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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]

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]

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]

Background and Objectives: Acute myeloid leukemia and myelodysplastic syndrome are both clonal hematologic malignancies that primarily affect older adults. Current treatments for AML/MDS are both limited in number and efficacy. This study aims to evaluate venetoclax-based therapies in AML/MDS, focusing on overall survival and recurrence-free survival rates, and to expand real-world data on its use. Materials and Methods: Clinical and laboratory data on patients with AML/MDS aged 18≥ treated with venetoclax between January 2019 and July 2022 were included. Survival analysis was calculated based on the period from 2019 to December 2023. Results: A total of 161 AML and 40 patients with MDS were included. The median age was 63.53 ± 15.30 years for AML and 70.12 ± 10.21 years for MDS. In both groups, over 55% are male. A total of 77.6% of patients with AML and 75% of patients with MDS received treatment prior to venetoclax. Venetoclax was administered in combination with azacitidine to 84.5% of AML and 67.5% of MDS. The relapse rate in AML is approximately 15%. Overall, the 2-year survival rate is 46% and 18.73 months. The overall CR/CRi rate for patients with AML is 49.1%, while for patients with MDS, it is 50%. The 2-year survival rate for patients with MDS is 52.7%. The 2-year RFS rate was 75.5% for AML and 90.9% for MDS. The relapse rate in AML is approximately 15%. The percentage of adverse events leading to treatment discontinuation among those with grade 3–4 toxicity is low; 26.7% for AML (n = 43) and 15% for MDS (n = 6). Conclusions: Our real-world data demonstrate that venetoclax has the potential to improve overall survival rates when used in combination with HMAs and supports its use in patients with AML/MDS. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with myeloid malignancies (blood cancers such as leukemia and myelodysplastic syndromes) that have returned or worsened despite chemotherapy or a stem cell transplant face limited treatment choices. Immunotherapy holds promise in deploying the body's own immune system to target and destroy cancer cells that are otherwise evading immune detection. This review article summarizes the most up to date information on immunotherapy options for patients with myeloid malignancies as well as discusses the challenges faced in this evolving field. Immunotherapy has revolutionized the treatment of myeloid oncologic diseases, particularly for patients resistant to chemotherapy or ineligible for allogeneic stem cell transplantation due to age or fitness constraints. As our understanding of the immunopathogenesis of myeloid malignancies expands, so too do the treatment options available to patients. Immunotherapy in myeloid malignancies, however, faces numerous challenges due to the dynamic nature of the disease, immune dysregulation, and the development of immune evasion mechanisms. This review outlines the progress made in the field of immunotherapy for myeloid malignancies, addresses its challenges, and provides insights into future directions in the field. [ABSTRACT FROM AUTHOR]

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May–2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal disease derived from hematopoietic stem cells, characterized by ineffective hematopoiesis (resulting in peripheral blood cytopenia) and an increased risk of transformation into acute myeloid leukemia. MDS is caused by a complex combination of genetic mutations resulting in a heterogeneous genotype. Genetic studies have identified a set of aberrations that play a central role in the pathogenesis of MDS. In this article, we present a clinical case of MDS transformation into acute myeloid leukemia in the context of two cell lines exhibiting morphological, immunophenotypic, and dysmyelopoiesis markers and the presence of two heterozygous mutations in the TET2 gene. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome/neoplasm (MDS) comprises a group of heterogeneous hematopoietic disorders that present with genetic mutations and/or cytogenetic changes and, in the advanced stage, exhibit wide-ranging gene hypermethylation. Patients with higher-risk MDS are typically treated with repeated cycles of hypomethylating agents, such as azacitidine. However, some patients fail to respond to this therapy, and fewer than 50% show hematologic improvement. In this context, we focused on the potential use of epigenetic data in clinical management to aid in diagnostic and therapeutic decision-making. First, we used the F-36P MDS cell line to establish an azacitidine-resistant F-36P cell line. We performed expression profiling of azacitidine-resistant and parental F-36P cells and used biological and bioinformatics approaches to analyze candidate azacitidine-resistance-related genes and pathways. Eighty candidate genes were identified and found to encode proteins previously linked to cancer, chronic myeloid leukemia, and transcriptional misregulation in cancer. Interestingly, 24 of the candidate genes had promoter methylation patterns that were inversely correlated with azacitidine resistance, suggesting that DNA methylation status may contribute to azacitidine resistance. In particular, the DNA methylation status and/or mRNA expression levels of the four genes (AMER1, HSPA2, NCX1, and TNFRSF10C) may contribute to the clinical effects of azacitidine in MDS. Our study provides information on azacitidine resistance diagnostic genes in MDS patients, which can be of great help in monitoring the effectiveness of treatment in progressing azacitidine treatment for newly diagnosed MDS patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present review is to summarize the main characteristics of immune thrombocytopenia (ITP) and to determine cases where persistent, isolated thrombocytopenia is misclassified as ITP. One of the most common misdiagnoses of ITP is myelodysplastic syndrome presented with thrombocytopenia as an isolated abnormality (MDS-IT). As MDS-IT has been poorly described in the literature, the precise characterization of patients with MDS-IT is essential and the extend diagnostic, clinical and laboratory work-up is necessary for determining which of the cases of persistent thrombocytopenia are refractory and which of them have mistakenly been attributed to a diagnosis other than MDS-IT. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The aim of this review is to summarize the conditions associated with isolated thrombocytopenia and highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases of persistent thrombocytopenia a detailed diagnostic work-up is applied—including evaluation of peripheral-blood smear, bone marrow examination and cytogenetic testing—to avoid unnecessary therapy delay. [ABSTRACT FROM AUTHOR]

