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Background: Patients with myelodysplastic syndrome (MDS) are characterized by chronic anemia and most of them require transfusion making them prone to developing transfusion dependence (TD) and inducing red blood cell (RBC) alloimmunization. Little information is available regarding the status of transfusions of MDS patients in China., Materials and Methods: Clinical history and transfusion information of MDS transfusion patients from 2004 to 2023 were collected from electronic medical and laboratory records. TD patients were divided into increased blasts (IB) and non-IB group. Blood component transfusion was evaluated and compared in different groups using Mann-Whitney and chi-square tests., Results: A total of 893 MDS patients received a median of 13 (range, 0 - 436) RBC units and 10 (range, 0 - 216) platelets (PLT) units. Seventy-one (8 %) patients formed 106 RBC specific antibodies of which Rh system was the most (82/106 = 77 %). Twelve patients (17 %) had 14 antibodies (13 %) evanescence whereas 7 patients had former antibodies reemerge. Alloimmunization was more common in female, older patients and patients with larger RBC transfusions. Among 222 TD patients, RBC transfusion and alloimmunization rate in IB group were lower than those in non-IB group whilst PLT was the opposite., Conclusions: Prophylactic Rh system compatible transfusion can reduce the risk of RBC alloimmunization in MDS patients' especially in TD and non-IB patients and can prevent reinduction of antibody evanescence. To our knowledge this is the first study we reveal RBC antibody induction and evanescence which may related to different disease stages and classifications of MDS patients., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: VEXAS is a syndrome described in 2020, caused by mutations of the UBA1 gene, and displaying a large pleomorphic array of clinical and hematological features. Nevertheless, these criteria lack significance to discriminate VEXAS from other inflammatory conditions at the screening step. This work hence first focused on singling out dysplastic features indicative of the syndrome among peripheral blood (PB) polymorphonuclears (PMN). A deep learning algorithm is then proposed for automatic detection of these features., Methods: A multicentric dataset, comprising 9514 annotated PMN images was gathered, including UBA1 mutated VEXAS (n = 25), UBA1 wildtype myelodysplastic (n = 14), and UBA1 wildtype cytopenic patients (n = 25). Statistical analysis on a subset of patients was performed to screen for significant abnormalities. Detection of these features on PB was then automated with a convolutional neural network (CNN) for multilabel classification., Results: Significant differences were observed in the proportions of PMNs with pseudo-Pelger, nuclear spikes, vacuoles, and hypogranularity between patients with VEXAS and both cytopenic and myelodysplastic controls. Automatic detection of these abnormalities yielded AUCs in the range [0.85-0.97] and a F1-score of 0.70 on the test set. A VEXAS screening score was proposed, leveraging the model outputs and predicting the UBA1 mutational status with 0.82 sensitivity and 0.71 specificity on the test patients., Conclusion: This study suggests that computer-assisted analysis of PB smears, focusing on suspected VEXAS cases, can provide valuable insights for determining which patients should undergo molecular testing. The presented deep learning approach can help hematologists direct their suspicions before initiating further analyses., (© 2024 John Wiley & Sons Ltd.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Chimerism test was evaluated to predict leukemia relapse. Increasing mixed chimerism (IMC), defined as recipient increase ≥0.1% in peripheral blood total cell chimerism, was used as a surrogate of disease activity. Combination of quantitative PCR and short-tandem repeat method was applied to achieve high assay sensitivity. Total of 184 patients received stem cell transplant for acute myeloid leukemia (N = 110), acute lymphocytic leukemia (N = 41), myelodysplastic syndrome (N = 30), and 2389 chimerism tests (median follow-up, 1054 days). Sixty-six patients relapsed, and 118 patients did not. Cumulative incidence of relapse increased after 1 IMC or ≥2 consecutive IMCs (hazard ratios, 9.9 and 44.4, respectively). Predicted percentage relapse by day 30 after IMC was 0% (0 IMC), 10% (1 IMC), and 40% (≥2 IMCs). The last chimerism results before relapse detected IMC in 57 of 66 relapsed patients (sensitivity, 86.4%). Nine patients had no IMC before relapse (false negative) because of rapidly evolving relapse (N = 4) or extramural relapse (N = 5). In 118 patients without relapse, 158 of 1873 tests detected IMC (false positive, 8.4%; specificity, 91.6%). The false-positive rates increased with higher percentage recipient T-cell chimerism levels, indicating T-cell contamination as a cause. Chimerism monitoring predicts relapse. However, caution must be taken for false-positive or false-negative IMCs. T-cell removal can improve chimerism test specificity in patients with mixed T-cell chimerism., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to assess the prognostic significance of serum direct bilirubin (DBIL) for patients newly diagnosed with myelodysplastic syndromes (MDS)., Methods: The clinical, laboratory, and follow-up data of MDS patients were collected, and the associations of DBIL levels with overall survival (OS) and leukemia-free survival (LFS) were analyzed., Result: In total, 262 MDS patients were assigned to the high DBIL level group or the normal DBIL level group in the retrospective study. High DBIL was associated with older age, reduced hemoglobin, higher levels of β2-microglobin, lactate dehydrogenase, and serum ferritin, along with the number of co-mutations (> 1) and a higher frequency of ASXL1, KIT, and KRAS mutations. Multivariate analyses found that high DBIL level was an independent adverse predictor for OS (p = 0.002, hazard ratio = 2.723, 95%CI = 1.442-5.143) but not for LFS (p = 0.057, hazard ratio = 1.678, 95%CI = 0.986-2.857). A novel nomogram based on DBIL, sex, age, β2-microglobulin, lactate dehydrogenase, the Revised International Prognostic Scoring System (IPSS-R) was constructed, which demonstrated superior accuracy compared with the IPSS-R (C-index, 0.790 vs. 0.731, respectively)., Conclusion: An elevated DBIL level was identified as an independent adverse prognostic factor for MDS patients. An individualized prediction model was established and validated to improve prediction of OS and LFS., Competing Interests: Declarations Ethical approval The studies involving human participants were reviewed and approved by Human Ethics Committee of The First Affiliated Hospital of Ningbo University. The ethics committee waived the need for additional informed consent due to the retrospective nature of the study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Although various relapse prediction models based on pretransplant information have been reported, they cannot update the predictive probability considering post-transplant patient status. Therefore, these models