patient population. To create effective education on new therapies for MDS, a two-phase educational initiative was designed. METHODS : The first phase consisted of a deep-dive survey evaluating current practice patterns, barriers, attitudes, and challenges in management of newly-diagnosed high-risk MDS which was launched in February 2023 and closed in March 2023. The survey was disseminated via a partnership with IQVIA with criteria for inclusion set as: treating physicians confirmed by ICD-10 code matching and at least one prescription for any pharmaceutical product for MDS during the prior 3 months from survey launch. The second phase of the initiative was a live and endured CME-certified activity led by two experts in MDS. This was hosted on OMedLive.com and remains on-demand through June 2024. Microlearning clips were disseminated via LinkedIn. The expert panel addressed the identified challenges from the survey results and discussed practice-changing clinical data. Knowledge and competence questions were administered pre-, immediate post-activity, and during the program as interactive polling. Attitude, perceptions, and practice patterns associated with management of MDS were also assessed. RESULTS : The phase one survey was completed by 23 hematologists/oncologists currently treating patients with MDS. The insights from the survey showed a preference for use of the IPSS-R classification system (96%); however, only 52% ‘always’ utilize a risk stratification scoring system. The top three factors influencing treatment decisions for newly-diagnosed MDS were: molecular and genetic prognostic factors (78%), comorbidities (70%), and long-term evidence/real-world data (48%). Across the continuum of care, the most challenging treatment setting was identified as intermediate/high-risk relapsed/refractory MDS. The top three challenges were requirements to follow specific treatment algorithms, access to investigational agents in clinical trial, and managing patients relapsed or are refractory to approved therapies. Clinical perceptions of emerging therapies revealed that 17% of survey respondents would not consider an investigational therapy for a newly diagnosed high-risk patient. To date, 1,371 clinicians have participated in the educational initiative, 91% of whom were physicians and 89% identified their specialty as hematology/oncology. Low baseline knowledge and competence (&amp;lt;40%) was observed across assessment questions. Insights gathered throughout the activity indicated intermediate/low and intermediate/high as the MDS risk categories that are most difficult to manage. Mixed reports of classifications systems was observed with IPSS-R as the highest at 35%, IPSS reported by 28%, and IPSS-M used by 20%. Participants reported equivalent difficulty in treatment of lower vs higher-risk MDS and newly diagnosed vs relapsed/refractory MDS. Following the educational activity, intended practice changes were reported as applying the latest guidelines, improve referral of patients, and refine treatment/management approaches. CONCLUSIONS: This initiative provided insights into provider current practices and perceptions on management of newly diagnosed high-risk MDS. These adequately informed the educational initiative with some differences in perceptions seen post activity compared with the survey analysis from phase one. There are gaps remaining for clinicians to align on use of risk stratification scoring systems and improve algorithmic approaches based on treatment setting and risk status. Educational interventions are needed to address these practice gaps, employ strategies to effectively integrate new therapies, and stay abreast of the rapidly changing MDS landscape.

Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk

Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low. Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT. Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

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.