Simple Summary: Azacitidine (AZA) is an essential drug in the treatment of myelodysplastic syndromes (MDS) that has made it possible to extend patients' survival and improve their quality of life. Unfortunately, despite the widespread use of AZA, its prognostic factors for response still remain unknown. Here, we retrospectively analyzed the efficacy and safety of AZA therapy in 79 patients with MDS in a real-life setting. Furthermore, we provided some potential biomarkers of response and survival. The study confirmed that the achievement of response to AZA is not mandatory for obtaining a survival benefit in patients with MDS. Unfavorable cytogenetic risk was determined to be the most negative prognostic factor for both response and survival. Moreover, older age, a complex or monosomal karyotype, higher IPSS or IPSS-R risk and a higher level of serum ferritin level were associated with significantly shorter survival. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Allogeneic stem cell transplantation (allo-SCT) represents the only potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but up to 50% of patients relapse after allo-SCT. The salvage therapy after disease recurrence is not standardized, and the outcome remains unfavorable. Therefore, there is a growing interest in determining the most effective approach to manage the post-transplant phase with the goal of promptly detecting disease recurrence or preventing it. In this context, we conducted a retrospective study to assess the overall survival (OS) of patients with relapsed AML or MDS after allo-SCT with the aim of acquiring useful information for identifying the best prospective therapeutic strategy. The OS was evaluated according to the type of therapy, whether it included donor lymphocyte infusion (DLI), the timing of administration, and whether it occurred during an overt hematological relapse or in a preemptive setting. Background: Disease relapse after allogeneic stem cell transplantation (allo-SCT) is the main challenge for curing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We investigated the overall survival (OS) after allo-SCT relapse according to different therapeutic approaches. Methods: We analyzed 134 patients who relapsed after allo-SCT performed between 2015 and 2021 at Saint-Antoine University Hospital, Paris and Spedali Civili di Brescia, Brescia. Of these, 103 (77%) were treated, comprising 69/103 (67%) who received therapy in overt relapse and 34/103 (33%) who were treated in a pre-emptive manner when molecular/cytogenetics recurrence or mixed chimerism occurred. The treatment was donor lymphocyte infusion (DLI)-based for 40/103 (39%) patients. Results: The 1-, 2-, and 5-year OS of patients treated with DLI (n = 40) was 67%, 34%, and 34%, respectively, for those treated preventively (n = 20) and 43%, 20%, and 20%, respectively, for those treated in overt relapse (n = 20) (p < 0.01). The 1-, 2-, and 5-year OS of patients treated without DLI (n = 63) was 54%, 40%, and 26%, respectively, for those treated preventively (n = 14) and 17%, 5%, and 0%, respectively, for those treated in overt relapse (n = 49) (p < 0.01). Conclusions: Relapse treatment with a pre-emptive strategy was associated with improved outcomes, particularly when DLI was employed. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5–14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/− 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing. [ABSTRACT FROM AUTHOR]

Simple Summary: There are several rare types of hematologic malignancies and germline predispositions syndromes in children and adolescent young adults. In this descriptive review, we briefly describe rare hematologic malignancies, myelodysplastic neoplasms, and predispositions syndromes in children for which we have cohort outcome data and summarize emerging concepts in pathogenesis, diagnosis, prognostication, and treatment. There are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associated with these rare entities. [ABSTRACT FROM AUTHOR]

Background: Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. Methods: This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. Results: Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3–4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. Conclusion: Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA. [ABSTRACT FROM AUTHOR]

The analysis of hematopoietic stem and progenitor cell populations (HSPCs) is fundamental in the understanding of normal hematopoiesis as well as in the management of malignant diseases, such as leukemias, and in their diagnosis and follow-up, particularly the measurement of treatment efficiency with the detection of measurable residual disease (MRD). In this study, I designed a 20-color flow cytometry panel tailored for the comprehensive analysis of HSPCs using a spectral cytometer. My investigation encompassed the examination of forty-six samples derived from both normal human bone marrows (BMs) and patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) along with those subjected to chemotherapy and BM transplantation. By comparing my findings to those obtained through conventional flow cytometric analyses utilizing multiple tubes, I demonstrate that my innovative 20-color approach enables a more in-depth exploration of HSPC subpopulations and the detection of MRD with at least comparable sensitivity. Furthermore, leveraging advanced analytical tools such as t-SNE and FlowSOM learning algorithms, I conduct extensive cross-sample comparisons with two-dimensional gating approaches. My results underscore the efficacy of these two methods as powerful unsupervised alternatives for manual HSPC subpopulation analysis. I expect that in the future, complex multi-dimensional flow cytometric data analyses, such as those employed in this study, will be increasingly used in hematologic diagnostics. [ABSTRACT FROM AUTHOR]

