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Myelodysplastic neoplasm (MDS) is a heterogeneous group of clonal hematological disorders that originate from the hematopoietic and progenitor cells and present with cytopenias and morphologic dysplasia with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML). Genetic evolution plays a critical role in the pathogenesis, progression, and clinical outcomes of MDS. This process involves the acquisition of genetic mutations in stem cells that confer a selective growth advantage, leading to clonal expansion and the eventual development of MDS. With the advent of next-generation sequencing (NGS) assays, an increasing number of molecular aberrations have been discovered in recent years. The knowledge of molecular events in MDS has led to an improved understanding of the disease process, including the evolution of the disease and prognosis, and has paved the way for targeted therapy. The 2022 World Health Organization (WHO) Classification and the International Consensus Classification (ICC) have incorporated the molecular signature into the classification system for MDS. In addition, specific germline mutations are associated with MDS development, especially in pediatrics and young adults. This article reviews the genetic abnormalities of MDS in adults with a brief review of germline predisposition syndromes.

Background: Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective. Methods: MSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function. Results: Our findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A. Conclusions: We suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelodysplastic syndromes (MDS) are a group of blood disorders which affect the bone marrow to produce healthy blood cells, leading to low blood counts and a risk of progressing to acute leukemia. The presentation of MDS varies widely among patients because it's caused by different genetic changes. Recent advances in genetics improved our understanding of MDS, including how it develops and how to classify its subtypes. New classification systems, like those from the World Health Organization (WHO) and the International Consensus Classification (ICC), help physicians better diagnose and categorize MDS. Treatments are also advancing, with a focus on precision medicine by targeting the specific genetic causes of the disease in each patient to improve outcomes. This review explains how MDS develops, explores the updated classification systems, and discusses the latest treatment options, offering a clearer picture of this complex condition for better patient care. Myelodysplastic syndromes (MDSs), either primary or secondary, are a heterogeneous group of clonal hematological neoplasms characterized by bone marrow dyshematopoiesis, peripheral blood cytopenia, and the potential risk of acute myeloid leukemia (AML) transformation. The clinical heterogeneity in MDS is a reflection of the underlying multitude of genetic defects playing a role in the pathogenesis. Recent advances in the clinicopathological, immunophenotypic, and molecular landscape in understanding the pathophysiology of MDS lead to evolving and refined classification systems with newer entities. Evolving MDS therapies will target the disease's core mechanisms, allowing for personalized treatment based on individual patient's genes and leading to better outcomes. This review provides an overview of MDS pathogenesis to enhance comprehension of its various subgroups. Additionally, we examine the updated classification systems of the World Health Organization (WHO) and the International Consensus Classification (ICC) pertaining to MDS, along with relevant therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) for intensive chemotherapy ineligible patients. Mouse models that engraft primary AML samples may further advance VEN + AZA resistance research. Methods: We generated a set of transplantable murine PDX models from MDS/AML patients who developed resistance to VEN + AZA and compared the differences in hematopoiesis of the PDX models with primary bone marrow samples at the genetic level. PDX were created in NSGS mice via intraosseal injection of luciferase-encoding Lentivirus-infected MDS/AML primary cells from patient bone marrow. We validated the resistance of PDX-leukemia to VEN and AZA and further tested candidate agents that inhibit the growth of VEN/AZA-resistant AML. Results and discussion: Transplantable PDX models for MDS/AML arise with 31 % frequency. The lower frequency of transplantable PDX models is not related to peritransplant lethality of the graft, but rather to the loss of the ability of short-term proliferation of leukemic progenitors after 10 weeks of engraftment. There exist subtle genetic and cytological changes between primary and PDX-AML samples however, the PDX models retain therapy resistance observed in patients. Based on in vitro testing and in vivo validation in PDX models, Panobinostat and Dinaciclib are very promising candidate agents that overcome dual VEN + AZA resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: TCR-T therapies have the potential to capture the power of adoptive cell therapy, as has been successfully developed for CAR-T therapies for several B cell malignancies and multiple myeloma. CAR-T therapies for myeloid malignancies are hindered by lack of safe target antigens and healthy cell toxicity. Therefore, TCR-T therapies recognizing other targets are explored for these blood cancers. The antigen PReferentially expressed Antigen in MElanoma, PRAME, was shown to be a T cell target for acute myeloid leukemia after stem cell transplantation, without overt toxicity. Therefore, PRAME-specific TCR-T therapies may serve well for treatment of AML and myelodysplastic syndrome. PRAME-specific TCR-T therapy may also be suited for relapsed multiple myeloma after CAR-T therapy, arising from outgrowth of malignant cells due to loss of CAR-T antigens. On this basis, MDG1011, a PRAME-specific TCR-T therapy, was developed to fill an unmet medical need for new treatment options for these myeloid malignancies. Background/Objectives: MDG1011 is an autologous TCR-T therapy developed as a treatment option for patients with myeloid malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). It is specific for the target antigen PReferentially expressed Antigen in MElanoma (PRAME). The recombinant TCR used in MDG1011 recognizes PRAME100–108 VLD-peptide presented by HLA-A*02:01-encoded surface molecules. Methods: Two preclinical batches of MDG1011, produced from enriched CD8+ T cells of healthy donors, underwent rigorous evaluation of on-target and off-target recognition of tumor cells and test cells representing healthy tissues. MDG1011 investigational medicinal products (IMPs) were produced for 13 patients. VLD-TCR surface expression was assessed using dual-marker flow cytometry using TCR V-beta-specific antibody and VLD/HLA-A2-specific multimer. Functionality was assessed by interferon-gamma (IFN-γ) secretion and cell-mediated cytotoxicity of target cells. Results: Preclinical MDG1011 batches displayed strong VLD-TCR expression, cytokine secretion, and cytotoxicity after antigen-specific activation, while showing no signals of on-target/off-tumor or off-target recognition. All IMPs had good VLD-TCR expression as well as functionality after activation by multiple target cells. Conclusions: Preclinical studies demonstrated that MDG1011 displayed key 3S attributes of high specificity, sensitivity, and safety required for regulatory approval of a first-in-human (FIH) clinical study of patients with myeloid malignancies (CD-TCR-001: ClinicalTrials.gov Identifier: NCT03503968). MDG1011 IMP manufacturing was successful at 92%, even including heavily pretreated elderly patients with very advanced disease. The IMPs applied in nine patients all displayed antigen-specific functionality. Elsewhere, clinical study results for MDG1011 showed no dose-limiting toxicity and signs of biological and/or clinical activity in several patients. [ABSTRACT FROM AUTHOR]