Real-World Retrospective Study of Non-Transfusion Dependent Patients with Myelodysplastic Syndromes Treated with Luspatercept: A Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are common hematologic malignancies in older adults that are characterized by abnormal bone marrow function leading to reduced blood cell production, persistent cytopenias, with a risk that patients may progress to acute myeloid leukemia (AML). Due to the high rate of anemia, many patients with MDS require red blood cell transfusions (RBCT), which, in turn, are associated with a high clinical and economic burden. In the phase 3 randomized COMMANDS and MEDALIST clinical trials, luspatercept reduced the severity of anemia among transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)-refractory and ESA-naive patients with lower-risk (LR)-MDS (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736(23)00874-7, Fenaux P, et al. N Engl J Med 2020;382:140-151). However, there are limited real-world data on the use of luspatercept in patients who are non-transfusion dependent (NTD) or have a low transfusion burden. This study aims to describe the real-world clinical outcomes and treatment patterns before and after the initiation of luspatercept in patients with LR-MDS who were NTD before luspatercept initiation, in the USA. Methods:In this retrospective claims-based cohort study, data from the Symphony Health database (Jan 1, 2010 to June 30, 2022) were used to identify adults with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Patients were considered NTD if they had no unique dates with a claim for RBCT during the 8-week period before or on the index date. Patients were excluded if they received chemotherapy or had a diagnosis of refractory anemia with excess blasts or AML during the study period, as they were presumed to have higher-risk MDS. Patients were also excluded if they had a diagnosis of β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months pre-index (baseline period) or prior use of hypomethylating agents (HMAs). Patient demographics and clinical characteristics were assessed during the baseline period, and patients' RBCT status (NTD or TD) was measured for 6 months after the index date. A patient was considered 8-week NTD if they had no RBCT in ≥ 1 rolling 8-week period; 12-week, 16-week, and 24-week NTD patients were defined similarly, using increasing durations of NTD. Administration of other MDS therapies (ie, chemotherapy, ESA, granulocyte colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD ®] agent) was measured pre-index and post-index until the end of clinical activity or data availability (follow-up). Results: Of the 871 eligible patients who received luspatercept 589 (67.6%) were NTD before luspatercept initiation. Among this NTD population, the mean (standard deviation [SD]) age was 74.7 (6.3) years and 57.2% were male. Before luspatercept initiation, 15.3% of patients received 2 treatment classes and 0.8% received ≥ 3 treatment classes. Almost all patients (98.5%) maintained 8-week NTD status in the 6 months after luspatercept initiation. Similarly, 96.8%, 94.1%, and 88.6% of patients maintained NTD status for at least 12, 16, and 24 weeks in the 6 months after luspatercept initiation, respectively (Figure 1). Most patients (64.7%) did not require any additional MDS-related treatments during the study follow-up period, (median [SD] 15.7 [7.4] months). Overall, 77.1% of patients were treated with luspatercept for &amp;gt; 6 months and 68.4% for &amp;gt; 12 months. After luspatercept initiation, patients most commonly received treatment with ESAs or HMAs (14.9%; Figure 2). Conclusion:This is the first real-world evidence study to address luspatercept treatment in patients who were NTD prior to luspatercept treatment, which resulted in positive clinical outcomes and few RBCTs.Almost all patients with LR-MDS who were NTD at luspatercept initiation maintained 8-week NTD status during the 6 months after luspatercept initiation. The majority of patients did not receive a RBCT for a 24-week period after luspatercept initiation. Finally, over three-quarters of the patients remained on luspatercept and two-thirds of patients did not receive additional MDS-related treatments after a median follow-up of 15.7 months.

Metabolic Syndrome Among Patients with Myelodysplastic Syndrome: A Population Analysis