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical–rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the UBA1 codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18–68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for UBA1 mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for UBA1 mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: GATA2 deficiency is a complex disorder associated with an increased risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia. In this study, we focused on pediatric MDS patients with or without an additional GATA2 deficiency and investigated the possible mechanisms underlying disease progression. We found that disease progression was associated with an upregulation in GATA2 mRNA levels, along with the reactivation of EZH2, a gene controlled by GATA2. This was accompanied by increased histone trimethylation, a key epigenetic mark linked to EZH2 function. Additionally, we found elevated levels of the antiapoptotic protein BCL2 in patients with an advanced GATA2 deficiency, together with alterations in apoptosis-related proteins. These findings suggest the potential drivers of disease progression in pediatric GATA2 deficiency, including increased histone trimethylation and deregulated apoptosis. Therefore, this study provides a rationale for the use of the therapeutic agents venetoclax and azacitidine, offering promising options for improving patient management in the future. GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual's risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB. [ABSTRACT FROM AUTHOR]

Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Current research is exploring the evolving landscape of Myelodysplastic Syndrome (MDS) treatment, a challenging condition often progressing to acute myeloid leukemia. For low-risk MDS, the focus is on personalized care through precise risk assessment and tailored interventions, utilizing means like erythropoiesis-stimulating agents, lenalidomide, and luspatercept. High-risk MDS treatments are shifting towards upfront doublet or triplet therapies and minimal residual disease (MRD) monitoring. A holistic approach integrates treatments like stem cell transplants and post-transplant maintenance, guided by individual patient circumstances. Precision medicine, driven by Next Generation Sequencing (NGS), aids in early diagnosis, prognosis, and customized interventions, allowing for investigations through clinical trials within more homogeneous patient cohorts characterized by similar molecular profiles. Based on these premises, the future of MDS treatment irrefutably moves towards personalized care, leveraging advanced technologies and molecular insights to enhance patient outcomes in the realm of hematological malignancies. This perspective delves into the evolving landscape of Myelodysplastic Syndrome (MDS) treatment. MDS presents a significant clinical challenge, often progressing to acute myeloid leukemia. For low-risk MDS, the emphasis is on personalized care through comprehensive risk assessment, clinical monitoring, and tailored interventions, including promising agents like erythropoiesis-stimulating agents, lenalidomide, and luspatercept, with the anticipation of an expanding therapeutic arsenal and early intervention for improved outcomes. In contrast, high-risk MDS treatment is evolving towards upfront doublet or triplet therapies with a focus on minimal residual disease (MRD) monitoring. A holistic approach integrates various modalities, including stem cell transplant and post-transplant maintenance, all guided by individual patient circumstances. Risk-adapted strategies are crucial for enhancing patient outcomes. Precision medicine for MDS treatment is budding, largely driven by Next Generation Sequencing (NGS). NGS aids in early diagnosis, prognostication, and the targeting of specific mutations, with molecular data increasingly informing treatment responses and allowing for tailored interventions. Clinical trials within homogeneous patient groups with similar molecular profiles are becoming more common, enhancing treatment precision. In conclusion, the future of MDS treatment is moving towards personalized medicine, leveraging advanced technologies like NGS and molecular insights to improve outcomes in the realm of hematological malignancies. [ABSTRACT FROM AUTHOR]

Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb–QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL. [ABSTRACT FROM AUTHOR]

The management of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is limited and remains an unmet need. Decitabine/cedazuridine (DEC-C, ASTX727) is Canada's first and only approved oral hypomethylating agent for MDS and CMML. We characterized the real-world use of DEC-C through a Canadian compassionate use program. Demographic and clinical data from 769 patients enrolled in Taiho Pharma Canada's Patient Support Program were collected and analyzed. These patients represent a collection period from 10 November 2020 to 31 August 2022 with a median age of 76 years. Among 651 patients who started DEC-C, the median treatment duration was 4.2 cycles. The median overall and progression-free survival were 21.6 and 10.7 months, respectively. Among 427 patients who discontinued treatment, the majority (69.5%) stopped due to death (n = 164) or disease progression (n = 133). Multivariable cox regression showed that age, province of residence, blast counts, antibiotic prophylaxis, and number of dose reductions and delays were not significantly associated with overall and progression-free survival. DEC-C is a promising alternative to parenteral hypomethylating agent therapy, and it likely addresses an important unmet need for effective and convenient therapies in this setting. [ABSTRACT FROM AUTHOR]

Simple Summary: The revised international prognostic scoring system (IPSS-R) represents the standard tool for prognostication in myelodysplastic syndromes (MDSs). It considers the degree of cytopenias together with the bone marrow blast count and the results of metaphase cytogenetics. Monocytes are a subgroup of white blood cells involved in host defense and tissue repair or remodelling. The goal of our study was to assess the prognostic impact of the absolute monocyte count (AMC) at the time point of diagnosis in patients with MDS. We found an IPSS-R-independent prognostic impact of the AMC, both when assessed as a continuous variable and when MDS patients with a low (<0.2 × 109/L) or a higher (>0.4 × 109) AMC were compared to MDS patients with an AMC of 0.2–0.4 × 109/L. A low AMC was associated with a higher risk of transformation to acute myeloid leukemia. Hence, considering the AMC might help to identify MDS patients who could benefit from more intense treatment strategies. The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 109/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 109/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 109/L. Accordingly, an AMC within the last quartile of the population (0.4 × 109/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis. [ABSTRACT FROM AUTHOR]