Objective Alloimmunization against red blood cell (RBC) antigen is an important concern in myelodysplastic syndromes (MDSs) patients with chronic transfusion, causing potential risk for hemolytic reaction and limited supply of compatible blood. However, there is little data addressing RBC alloimmunization in this patient cohort among the Chinese population. This study aims to evaluate the incidence, specificity of antibodies, and RBC units transfused before antibody formation and its significance in a population of patients consistently receiving RhD-matched RBC units. Methods We retrospectively reviewed the transfusion and clinical information of all transfused patients with MDS enrolled in our hospital from 2012 to 2022. The cumulative incidence of alloimmunization was analyzed by a Kaplan-Meier plot. Alloimmunization incidence was compared based on different transfused RBC units using the log-rank test. Results A total of 103 patients with MDS were included in this study; alloantibody formed in 8 (7.8%) patients. Before reaching 32 RBC units, 87.5% of the alloimmunized patients had developed their alloantibodies. All but 1 of the alloantibodies developed were antibodies to Rh antigens. The RBC transfusion intensity and frequency were significantly higher following alloimmunization in the alloimmunized patients (P  = .008, P  = .008, respectively). Conclusion The antibodies detected mostly involve the Rh system among MDS patients in China. The alloimmunization tended to occur early prior to reaching 32 RBC units in patients with MDS. Rh antigen matching should be considered early in the patient's transfusion history and completed before receiving 32 RBC units. [ABSTRACT FROM AUTHOR]

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS. Methods: Eighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800–1000 mg/m2, pevonedistat 20–50 mg/m2). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed. Results: No dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1. Conclusions: Patterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually. Trial registration: ClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246. [ABSTRACT FROM AUTHOR]

Background: Patients with secondary acute myeloid leukemia who previously received hypomethylating agents for prior myeloid neoplasms (HMA‐sAML) face a dismal prognosis. Methods: The authors analyze the characteristics, therapeutic approaches, and outcomes of patients with HMA‐sAML from the Programa Español para el Tratamiento de Hemopatías Malignas (PETHEMA) registry. Results: A total of 479 patients were included, mostly from prior myelodysplastic syndrome (84%). Frontline therapy consisted of intensive chemotherapy (IC) in 31%, low‐dose cytarabine‐based in 19%, supportive care and clinical trial 17% each, and HMA‐based therapy in 12% and 4% in venetoclax‐based regimen. Complete remission was achieved in 95 patients (27%), with higher rate among IC and venetoclax‐based groups (44% and 41%, respectively). The median overall survival (OS) was 4.93 months, with 7.68 months for IC patients, 7.82 months after HMA monotherapy, and 4.66 months after venetoclax‐based regimens. Patients who underwent allogeneic hematopoietic stem cell transplantation in first remission (n = 33, 9%) had a better survival outcome (median OS not reached). Multivariate analyses identified age (≥65 years), Eastern Cooperative Oncology Group >2, higher white blood cell count, and adverse risk cytogenetic as adverse prognostic factors, whereas NPM1 mutation was a favorable factor. Conclusions: Patients with HMA‐sAML have a poor prognosis and suboptimal outcomes with conventional treatments, including BCL2 inhibitors, highlighting the need for clinical trials targeting this population. This study analyzes the characteristics and outcomes of adults with secondary acute myeloid leukemia who previously received hypomethylating agents for prior myeloid neoplasms (HMA‐sAML). This analysis of 479 patients from the PETHEMA registry shows a poor overall survival of 4.93 months with suboptimal outcomes, highlighting the unmet clinical need for this population. Whenever is feasible, fit HMA‐sAML patients should undergo an allo‐hematopoietic stem cell transplantation in first remission. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukaemia (AML) are neoplastic haematopoietic cell proliferations that are diagnosed and classified based on a combination of morphological, clinical and genetic features. Specifically, the percentage of myeloblasts in the blood and bone marrow is a key feature that has historically separated MDS from AML and, together with several other morphological parameters, defines distinct disease entities within MDS. Both MDS and AML have recurrent genetic abnormalities that are increasingly influencing their definitions and subclassification. For example, in 2022, two new MDS entities were recognised based on the presence of SF3B1 mutation or bi‐allelic TP53 abnormalities. Genomic information is more objective and reproducible than morphological analyses, which are subject to interobserver variability and arbitrary numeric cut‐offs. Nevertheless, the integration of genomic data with traditional morphological features in myeloid neoplasm classification has proved challenging by virtue of its sheer complexity; gene expression and methylation profiling also can provide information regarding disease pathogenesis, adding to the complexity. New machine‐learning technologies have the potential to effectively integrate multiple diagnostic modalities and improve on historical classification systems. Going forward, the application of machine learning and advanced statistical methods to large patient cohorts can refine future classifications by advancing unbiased and robust previously unrecognised disease subgroups. Future classifications will probably incorporate these newer technologies and higher‐level analyses that emphasise genomic disease entities over traditional morphologically defined entities, thus promoting more accurate diagnosis and patient risk stratification. [ABSTRACT FROM AUTHOR]