are not appropriate for deciding on treatment adjustment and preemptive intervention during post-transplant follow-up. A dynamic prediction model can update the predictive probability by considering the information obtained during follow-up. This study aimed to develop and assess a dynamic relapse prediction model after allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using peripheral blood Wilms' tumor 1 messenger RNA (WT1mRNA). We retrospectively analyzed patients with AML or MDS who underwent allo-HCT at our institution. To develop dynamic models, we employed the landmarking supermodel approach, using age, refined disease risk index, conditioning intensity, and number of transplantations as pretransplant covariates and both pre- and post-transplant peripheral blood WT1mRNA levels as time-dependent covariates. Finally, we compared the predictive performances of the conventional and dynamic models by area under the time-dependent receiver operating characteristic curves. A total of 238 allo-HCT cases were included in this study. The dynamic model that considered all pretransplant WT1mRNA levels and their kinetics showed superior predictive performance compared to models that considered only pretransplant covariates or factored in both pretransplant covariates and post-transplant WT1mRNA levels without their kinetics; their time-dependent areas under the curve were 0.89, 0.73, and 0.87, respectively. The predictive probability of relapse increased gradually from approximately 90 days before relapse. Furthermore, we developed a web application to make our model user-friendly. This model facilitates real-time, highly accurate, and personalized relapse prediction at any time point after allo-HCT. This will aid decision-making during post-transplant follow-up by offering objective relapse forecasts for physicians., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Anemia is the most common symptom in patients with myelodysplastic syndromes (MDS). Programmed cell death of erythrocytes is one of the contributing factors to anemia. Ferroptosis is a newly identified form of iron-dependent cell death. The aim of this study is to investigate whether anemia in MDS patients is associated with ferroptosis of nucleated erythrocytes(NEs).We detected lipid peroxidation levels, Fe 2+ contents, cell death rates, glutathione (GSH) and malondialdehyde (MDA) levels in bone marrow CD235a + NEs of MDS patients. Expression levels of ferroptosis-related molecules (ACSL4, GPX4, and SLC7A11) were evaluated through qRT-PCR and Western Blotting. Correlation between these markers and clinical parameters were analyzed. To further substantiate that the mode of cell death with CD235a + NEs of MDS patients was attributed to the ferroptosis pathway, we applied Fer-1 to inhibit ferroptosis. Cell viability was assessed using CCK8, and changes in ferroptosis-related indicators were simultaneously evaluated. We discover that the ferroptosis level of bone marrow NEs in MDS patients was increased, which is related to anemia and iron overload. Ferroptosis might be one of the causes of anemia in MDS patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1β, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1β with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Myelodysplastic syndromes (MDS) present with polymorphic and non-specific diagnostic features Research parametersfrom hematology analyzers may be useful to discriminate MDS-related cytopenia.Parameters such as Neu X (related to the cytoplasmic complexity) and Neu Y (related to nucleic acid content) show promise to detect dysplasia of MDS and aid to recognize MDS from cytopenias of other etiologies., Competing Interests: Disclosure Author has nothing to disclosure., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pancytopenia is a common blood disorder defined as the decrease of red blood cells, white blood cells and platelets in the peripheral blood. Its genesis mechanism is typically complex and a variety of diseases have been found to be capable of causing pancytopenia, some of which are featured by their high mortality rates. Early judgement on the cause of pancytopenia can benefit timely and appropriate treatment to improve patient survival significantly. In this study, a serum surface-enhanced Raman spectroscopy (SERS) method was explored for the early differential diagnosis of three pancytopenia related diseases, i.e., aplastic anemia (AA), myelodysplastic syndrome (MDS) and spontaneous remission of pancytopenia (SRP), in which the patients with those pancytopenia related diseases at initial stage exhibited same pancytopenia symptom but cannot be conclusively diagnosed through conventional clinical examinations. The SERS spectral analysis results suggested that certain amino acids, protein substances and nucleic acids are expected to be potential biomarkers for their early differential diagnosis. In addition, a diagnostic model was established based on the joint use of partial least squares analysis and linear discriminant analysis (PLS-LDA), and an overall accuracy of 86.67 % was achieved to differentiate those pancytopenia related diseases, even at the time that confirmed diagnosis cannot be made by routine clinical examinations. Therefore, the proposed method has demonstrated great potential for the early differential diagnosis of pancytopenia related diseases, thus it has significant clinical importance for the timely and rational guidance on subsequent treatment to improve patient survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: We assessed the utility of red blood cell (RBC) CD105 and side scatter (SSC) parameters by flow cytometry for the detection of low-grade myelodysplastic neoplasms (MDS) in bone marrow specimens., Methods: Ten RBC parameters incorporating CD105 or SSC combined with the Meyerson-Alayed scoring system (MASS) metrics were retrospectively evaluated by flow cytometry for utility in detecting low-grade MDS (n = 56) compared with cytopenic controls (n = 86)., Results: Myelodysplastic neoplasms were associated with 7 of the RBC parameters in univariate analysis. Multivariate analysis using cutoff values based on optimal and 95% specificity levels of the RBC metrics and the MASS parameters revealed the SSC ratio of CD105-positive and CD105-negative RBC fractions (CD105+/- SSC); the percentage and coefficient of variation of the CD105-positive fraction of RBCs (CD105%, CD105+CV) emerged as significant RBC variables. Two simple scoring schemes using these RBC values along with MASS parameters were identified: 1 using CD105+/- SSC, CD105%, and CD105+CV combined with the percentage of CD177-positive granulocytes (CD177%), myeloblast percentage (CD34%), and granulocyte SSC (GranSSC), and the other incorporating CD105+/- SSC, CD105+CV, CD177%, CD34%, GranSSC, and B-cell progenitor percentage. Both demonstrated a sensitivity of approximately 80%, with a specificity of roughly 90% for the detection of MDS compared with cytopenic controls., Conclusions: The red blood cell parameter, CD105+/- SSC, appears to be beneficial in the evaluation of low-grade MDS by flow cytometry., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.