Iron plays an important role in the pathogenesis of infections, including invasive fungal infections (IFIs). Studies suggested that iron overload might represent an additional risk factor for IFIs among patients with hematological malignancies. We conducted a prospective, multi-center study amongst adult patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in transformation to determine whether baseline iron overload as measured using the bone marrow iron store (BMIS) score is an independent risk factor for the development of IFIs. We also measured baseline serum iron and ferritin levels. A total of 98 patients were enrolled (76 with AML) and were followed for 12 months. Twenty-two patients developed IFI during the follow-up period (invasive aspergillosis n = 16, candidemia n = 5, mucormycosis n = 1). A baseline BMIS score ≥ 3 indicated that iron overload was relatively common (38/98 patients, 38%), and its frequency was comparable between patients with no IFIs (31/76, 40.7%) and in those with IFIs (8/22, 36.4%). Univariate analysis showed that only the presence of AML was associated with increased risk for IFIs [OR (95% CI) 7.40 (1.05–325.42)]. Both univariate and multivariate analyses showed that an increased BMIS score (≥3) at baseline was not an independent risk factor for IFIs. Similarly, there was no difference in serum iron and ferritin between the two groups that had similar demographic characteristics. Indices of iron overload were not independent risk factors for IFIs in our cohort of Greek patients with newly diagnosed AML/MDS in transformation. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from multiple myeloma receive many lines of treatment including chimeric antigen receptor T cell (CART) therapy. Myeloma patients may develop devastating secondary malignancies such as myelodysplastic syndrome (MDS). The causative relationship between various anti-myeloma treatments and MDS is not fully understood. We report a study of five CART-treated patients myeloma patients who had MDS (four only after CART and one already prior to CART). We found that all these patients had all their MDS-related molecular changes (mutations) already prior to CART even if they did not have overt MDS in bone marrow evaluation before CART. No new mutations developed after CART, but the frequency of pre-existing mutations did increase. Our study presents evidence that anti-myeloma CART therapy may promote the expansion of pre-existing MDS clones rather than causing the development of new ones. 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 FROM AUTHOR]

Simple Summary: The assessment of the new hematological neutrophil- and monocyte-related parameters may be important in myelodysplastic syndrome (MDS) patients for rapid diagnostics. The aim of the study was to assess the new hematological parameters in the bone marrow of MDS patients with and without cytogenetic changes. A total of 45 patients with MDS, including 17 patients with cytogenetic changes, were examined. The study was conducted using the Sysmex XN-Series hematological analyzer. New neutrophil and monocyte data relating to granularity, activity, volume and maturity (NE-WX/MO-WX, NE-WY/MO-WY, NE-WZ/MO-WZ, MO-X, MO-Y, MO-Z, and IG) were evaluated. We observed higher median proportions of NE-WX, NE-WY, NE-WZ, and IG count in MDS patients with cytogenetic changes than in patients without cytogenetic changes. The NE-FSC parameter was lower in MDS patients with cytogenetic changes than in patients without cytogenetic changes. New neutrophil-related parameters are shown to be useful in the rapid detection of patients with cytogenetic changes. Myelodysplastic syndromes (MDS) are common malignant disorders with a poor prognosis. It is necessary to search for new rapid diagnostic methods to detect MDS patients with cytogenetic changes. The aim of the study was to assess new hematological neutrophil- and monocyte- related parameters I then bone marrow of MDS patient with and without cytogenetic changes. A total of 45 patients with MDS, including 17 patients with cytogenetic changes, were examined. The study was conducted using the Sysmex XN-Series hematological analyzer. New neutrophil and monocyte parameters, such as immature granulocytes (IG), neutrophil reactivity intensity (NEUT-RI), neutrophil granularity intensity (NEUT-GI), neutrophil size (NE-FSC) and neutrophil/monocyte data relating to granularity, activity and volume (NE-WX/MO-WX, NE-WY/MO-WY, NE-WZ/MO-WZ, MO-X, MO-Y, MO-Z) were evaluated. We observed higher median proportions of NE-WX, NE-WY, NE-WZ, and IG counts in MDS patients with cytogenetic changes than in patients without cytogenetic changes. The NE-FSC parameter was lower in MDS patients with cytogenetic changes than in patients without cytogenetic changes. The combination of new neutrophil parameters was found to be a new successful approach in distinguishing MDS patients with cytogenetic changes from patients without cytogenetic changes. It appears that there may be unique neutrophil parameter signatures associated with an underlying mutation. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) describes a group of bone marrow malignancies with variable morphologies and heterogeneous clinical features. The aim of this study was to systematically appraise the published clinical, laboratory, and pathologic characteristics and identify distinct clinical features of MDS in the Middle East and North Africa (MENA) region. We conducted a comprehensive search of the PubMed, Web of Science, EMBASE, and Cochrane Library databases from 2000 to 2021 to identify population-based studies of MDS epidemiology in MENA countries. Of 1935 studies, 13 independent studies published between 2000 and 2021 representing 1306 patients with MDS in the MENA region were included. There was a median of 85 (range 20 to 243) patients per study. Seven studies were performed in Asian MENA countries (732 patients, 56%) and six in North African MENA countries (574 patients, 44%). The pooled mean age was 58.4 years (SD 13.14; 12 studies), and the male-to-female ratio was 1.4. The distribution of WHO MDS subtypes was significantly different between MENA, Western, and Far East populations (n = 978 patients, p < 0.001). More patients from MENA countries were at high/very high IPSS risk than in Western and Far East populations (730 patients, p < 0.001). There were 562 patients (62.2%) with normal karyotypes and 341 (37.8%) with abnormal karyotypes. Our findings establish that MDS is prevalent within the MENA region and is more severe than in Western populations. MDS appears to be more severe with an unfavorable prognosis in the Asian MENA population than the North African MENA population. [ABSTRACT FROM AUTHOR]

