Myelodysplastic Syndromes Patients Research Articles

Efficacy and safety analysis of hypoxia-inducible factor prolyl hydroxylase inhibitors for anemia in low-risk myelodysplastic syndromes patients

Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.

Nephrotic Syndrome in a 24-Year-Old Female with Myelodysplastic Syndrome: A Case Report

Background: Nephrotic syndrome is rare in the normal population but is reported more frequently in patients with myelodysplastic syndrome (MDS). The pathogenesis is not clearly known, but it is thought to be related to immune dysregulation.
 Case presentation: We report a case of nephrotic syndrome in a 24-year-old woman with MDS. Patients complain of swelling, foamy urination, paleness, weakness, bleeding gums, and reddish spots on the body. Physical examination revealed hypertension, anemia, petechiae, and edema. Laboratory examination showed anemia, thrombocytopenia, hypoalbuminemia, dyslipidemia, and proteinuria. Abdominal ultrasound showed chronic processes in the kidneys, ascites, and pleural effusion. A renal biopsy showed membranoproliferative glomerulonephritis.
 Conclusion: Nephrotic syndrome in MDS patients is rarely reported, and its pathogenesis is still not clearly understood. Further research is needed to understand the pathogenesis and optimal therapeutic options.

Cytogenetic profile and risk of transformation to acute myeloid leukemia (AML) in Indonesian patients with myelodysplastic syndrome (MDS): a pilot study

Background Cytogenetics is a fundamental examination in the course and management of myelodysplastic syndrome (MDS) since it is widely used as a diagnostic and prognostic indicator for the disease. Some cytogenetic profiles are associated with a higher risk of acute myeloid leukemia (AML) transformation. This is the first study to evaluate the cytogenetic profile of Indonesian patients with MDS. Methods This prospective cohort study was conducted at the Cancer Center and several other referral hospitals. Patients with primary MDS aged >18 years were included in the study. Clinical examination, peripheral blood smear, and bone marrow aspiration were performed, followed by cytogenetic examination. The results were further categorized into revised international prognostic scoring system (IPSS-R) scores, and cytogenetic profiles were descriptively presented. Patients were followed up for one year to evaluate AML transformation. Results A total of 28 MDS patients, aged 66±12 years, were included in this study. The majority of the patients were male (n=17;60.7%), aged 65 years or above (n=19;67.9%), diagnosed with MDS-MLD (n=14;50%), and had an intermediate cytogenetic group (n=4;14.3%). The IPSS-R score was high in 6 (21.4%) patients and very high risk in 3 (10.7%) patients. During one-year follow-up, AML transformation occurred in 3 (10.7%) patients, and 10 (35.7%) patients ceased. Monosomy 7 was observed in 6 (21.4%) patients but in one metaphase each. Deletion of chromosome 5 (del(5)(q31)), del (16)(q21.1), and del (16)(q11.2) were found in a male patient with MDS-EB1. Conclusions Monosomy 7 and deletion of chromosome 5 have been identified in Indonesian patients with MDS. MDS-EB has the highest risk of AML transformation.

Analyzing Blood Cells of High-Risk Myelodysplastic Syndrome Patients Using Interferometric Phase Microscopy and Fluorescent Flow Cytometry.

Myelodysplastic syndromes (MDSs) are a group of potentially deadly diseases that affect the morphology and function of neutrophils. Rapid diagnosis of MDS is crucial for the initiation of treatment that can vastly improve disease outcome. In this work, we present a new approach for detecting morphological differences between neutrophils isolated from blood samples of high-risk MDS patients and blood bank donors (BBDs). Using fluorescent flow cytometry, neutrophils were stained with 2',7'-dichlorofluorescin diacetate (DCF), which reacts with reactive oxygen species (ROS), and Hoechst, which binds to DNA. We observed that BBDs possessed two cell clusters (designated H and L), whereas MDS patients possessed a single cluster (L). Later, we used FACS to sort the H and the L cells and used interferometric phase microscopy (IPM) to image the cells without utilizing cell staining. IPM images showed that H cells are characterized by low optical path delay (OPD) in the nucleus relative to the cytoplasm, especially in cell vesicles containing ROS, whereas L cells are characterized by low OPD in the cytoplasm relative to the nucleus and no ROS-containing vesicles. Moreover, L cells present a higher average OPD and dry mass compared to H cells. When examining neutrophils from MDS patients and BBDs by IPM during flow, we identified ~20% of cells as H cells in BBDs in contrast to ~4% in MDS patients. These results indicate that IPM can be utilized for the diagnosis of complex hematological pathologies such as MDS.