Introduction: Many patients referred for suspicion of myelodysplastic neoplasm (MDS) are subjected to unnecessary discomfort from bone marrow aspiration, due to the low disease prevalence in this population. Flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression could rule out MDS with sensitivity and negative predictive value estimates close to 100%, ultimately obviating the need for bone marrow aspiration in up to 35% of patients. However, the generalisability of these findings is uncertain due to the limited sample size, the enrolment of patients at a single study site, and the reliability issues associated with laboratory-developed tests and varying levels of operator experience. This study aims to validate the accuracy attributes of peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis in an independent multicentre sample., Methods and Analysis: The MPO-MDS-Valid project is a cross-sectional diagnostic accuracy study comparing an index test to a reference standard. Consecutive adult patients referred for suspicion of MDS are being recruited at seven university hospitals and one cancer centre in France. At each site, flow cytometric analysis of peripheral blood samples is performed by operators who are blinded to the reference diagnosis. A central adjudication committee whose members are unaware of the index test results will determine the reference diagnosis of MDS, based on cytomorphological evaluation of bone marrow performed in duplicate by experienced hematopathologists. The target sample size is 400 patients and the anticipated study recruitment completion date is 31 December 2025., Ethics and Dissemination: An institutional review board (Comité de Protection des Personnes Nord-Ouest III, Caen, France) approved the protocol, prior to the start of the study. Participants are recruited using an opt-out approach. Efforts will be made to publish the primary results within 6 months after study completion., Trial Registration Number: NCT05175469., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A previously published web-based App using Gradient-boosted models (GBMs) of eight laboratory parameters was established by Oster et al. to facilitate diagnosis or exclusion of myelodysplastic syndromes (MDS) in patients., Methods: To validate their algorithm, we compared 175 anemic patients with MDS diagnosis from our German MDS Registry with 1378 non-MDS anemic patients who consulted various specialties in the Düsseldorf university hospital., Results: Based on hemoglobin level, leukocyte and platelet count, mean corpuscular volume, absolute neutrophil count, absolute monocyte count, glucose and creatinine, plus the patients' gender and age, we could not reproduce a high negative predictive value (NPV), but confirmed a useful specificity of 90.9% and a positive predictive value (PPV) of 77.1%. 1192 of 1378 controls were correctly categorized as "probably not MDS (pnMDS)" patients. A total of 65 patients were wrongly classified as "probable MDS (pMDS)," of whom 48 had alternative explanations for their altered laboratory results. In a second analysis, we included 29 patients with chronic myelomonocytic leukemia (CMML) resulting in only one label as possible MDS, suggesting that highly proliferative bone marrow disorders are correctly excluded., Conclusion: The possibility of reliably excluding MDS from differential diagnosis based on peripheral blood lab work appears to be attractive for patients and physicians alike while the confirmation of MDS diagnosis still requires a bone marrow biopsy., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Background: Genetic mutations play a crucial role in the development and progression of myelodysplastic syndromes (MDS), impacting the immune microenvironment and influencing the choice of treatment regimen, as well as the efficacy and prognosis of patients. The objective of this study was to examine variations in hematological and immunological characteristics associated with common gene mutations in MDS patients and establish a foundation for the precise treatment of MDS., Methods: The hematological, immunological, and other clinical features of 71 recently diagnosed MDS patients from January 1, 2019, to July 31, 2023, were retrospectively analyzed. These patients were categorized based on their gene mutations, and the variances in hematological and immunological characteristics among distinct groups were compared., Results: Hematological variances were observed among different gene mutation groups. Specifically, platelet counts in the splicing factor 3B subunit 1 ( SF3B1 ) mutation group were notably higher compared to the wild-type group ( p = 0.009). Conversely, in the additional sex combs like 1 ( ASXL1 ) mutation groups, monocyte ratios were significantly elevated in comparison to the wild-type group ( p = 0.046), and in the ten-eleven translocation 2 ( TET2 ) mutation group, lymphocyte ratios were significantly lower ( p = 0.022). Additionally, the leukocyte ( p = 0.005), neutrophil ratio ( p = 0.002), and lymphocyte ratio ( p = 0.001) were significantly higher in the Runt-related transcription factor 1 ( RUNX1 ) mutation group. Regarding immunological distinctions, the Natural Killer (NK) cell ratio demonstrated a significant increase in the SF3B1 mutation group ( p = 0.005). Moreover, the TET2 mutation group exhibited a significantly higher Interleukin-8 (IL-8) level ( p = 0.017). In contrast, the U2 small nuclear RNA auxiliary factor 1 ( U2AF1 ) group displayed significantly lower levels of IL-1β ( p = 0.033), IL-10 ( p = 0.033), and Tumour Necrosis Factor-α (TNF-α) ( p = 0.009)., Conclusion: Distinct variations exist in the immune microenvironment of MDS associated with different genetic mutations. Further studies are imperative to delve into the underlying mechanisms that drive these differences.