Purpose of the review: Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by high molecular and genomic heterogeneity. Accordingly, efforts in risk assessment and therapeutic intervention mostly target unique profiles that individualize specific MDS subtypes. In this review, we explored the contributions of population based studies accounting for MDS as a group. Recent findings: Large population based studies have been critical to define important details of our current knowledge of the disease. We summarized the most important population research contributions in MDS, focusing on its epidemiology, population risk factors, and relevant clinical associations. We discuss how these population data can provide vital insights to inform prevention measures, testing strategies, and treatment decisions. Summary: Population studies play an important role in guiding clinical and research efforts in MDS. Despite its complex molecular and genomic landscape, population data is integral to define the burden of disease, identify risk factors and clinical associations, and can help elucidate pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

The management of patients with myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) remains a challenge with few reliably effective treatments. Preclinical studies have shown that the inhibition of the nuclear export protein XPO1 causes nuclear accumulation of p53 and disruption of NF-κB signaling; both of which are relevant targets for MDS. Selinexor is an XPO1 inhibitor with demonstrated efficacy in MDS patients. Herein, we report three patients with MDS refractory to HMAs, however, when selinexor and venetoclax were added to the treatment regimen, the patients achieved a complete response and a significant reduction in spleen size. All patients successfully underwent hematopoietic stem cell transplantation. These cases demonstrate that the combination therapy can achieve CR and significant reductions in spleen size, offering a promising therapeutic option for patients with limited treatment choices. Combination therapy would also offer a potential way for patients to bridge to transplantation. Formal evaluations of this regimen in patients with MDS refractory to HMAs may be meaningful. [ABSTRACT FROM AUTHOR]

Background: The Molecular International Prognostic Scoring System (IPSS-M) has improved the prediction of clinical outcomes for myelodysplastic syndromes (MDS). The Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS), based on classical clinical parameters, has outperformed the IPSS, revised version (IPSS-R). For the first time, we validated the IPSS-M and other molecular prognostic models and compared them with the established IPSS-R and AIPSS-MDS models using data from South American patients. Methods: Molecular and clinical data from 145 patients with MDS and 37 patients with MDS/myeloproliferative neoplasms were retrospectively analyzed. Results: Prognostic power evaluation revealed that the IPSS-M (Harrell's concordance [C]- index: 0.75, area under the receiver operating characteristic curve [AUC]: 0.68) predicted overall survival better than the European MDS (EuroMDS; C-index: 0.72, AUC: 0.68) and Munich Leukemia Laboratory (MLL) (C-index: 0.70, AUC: 0.64) models. The IPSS-M prognostic discrimination was similar to that of the AIPSS-MDS model (C-index: 0.74, AUC: 0.66) and outperformed the IPSS-R model (C-index: 0.70, AUC: 0.61). Considering simplified low- and high-risk groups for clinical management, after restratifying from IPSS-R (57% and 32%, respectively, hazard ratio [HR]: 2.8; P =0.002) to IPSS-M, 12.6% of patients were upstaged, and 5% were downstaged (HR: 2.9; P =0.001). The AIPSS-MDS recategorized 51% of the low-risk cohort as high-risk, with no patients being downstaged (HR: 5.6; P <0.001), consistent with most patients requiring disease-modifying therapy. Conclusions: The IPSS-M and AIPSS-MDS models provide more accurate survival prognoses than the IPSS-R, EuroMDS, and MLL models. The AIPSS-MDS model is a valid option for assessing risks for all patients with MDS, especially in resource-limited centers where molecular testing is not currently a standard clinical practice. [ABSTRACT FROM AUTHOR]

In 2022, the World Health Organization (WHO) and International Consensus Classification (ICC) recognized TP53 as an entity-defining alteration in myeloid neoplasms, yet with differing criteria that could lead to discrepant diagnoses and affect clinical trial eligibility. We studied 67 patients with TP53 mutant myeloid neoplasms, reclassifying them using both criteria. While most cases fulfill the criteria for TP53 mutant defined entities, most discrepancies were found in cases with ≥20% blasts. Patients were stratified into three groups based on blast count (<10%, 10–19%, and ≥20%) which revealed comparable clinicopathologic features, genetic characteristics, and outcomes. Notably, patients with ≥10% blasts had shorter overall survival compared to those with <10% blasts (8.1 vs. 12.4 months; p = 0.03). This study is among the few to examine TP53 mutant myeloid neoplasms as a single entity and suggests that the 10% blast count threshold could serve as a gateway to a more harmonized classification for these patients. [ABSTRACT FROM AUTHOR]

AbstractAccess to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM’s impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK. [ABSTRACT FROM AUTHOR]