Objectives: To investigate and characterize JAK2 mutations in myelodysplastic syndrome (MDS), we present three cases with diverse JAK2 mutations and review the literature. Methods: The institutional SoftPath software was used to find MDS cases between January 2020 and April 2022. The cases with a diagnosis of a myelodysplastic/myeloproliferative overlap syndrome including MDS/MPN with ring sideroblasts and thrombocytosis were excluded. The cases with molecular data by next generation sequencing looking for gene aberrations commonly seen in myeloid neoplasms were reviewed for the detection of JAK2 mutations including variants. A literature review on the identification, characterization, and significance of JAK2 mutations in MDS was performed. Results: Among 107 cases of the MDS reviewed, a JAK2 mutation was present in three cases, representing 2.8% of the overall cases. A JAK2 V617F mutation was found in one case representing slightly less than 1% of all the MDS cases. In addition, we found JAK2 R564L and JAK2 I670V point mutation variants to be associated with a myelodysplastic phenotype. Conclusions: JAK2 mutations in MDS are rare and represent less than 3% of cases. It appears that JAK2 variant mutations in MDS are diverse and further studies are needed to understand their role in the phenotype and prognosis of the disease. [ABSTRACT FROM AUTHOR]

Although daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, and dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, have been approved for the treatment of renal anemia in Japan, their efficacy and safety for patients aged 80 years or older with low-risk myelodysplastic syndrome (MDS)-related anemia have not been demonstrated. Our case series comprised two men and one woman aged >80 years with low-risk MDS-related anemia and diabetic mellitus (DM)-related chronic kidney disease who were dependent on red blood cell transfusions and in whom erythropoiesis-stimulating agents had been insufficient. All three patients received daprodustat and additional dapagliflozin achieved red blood cell transfusion independence and were followed up for >6 months. Daily oral daprodustat was well tolerated. There were no fatalities or progression to acute myeloid leukemia during the >6-month follow-up after daprodustat initiation. On the basis of these outcomes, we consider 24 mg of daprodustat combined with 10 mg of dapagliflozin daily an effective form of treatment for low-risk MDS-related anemia. Further studies are required to clarify the synergistic effects of daprodustat and dapagliflozin, which correct chronic kidney disease-related anemia by promoting endogenous erythropoietin production and normalizing iron metabolism to manage low-risk MDS in the long term. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) immunity plays an important role in the proliferation and apoptosis of aberrant cells. Immune dysregulation has been studied in various prognostic subgroups. This study analyzed 60 patients with MDS via multidimensional flow cytometry to evaluate the expression of aberrant markers, such as CD7 and cytoplasmic CD3 on lymphocytes. The Revised International Prognostic Scoring System (IPSS-R) scores were used to classify the patients into risk groups. The results showed a significant downregulation of CyCD3− T cells in low–intermediate versus high-risk patients (p = 0.013). This study is the first to show that a significant decrease in cyCD3− T cells in patients with a lower IPSS-R score may indicate microenvironmental changes conducive to transformation in MDS [ABSTRACT FROM AUTHOR]

Sweet syndrome (SS) is a rare disease described as a febrile neutrophilic dermatosis with acute onset, the pathogenesis of which has not yet been elucidated. The syndrome is characterized by the sudden onset of erythematous infiltrated papules or plaques located on the upper body and is associated with fever, leukocytosis and neutrophilia. The lesions show a dense dermal infiltration with mature neutrophils. The condition is responsive to systemic steroids. The central nervous system, bones, muscles, eyes, ears, mouth, heart, lung, liver, kidneys, intestines, and spleen may be affected by SS as extracutaneous manifestations. More and more cases have been found to be associated with malignancies, particularly myelodysplastic syndrome, and, less frequently, other hematologic malignancies or solid tumors. Approximately 21% of patients with SS have an associated malignancy and up to 80% of MASS cases are associated with hematological diseases, predominantly myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Myelodysplastic syndrome is a clonal disease of the bone marrow characterized by inefficient hematopoiesis, dysplasia of the bone marrow and peripheral cytopenias. Affected patients have a high risk of leukemic transformation. After analyzing later studies and current practical aspects regarding MDS-related SS, we suggest an algorithm for evaluating these patients. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) treatment remains a big challenge due to the heterogeneous nature of the disease and its ability to progress to acute myeloid leukemia (AML). The only curative option is allogeneic hematopoietic stem cell transplantation (HSCT), but most patients are unfit for this procedure and are left with only palliative treatment options, causing a big unmet need in the context of this disease. Natural killer (NK) cells are attractive candidates for MDS immunotherapy due to their ability to target myeloid leukemic cells without prior sensitization, and in recent years we have seen an arising number of clinical trials in AML and, recently, MDS. NK cells are reported to be highly dysfunctional in MDS patients, which can be overcome by adoptive NK cell immunotherapy or activation of endogenous NK cells. Here, we review the role of NK cells in MDS, the contribution of the tumor microenvironment (TME) to NK cell impairment, and the most recent data from NK cell-based clinical trials in MDS. [ABSTRACT FROM AUTHOR]