Introduction: Metabolic syndrome (MS) comprises a cluster of cardiovascular risk factors, including central obesity, dysglycemia, elevated blood pressure (BP), increased triglyceride levels (HyperTG), and low HDL cholesterol levels. Epidemiologic and clinical data suggest that MS may be an important etiologic factor in the progression of certain cancer types. These studies have excluded patients with myelodysplastic syndromes (MDS), but MS may be relevant in these patients owing to the link between cardiovascular disease and MDS derived from clonal hematopoiesis. We conducted a population-based analysis to define the prevalence of MS and its components among patients with MDS and explore the effect of MS on MDS outcomes. Methods: We identified patients aged 66 and older diagnosed with MDS between 2007 and 2017 using the SEER-Medicare database. Preexisting MS was identified using ICD-9/10 codes in claims from at least 12 months before MDS diagnosis. MS was defined as the presence of 3 or more of the 5 MS components. MDS histologic risk was defined based on ICD-O-3 morphology codes. Transfusion dependence, defined as 2 or more transfusions within 8 weeks of MDS diagnosis date, and therapy with hypomethylating agents (HMA), lenalidomide and erythropoietin stimulating agents (ESA) were defined from HCPCS codes and prescription records. Other variables defined included age, sex, race/ethnicity, rurality (using RUCC codes), marital status, and socioeconomic status [SES] (using the Yost index). Descriptive statistics were used to define the frequency of MS and its components. MDS outcomes of interest were transformation to acute myeloid leukemia (AML), defined from ICD-9/10 codes for AML, and overall survival (OS), defined as the time between MDS diagnosis and death from any cause. Cox proportional hazards regression was used to determine the association between MS and AML transformation and OS, through adjusted hazard ratios (HR). Results: A total of 15,227 cases diagnosed with MDS between 2007 and 2017 were analyzed, including 3,402 (22.3%) with baseline MS. High BP was present in 72.2%, HyperTG in 47.8%, dysglycemia in 35.5%, central obesity in 4.6% and 0.5% had low HDL cholesterol. The prevalence of MS and the distribution of its components did not significantly differ based on MDS histologic risk (Table 1). The prevalence of hyperTG was notably higher in patients with MDS, especially in the high histologic risk category (50.4%). Compared to other MDS patients, those with preexisting MS were predominantly male (55.5% vs 53.3%, p=0.03) of non-White race (6.7% vs 4.8% non-Hispanic Black, p&amp;lt;0.01, and 2.1% vs 1.5% Hispanic, p&amp;lt;0.01), from urban/metropolitan areas (87.7% vs 86%, p=0.01) and lower SES quintiles 1 and 2 (34.2% vs 31.5%, p&amp;lt;0.01). In a model adjusting for age, sex, race/ethnicity, rurality, marital status, SES, MDS risk, transfusion dependence and MDS therapies (HMA, lenalidomide and ESA), baseline MS at the time of MDS diagnosis was not associated with a significant effect on the risk of AML transformation (HR=1.0, 95%CI 0.9-1.2) or the risk of death from any cause (HR=1.0, 95%CI 0.9-1.1) (Table 2). In models assessing the effect of MS subcomponents on MDS outcomes, high BP (HR=1.0, 95CI% 1.0-1.1) and obesity (HR=1.1, 95CI% 1.0-1.2) were associated with an increased risk of mortality. Obesity was also associated with an increased risk of transformation to AML (HR=1.3, 95CI% 1.0-1.6). Conclusions: The overall prevalence of MS among patients with MDS appears similar to that reported in the general population and does not differ based on the histologic risk category. The observed prevalence of HyperTG was higher than expected, particularly in high-risk MDS patients. Older males of non-White race from urban/metropolitan areas of lower SES are more likely affected across all groups. Though preexisting MS is present in an important proportion of MDS patients, it was not significantly associated with an increased risk of mortality or AML transformation after adjusting for confounders. Obesity was associated with higher mortality and linked to increased transformation to AML. Given recent data suggesting that statins may improve survival and decrease AML transformation in MDS, future studies should investigate the potential association between other metabolic parameters and MDS outcomes.

Clinical Characteristics of Patients with TP53 Multihit MDS and AML. a Single-Center Experience