Background: Pancytopenia is characterized by a decrease in all three types of blood cells. Instead of being a standalone disease, it acts as a common outcome resulting from various factors, including infections, autoimmune disorders, genetic issues, nutritional deficiencies, and malignancies. Pinpointing the root cause of pancytopenia poses a challenge but is essential for devising an effective treatment plan and predicting the likely prognosis. Vitamin B12 deficiency is a common cause of megaloblastic anemia, pancytopenia, and various neuropsychiatric symptoms. However, diagnosing vitamin B12 deficiency lacks a definitive gold standard. Case Presentation: We present two cases where patients initially exhibited pancytopenia with seemingly normal vitamin B12 levels. Based on a bone marrow biopsy, they were initially diagnosed with myelodysplastic syndrome (MDS). Subsequent investigations revealed elevated serum methylmalonic acid (MMA) levels, leading to a revised diagnosis of vitamin B12 deficiency. Both patients showed positive responses to adequate vitamin B12 supplementation. Conclusion: Our case series highlights the importance of ruling out alternative causes of dysplasia in MDS when solely morphological abnormalities are observed on a bone marrow biopsy. It also underscores the crucial aspect of assessing MMA and homocysteine levels in individuals with normal vitamin B12 levels when there is a high clinical suspicion of B12 deficiency. [ABSTRACT FROM AUTHOR]

Background: By 2023, COVID-19 had caused 6.8 million deaths in the United States. COVID-19 presents more severely in leukemia compared to solid tumors (OR 1.6, p<0.05). However, data on Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are limited. We investigated the mortality in AML and MDS patients with COVID-19. Methods: Data from the 2020-2021 National Inpatient Sample was used to conduct a cross-sectional analysis. We identified AML and MDS patients with COVID-19 hospitalizations through ICD-10 codes. Analysis was done by propensity matching and multivariate regression with a p-value of ≤0.05. Results: Of 28,028 AML admissions, 336 (1.2%) were admitted for COVID-19. AML-COVID-19 cohort had a lower hospitalization risk (aOR 0.3, p=0.000) and higher mortality (21.7% vs 8.7%; aOR 1.6, p=0.023) than AML patients admitted for other causes. AML patients post-HSCT (Hematopoietic Stem Cell Transplantation) had a higher risk of COVID-19 (20.2% vs 9.8%; aOR 2.6, p=0.000) and increased mortality (19.1% vs 6.7%; aOR 4.1, p=0.000) compared to other causes. Similarly, of 28,148 MDS patients, 769 (2.7%) were admitted for COVID-19. The MDS-COVID-19 cohort had a lower hospitalization risk (aOR 0.59, p=0.000) and higher mortality (19.6% vs 6.6%; aOR 2.2, p=0.000) compared to other causes. In MDS, HSCT did not alter the risk of COVID-19 hospitalizations (3% vs 3.9%; aOR 0.9, p=0.662), but these patients had higher mortality (17.4% vs 5.1%; aOR 4.0, p=0.032). Conclusion: COVID-19 hospitalization was low in AML and MDS but carried a high mortality risk. Post-HSCT, the mortality is high, warranting research into understanding the underlying factors. [ABSTRACT FROM AUTHOR]

The boundary between myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) has been revised in the latest World Health Organization classification of myeloid malignancies. These changes were motivated by the description of a subgroup of MDS patients identified as oligomonocytic chronic myelomonocytic leukemia (OM-CMML) at risk of evolving into overt CMML. Various studies will be reviewed describing the clinical and biological features of MDS patients evolving to CMML. The efforts to discover biomarkers enabling the identification of these patients at the time of MDS diagnosis will be discussed. Finally, the molecular landscape of these patients will be presented with a specific focus on the biallelic inactivation of TET2 in light of its functional impact on hematopoietic stem cells, granule-monocytic differentiation, and its tight interplay with inflammation. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk myelodysplastic syndrome (HR MDS) patients. However, the management of patients with relapsed disease post allo-HSCT remains a challenge with few standard treatments. Chidamide, a new selective histone deacetylase, has shown synergistic anti-leukemia effect combined with azacitidine in acute myeloid leukemia patients. Herein, we reported a 50-year-old HR MDS patient who experienced molecular relapse post allo-HSCT and was successfully salvaged by preemptive treatment of chidamide combined with azacitidine (CHI-AZA). This patient maintained a deep remission lasting over 2 years by regular maintenance treatment of CHI-AZA, without sever treatment-related adverse events or increased risk of graft versus host disease. This case report demonstrated that double epigenetic regimen of CHI-AZA was effective and tolerable. Formally evaluating this regimen in HR MDS patients post allo-HSCT may be meaningful. [ABSTRACT FROM AUTHOR]

Trisomy 8 is a frequent chromosomal abnormality that occurs among patients with myelodysplastic syndrome (MDS). This abnormality is more common among MDS patients with concurrent Behcet's disease (BD) than among patients with MDS alone. This comorbidity is also associated with a higher prevalence of intestinal ulcers. In this case report, we describe a 45-year-old woman who was diagnosed with BD at age 35. Eight years later, her Behcet's disease relapsed with trisomy 8-positive MDS. After the disease was controlled by azacitidine, the patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT), which involved the use of both peripheral blood stem cells and bone marrow stem cells. Although the patient experienced grave oral mucositis and chronic intestinal graft-versus-host disease (GVHD), remission of both MDS and BD was maintained. This case highlights the potential efficacy of allo-HSCT in treating patients with refractory autoimmune diseases complicated by MDS, particularly patients with trisomy 8 abnormalities. We also discuss the immunological implications and suggest allo-HSCT as a viable curative option for patients with BD and MDS. [ABSTRACT FROM AUTHOR]