Comprehensive Study of Chromosomal Copy Number Variations and Genomic Variations Predicting Overall Survival in Myelodysplastic Syndromes

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenia, marrow dysplasia and has a propensity to develop into acute myeloid leukemia. The disease progression is majorly affected by genetic defects. However, about 40–50% of patients with MDS present with a normal karyotype and develop different courses of disease. Hence, there remains a room to advance the biological understanding and find molecular prognostic markers for cytogenetically normal MDS. Methods: We performed a high-resolution CGH + SNP array along with next-generation sequencing (NGS) of 77 primary diagnosed MDS patients, and also they were clinically followed up. Results: Our study revealed 82 clinically significant genomic lesions (losses/gains) in 49% of MDS patients. CGH + SNP array reduced the proportion of normal karyotype by 30%. SNP array in combination with NGS confirmed the biallelic loss of function of the TP53 gene (2/6), which is a clinically relevant biomarker and new genetic-based MDS entity, i.e., MDS-biTP53, as per the new WHO classification 2022. Genomic region 2p22.3 presented with frequent lesions and also with a more hazard ratio (2.7, 95% CI: 0.37–21) when analyzed by Kaplan-Meier survival analysis. Conclusion: CGH + SNP array changed the cytogenetic and IPSS-R risk group in 18% and 13% of patients, respectively, with an improved prediction of prognosis. This study emphasizes the cytogenetic heterogeneity of MDS and highlights that abnormality with chromosome 2 may have a diagnostic and prognostic impact.

Abstract P26: Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS

Abstract SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Specifically, the combination of eltanexor and venetoclax could be a promising SF3B1-specific therapy. Citation Format: Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, Skye Montoya, Daniel Bilbao, Jumana Afaghani, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor. Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P26.

Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

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. 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. 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. Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes.

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients – A clinical trial to registry data comparison

A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.

Clinical Outcomes, Survival, and Predictors in Lower-Risk Myelodysplastic Syndrome Patients Treated with Cyclosporine A

Plain Language SummaryTherapeutic options to improve myelodysplastic syndrome (MDS)-related cytopenias in patients with lower-risk MDS are limited, and cyclosporin A (CSA) is an available option. We retrospectively assessed the effects of CSA on patients with lower-risk MDS at Shuguang Hospital affiliated with Shanghai University of Traditional Chinese Medicine. After statistical analysis, we found that more patients treated with CSA improved cytopenias than those treated without CSA. Patients with hypocellular marrow were more likely to get responses to CSA. Hypocellular marrow was defined as marrow cellularity of <30%. However, CSA did not delay disease progression and prolong survival span. The results of this study suggest that CSA is a safe treatment and can significantly improve cytopenias of a substantial proportion of patients with lower-risk MDS, especially in individuals with hypocellular bone marrow.

Infectious Complications in Patients with Myelodysplastic Syndromes: A Report from the Düsseldorf MDS Registry.

Despite notable advancements in infection prevention and treatment, individuals with hematologic malignancies still face the persistent threat of frequent and life-threatening complications. Those undergoing chemotherapy or other disease-modifying therapies are particularly vulnerable to developing infectious complications, increasing the risk of mortality. Myelodysplastic syndromes (MDS) predominantly affect the elderly, with the incidence rising with age and peaking at around 70 years. Patients with MDS commonly present with unexplained low blood-cell counts, primarily anemia, and often experience varying degrees of neutropenia as the disease progresses. In our subsequent retrospective study involving 1593 patients from the Düsseldorf MDS Registry, we aimed at outlining the incidence of infections in MDS patients and identifying factors contributing to heightened susceptibility to infectious complications in this population.