Introduction TP53 is a tumor suppressor protein encoded by the TP53 gene that plays a pivotal role in maintaining genomic stability in response to DNA damage, activates DNA repair programs and triggers cell-cycle arrest. Mutations in TP53 (TP53-mut) are present in approximately 5-10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), and confer an extremely poor prognosis, irrespectively of the treatment administered. The frequency of TP53 abnormalities increases up to 25-40% in therapy-related MDS and AML, up to 70%-80% in patients with complex karyotype and in patients with loss of chromosome 17/17p, 5/5q, or 7/7q. “Multihit” TP53-mut present with the loss of both wildtype TP53-alleles, either through point mutations or larger aberrations to chromosome 17, in complex monosomal karyotypes. Recent data strongly support the concept that TP53mut, particularly multi-hit TP53, results in similarly poor clinical outcomes, regardless of its classification as MDS or AML, arguing for a revised TP53 mutant myeloid entity that includes both MDS and AML. The aim of our analysis is to assess the impact of the multihit TP53-mut on clinical outcomes according to the type of treatment received. We will particularly focus on the presence of mono or biallelic mutation status of TP53 mutation. Methods We retrospectively evaluated 42 patients with TP53 mutated MDS or AML diagnosed from October 2016 to June 2023 in our department at the Catalan Institute of Oncology-L'Hospitalet in Spain. We analyze the prognosis of these two diseases, focusing on single-hit or multi-hit status of TP53 mutation and treatments received. Results Median age at diagnosis was 71 years (range, 44-87 years) with a male predominance (67%). Thirty-five (84%) patients were diagnosed of AML and 7 (16%) of MDS. Among AML patients, 17% had a prior diagnosis of dysplasia, 78% were diagnosed of AML with dysplasia-related changes, 13% with therapy-related neoplasms, and 9% were AML with maturation and/or AML with mutated NPM1. Regarding MDS patients, 57% had an excess of blast-2 (EB2) MDS, 43% MDS multilineage dysplasia (MLD) and MDS with excess of blast-1(EB1). Complex karyotype was present in 79% of the patients. The median variant allele frequency (VAF) of TP53mut was 36%. Multi-hit TP53 status was observed in 24 patients (57%). In this group of multi-hit TP53mut median age was 72 years (range,44-81 years) with a male predominance (67%), the median VAF of TP53mut was 40%. Twenty (83%) patients had MDS diagnosis and 4 (17%) had AML diagnosis; all of them presented complex karyotype. In the whole group the most concurrent mutations associated with TP53 were TET2 in 17%, ASXL1 in 14% and DNMT3A, NRAS y CREBBP in 12% of patients. Intensive chemotherapy (IC) was administrated as first-line treatment in 17% of patients, 45% received hypomethylating agents (HMA) monotherapy, 24% venetoclax-based combination with HMA, and 14% exclusively supportive treatment. 16 patients (38%) achieved a complete response (CR), 44%, 31% and 25% with HMA+venetoclax, IC and with HMA monotherapy, respectively. Eight patients (19%) achieved a partial response (PR), 88% with HMA and 12% with IC, 7 patients (17%) stable disease, 86% with HMA monotherapy and 14% with HMA+venetoclax and 2 patients (5%) were refractory to IC. In 2 patients (5%), disease was not evaluable. The treatment related mortality was 4.2%. Median overall survival (OS) was 12.5 months [IC 95 % (0.0, 23.54)] and median progression free survival (PFS) was 9, 2 months [IC 95% (3.2, 32.6)]. Median OS of patients with multihit TP53 was 9.8 months, vs 25.7 months in patients with single-hit TP53-mut (P=0.026) (Figure1). Median PFS of the patients with multi-hit and single-hit TP53 was 9.1 and 11.6 months (P=0.07), respectively. The impact of multi-hit TP53 on OS and PFS according to the treatment received (HMA monotherapy vs HMA + venetoclax vs IC) was not statistically significant, just like in the single-hit TP53 (Figure1). Conclusions The presence of multihit TP53 -mut is a prognostic variable for survival in our group of patients analyzed with TP53-Mut. Survival is poor, around one year, in this group of patients independently on the treatment strategy received; this fact would call into question the benefit of IC with the toxicity it entails, in this group of patients. Further development of new effective therapies for multihit TP53-mut AML and MDS is needed.

Selinexor in Combination with Azacitidine (AZA) in Patients with Myelodysplastic Syndrome (MDS): A Real-World Retrospective Study