Vacuoles, E1 enzyme, X-linked, auto inflammatory, somatic (VEXAS) syndrome is an inflammatory disorder caused by somatic UBA1 variants and is characterized by late-onset systemic autoimmune inflammation and blood abnormalities. Glucocorticoids ameliorate symptoms effectively. However, other treatment options have limited efficacy and a transient effect. Herein, we describe a case of a 69-year-old male patient with VEXAS syndrome with skin, lung and hematologic involvement. He was treated with glucocorticoids and after the failure with anti IL-1 he began treatment with azacitidine with excellent hematological and clinical response. Azacitidine may be a suitable option for treating VEXAS syndrome, especially due to the relationship between inflammatory symptoms and response to azacitidine. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for myelodysplastic syndrome (MDS). However, relapse remains the primary cause of transplantation failure. This single-center study aimed to evaluate factors influencing therapeutic interventions to prevent overt relapse of MDS and to identify treatment approaches that ensure optimal response and safety. We enrolled 149 patients with relapsed MDS who had undergone allo-HSCT between May 2009 and December 2017, among whom 87 patients had hematologic relapse (HemRel; marrow blasts ≥ 5%, blasts in peripheral blood or dysplasia fulfilling MDS diagnostic criteria) and 62 patients had pre-HemRel; pre-HemRel included imminent (n = 28; donor chimerism ≤ 95%), WT1-based molecular (n = 17; WT1 transcript > 250 copies/104ABL1), and cytogenetic (n = 17; recurrence of chromosomal aberrations) relapses. The estimated 4-year overall survival (OS) rate from the time of relapse was 44.1% among 62 pre-HemRel patients. However, the OS rate was significantly lower in 87 HemRel patients. In a multivariate analysis, preemptive use of cellular immunotherapy (cIMTx, either donor lymphocyte infusion, second allo-HSCT, or both) emerged as an independent factor in preventing HemRel and was more effective, particularly in the presence of other unfavorable factors, such as the absence of chronic graft-versus-host disease and a higher-risk group based on the MDS-transplantation prognostic scoring system. In HemRel, using cIMTx demonstrated a significantly superior OS rate compared to non-cIMTx modalities (25.8% vs. 6.1% vs. 0%, P <.001). In summary, cIMTx demonstrated superior outcomes in both pre-HemRel and HemRel groups, proving particularly advantageous in pre-HemRel cases with progression risk factors, while its benefits remained consistent in HemRel cases. [ABSTRACT FROM AUTHOR]

GATA2 deficiency syndrome is a heterogeneous disorder characterized by a high risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). We conducted a meta-analysis of the literature to explore the prognostic significance of GATA2 mutations in patients diagnosed with MDS/AML, as previous studies have yielded conflicting findings regarding the impact of GATA2 mutations on patient outcomes. We conducted a comprehensive literature search of databases such as PubMed, Embase, the Cochrane Library, and the Web of Science to obtain studies on the prognostic significance of GATA2 mutations in patients with MDS/AML that were published through January 2024. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The meta-analysis was conducted by choosing either a fixed-effect model or a random-effect model, depending on the variability observed among the studies. A total of 13 cohort studies were included in the final meta-analysis, including 2714 patients with MDS, of whom 644 had GATA2 mutations. The results revealed that GATA2 mutations had an adverse impact on OS (HR = 1.54, 95% CI = 1.08–2.18, P = 0.02) and EFS (HR = 1.32, 95% CI = 1.01–1.72, P = 0.04), but no significant effect on DFS (HR = 1.21, 95% CI = 0.89–1.64, P = 0.23). GATA2 mutations were associated with a significantly shorter OS in MDS patients (HR = 2.56, 95% CI = 1.42–4.06, P = 0.002) but not in AML patients (HR = 1.08, 95% CI = 0.92–1.26, P = 0.37). Our meta-analysis revealed that GATA2 mutations are associated with unfavourable outcomes in patients with MDS/AML. Furthermore, patients harbouring these mutations should be prioritized for aggressive therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Angiosarcomas are highly aggressive malignancies with endothelial differentiation, presenting considerable challenges in oncology, especially when arising in rare locations such as the spleen. These tumors predominantly affect adults and are commonly found in the skin, breast, liver, or soft tissues, with more unusual occurrences in other organs. Angiosarcomas have a high propensity for metastasis, typically spreading to the liver, lungs, lymph nodes, and gastrointestinal tract. Splenic angiosarcoma, with fewer than 300 documented cases, is an especially rare and complex form of this malignancy. Case presentation: This report details a case of splenic angiosarcoma in a 45-year-old male, where bone marrow metastases were the first clinical presentation, initially mimicking myelodysplastic syndrome (MDS) due to persistent pancytopenia. Conclusions: The eventual identification of the splenic origin underscores the diagnostic difficulties and clinical challenges inherent in managing such atypical and rare presentations. [ABSTRACT FROM AUTHOR]

Objectives: MDS and AML characterized by TP53 variations have a poor prognosis in general. However, specifically, differences in prognosis have also been observed in patients with different TP53 variants and VAFs. Methods: Here, we retrospectively analyzed datasets of patients with MDS, MPN, and AML who underwent targeted DNA sequencing from February 2018 to December 2023, and patients with reportable TP53 variations were screened. Demographic data and clinical data were collected, and the relationship between TP53 alterations and patient prognosis (AML/MDS) was analyzed using the cBioPortal and Kaplan–Meier Plotter databases. The relationship between the VAFs of TP53 variations and prognoses was analyzed using data from the present study. Results: Sixty-two variants of TP53 were identified in 58 patients. We mainly identified single mutations (79.31%, 46/58), followed by double (17.24%, 10/58) and triple (3.45%, 2/58) mutations. The variations were mainly enriched in exon4–exon8 of TP53. Missense (72.58%, 45/62) mutations were the main type of variations, followed by splice-site (9.68%, 6/62), nonsense (9.68%, 6/62), frameshift (6.45%, 4/62), and indel (1.61%, 1/62) mutations. In this study, p.Arg175His and p.Arg273His were high-frequency TP53 mutations, and DNMT3A and TET2 were commonly co-mutated genes in the three types of myeloid neoplasms; However, we reported some new TP53 variants in MPN that have not been found in the public database. Moreover, MDS or AML characterized by altered TP53 had a shorter OS than patients in the unaltered group (P<0.01), low TP53 mRNA levels were associated with shorter OS in patients with AML (P<0.01). Data from our center further found higher VAF (≥10%) associated with shorter OS in patients with MDS (median 2.75 vs. 24 months) (P<0.01). Conclusion:TP53 mutations are mainly enriched in exon4–exon8, are missense and single mutations in myeloid neoplasms, and are associated with poor prognosis of MDS/AML, and higher VAF (≥10%) of TP53 mutations associated with a shorter OS in patients with MDS. [ABSTRACT FROM AUTHOR]