Efficacy and safety analysis of venetoclax combined with hypomethylating agents for the treatment of higher-risk myelodysplastic syndromes in the real world

Objective: To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) . Methods: From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis. Results: ①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five naïve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions: There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

Factors affecting prognosis in myelodysplastic syndrome: an 11 years’ experience from a tertiary care center

Aims: Myelodysplastic syndrome (MDS) is a clonal bone marrow neoplasia characterized by morphological findings of dysplasia in hematopoietic cells, peripheral cytopenia(s), ineffective hematopoiesis, recurrent genetic abnormalities, and an increased risk of conversion to acute myeloid leukemia (AML). The International Prognostic Scoring System (IPSS) is the most commonly used prognostic classification system for MDS. Classification was made by a combination of morphology, cytopenia, and genetic studies. In this study, we aimed to examine the parameters that affect prognosis in MDS patients, show their effects on mortality, and evaluate their positive or negative effects on the course of the disease. Methods: Two hundred twenty-nine patients who applied to Erciyes University Faculty of Medicine, Department of Hematology, and were diagnosed with MDS according to WHO classification between 2010 and 2020 were included in this retrospective study. Age, gender, additional disease status, laboratory parameters, bone marrow biopsy materials, and genetic mutation analysis data were available. The bone marrow aspiration and biopsy examinations of each patient were evaluated and categorized according to the WHO classification. The prognosis was evaluated according to the data of the patients, survival-exitus, and survival after MDS-AML conversion. Risk scoring was analyzed with three different scoring systems (IPSS, WPSS, and R-IPSS). Results: Of the 229 MDS patients included in the study, 57% (131) were male. The mean age of the patients was 67 years. Age, MDS-AML conversion times, disease duration, cellularity, and pathology blast rate were found to be statistically significant between the groups (p&lt;0.05). Leukocyte, neutrophil, platelet, hematocrit, lymphocyte, monocyte, CRP, erythropoietin, ferritin, and LDH data were found to be statistically significant regarding survival (p&lt;0.05). Age, IPSS risk status 3, and W-PSS risk status 3 were found to be independent risk factors affecting survival. Conclusion: Age, IPSS high risk, and WPSS high risk status were found to be independent risk factors affecting survival. Although our study revealed important data in the analysis of MDS patients, single-center analysis of patients and retrospective analysis revealed the need for further studies.

Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy.

MDS are myeloid clonal hemopathies with a low 5-year survival rate, and approximately half of the cases do not respond to standard HMA therapy. Our innovative single-cell multiomics approach offers valuable biological insights and potential biomarkers associated with the demethylating agent efficacy. It also identifies vulnerabilities that can be targeted using personalized combinations of small drugs and antibodies.

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation.