Background: Patients with higher-risk MDS face limited treatment options and poor outcomes. While HMAs are approved as frontline therapy for higher-risk MDS, primary failure occurs in 50% of HMA-treated patients, and most responders progress within 2 years. There is an unmet need to improve the efficacy of AZA frontline therapy while maintaining a tolerable safety profile. Preclinical studies have demonstrated that the combination of selinexor and azacitidine synergistically inhibits MDS cell proliferation and arrests the cell cycle at the G2/M phase (Yixuan Guo, 2022). The combination of selinexor and azacitidine may be a promising approach for treating MDS. Here, we present this single-center, real-world evidence supporting the use of selinexor in combination with AZA in MDS patients. Methods: Medical records of 19 patients with MDS receiving selinexor in combination with AZA at the First Affiliated Hospital of Soochow University between Jan 2022 and March 2023 were reviewed. Inclusion criteria were a pathologically confirmed diagnosis of MDS, and receipt of ≥1 cycle of azacitidine in combination with selinexor. HMA-naïve patients and those previously treated with HMAs were included. Patients with a diagnosis other than MDS or progression to AML before treatment with selinexor + AZA were excluded. Patients received selinexor 40-60 mg QW orally and AZA 75 mg/m 2 intravenously or subcutaneously on days 1-5 or 7 of each 28-day cycle. Responses were evaluated per the International Working Group criteria. Results: A total of 19 pts (median age, 54 y [range, 13-68 y]) were treated (Table 1). IPSS-R risk was high or very high in 15.8% and 68.4% of pts, respectively. IPSS-M risk was high or very high in 10.5% and 78.9% of pts, respectively. 57.9% of pts were previously treated with HMA. 63.2% had myelofibrosis, 42.1% had hepatosplenomegaly, 31.6% had a TP53 mutation, and 63.2% had poor or very poor-risk cytogenetics. As of Jun 10, 2023 at a median follow-up of 5.9 months (range 1.5-17.4 months), eight pts died (42.1%) due to disease progression. For the total cohort, the overall response rate (ORR) was 73%. In pts with worse survival prognosis, such as relapse and refractory, high and very high in IPSS-R, high and very high in IPSS-M, myelofibrosis and TP53 mut, the ORR was 64%, 81%, 76%, 75% and 83%, respectively (Figure 1). In seven pts with splenomegaly, six pts had reduced spleen volume, and one pt had no significant change by abdominal palpation or imaging examination. The 6-month overall survival (OS) was 74.7% in total pts, and 70.0% in pts previously exposed to HMA (Figure 2a, 2b). Selinexor + AZA therapy improved survival of patients with poor prognosis, such as TP53 mut (0.099), MF (+) (0.613), ≥high in IPSS-R (0.938) (Figure 2c, 2d, 2e). The survival of six pts who received transplantation after combination therapy was significantly prolonged, with 6-month OS was 83.3% (Figure 2f). Conclusion: Selinexor + AZA combination therapy was well tolerated with promising efficacy in patients with untreated or relapse/refractory MDS, including those with TP53 mutation, myelofibrosis, and higher risk in IPSS-R.

Downregulation of Mitochondrial Complex II (MC II) in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a group of diseases of hematopoietic stem cells (HSCs) that occur in the aging population and following therapy for unrelated cancers. The standard of care for MDS involves hypomethylating agents (HMAs) that invariably result in resistance and disease progression. We previously determined the role of mitochondrial metabolism in MDS pathophysiology, whereby suppression of mitochondrial activity leads to the accumulation of oncometabolites that competitively inhibit α-ketoglutarate-dependent dioxygenases (2OGDDs). Consequently, hypermethylation of epigenomes and hypoxia-inducible factor 1A (HIF1A) activation ensues a pseudohypoxia state that drives MDS pathogenesis. Our recent informatics analyses of primary MDS samples identified a patient subset with high TGF-β signaling in which mitochondrial complex II (MC II) genes were downregulated. MC II, or succinate dehydrogenase (SDH) is the smallest complex of the oxidative phosphorylation system that oxidizes succinate to fumarate and thereby donates electrons to reduce FAD to FADH 2 and the ubiquinone pool. Its downregulation results in the accumulation of Krebs cycle intermediate metabolites that can act as antagonists for 2OGDDs. To understand whether SDH dysregulation alone can contribute to MDS pathobiology, we generated a doxycycline-inducible and reversible mouse model (SDH-KD) that expresses shRNAs against the SDH subunits (SDHA, B, and D) in HSCs. These mice showed a gradual buildup of intracellular succinate in c-Kit + bone marrow (BM) cells and the peripheral blood, and a corresponding decrease of fumarate levels after induction for 2 weeks, 4 weeks, and 2 months. We found that knocking down Sdh was sufficient to induce pancytopenia and trilineage dysplasia in SDH-KD mice, while intracellular iron granules that surround the nucleus of erythroblasts, similar to ring sideroblasts commonly observed in MDS patients were also detected in BM and spleen smears. Of note, removing doxycycline and restoring Sdh expression rescued macrocytic anemia among other MDS phenotypes. Furthermore, treating SDH-KD mice with HMAs restored mitochondrial respiration and reversed HIF1A activation through the upregulation of SDH subunits. Using another MDS model, Mll PTD/WT/ Vav1-Cre/Runx1 Flox/Flox, we found that HMA-treated HSCs differentiate towards CD11b +Gr1 + mature myeloid cells and that this requires Sdh expression. In conclusion, our results indicate that pseudohypoxia- and TGF-β signaling-associated changes in metabolic regulation caused by SDH downregulation underlie MDS pathogenesis. Elucidating the role of MC II in MDS pathobiology may provide alternative targets that can be combined with HMA or luspatercept therapy for MDS.