Chromosomes 5 and 7 are large chromosomes that contain close to 1,000 genes each. Deletions of the long arms or loss of the entire chromosome (monosomy) are common defects in myeloid disorders, particularly MDS and AML. Loss of material from either chromosome 5 or 7 results in haploinsufficiency of multiple genes, with some implicated in leukemogenesis. Abnormalities of one or both occur in up to 15% of MDS and AML cases and co-segregate in half of these. Generally, these chromosomal abnormalities are harbingers of adverse risk in both myeloid disorders. A notable exception is del(5q) in 5q– syndrome, a subtype of MDS. In this review, we describe the pathogenesis and genetic consequences of deletions in chromosomes 5 and 7. Furthermore, we provide an overview of current testing methodologies used in the assessment of these chromosomal defects in hematological malignancies and describe the disease associations and prognostic implications of aberrations in chromosomes 5 and 7 in both MDS and AML. [ABSTRACT FROM AUTHOR]

Germline variants in RUNX1 and DDX41 are well-established contributors to hereditary myeloid neoplasms and are increasingly recognized as critical predisposing factors in the developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This case report details a 51-year-old male diagnosed with MDS with excess blasts-1 (MDS-EB1), who harbored a rare combination of pathogenic germline variants in RUNX1 and a novel potentially pathogenic variant in DDX41 variant, alongside a somatic DDX41 mutation. The coexistence of these germline variants highlights the genetic complexity underlying hereditary myeloid neoplasms and reinforces the necessity of comprehensive genomic testing to ensure accurate diagnosis and informed clinical management. The interplay between RUNX1 and DDX41 variants may drive leukemogenesis, with the germline RUNX1 variant potentially fostering a cellular environment that enables the acquisition of somatic DDX41 mutations, leading to hematological malignancies. Conversely, the germline DDX41 variant may disrupt hematopoiesis and, when combined with RUNX1 dysfunction, contribute to disease progression. This case underscores the importance of screening germline variants in patients with myeloid neoplasms. It emphasizes the need to confirm the origin of these variants in non-hematopoietic tissues, such as fibroblasts (gold standard), to avoid misinterpretation caused by clonal hematopoiesis. Further research is warranted to elucidate the molecular mechanisms driving the interaction between RUNX1 and DDX41 variants and their collective impact on disease progression, treatment outcomes, and familial risk. [ABSTRACT FROM AUTHOR]

Objective: Protein tyrosine phosphatase non-receptor type 6 (PTPN6) is a cytoplasmic phosphatase that acts as a key regulatory protein in cell signaling to control inflammation and cell death. In order to investigate the role of PTPN6 in hematologic tumor myelodysplastic syndrome (MDS), this study infected SKM-1 cell line (MDS cell line) with packaged H_PTPN6-shRNA lentivirus to obtain H_PTPN6-shRNA SKM-1 stable strain. The effect of PTPN6 knockdown on apoptosis, erythroid differentiation, and inflammations in SKM-1 cell line was examined. Methods: The stable knockdown SKM-1 cell line was validated using qPCR and Western blot assays. The proliferation activity, apoptosi, erythroid differentiation, and inflammatory cytokines in SKM-1 cells were assessed before and after transfection. Results: qPCR confirmed that the expression level of H_PTPN6-shRNA in SKM-1 cells was significantly reduced, and Western blot showed that the protein expression level of H_PTPN6-shRNA in SKM-1 cells was also significantly reduced. The CCK-8 cell viability assay confirmed that stable gene knockdown did not affect cell viability. Flow cytometry revealed that the apoptosis rate of cells in the PTPN6 knockdown group was 0.8%, lower than the 2.7% observed in the empty plasmid group; the expression rate of the erythroid differentiation marker CD235a was 13.2%, lower than the 25.0% observed in the empty plasmid group. The expression levels of the proinflammatory factors IL-6 and IL-8 increased, and the expression levels of the inhibitor factor IL-4 decreased. Conclusions: The PTPN6 gene was successfully knocked down using lentivirus-mediated transduction, and the constructed cell line was validated using PCR and Western blot. The CCK-8 cell viability assay confirmed that stable gene knockdown did not affect cell proliferation viability. Flow cytometry analysis of apoptosis and erythroid differentiation indicated that PTPN6 knockdown inhibits apoptosis and erythroid differentiation in SKM-1 cells and also alters the level of inflammations in the bone marrow microenvironment. It suggests that the PTPN6 gene acts as a tumor suppressor in myelodysplastic syndrome cells, influencing hematopoietic cell apoptosis, erythroid differentiation, and inflammations. This provides a reliable experimental basis for further in-depth studies on the mechanism of PTPN6 in MDS and related pharmacological research.

Abstract Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2 +/− and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.