Purpose: DNA methylation alterations are widespread in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. Although the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory., Experimental Design: We performed global DNA methylation profiling in a case control study nested within the Singapore Chinese Health Study to evaluate whether DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years before diagnosis of AML or MDS, together with age-matched still-healthy individuals as controls., Results: Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow-up period. Alterations in methylation in the differentially methylation regions were associated with increased odds of developing AML/MDS., Conclusions: The epigenetic changes may be acquired independently and before somatic mutations that are relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre-AML/MDS screening., (©2024 American Association for Cancer Research.)

Acute hemolytic transfusion reaction (AHTR) is a rare but life-threatening complication of transfusion. We herein report a case of anti-Jk b IgM-related AHTR. Two hours after an 80-year-old man with myelodysplastic syndrome received a packed red blood cell (RBC) A + /Rh - /Jk b+/ c - transfusion, he developed acute respiratory failure and a fever. Although he had tested negative in routine screening tests, the 37°C normal saline test was weakly positive for Jk b . We confirmed the presence of anti-Jk b IgM in the patient's serum by flow cytometry. This case demonstrates the potential utility of flow cytometry for IgM detection.

Background: Increasing germline gene mutations have been discovered in haematological malignancies with the development of next-generation sequencing (NGS), which is critical for proper clinical management and long-term follow-up of affected individuals. Tet methylcytosine dioxygenase 2 (TET2) is one of the most common mutations in haematological neoplasms. We aimed to compare the clinical characteristics of patients with germline and somatic TET2 mutations in haematological diseases and to analyse whether germline TET2 mutations have a family aggregation and tumour predisposition., Methods: Out of 612 patients who underwent NGS of 34 recurrently mutated genes in haematological diseases, 100 haematological patients with TET2 mutations were selected for further study. Somatic mutations were detected by NGS in bone marrow/peripheral blood genomic DNA (gDNA). Germline TET2 mutations were validated in nail/hair gDNA by Sanger sequencing. Digital data were extracted from the haematology department of the West China Hospital of Sichuan University. TET2 mutation results were analysed by referencing online public databases (COSMIC and ClinVar)., Results: One hundred patients were studied, including 33 patients with germline and 67 patients with somatic TET2 mutations. For germline TET2 mutations, the variant allele frequency (VAF) was more stable (50.58% [40.5-55], P < 0.0001), and mutation sites recurrently occurred in three sites, unlike somatic TET2 mutations. Patients with germline TET2 mutations were younger (median age 48, 16-82 years) (P = 0.0058) and mainly suffered from myelodysplastic syndromes (MDS) (n = 13, 39.4%), while patients with somatic TET2 mutations were mainly affected by acute myeloid leukemia (AML) (n = 26, 38.8%) (P = 0.0004). Germline TET2 mutation affected the distribution of cell counts in the peripheral blood and bone marrow (P < 0.05); it was a poor prognostic factor for MDS patients via univariate analysis (HR = 5.3, 95% CI: 0.89-32.2, P = 0.0209) but not in multivariate analysis using the Cox regression model (P = 0.062)., Conclusions: Germline TET2 mutation might have a family aggregation, and TET2 may be a predisposition gene for haematological malignancy under the other gene mutations as the second hit. Germline TET2 mutation may play a role in the proportion of blood and bone marrow cells and, most importantly, may be an adverse factor for MDS patients., (© 2022. The Author(s).)

Background: Myelodysplastic syndromes (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. It has been demonstrated that apolipoproteins A1(ApoA1) are associated with disease risk in many cancer types. However, there still lacks evidence regarding the link between ApoA1 and MDS. This study was designed to investigate the prognostic value of pretreatment ApoA1 levels in MDS patients., Methods: We retrospectively analyzed a cohort of 228 MDS patients to explore the prognostic value of the serum ApoA1 levels at diagnosis. Patients were divided into the high ApoA1 group and the low ApoA1 group. The prognostic significance was determined by univariate and multivariate Cox hazard models., Results: MDS patients with low ApoA1 levels had significantly shorter overall survival (OS, P < 0.0001) along with a higher frequency of TP53 mutation (P = 0.002). Based on univariate analysis, age (≥ 60 years), gender (male), lower levels of hemoglobin (< 10 g/dl), HDL (≤0.91 mmol/L), higher bone marrow blast percentage (> 5%), higher IPSS-R scores and poorer karyotype were significantly associated with decreased OS. However, low ApoA1 level did not influence leukemia-free survival (LFS, P = 0.367). Multivariate Cox proportional hazards regression analysis indicated that low ApoA1 level (≤ 1.02 g/L) was also an independent adverse prognostic factor for OS in MDS (P = 0.034)., Conclusions: Decreased ApoA1 level predicts a poor prognosis of MDS patients and thus provides a novel evaluation factor for them that is independent of the IPSS-R system., (© 2022. The Author(s).)

Introduction: Erythropoiesis stimulating agents (ESAs) represents the principal treatments for anemia in patients with lower-risk myelodysplastic syndromes (MDS). Pre-treatment erythropoietin (EPO) level and previous blood transfusion requirement are the two major predictors for response to ESAs. However, most evidence was derived from Western countries whereas there have been limited data in patients with Asian background., Methods: We retrospectively collected data on patients with low-risk MDS who received ESAs. Erythroid response was evaluated according to IWG 2006 criteria. MDS subtypes, r-IPSS, baseline hemoglobin (Hb), ESAs dosage and erythropoietin level were reviewed from medical records. Gene mutations were analyzed in patients' blood or bone marrow at diagnosis by 40-gene myeloid panel targeted sequencing. Clinical and laboratory parameters were compared between erythroid responder and non-responder groups., Results: A total of 47 patients were recruited in the study. The median age at diagnosis of the patients in this cohort was 77 years (IQR, 70-83) and 44.7% were male. The median revised international prognostic scoring system (R-IPSS) score of patients was 2.5. Response rate to ESAs was 46.8% (22/47). Median EPO level in responders was significantly lower than non-responders (27.7 vs. 59.1 U/L, p=0.02). Median ESAs dosage in responder group was 30,000 units per week. Cytogenetic abnormalities were detected in 27.3% and 24% of the responder and non-responder groups, respectively. Of 22 patients with available 40 gene mutation targeted sequencing, ASXL1, IDH2 and TET2 represented the 3 most common mutations and were found in 22%, 22% and 17%, respectively. There were no differences in cytogenetic abnormalities and gene mutations between groups. Patients who responded to ESAs showed a higher 5-year overall survival (OS) compared to non-responders (5-year OS 75% vs. 60.9%; p=0.008)., Conclusion: We conclude that a low serum EPO level is a predictive factor for responsiveness to ESAs in Asian patients with low-risk MDS.