Treosulfan-Based Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Patients with Myelodysplastic Syndrome (MDS): Comparative Analysis of a Randomized Controlled Trial and Real-World Data

Introduction MDS is a clonal myeloid disorder manifested by diverse genotypes and phenotypes, characterized by ineffective hematopoiesis. AlloHSCT is the only potential curative therapy for MDS. Myeloablative conditioning regimens are integral part of alloHSCT that allow engraftment and provide a therapeutic effect. Treosulfan has myeloablative and immunosuppressive properties and provides less transplantation related mortality than some of the traditionally used myeloablative conditioning regimens like busulfan-based treatments. In our analysis, we compared the results from the MDS subgroup of the randomized controlled trial (RCT) MC-FludT.14/L (NCT00822393) with real-world data (RWD) of patients treated at the University Hospital Münster and the University Hospital Dresden. Methods MDS patients conditioned with treosulfan (30 g/m²) and fludarabine in the RCT (June 2013 to January 2018) and the data obtained from 2 hospitals (RWD) (August 2017 to February 2023) were compared. Baseline characteristics, overall survival, relapse-free survival, relapse (or progression), non-relapse mortality, time to engraftment, and safety profiles between the RCT and RWD were compared. A sensitivity analysis was conducted using propensity score matching (PSM). Additionally, subgroup analyses evaluated the clinical effectiveness of treosulfan by baseline morphologic blast count and the revised International Prognostic Scoring System (IPSS-R). Results Overall, 195 MDS patients (RCT 84, RWD 111) with at least 12 months follow-up were analyzed. Median age was 62 years (range 39-76 years). Baseline characteristics only differed between the RCT and RWD with respect to age, IPSS-R categories, Hematopoietic Cell Transplantation Co-Morbidity Index total score (HCT-CI), and neutrophil count, indicating some heterogeneity between the RCT and RWD patients. In the PSM analysis, 106 (RCT 53, RWD 53) patients were matched to address the heterogeneity. The Kaplan-Meier estimates for overall survival (OS) at 2 years were 73% (95% CI 62-81%) and 72% (95% CI 62-81%) for the RCT and RWD (Figure 1), and for relapse-free survival (RFS) at 2 years were 68% (95% CI 57-77%) and 67% (95% CI 56-76%), respectively. Cumulative incidence of relapse at 2 years was 11% (95% CI 4-18%) and 15% (95% CI 7-23%), and for non-relapse mortality (NRM) was 21% (95% CI 12-30%) and 18% (95% CI 10-26%) for the RCT and RWD, respectively. In addition, cumulative incidence of neutrophil engraftment at 28 days was 93% (95% CI 87-98%) and 94% (95% CI 89-98%) for the RCT and RWD, while the median engraftment time was later in the RCT (19 days vs 15 days). Cumulative incidence of platelet engraftment at 28 days was 89% (95% CI 83-96%) and 93% (95% CI 88-98%) for the RCT and RWD, with the same median time 14 days. Further, the PSM sensitivity analysis showed comparable efficacy between the RCT and RWD. Interestingly, bone marrow blast count prior to conditioning and IPSS-R subgroups only had minor, statistically not significant impact on survival endpoints (Table 1). The number of deaths were 27 (32%) and 28 (25%) in the RCT and RWD, respectively. The most frequent cause of death was transplantation related (20% vs 14%). One patient experienced primary graft failure in the RCT and none in the RWD. More patients had acute GVHD with at least grade 2 in the RCT (27%) than in RWD (18%). Conclusions The efficacy and safety of treosulfan-based conditioning therapy prior to alloHSCT in post-authorization real world setting was comparable with the results obtained from the RCT. Our data suggest that bone marrow blast count is no strong predictor for survival after alloHSCT. Therefore, we conclude that the approved treosulfan-based conditioning therapy for patients with MDS, including those with increased blasts, has promising outcomes after alloHSCT.

LacNAc modification in bone marrow stromal cells enhances resistance of myelodysplastic syndrome cells to chemotherapeutic drugs.