Abstract DNA methyltransferase 3 A mutations (DNMT3A MT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A MT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3A MT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3A MT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3A MT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3A MT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3A MT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P

Abstract Background The karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available. Methods We performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC). Results There were 936 patients aged 18–86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1–3% each. Conclusion The most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS.

Evaluation of bone marrow cytogenetic abnormalities in myelodysplastic syndrome is of great importance for confirming the clonal disease nature, determining the prognosis and choosing treatment tactics. Cytogenetic abnormalities are detected in 40–70 % of patients with myelodysplastic syndrome, and the variety of these abnormalities reflects the disease characteristics.This article describes the clinical follow-up of a patient with a myelodysplastic neoplasia with blast excess 1 and trisomy of chromosome 14.

AbstractThe mutations in SRSF2 and TET2 genes are frequently present in various myeloid neoplasms. The potential impact of SRSF2/TET2 co-mutations on patient survival is incompletely understood. We identified 412 patients with SRSF2/TET2 co-mutations from our NextGen sequencing database of around 8000 patients and reported likely the largest cohort study. Our study demonstrated the presence of these co-mutations in a spectrum of myeloid neoplasms, which show different genetic and molecular characteristics. Most of the patients with these co-mutations had normal karyotype. Interestingly, our study provided insights into the prevalence of additional mutations such as ASXL1, RUNX1, and KRAS with this co-mutation and their potential impact on patients’ prognosis. We found that ASXL1, RUNX1, and KRAS can negatively impact these patients’ survival with different impacts in different morphological diagnosis categories, suggesting a complex interaction between these genes. This study underscores the need for personalized approaches in the treatment of myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis (SM) is a rare hematologic disorder characterized by clonal proliferation of mast cells in the bone marrow and/or other organs. SM‐associated hematologic neoplasm (SM‐AHN) is one of the advanced SM variants that usually confer a poor prognosis. We present a case of a 75‐year‐old female patient with SM‐AHN, specifically myelodysplastic syndrome (MDS), that harbored a unique KIT mutation KIT V560D, not previously described in the literature in this setting. We describe the clinical course and the outcome with the use of avapritinib, midostaurin, and decitabine‐cedazuridine. Trial Registration: ClinicalTrials.gov identifier: NCT00782067 [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of intragastric administration of Qinghuang powder on apoptosis and cycle of bone marrow cells in myelodysplastic syndrome (MDS) mice and the mechanism. Methods The Tg (Vav1-NUP98/HOX D13) G2Apla/J transgenic MDS mouse models were used for sperm extraction and propagation, and 40 model mice were randomly divided into the model group, the low-dose, medium-dose, and high-dose Qinghuang powder groups, and the azacitidine group, with eight mice in each group, and eight C57BL/6J mice were taken as the blank group. Mice in the blank and model groups were given 100 µL of normal saline by gavage once a day; mice in the low-dose, mediumdose, and high-dose Qinghuang powder groups were given 36. 4, 72. 8, and 145. 6 mg/kg of Qinghuang powder by gavage once a day; and mice in the azacitidine group were given 100 µL of 1 mg/kg azacitidine by subcutaneous injection in the neck once every 3 days. After 4 weeks of intervention, mice were killed, peripheral blood was collected, and bone marrow cells were extracted. Blood routine [white blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), and platelets (PLT)] was detected in each group, apoptosis rate and cycle of bone marrow cells were detected by flow cytometry, and intracellular DNA methyltransferase 1 (DNMT-1), receptor tyrosine kinase (c-KIT), GATA binding protein 1 (GATA-1) mRNA, and DNMT-1, c-KIT, and GATA-1 proteins in myeloid cells were detected by Western blotting. Results Compared with the blank group, the model group had lower levels of WBC, RBC, HGB and PLT (all P< 0. 05), indicating the modeling was successful; WBC, RBC, HGB and PLT were higher in the low-dose and mediumdose Qinghuang powder groups and the azacitidine group (all P<0. 05); there were no statistically significant differences in the WBC, RBC, HGB, or PLT among the low-dose, medium-dose, and high-dose Qinghuang powder groups and the azacitidine group (all P>0. 05). Compared with the blank group, the apoptosis rate of bone marrow cells in the model group was lower (P<0. 05); compared with the model group, the apoptosis rates of bone marrow cells in the low-dose, medium-dose, and high-dose Qinghuang powder groups and the azacitidine group were higher (all P<0. 05). Compared with the blank group, the bone marrow cell cycle of the model group changed and the difference was statistically significant (P<0. 05); compared with the model group, there were fewer S-phase bone marrow cells and more G1-phase bone marrow cells in the low-dose, medium-dose, and high-dose Qinghuang powder groups and the azacitidine group (all P<0. 05). Compared with the blank group, the model group had lower expression levels of DNMT-1, c-KIT and GATA-1 mRNA (all P<0. 05); compared with the model group, the low-dose, medium-dose, and high-dose Qinghuang powder groups and the azacitidine group had lower DNMT-1 expression and GATA-1 mRNA expression levels (all P<0. 05); and the low-dose, medium-dose Qinghuang powder groups had higher expression levels of c-KIT mRNA (all P<0. 05). Compared with the blank group, DNMT-1, c-KIT and GATA-1 protein expression levels were lower in the model group (all P<0. 05); compared with the model group, the c-KIT protein expression levels were lower, GATA-1 protein expression levels were higher, and DNMT-1 protein expression levels were lower in the low-dose, medium-dose, and high-dose Qinghuang powder groups and the azacitidine group (all P<0. 05). Conclusion The intragastric administration of Qinghuang powder can promote apoptosis and block the cell cycle of bone marrow cells in MDS mice, and its mechanism of action may be related to the regulation of the expression of DNMT-1, c-KIT, and GATA-1. [ABSTRACT FROM AUTHOR]