Aberrant inflammatory signaling has been shown to be a key pathogenic driver in myelodysplastic syndromes (MDS). Abnormal IL-33 expression has been implicated in inflammatory, immune-related disorders and, some tumors. However, its role in MDS remains widely unknown. This study aimed to evaluate the relationship between plasma levels of IL-33, clinical and prognostic data and, IL-6 levels in 101 patients with MDS. A comparative group of 59 healthy individuals was also evaluated. Plasma levels of cytokines were determined by enzyme-linked immunosorbent assay. Lower levels of IL-33 were found in patients with MDS when compared to the control group (p = 0.001), mainly in patients with more advanced stages of the disease and worse prognosis. No significant correlation between the levels of IL-33 and IL-6 was observed (r = 0.175; p = 0.081). These results reinforce the close association between immunological disorders and the pathogenesis of MDS. A greater understanding of the role of inflammatory cytokines in the disease can potentially provide new diagnosis and prognosis markers and new therapeutic targets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndrome (HR-MDS) patients ineligible for intensive therapy. Clinical outcome discrepancies reported in clinical trials and real-life settings stimulate the search for new prognostic factors., Methods: We retrospectively evaluated 315 MDS, 20-30% blast acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) patients treated with azacitidine in 12 centers cooperating within the Polish Adult Leukemia Group (PALG)., Results: The median number of AZA cycles was 7 (1-69) and 24% patients received fewer than 4 cycles (early failure, EF). Serum albumin level was an independent predictor of EF occurrence. Complete remission (CR) was obtained in 20% and partial remission (PR) in 12% of patients. Hematologic improvement - erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) was achieved in 51%, 36%, and 48% of patients, respectively. No factors significantly predicted CR or PR in the multivariate analysis. For HI-E and HI-P, lower LDH level predicted response. Median survival was 15 (13-19) months. Lower serum albumin level, serious infection and receiving <4 AZA cycles independently predicted a worse overall survival (OS) ( p < 0.05)., Conclusion: Serum albumin assessment before azacitidine treatment can help to identify patients with higher risk of early failure and worse clinical outcome.

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135-8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235-1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196-0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background/aim: Activation-induced cytidine deaminase (AID) enables antibody diversity in B lymphocytes. It may also have an effect on MDS pathogenesis by causing somatic mutations and by inducing epigenetic changes in myeloid cells. This study aimed to compare AID expression of MDS patients with healthy controls, of MDS patients in different risk groups, and of MDS patients according to their treatment., Materials and Methods: Total RNA was isolated and complementary DNA (cDNA) was transcribed from the peripheral blood samples of MDS patients and healthy controls. AID and the reference gene HPRT1 were analyzed using quantitative real-time PCR (QRT-PCR). AID expression relative to HPRT1 was calculated. Patients were classified into “lower risk” and “higher risk” subgroups according to their initial IPSS and IPSS-R scores and their MDS subtypes at the time of study. Patients were also divided into two groups based on receiving treatment with hypomethylating agents. AID expressions of different groups were compared using the Mann–Whitney U test., Results: Thirty MDS patients and thirty healthy controls were included. AID expression in MDS patients was significantly higher compared to healthy controls (p < 0.001). There was no significant difference in AID expression of “lower risk” and “higher risk” subgroups of patients. Patients that received hypomethylating agents did not have a significant difference in AID expression compared with patients that did not receive hypomethylating agents., Conclusion: AID expression is increased in the peripheral blood of MDS patients compared to healthy controls. However, AID expression is not significantly different in “lower risk” and “higher risk” subgroups and in patients treated with hypomethylating agents. Increased AID expression may be an early step in MDS pathogenesis., Competing Interests: The authors declare that they have no conflicts of interest., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Inflammatory cytokines play a role in hematopoiesis and development of myelodysplastic syndromes (MDS). Although increased serum levels of inflammatory cytokines are associated with poor survival in MDS patients, clinical management does not include assessment of inflammation. We investigated the significance of inflammation in MDS using serum C-reactive protein (CRP) levels, an indicator of the degree of systemic inflammation that can be used in routine practice. We hypothesized that serum CRP levels can be used to further classify low-risk MDS. We conducted a retrospective analysis of 90 patients with low-risk MDS, defined by the international prognostic scoring system (IPSS). We examined the prognostic relevance of CRP and known prognostic factors at diagnosis. Increased serum CRP (≥ 0.58 mg/dL) was associated with poor survival (hazard ratio [HR]: 17.63, 95% confidence interval [CI] 5.83-53.28, P < 0.001) both overall and among the 73 patients with low-risk MDS as defined by the revised IPSS (HR: 28.05, 95% CI 6.15-128.04, P < 0.001). Increased CRP might predict poor prognosis and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in patients with low-risk MDS., (© 2021. Japanese Society of Hematology.)

Myelodysplastic syndrome (MDS) is a neoplastic disease originating from hematopoietic stem cells. Currently, hematopoietic stem cell transplantation (HSCT) is the most effective cure, although lenalidomide, azacytidine, and decitabine have been applied to relieve symptoms of MDS. The purpose of this study was to evaluate the changes in endogenous metabolites by applying a UHPLC-MS (ultra-high-performance liquid chromatography-MS) metabolomics approach and to investigate metabolic pathways related to MDS. An untargeted metabolomics approach based on UHPLC-MS in combination with multivariate data analysis, including partial least squares discrimination analysis and orthogonal partial least squares discriminant analysis, was established to investigate potential biomarkers in the plasma of MDS patients. As a result, 29 biomarkers were identified to distinguish between MDS patients, HSCT patients, and healthy controls, which were mainly related to inflammation regulation, amino acid metabolism, fatty acid metabolism, and energy metabolism. To our knowledge, this is the first time where plasma metabolomics was combined with HSCT to study the pathogenesis and therapeutic target of MDS. The identification of biomarkers and analysis of metabolic pathways could offer the possibility of discovering new therapeutic targets for MDS in the future., (© 2021 John Wiley & Sons, Ltd.)