Simple Summary: The DEAD-box RNA helicase 41, DDX41, is one of the most frequently identified mutations in myeloid neoplasms with germline predispositions, which represents 2% of the entire MDS/AML population. DDX41 is located at 5q35.3, and its mutation has unique features of male predominance and long-term cytopenia before the development of myeloid neoplasms. So far, mechanism studies revealed that DDX41 mutations, affected by both germline and somatic mutations, can be pathogenic by impairments in the normal function of genes involving RNA splicing and processing, ribosomal biogenesis, metabolism, cycle progression, and innate immunity. We are gaining a better understanding of disease from more studies coming out with larger cohorts. The survival impact of the mutation remains unclear, although recent larger studies suggest a better treatment response and survival in higher risk MDS/AML. Several studies showed a good response to lenalidomide in certain patients with MDS with DDX41 mutations. Early identification of stem-cell transplant donors in the family for patients with DDX41 mutations is crucial to avoid donor-derived leukemia from germline carriers. In this article, we reviewed the current understanding of DDX41 mutations in AML/MDS, including its pathogenesis and clinical characteristics, outcome, and treatment. The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications. [ABSTRACT FROM AUTHOR]

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15–18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as "Award Recipient" with the relevant category. We congratulate all the presenters on their research and contribution to the field. [ABSTRACT FROM AUTHOR]

The safety profile of hydroxyurea (HU) in patients with sickle-cell disease (SCD) is relatively well known. However, despite the suspected association of HU with myeloid neoplasms in myeloproliferative neoplasms (MPN), and the publication of sporadic reports of myeloid malignancies in SCD patients treated with HU, the possible excess risk imparted by HU in this population having an increasing life expectancy has failed to be demonstrated. Herein, we report one case of myelodysplastic syndrome emanating from the results on safety and effectiveness of HU on the largest European cohort of 1903 HU-treated adults and children who were followed-up prospectively in an observational setting over 10 years, accounting for a total exposure of 7309.5 patient-years. A comparison of this single case with previously published similar cases did not allow us to draw any significant conclusions due to the paucity of these events. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we provide a brief account of recent genomic findings, updated guidelines and emerging promising tools to help refine our diagnostic abilities in the setting of myelodysplastic neoplasms; We also discuss limitations of current practices during disease follow-up, to shed light on the pressing need to enhance our prognostic armamentarium in the near future. Until recently, conventional prognostication of myelodysplastic neoplasms (MDS) was performed using the revised International Prognostic Scoring System (IPSS-R), with additional adverse prognoses conferred by select mutations. Nonetheless, the clonal diversity and dynamics of coexisting mutations have been shown to alter the prognosis and treatment response in patients with MDS. Often in the process of clonal evolution, various initial hits are preferentially followed by a specific spectrum of secondary alterations, shaping the phenotypic and biologic features of MDS. Our ability to recapitulate the clonal ontology of MDS is a necessary step toward personalized therapy and the conceptualization of a better classification system, which ideally would take into consideration all genomic aberrations and their inferred clonal architecture in individual cases. In this review, we summarize our current understanding of the molecular landscape of MDS and the role of mutational combinations, clonal burden, and clonal hierarchy in defining the clinical fate of the disease. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a heterogeneous hematopoietic disorder associated with cellular proliferative and apoptotic activity. We retrospectively investigated these activities in bone marrow samples from 76 MDS patients using immunohistochemical staining for Ki-67 and cleaved caspase-3. We divided cleaved caspase-3 into two groups based on median value and compared the differences according to MDS risk scoring systems. We compared MDS patient indices with idiopathic cytopenia of undetermined significance (ICUS) and healthy control (HC) indices using our previously published data. Cleaved caspase-3 immunohistochemistry was highest in MDS patients, followed by ICUS patients and HCs. Similarly, the mean Ki-67 grade was also highest in MDS patients, followed by ICUS patients and HCs. Higher cleaved caspase-3 grade was significantly associated with lower IPSS-R score (p = 0.020), whereas Ki-67 was not associated with MDS. Interestingly, TET2 mutation was associated with decreased cleaved caspase-3 levels (p = 0.03). However, there was no significant association between proliferative/apoptotic activity and survival. Our results suggest that apoptotic activity gradually increases from healthy controls and ICUS patients to MDS patients. Furthermore, higher apoptotic activity was associated with better MDS patient prognostic scores. Further studies are needed to reveal the differences in apoptotic activity between lower- and higher-risk MDS. [ABSTRACT FROM AUTHOR]

The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated. [ABSTRACT FROM AUTHOR]

Renal leukemic infiltration is uncommon in myeloid neoplasms, including myelodysplastic syndromes (MDS). A 76-year-old male patient was admitted to our hospital with complaints of fever and dyspnea. He was diagnosed with MDS with multilineage dysplasia and acute focal bacterial nephritis (AFBN) based on clinical, laboratory, and radiological investigations. Antibiotic treatment temporarily improved his condition, but the radiological image of AFBN remained. His condition gradually deteriorated into multiple organ failure, and he unfortunately died on the 31st day of hospitalization. Autopsy findings revealed significantly increased p53-positive blasts in the bone marrow and renal parenchyma overlapping AFBN, suggesting leukemic transformation and renal infiltration. This case emphasizes the need to review the diagnosis when antibiotic treatment is ineffective in MDS patients with AFBN. [ABSTRACT FROM AUTHOR]