To investigate the clinical characteristics and risk factors of specific human leukocyte antigen loss (HLA loss) in relapsed acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT), and compare the responses of patients with HLA loss relapse with those without HLA loss (non-HLA loss) to different treatment regimens. Clinical data of traceable patients with AML/MDS after myeloablative allo-HSCT in our centre between January 2010 and June 2021, who experienced disease relapse after the transplantation, were collected. The patients were divided into the HLA loss relapse group and the non-HLA loss relapsed group based on HLA loss gene test findings by next-generation sequencing. The patients' median overall survival (OS) after the relapse were compared, and univariate and multivariate analyses were performed using the Kaplan-Meier survival curve and Cox proportional hazard model to explore the responses to different treatments after relapse. A total of 2359 patients were selected. Retrospective HLA gene loss gene detection was performed for the deoxyribonucleic acid in 179 relapsed patients, including 47 patients in the HLA loss group (27.2%), 126 patients in the non-HLA loss group (72.8%) and 6 patients were excluded due to a lack of confirmed results. There was no significant statistical difference in the baseline characteristics of patients between the two groups, but as to transplantation-related characteristics, the donor-recipient relationship and HLA mismatched loci were statistically different between the two groups (both p < 0.001). Multivariate Cox analysis showed that more HLA mismatched loci ≥3 (HR = 3.66; 95% CI: 1.61-8.31; p = 0.002), time (≤6 months) from HSCT to relapse (HR = 7.92; 95% CI: 3.35-18.74; p < 0.001) and donor chimerism (CD3) in bone marrow at relapse (HR = 1.02; 95% CI: 1.00-1.03; p = 0.036) were independent factors affecting HLA loss relapse. The ratio of negative conversion of FLT3-ITD or CEBPA mutation was significantly lower in patients with post-transplantation HLA loss relapse than in the non-HLA loss group (0.0% vs. 45.5%, p = 0.003; 0.0% vs. 80.0%, p = 0.035), with none of the patients with FLT3-ITD or CEBPA mutation turned negative in the HLA loss group. The number of gene mutations turned negative when relapse in the non-HLA loss group was remarkably higher than that in the HLA loss group (p = 0.001). Using donor lymphocyte infusion (DLI) could not prolong OS for the HLA loss group (p = 0.42). Nevertheless, second transplantation had a significant positive impact on OS in the HLA loss group (p = 0.017), although only five patients in the HLA loss group underwent second transplantation. However, patients in the non-HLA loss group using DLI had a relatively longer OS time than those without DLI (p = 0.017). Second transplantation could also prolong OS in the non-HLA loss group, but the effect was not as significant as in the HLA loss group (p = 0.053). In summary, HLA loss detection is essential for patients with recurrence after transplantation, especially for those with more HLA mismatched loci and non-sibling donor. Furthermore, the detection of HLA loss has a guiding role in choosing subsequent therapy when relapsed, as secondary transplantation is more suitable than DLI for those with HLA loss.

The clinical characteristics, gene mutations and outcomes of myelodysplastic syndromes with diabetes mellitus

PurposeDiabetes mellitus (DM) is the second most common comorbidity in myelodysplastic syndromes (MDS). The purpose of the study was to investigate the clinical characteristics of MDS patients with DM.MethodsA retrospective analysis was performed on the clinical data of 890 MDS patients with or without DM. Clinical data, including genetic changes, overall survival (OS), leukemia-free survival (LFS) and infection, were analyzed.ResultsAmong 890 patients, 184 (20.7%) had DM. TET2 and SF3B1 mutations occurred more frequently in the DM group than those in the non-DM group (p = 0.0092 and p = 0.0004, respectively). Besides, DM was an independent risk factor for infection (HR 2.135 CI 1.451–3.110, p = 0.000) in MDS. Compared to non-DM patients, MDS patients with DM had poor OS and LFS (p = 0.0002 and p = 0.0017, respectively), especially in the lower-risk group. While in multivariate analysis, DM did not retain its prognostic significance and the prognostic significance of infection was maintained (HR 2.488 CI 1.749–3.538, p = 0.000).ConclusionsMDS patients with DM have an inferior prognosis which may due to higher infection incidence, with TET2 and SF3B1 mutations being more frequent in those cases.