Chemotherapeutic drugs are used routinely for treatment for myelodysplastic syndrome (MDS) patients but are ineffective in a substantial proportion of patients. Abnormal hematopoietic microenvironments, in addition to spontaneous characteristics of malignant clones, contribute to ineffective hematopoiesis. In our study, we found expression of enzyme β1,4-galactosyltransferase 1 (β4GalT1), which regulates N-acetyllactosamine (LacNAc) modification of proteins, is elevated in bone marrow stromal cells (BMSCs) of MDS patients, and also contributes to drug ineffectiveness through a protective effect on malignant cells. Our investigation of the underlying molecular mechanism revealed that β4GalT1-overexpressing BMSCs promoted MDS clone cells resistant to chemotherapeutic drugs and also showed enhanced secretion of cytokine CXCL1 through degradation of tumor protein p53. Chemotherapeutic drug tolerance of myeloid cells was inhibited by application of exogenous LacNAc disaccharide and blocking of CXCL1. Our findings clarify the functional role of β4GalT1-catalyzed LacNAc modification in BMSCs of MDS. Clinical alteration of this process is a potential new strategy that may substantially enhance effectiveness of therapies for MDS and other malignancies, by targeting a niche interaction.

Clonal Myeloid Dysplasia Following CAR T-Cell Therapy: Chicken or the Egg?

Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones.

Abstract A23: Less is more: Ultra-low input sequencing allows for evaluation of stem cells as a predictor of post-transplant relapse in the myelodysplastic syndromes

Abstract Malignant hematopoietic stem cells (HSCs) initiate the myelodysplastic syndromes (MDS) and drive treatment failure through their resistance to all non-transplant therapies. As a result, allogeneic stem cell transplantation (allo-SCT) is the only curative therapy for MDS. However, relapse remains the leading cause of treatment failure after allo-SCT. Improved tools to predict relapse in this setting are necessary to allow for pre-emptive therapeutic interventions, which may be more effective when the burden of disease is still low. Given prior evidence that HSCs serve as the functional unit of resistance to non-transplant therapies, we asked whether relapse after transplant originates from MDS HSCs, and whether their persistence can predict relapse. To overcome the limiting number of HSCs available in clinical bone marrow (BM) samples, we adapted a workflow developed for assessment of cell-free DNA and utilized a hybridization capture-based targeted sequencing panel covering 260 myeloid malignancy-associated genes. Unique dual index primers (UDIs) were utilized to tag input DNA, improving PCR duplicate identification, which overcome issues with amplification bias typically faced by low-input sequencing. This ultimately allowed us to consistently capture evaluable read depths from as few as 10 sorted cells. We assembled an initial cohort of 21 patients who underwent allo-SCT for MDS or secondary acute myeloid leukemia. Inclusion criteria were follow-up time greater than 1.5 years (or relapse in this timeframe), BM sampling prior to Day+120 post-transplant and relapse, and biospecimens allowing for sorting of greater than 10 HSCs. We sequenced sorted CD34+CD38-CD45RA- HSCs and multipotent progenitors (MPPs), CD34+CD38- CD45RA+ lymphoid-primed multipotent progenitors (LMPPs), and CD34+CD38+ progenitors, as well as bulk BM. With a median follow-up of two years, 9 of the 21 patients relapsed, with an average time to relapse of 362 days. Detection of disease mutations in HSCs/MPPs in any BM at D+30-D+120 post-transplant was 100% specific and 88% sensitive for relapse, showing improvements in both metrics over bulk BM assessment (22% sensitive and 66% specific), despite far lower cell input and read depth. Average time from detection to relapse was 6.9 months. In patients destined to relapse, disease mutations are often present in HSCs at a variant allele frequency of greater than 45%, while simultaneously undetectable on high-depth sequencing of bulk cells (&amp;gt;400x coverage). While even higher depth error-corrected sequencing bulk BM could likely detect such mutations, it would require &amp;gt;20x the sequencing depth, and could not identify the involved cell populations. In conclusion, we show for the first time that relapse of MDS after allo-SCT is driven by failure to eradicate MDS HSCs. Detection of MDS HSCs early post-transplant is highly predictive for relapse and opens new doors for pre-emptive interventions to prevent relapse. These findings are being validated in an independent cohort of 46 patients and updated data will be presented at the meeting. Citation Format: Benjamin Kroger, Yi Huang, Prapti Patel, Aimaz Afrough, Gurbakhash Kaur, Larry Anderson, Farrukh Awan, Praveen Ramakrishnan, Kunal Verma, Russell Vittrup, Robert H Collins, Madhuri Vusirikala, Yazan F Madanat, David Sallman, Carmelo Gurnari, Jaroslaw Maciejewski, Roni Tamari, Stephen Chung. Less is more: Ultra-low input sequencing allows for evaluation of stem cells as a predictor of post-transplant relapse in the myelodysplastic syndromes [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A23.