Genetic alterations that affect the function of p53 tumor suppressor have been extensively investigated in myeloid neoplasms, revealing their significant impact on disease progression, treatment response, and patient outcomes. The identification and characterization of TP53 mutations play pivotal roles in subclassifying myeloid neoplasms and guiding treatment decisions. Starting with the presentation of a typical case, this review highlights the complicated nature of genetic alterations involving TP53 and provides a comprehensive analysis of TP53 mutations and other alterations in myeloid neoplasms. Currently available methods used in clinical laboratories to identify TP53 mutations are discussed, focusing on the importance of establishing a robust testing protocol within clinical laboratories to ensure the delivery of accurate and reliable results. The treatment implications of TP53 mutations in myeloid neoplasms and clinical trial options are reviewed. Ultimately, we hope that this review provides valuable insights into the patterns of TP53 alterations in myeloid neoplasms and offers guidance to establish practical laboratory testing protocols to support the best practices of precision oncology. [ABSTRACT FROM AUTHOR]

Objective This study aimed to investigate the utility of neutrophil-related cell population data obtained by automated hematology analyzers in assessing myelodysplastic syndrome cases with decreased granules in neutrophils. Methods A total of 108 subjects were classified into normal granule (n = 35), hypogranulation (n = 37), or hypergranulation (n = 36) groups. Neutrophil cell area and granule area were measured by ImageJ. All samples were analyzed on the XR-1000 and UniCel DxH 800, and neutrophil-related parameters were compared among the 3 groups. Results Neutrophil cell area and the ratio of the granular area showed significant differences among the 3 groups; they were the highest in the hypergranulation group and lowest in the hypogranulation group. XR-1000 data showed significant differences in NE-SFL and NE-FSC among the 3 groups (P <.0001). NE-SFL and NE-FSC discriminated most accurately hypogranulation group against other groups. UniCel DxH 800 data showed significant differences in MN-V-NE, MN-MALS-N, MN-UMALS-NE, SD-UMALS-NE (P <.01), MN-LMALS-NE, and SD-LMALS-NE (P <.05) among the 3 groups. The combination of SD-V-NE and SD-LMALS-NE discriminated most accurately the hypogranulation group against the other groups. Conclusion NE-SFL and NE-FSC and the combination of SD-V-NE and SD-LMALS-NE are useful in detecting cases with decreased granules in neutrophils. [ABSTRACT FROM AUTHOR]

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient. [ABSTRACT FROM AUTHOR]

Summary: Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra‐haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety‐three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow‐up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p = 0.007), and had a better outcome (4‐year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus‐related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high‐risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome. [ABSTRACT FROM AUTHOR]

Summary: In this study, we used the whole‐exome sequencing (WES) approach to obtain genomic profiles from 92 marrow samples of myelodysplastic syndrome (MDS) patients before haematopoietic stem cell transplantation. We identified 129 mutations in 45 driver genes. Fifty‐five patients (59.8%) carried at least 1 driver mutation. The splicing factor U2AF1 was the most frequently mutated in the cohort (21 cases, 23%), followed by BCOR (9 cases, 10%), ASXL1 (8 cases, 9%), TET2 (6 cases, 7%), NPM1 (5 cases, 5%), RUNX1 (5 cases, 5%), and SETBP1 (5 cases, 5%). WES also identified 49 possible oncogenic variants in six genes (PIEZO1, LOXHD1, MYH13, DNAH5, DPH1, and USH2A) that were associated with overall survival (OS) or relapse‐free survival (RFS) in MDS after transplantation. Multivariate analysis showed mutations in DNAH5 and USH2A to be independent risk factors for OS. Mutations in DNAH5 and LOXHD1 were risk factors for worse RFS. The Molecular International Prognostic Scoring System retained its independent prognostic significance for RFS after multivariate analysis. [ABSTRACT FROM AUTHOR]

Introduction: Currently, no study has determined whether platelet transfusion refractoriness (PTR) post-hematopoietic stem cell transplantation (HSCT) before engraftment in patients with myelodysplastic syndrome (MDS) would impacts clinical outcomes. Methods: We performed a MDS-specific retrospective analysis to determine whether PTR in one-month post-HSCT in patients with MDS could influence outcomes. Results and discussion: Among the 315 patients enrolled, 110 (34.9 %) had PTR from stem cell infusion to one-month post-HSCT. Baseline characteristics of the PTR and non-PTR groups were similar. We found that patients with PTR had a slower and lower rate of platelet engraftment by day 28, as well as a slower recovery of neutrophils. The median days of neutrophil and platelet engraftment were 14 days (9-23) and 17 days (8-28) in the PTR groups versus 13 days (9-23) and 15 days (7-28) in the non-PTR group (P<0.001). By day 28, 84 of 110 patients (76.4%) with PTR achieved platelet engraftment compared with 181 of 205 patients (88.3%) without PTR achieving platelet engraftment (P=0.007). In addition, patients in the PTR group received significantly more red blood cell (median, 17 units vs. 10 units, P<0.001) and platelet transfusions (median, 13 units vs. 7 units, P<0.001). However, the overall survival was similar between the two groups. PTR in onemonth post-HSCT, haploidentical donor, and ferritin level>1041ng/ml (median level) were independent adverse factors of platelet engraftment. [ABSTRACT FROM AUTHOR]

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Copyright of Cirugía y Cirujanos is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)