5-Azacitidine (AZA) therapy is used in high-risk myelodysplastic syndrome (MDS) patients who often show abnormalities in their immunophenotype. We explored the potential impact of AZA on these immunophenotypic abnormalities in serial bone marrow studies performed in 81 patients from five centers. We compared the immunophenotypic features before and after therapy with AZA, established definitions consistent with flow cytometry immunophenotyping (FCI) improvement, and explored its clinical significance. After a median of 6 cycles of AZA, 41% of patients showed a FCI improvement and this finding associated with best possible clinical response (P < 0.001). FCI improvement also correlated with hematological improvement (HI) (53/78 patients; 68%), independently of their eligibility for stem cell transplantation. Among patients who achieved a HI after 6 cycles of AZA, the probability of maintaining this response at 12 cycles of AZA was twice as large (67%) for those patients who also achieved a FCI improvement after 6 cycles of AZA as compared to patients who did not (33%, P < 0.01). These findings support that monitoring of the immunophenotypic abnormalities during therapy with AZA may assist in redefining the quality of response in patients with MDS.

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co-infused a single UCB unit with CD34 + -selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20 years), 97% had neutrophil recovery (median 10 days), and 93% had platelet recovery (median 32 days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 21% and 41%, respectively. With a median follow-up of 7·5 years, overall survival was 83% and GVHD/relapse-free survival was 69%. Patient- and transplant-related factors had no impact on engraftment and survival although transplants with haplo-versus-cord killer-cell immunoglobulin-like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long-term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)-matched donors., (© 2021 British Society for Haematology and John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Suspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. This study aimed to prospectively validate the accuracy for flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression in ruling out MDS. We enrolled 62 consecutive patients who were referred for suspected MDS, based on medical history and peripheral blood cytopenia. The accuracy of intra-individual robust coefficient of variation (RCV) for peripheral blood neutrophil myeloperoxidase expression was assessed with a prespecified 30% threshold. Cytomorphological evaluation of bone marrow aspirate performed by experienced hematopathologists confirmed MDS in 23 patients (prevalence, 37%), unconfirmed MDS in 32 patients (52%, including 3 patients with idiopathic cytopenia of undetermined significance (ICUS)), and was uninterpretable in 7 patients (11%). The median intra-individual RCV values for neutrophil myeloperoxidase expression in peripheral blood were 37.4% (range, 30.7-54.1), 29.2% (range, 28.1-32.1), and 29.1% (range, 24.7-37.8) for patients with confirmed suspicion of MDS, ICUS, and unconfirmed suspicion of MDS, respectively (P<0.001). The area under the ROC curve was 0.92 (95% confidence interval, 0.86-0.99). An intra-individual RCV value lower than 30% ruled out MDS for 35% (i.e., 19/55) patients referred for suspected disease, with 100% sensitivity (95% CI, 85-100%) and 100% negative predictive value (95% CI, 82-100%) estimates. This study shows that flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression might obviate the need for bone marrow aspirate for 35% of patients with suspected MDS. Trial registration: ClinicalTrials.gov identifier: NCT03363399 (first posted on December 6, 2017).

Circular RNAs (circRNAs) have been identified to exert vital biological functions and can be used as new biomarkers in a number of tumors. However, little is known about the functions of circRNAs in myelodysplastic syndrome (MDS). Here, we aimed to investigate circRNA expression profiles and to investigate the functional and clinical value of circRNAs in MDS. Differential expression of circRNAs between MDS and control subjects was analyzed using circRNA arrays, in which we identified 145 upregulated circRNAs and 224 downregulated circRNAs. Validated by real-time quantitative PCR between 100 MDS patients and 20 controls, three upregulated (hsa&#95;circRNA&#95;100352, hsa&#95;circRNA&#95;104056, and hsa&#95;circRNA&#95;104634) and three downregulated (hsa&#95;circRNA&#95;103846, hsa&#95;circRNA&#95;102817, and hsa&#95;circRNA&#95;102526) circRNAs matched the arrays. The receiver operating characteristic curve analysis of these circRNAs showed that the area under the curve was 0.7266, 0.8676, 0.7349, 0.7091, 0.8806, and 0.7472, respectively. Kaplan-Meier survival analysis showed that only hsa&#95;circRNA&#95;100352, hsa&#95;circRNA&#95;104056, and hsa&#95;circRNA&#95;102817 were significantly associated with overall survival. Furthermore, we generated a competing endogenous RNA network focused on hsa&#95;circRNA&#95;100352, hsa&#95;circRNA&#95;104056, and hsa&#95;circRNA&#95;102817. Analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes showed that the three circRNAs were linked with some important cancer-related functions and pathways., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Natural killer (NK) cells are key innate immunity effectors that play a major role in malignant cell destruction. Based on expression patterns of CD16, CD56, CD57, and CD94, three distinct NK cell maturation stages have been described, which differ in terms of cytokine secretion, tissue migration, and the ability to kill target cells. Our study addressed NK cell maturation in bone marrow under three conditions: a normal developmental environment, during pre-leukemic state (myelodysplastic syndrome, MDS), and during leukemic transformation (acute myeloblastic leukemia, AML). In this study, we used a new tool to perform multicolor flow cytometry data analysis, based on principal component analysis, which allowed the unsupervised, accurate discrimination of immature, mature, and hypermature NK subpopulations. An impaired NK/T cell distribution was observed in the MDS bone marrow microenvironment compared with the normal and AML settings, and a phenotypic shift from the mature to the immature state was observed in NK cells under both the MDS and AML conditions. Furthermore, an impaired NK cell antitumor response, resulting in changes in NK cell receptor expression (CD159a, CD158a, CD158b, and CD158e1), was observed under MDS and AML conditions compared with the normal condition. The results of this study provide evidence for the failure of this arm of the immune response during the pathogenesis of myeloid malignancies. NK cell subpopulations display a heterogeneous and discordant dynamic on the spectrum between normal and pathological conditions. MDS does not appear to be a simple, intermediate stage but rather serves as a decisive step for the mounting of an efficient or ineffective immune response, leading to either the removal of the tumor cells or to malignancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cianga, Campos Catafal, Cianga, Pavel Tanasa, Cherry, Collet, Tavernier, Guyotat, Rusu and Aanei.)