A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes

BackgroundmiRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven.ResultsPatients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders.ConclusionsThis study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.

High Co-Expression of PDCD1/TIGIT/CD47/KIR3DL2 in Bone Marrow Is Associated with Poor Prognosis for Patients with Myelodysplastic Syndrome.

Cellular immune disorder is a common characteristic of myelodysplastic syndrome (MDS). Abnormal natural killer (NK) cell function has been reported in MDS patients, and this is closely related to disease progression and poor prognosis. However, little is known about the association between the abnormal immune checkpoint (IC) that results in abnormal immune NK cell function and the prognosis of MDS. In this study, RNA-sequencing data from 80 patients in the GSE114922 dataset and bone marrow (BM) samples from 46 patients with MDS in our clinical center were used for overall survival (OS) analysis and validation. We found that the NK cell-related IC genes PDCD1, TIGIT, CD47, and KIR3DL2 had higher expression and correlated with poor OS for MDS patients. High expression of PDCD1 or TIGIT was significantly associated with poor OS for MDS patients younger than 60 years of age. Moreover, co-expression of PDCD1 and TIGIT had the greatest contribution to OS prediction. Interestingly, PDCD1, TIGIT, CD47, and KIR3DL2 and risk stratification based on the Revised International Prognostic Scoring System were used to construct a nomogram model, which could visually predict the 1-, 2-, and 3-year survival rates of MDS patients. In summary, high expression of IC receptors in the BM of MDS patients was associated with poor OS. The co-expression patterns of PDCD1, TIGIT, CD47, and KIR3DL2 might provide novel insights into designing combined targeted therapies for MDS.

Synergistic Interactions between the Hypomethylating Agent Thio-Deoxycytidine and Venetoclax in Myelodysplastic Syndrome Cells

Interactions between the novel hypomethylating agent (HMA) thio-deoxycytidine (T-dCyd) and the BCL-2 antagonist ABT-199 (venetoclax) have been examined in human myelodysplastic syndrome (MDS) cells. The cells were exposed to agents alone or in combination, after which apoptosis was assessed, and a Western blot analysis was performed. Co-administration of T-dCyd and ABT-199 was associated with the down-regulation of DNA methyltransferase 1 (DNMT1) and synergistic interactions documented by a Median Dose Effect analysis in multiple MDS-derived lines (e.g., MOLM-13, SKM-1, and F-36P). Inducible BCL-2 knock-down significantly increased T-dCyd's lethality in MOLM-13 cells. Similar interactions were observed in the primary MDS cells, but not in the normal cord blood CD34+ cells. Enhanced killing by the T-dCyd/ABT-199 regimen was associated with increased reactive oxygen species (ROS) generation and the down-regulation of the anti-oxidant proteins Nrf2 and HO-1, as well as BCL-2. Moreover, ROS scavengers (e.g., NAC) reduced lethality. Collectively, these data suggest that combining T-dCyd with ABT-199 kills MDS cells through an ROS-dependent mechanism, and we argue that this strategy warrants consideration in MDS therapy.

Immune dysregulation and potential targeted therapy in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematological diseases and a high risk for transformation to acute myeloid leukemia (AML). The identification of key genetic alterations in MDS has enhanced our understanding of the pathogenesis and evolution. In recent years, it has been found that both innate and adaptive immune signaling are activated in the hematopoietic niche of MDS with aberrant cytokine secretion in the bone marrow microenvironment. It is also clear that immune dysregulation plays an important role in the occurrence and progression of MDS, especially the destruction of the bone marrow microenvironment, including hematopoiesis and stromal components. The purpose of this review is to explore the role of immune cells, the immune microenvironment, and cytokines in the pathogenesis of MDS. Insights into the mechanisms of these variants may facilitate the development of novel effective treatments to prevent disease progression.