The Correlation of Gene Mutation and Clinical Characteristics in Patients with Myelodysplastic Syndrome and Prognostic Analysis

To explore the correlation between gene mutations and clinical characteristics, prognosis of myelodysplastic syndromes (MDS). Clinical data of 131 patients with MDS were collected from the First Hospital of Lanzhou University from June 2015 to February 2023, which 19 of them developed into secondary acute myeloid leukemia (sAML) during follow-up time. Second generation sequencing technology was used to detect the mutation types of MDS disease-related genes, drawn gene maps, and analyzed their correlation and prognosis based on the clinical data of patients. The median age of 131 MDS patients was 58(17-86) years old. The ratio of male to female was 1.3∶1. A total of 148 gene mutations and 25 types were found in the center. U2AF1 and ASXL1 were often co-mutations with other genes, which were accompanied by 20q- and normal karyotype (NK) respectively. SETBP1 and SRSF2 were more common in patients over 60 years old, while NPM1 and WT1 under 60 years. Older patients had a higher the number of genetic mutations than younger patients. The incidence of SF3B1 and RUNX1 in males was higher than females and DNMT3A in females was higher than males. The number of gene mutations in sAML was higher than MDS (1.8 vs 1.0, P =0.006). The univariate and multivariate analysis showed that IPSS-R prognostic score≥3.5, TP53 were adverse factors for poor prognosis in MDS patients. Patients with monoallelic mutation（ma-TP53）and wild-type（wt-TP53） TP53 had OS better than biallelic mutation（bi-TP53）(P =0.003). The OS of MDS patients was better than sAML(P =0.01) and transplant patients was significantly better than nontransplant patients(P =0.036). Gene mutation is closely related to cytogenetic indexes and clinical features (peripheral blood cell count, sex, age). IPSS-R prognostic score and TP53 were risk factors affecting OS in MDS patients.

Platelet Count Doubling after One Course of Demethylated Drug Therapeutic Predicts the Treatment Response and Efficacy of Patients with Myelodysplastic Syndrome

To investigate the predictive value of platelet doubling (platelet count doubling) after one course of hypomethylating agents (HMA) on the treatment response and efficacy of myelodysplastic syndrome (MDS). Clinical and pathological data of 75 patients who received HMA in our hospital from January 2017 to March 2022 were collected and analyzed. All patients were divided into two groups according to whether their platelet count doubled after one course of treatment, including platelet doubling group and non-doubling group, and statistical analysis was performed to compare the treatment response and efficacy between the two groups. In addition, platelet count changes were compared between azacitidine and decitabine therapy. Compared with the non-doubling platelet count group, the ORR of the doubling platelet group was significantly better after 3 courses of treatment (P =0.002), and there was a statistically significant difference in the number of HI between the two groups (P =0.005). In addition, the median survival time (MST) was 26 months in the platelet doubling group and 11 months in the non-doubling group (P =0.001). The overall survival (OS) and 1- and 2-year survival rates of the platelet doubling group were also significantly better than those of the non-doubing group. Multivariate COX analysis showed that platelet count doubling was an independent predictor of OS in MDS patients after 1 course of treatment (P =0.013). There was no significant difference in the response rate of platelet count doubling between MDS patients treated with azacitidine and decitabine (33.3% vs 23.8%, P >0.05). Platelet count doubling after one course of treatment can be used as a predictor of response rate and survival of demethylated drug therapy in MDS patients. In addition, there was no significant difference in the response rate of platelets in MDS patients treated with azacitidine or dicetabine.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients.

Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that requires the integration of morphologic, cytogenetic, hematologic, and clinical findings for a successful diagnosis. Trying to find ancillary tests such as biomarkers improve the diagnosis process. Several studies showed that a disordered immune system is associated with MDS. The chronic activated innate immune system, particularly the Toll-like receptors (TLRs) pathway could be involved in the induction of the inflammation. In the present study, we investigated the expression of TLR2, TLR4, and IRAK4 in bone marrow (BM) of MDS patients, the leukemia group, and the healthy group. For this purpose, we assessed the expression of TLR2, TLR4, and IRAK4 by real time-PCR. In line with new findings, we demonstrated that the expression of TLR2, TLR4, and IRAK4 significantly increased in MDS BM compared with the healthy group. Moreover, IRAK4 expression raised significantly in MDS patients compared with other studied hematologic neoplasms. Also, the expression levels of TLR2 and TLR4 significantly increased in MDS in comparison to some studied non-MDS malignancies (P ˂ 0.05). Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.