Abstract: We evaluated the clinical characteristics of autoimmune manifestations (AIMs) associated with myelodysplastic syndrome (MDS) to elucidate whether AIMs impacted MDS outcomes in Japan.This retrospective study including 61 patients who received a new diagnosis of MDS between January 2008 and December 2015 was conducted by the review of electronic medical records for the presence of AIMs within a 1-year period prior to or following the diagnosis of MDS.AIMs were identified in 12 of the 61 (20.0%) patients with MDS. The neutrophil counts and C-reactive protein levels in peripheral blood were significantly elevated in patients with AIMs, and the survival was shorter in those with AIMs compared to those without AIMs. Multivariate analysis demonstrated that the presence of AIMs and higher-risk disease according to the International Prognositic Scoring System (IPSS) were independent risk factors for increased mortality (hazard ratio, 4.76 and 4.79, respectively).This retrospective study revealed that the prognosis was poor in patients with MDS-associated AIMs. The treatment of MDS using the current algorithms is based on prognostic scoring systems such as IPSS. Treatment strategies for patients with MDS-associated AIMs should be reconsidered, even in those with low-risk MDS according to the IPSS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Although morphologic dysplasia is not typically considered a feature of CCUS, we have consistently observed low-level bone marrow (BM) dysplasia among CCUS patients. We sought to determine whether sub-diagnostic BM dysplasia in CCUS patients is associated with other clinico-pathologic findings of myelodysplastic syndrome (MDS)., Methods: We identified 49 CCUS patients, 25 with sub-diagnostic dysplasia (CCUS-D), and 24 having no dysplasia (CCUS-ND). We compared the clinical, histologic, and laboratory findings of CCUS-D and CCUS-ND patients to 49 MDS patients, including blood cell counts, BM morphology, flow cytometry, cytogenetics, and results of next-generation sequencing., Results: No statistically significant differences were observed between CCUS-D and CCUS-ND patients in the degree of cytopenias, BM cellularity, myeloid-to-erythroid ratio, or the presence of flow cytometric abnormalities. However, compared to CCUS-ND, CCUS-D patients exhibited increased mutations in myeloid malignancy-associated genes, including non-TET2/DNMT3A/ASXL1 variants, spliceosome (SF3B1, SRSF2, ZRSR2, or U2AF1) variants, and IDH2/RUNX1/CBL variants. CCUS-D patients were also enriched for higher variant allele frequencies and co-mutation of TET2/DNMT3A/ASXL1 with other genes., Conclusions: CCUS-D patients exhibit a molecular (but not clinical) profile more similar to MDS patients than CCUS-ND, suggesting CCUS-D may represent a more immediate precursor to MDS and may warrant closer clinical follow-up., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2 f/+ Vav1 cre ) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2 f/+ Vav1 cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2 f/+ Vav1 cre CD4 + T cells (T H 22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2 f/+ Vav1 cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.

Inflammation is a major hallmark of several cancers. The present study evaluated the prognostic value of the Fibrinogen-Albumin Ratio Index (FARI) at the diagnosis in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) treated with azacitidine (AZA). A retrospective study was conducted in a single cohort of 99 patients with de novo MDS and AML-MRC who were treated with AZA between May 2011 and June 2019 in our hospital. Plasma fibrinogen and serum albumin levels were measured before the start of AZA treatment. A total of 99 patients were included in the analysis. The optimal cut-off value of FARI for predicting the 1-year overall survival (OS) was determined by a receiver operating characteristic (ROC) analysis to be 0.079. A total of 59 (60%) and 40 (40%) patients had an FARI ≥0.079 (high-FARI group) and < 0.079 (low-FARI group), respectively. The high-FARI patients had a significantly shorter OS than low-FARI patients (1-year OS, 35.6% vs. 77.5%, p < 0.001). In a multivariate analysis, parameters with independent adverse significance for the OS were a high FARI (≥0.079) (hazard ratio (HR) 2.41, 95% confidence interval (CI), 1.36-4.29; p = 0.006), and Revised-International Prognostic Scoring System (IPSS-R) very high (HR 1.483, 95% CI, 1.12-1.963, p = 0.006). A high FARI was found to be associated with a poor outcome in MDS and AML-MRC patients treated with AZA, and FARI was an independent prognostic factor for the OS in these patients. Further internal and external validations are needed to clarify the prognostic role of the FARI for MDS and AML-MRC patients.