Fever, inflammation and vacuoles in hematopoietic cells represent the main features associated with VEXAS syndrome, a new prototype of autoinflammatory disorders genetically characterized by somatic mutation of the UBA1 gene which encodes the enzyme1-activating enzyme (E1) required for ubiquitin signaling. Described very recently, patients with VEXAS syndrome present a systemic autoinflammatory syndrome associated with hematological impairments, especially cytopenias whose pathophysiology is mainly non-elucidated. Initially diagnosed in elderly male patients, VEXAS syndrome was frequently associated with a diagnosis of myelodysplastic syndromes (MDS) leading the medical community to first consider VEXAS syndrome as a new subtype of MDS. However, since the first description of VEXAS patients in 2021, it appears from the multitude of case reports that MDS associated with VEXAS are different from the classically described MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDSs) are clonal hematopoietic diseases of the elderly, characterized by chronic cytopenia, ineffective and dysplastic hematopoiesis, recurrent genetic abnormalities and increased risk of progression to acute myeloid leukemia. Diagnosis on a complete blood count (CBC) can be challenging due to numerous other non-neoplastic causes of cytopenias. New generations of hematology analyzers provide cell population data (CPD) that can be exploited to reliably detect MDSs from a routine CBC. In this review, we first describe the different technologies used to obtain CPD. We then give an overview of the currently available data regarding the performance of CPD for each lineage in the diagnostic workup of MDSs. Adequate exploitation of CPD can yield very strong diagnostic performances allowing for faster diagnosis and reduction of time-consuming slide reviews in the hematology laboratory. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) and Waldenstrom's macroglobulinemia (WM) are rarely synchronous. Ineffective myelopoiesis/hematopoiesis with clonal unilineage or multilineage dysplasia and cytopenias characterize MDS. Despite a myeloid origin, MDS can sometimes lead to decreased production, abnormal apoptosis or dysmaturation of B cells, and the development of lymphoma. WM includes bone marrow involvement by lymphoplasmacytic lymphoma (LPL) secreting monoclonal immunoglobulin M (IgM) with somatic mutation (L265P) of myeloid differentiation primary response 88 gene (MYD88) in 80–90%, or various mutations of C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene in 20–40% of cases. A unique, progressive case of concurrent MDS and WM with several somatic mutations (some unreported before) and a novel balanced reciprocal translocation between chromosomes 10 and 13 is presented below. [ABSTRACT FROM AUTHOR]

Simple Summary: To understand the role of bone marrow fibrosis and its molecular changes in myelodysplastic syndrome, we retrospectively analyzed data from 814 patients. Older age, lower hemoglobin, unfavorable karyotype and higher BM blast were more often observed in patients with moderate/severe fibrosis. Cases with bone marrow fibrosis had reduced overall survival. TP53, U2AF1 and KMT2D mutations were more frequent in patients with moderate/severe fibrosis. In addition, 15.1% of patients progressed to moderate/severe fibrosis during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those patients with moderate/severe fibrosis at diagnosis. We concluded that bone marrow fibrosis was associated with reduced overall survival in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. The prognostic significance of bone marrow fibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) is still debated and the molecular changes remain unclear. In our large cohort, a normal reticulum was found in 211 (25.9%) patients, whereas MF1, MF2 and MF3 were detected in 478 (58.7%), 90 (11.1%) and 35 (4.3%) patients at initial diagnosis, respectively. Patients with MF often correlated with some poor prognostic characteristics, including older age, anemia, unfavorable karyotype, higher BM blast and a higher IPSS-R category. For the entire cohort, the median OS was not reached, 30, 16 and 15 months for patients with MF 0, 1, 2 and 3, respectively. After adjusting for IPSS-R, the hazard ratio for mortality was 1.56 (95% CI, 1.18–2.06) for patients with MF1, 2.29 (95% CI, 1.61–3.27) for patients with MF2 and 2.75 (95% CI, 1.69–4.49) for patients with MF3 compared with those with MF0. The mutational landscape of 370 patients showed that TP53, U2AF1 and KMT2D mutations were more frequent in patients with MF2-3. In addition, of the 408 patients with MF0-1, 62 patients (15.1%) progressed to MF2-3 during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those of patients with MF2-3 at diagnosis. We concluded that BM fibrosis (MF1, 2 and 3) was an adverse prognosis feature in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. Therefore, BM fibrosis should be included in the revised prognostic scoring system and carefully considered in treatment selection. [ABSTRACT FROM AUTHOR]