Aim: To assess the level of erythropoietin (EPO) in blood sera of patients with different subtypes of myelodysplastic syndromes (MDS) from different risk subgroups and to determine its prognostic role., Materials and Methods: EPO was measured by enzyme-linked immunosorbent assay in peripheral blood of 54 patients with different MDS subtypes according to the French-American-British (FAB) classification. The comparison group consisted of 15 healthy individuals. Complete blood count (hemoglobin, leukocyte and platelet levels) was determined and bone marrow cells were characterized morphologically. The overall and leukemia-free survivals were estimated by Kaplan - Meier method., Results: The level of ЕРО in MDS was reliably higher in comparison with healthy persons (p < 0.01, Mann - Whitney test). No statistically significant difference was found in serum EPO concentration between the groups of patients with low- and high-risk MDS (603.5 pg/ml vs 721.0 pg/ml; p > 0.05). In transfusion-dependent patients, the level of EPO was significantly higher than in other patients, which may be due to increased endogenous EPO secretion resulting from chronic hypoxia. A negative correlation was revealed between EPO level and Hb level as well as between EPO level and percentage of blast cells in bone marrow in high-risk MDS patients but not in patients with less aggressive variants of MDS. Instead, patients with low-risk MDS had a negative relationship between concentrations of EPO and tumor necrosis factor alpha (p = 0.06, Kendall's tau test). No significant difference was found between EPO concentration in cases differing by bone marrow cellularity or the presence of cytogenetic abnormalities. An EPO concentration below 200 pg/ml was a predictor of shorter overall survival in patients with all MDS subtypes (p < 0.05, Mann - Whitney test). In patients with all FAB disease subtypes, there was no relationship between the leukemia-free survival and serum EPO concentration., Conclusion: This study shows that lower serum EPO level may be considered as one of the additional adverse prognostic factors in MDS patients.

Background: Alloantibodies against human platelet antigen (HPA)-15 are sometimes detected in patients with platelet transfusion refractoriness (PTR); however, little is known about their impact on PTR., Study Design and Methods: Two patients who possessed HPA-15 alloantibodies (Patient 1, anti-HPA-15b; Patient 2, anti-HPA-15a) and human leukocyte antigen (HLA) antibodies were enrolled. The efficacy of HPA-15-compatible vs -incompatible platelet transfusion was compared by focusing on ABO- and HLA-matched transfusions on the basis of the 24-hour corrected count increment (CCI-24 hours) for platelets. The titers of HPA-15 antibodies in the patients' sera were also monitored., Results: The patients received 71 and 12 ABO-compatible, HLA-matched platelet transfusions, respectively, during the monitoring periods. Among these transfusions, CCI-24 hours could be calculated in 27 and 10 transfusions, respectively, and the HPA-15 genotype of the donors was determined. There were no significant differences in the CCI-24 hours between the HPA-15 compatible and incompatible transfusions in both patients (P = .30 and .56, respectively, Mann-Whitney U test). There was no significant change in the HPA-15b antibody titer in Patient 1 during the monitoring period, while the HPA-15a antibody level in Patient 2 was undetectable at the end of the monitoring period, although the titer was low at the beginning., Conclusion: The efficacy of HPA-15-incompatible platelet transfusions was not necessarily inferior to that of HPA-15 compatible ones. Although the case number was limited, our results suggest that HPA-15 antibodies do not have a significant impact on the effects of platelet transfusion., (© 2020 AABB.)

Myelodysplasticsyndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs. Here, we provide an overview of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weber, Parmon, Kurrle, Schnütgen and Serve.)

Minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) heralds high risk of relapse. Whether preemptive recombinant interleukin-2 (pre-IL2) is effective for patients with late-onset MRD (LMRD) remains unknown. We retrospectively compared the efficacy and safety of pre-IL2 (n = 30) and pre-DLI (n = 25) for LMRD in patients receiving allo-HSCT for acute leukemia or myelodysplastic syndrome. The 1-year overall survival (OS) and disease-free survival (DFS) rates were 86.7% and 78.4% (P = 0.267), 83.3% and 75.6% (P = 0.329), the cumulative incidence of grades III-IV acute graft-versus-host disease (aGVHD) at 100 days post-preemptive intervention was 3.3% and 12.0% (P = 0.226) in the pre-IL2 group and pre-DLI group, respectively. The 1-year cumulative incidence of moderate/severe chronic GVHD (cGVHD), relapse (CIR), and non-relapse mortality (NRM) were 7.7% and 27.9% (P = 0.018), 13.6% and 20.0% (P = 0.561) and 3.3% and 5.5% (P = 0.321) in the two groups, respectively. No remarkable differences in CIR, OS, and DFS between the two intervention groups were found in multivariate analysis. The GVHD-free and relapse-free survival (GRFS) were better in the pre-IL2 group than in the pre-DLI group (HR = 0.31, 95% confidence interval (CI), 0.12-0.76; P = 0.011). In conclusion, preemptive low-dose IL2 and preemptive DLI yield comparable outcomes for patients with LMRD receiving allo-HSCT, in terms of aGVHD, NRM, relapse, OS, and DFS. However, preemptive low-dose IL2 has a lower incidence of moderate/severe cGVHD and a higher CRFS. Preemptive low-dose IL2 may be an alternative method for patients who develop LMRD after allo-HSCT, particularly for patients who cannot receive preemptive DLI.

Immune deregulation has a critical role in the pathogenesis of lower risk myelodysplastic syndromes (MDS). The cells of the macrophage/monocyte lineage have been reported to contribute to the inflammatory process in MDS through impaired phagocytosis of the apoptotic hemopoietic cells and abnormal production of cytokines. In the present study we assessed the number of peripheral blood (PB) monocyte subsets, namely the classical CD14 bright /CD16 - , intermediate CD14 bright /CD16 + and non-classical CD14 dim /CD16 + cells, in patients with lower risk (low/intermediate-I) MDS (n = 32). We also assessed the production of tumor necrosis factor (TNF)α by patient PB monocytes in response to immune stimulus as well as their transcriptome profile. Compared to age- and sex-matched healthy individuals (n = 19), MDS patients had significantly lower number of classical and increased number of intermediate monocytes. Patient intermediate monocytes displayed increased production of TNFα following stimulation with lipopolysaccharide, compared to healthy individuals. Transcriptional profiling comparison of CD16 + monocytes from patients and controls revealed 43 differentially expressed genes mostly associated with biological pathways/processes relevant to hemopoiesis, immune signaling and cell adhesion. These data provide evidence for the first-time that distinct monocyte subsets display abnormal quantitative and functional characteristics in lower risk MDS substantiating their role in the immune deregulation associated with the disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)