In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in azacitidine-resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelodysplastic syndrome (MDS) is a myeloid neoplasm associated with complex clonal architecture. The application of single-cell sequencing is capable of revealing the clonal dynamics of MDS during disease progression and treatment resistance. This has advantages over bulk-tumor sequencing which is limited by its resolution. In this study, we evaluated two patients with MDS for the clonal dynamics of pathogenic mutations at the single-cell level of disease progression and resistance to hypomethylating agents (HMAs). There were two key observations. First, changes in the clonal heterogeneity of the pathogenic FLT3-ITD, IDH2, EZH2, or GATA2 mutations was associated with disease progression and resistance to HMA. Secondly, disease progression and resistance to HMA was accompanied by the acquisition of copy number variations of DNMT3A, TET2, and GATA2. Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective hematopoiesis, cytopenia, dysplasia, and clonal instability, leading to leukemic transformation. Hypomethylating agents are the mainstay of treatment in higher-risk MDS. However, treatment resistance and disease transformation into acute myeloid leukemia (AML) is observed in the majority of patients and is indicative of a dismal outcome. The residual cell clones resistant to therapy or cell clones acquiring new genetic aberrations are two of the key events responsible for drug resistance. Bulk tumor sequencing often fails to detect these rare subclones that confer resistance to therapy. In this study, we employed a single-cell DNA (sc-DNA) sequencing approach to study the clonal heterogeneity and clonal evolution in two MDS patients refractory to HMA. In both patients, different single nucleotide variations (SNVs) or insertions and deletions (INDELs) were detected with bulk tumor sequencing. Rare cell clones with mutations that are undetectable by bulk tumor sequencing were detected by sc-DNA sequencing. In addition to SNVs and short INDELs, this study also revealed the presence of a clonal copy number loss of DNMT3A, TET2, and GATA2 as standalone events or in association with the small SNVs or INDELs detected during HMA resistance and disease progression. [ABSTRACT FROM AUTHOR]

Simple Summary: The present work comes up after detecting stakeholders' need to test for manifold molecular biomarkers in each sample from an individual diagnosed with myeloid neoplasm or acute leukemia. The development of gene panels based on NGS technology is considered a potentially effective testing alternative with less human effort, compared to that required by other conventional techniques (PCR, FISH, conventional karyotype, etc.). The validation of this panel aims to propose a new solution for hospitals to face the challenges posed by the molecular study of this group of onco-hematological diseases. A suitable diagnostic classification of myeloid neoplasms and acute leukemias requires testing for a large number of molecular biomarkers. Next-generation sequencing is a technology able to integrate identification of the vast majority of them in a single test. This manuscript includes the design, analytical validation and clinical feasibility evaluation of a molecular diagnostic kit for onco-hematological diseases. It is based on sequencing of the coding regions of 76 genes (seeking single-nucleotide variants, small insertions or deletions and CNVs), as well as the search for fusions in 27 target genes. The kit has also been designed to detect large CNVs throughout the genome by including specific probes and employing a custom bioinformatics approach. The analytical and clinical feasibility validation of the Haematology OncoKitDx panel has been carried out from the sequencing of 170 patient samples from 6 hospitals (in addition to the use of commercial reference samples). The analytical validation showed sensitivity and specificity close to 100% for all the parameters evaluated, with a detection limit of 2% for SNVs and SVs, and 20% for CNVs. Clinically relevant mutations were detected in 94% of all patients. An analysis of the correlation between the genetic risk classification of AML (according to ELN 2017) established by the hospitals and that obtained by the Haematology OncoKitDx panel showed an almost perfect correlation (K = 0.94). Among the AML samples with a molecular diagnosis, established by the centers according to the WHO, the Haematology OncoKitDx analysis showed the same result in 97% of them. The panel was able to adequately differentiate between MPN subtypes and also detected alterations that modified the diagnosis (FIP1L1-PDGFRA). Likewise, the cytogenetic risk derived from the CNV plot generated by the NGS panel correlated substantially with the results of the conventional karyotype (K = 0.71) among MDS samples. In addition, the panel detected the main biomarkers of prognostic value among patients with ALL. This validated solution enables a reliable analysis of a large number of molecular biomarkers from a DNA sample in a single assay. [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&#95; PTPN6 -shRNA lentivirus to obtain H&#95; 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&#95; PTPN6 -shRNA in SKM-1 cells was significantly reduced, and Western blot showed that the protein expression level of H&#95; 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.

Background Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenias, with most patients developing significant anemia and dependence on red blood cell (RBC) transfusion. In paroxysmal nocturnal hemoglobinuria (PNH), mutations in the PIGA gene lead to lack of cell-surface glycosylphosphatidylinositol, allowing complement-mediated lysis to occur. Paroxysmal nocturnal hemoglobinuria results in direct antiglobulin test--negative hemolysis and cytopenias, and up to 50% of patients with mds test positive for PNH cells. We wanted to determine whether PNH is considered to be a contributor to anemia in MDS. Methods Patients with a diagnosis of mds confirmed by bone-marrow biopsy since 2009 were reviewed. Highresolution PNH testing by flow cytometry examined flaer (fluorescein-labeled proaerolysin) binding and expression of CD14, CD15, CD24, CD45, CD59, CD64, and CD235 on neutrophils, monocytes, and RBCS. Results In 152 patients with MDS diagnosed in 2009 or later, the MDS diagnosis included subtypes associated with PNH positivity (refractory anemia, n = 7, and hypoplastic MDS, n = 4). Of 11 patients who underwent pnh testing, 1 was positive (9.0%). Reasons for PNH testing were anemia (n = 3), new MDS diagnosis (n = 2), hypoplastic MDS (n = 2), decreased haptoglobin (n = 1), increased RBC transfusion requirement (n = 1), and unexplained iron deficiency (n = 1). Conclusions Testing for PNH was infrequent in MDS patients, and the criteria for testing were heterogeneous. Clinical indicators prompted PNH testing in 6 of 11 patients. Given that effective treatment is now available for PNH and that patients with PNH-positive MDS can respond to immunosuppressive therapy, PNH testing in MDS should be considered. Prospective analyses to clarify the clinical significance of PNH positivity in MDS are warranted. [ABSTRACT FROM AUTHOR]