CPX-351 vs daunorubicin, cytarabine, and gemtuzumab ozogamicin in older adults with non-adverse-risk AML: the NCRI AML18 trial.

Machine learning (ML) accelerates progress in many areas, including biomedical and clinical research. ML algorithms provide powerful options for efficiently analyzing multivariate data sets. We developed and validated an ML pipeline to detect myelodysplastic syndrome (MDS)-associated pathological alterations of extracellular matrices (ECMs) by time-of-flight secondary ion mass spectrometry (ToF-SIMS). A Bayesian-optimized neural network (NN) was trained and applied to classify ToF-SIMS spectra of ECM secreted by mesenchymal stromal cells (MSCs) derived from MDS patients and healthy reference donors. Validated by principal component analysis, the explainer tool SHapley Additive exPlanations (known as SHAP) was integrated into the analysis pipeline to unravel characteristic compositional and structural differences of the ECM variants. Our results demonstrate the potential of ToF-SIMS-ML for the label-free investigation of pathogenic alterations of the ECM. Integrated into the multiscale ECM analysis of cell and organoid-based disease models, the introduced methodology may facilitate advances in the development of novel diagnostic and therapeutic strategies.

Introduction: Myelodysplastic Syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, and high risk of transformation to Acute Myeloid Leukemia (AML). While extensive research has elucidated the role of leukemic stem cells (LSCs) in AML pathogenesis, the stem cell compartment driving MDS remains less defined. Current evidence suggests that MDS originates from immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for leukemic evolution. These cells share phenotypic features with normal Hematopoietic Stem Cells (HSCs) but aberrantly express AML-associated markers such as CD123, CD371 (CLL1), and CD366 (TIM-3). Aims and Methods: Bone marrow (BM) samples from MDS patients (pts) at diagnosis were collected and a flow cytometry antibodies panel including CD34, CD38, CD90, CD45RA, CD123, CLL-1, and TIM-3 was designed. The entire CD34+ compartment was analyzed, focusing on CD34+CD38-CD90+ (HSC-like) and CD34+CD38-CD45RA+ (LSC-like) subsets. The aims are to determine whether AML-like LSCs are already detectable in MDS samples; to define a distinct MDS-SC phenotype within the patient cohort. The final goal is to identify phenotypic signatures that could facilitate the prognostic stratification and therapeutic monitoring of MDS pts.Results: 60 pts with diagnosis of MDS were studied. Using a flow cytometry gating strategy, we analyzed the CD34+CD38- compartment, focusing on 2 distinct subsets: CD34+CD38-CD90+ HSCs and CD34+CD38-CD45RA+ LSCs. Based on the presence/absence of these 2 populations, the 60 MDS pts were stratified as follows:Group 1 (18/60; 30%) – Negative for both HSCs and LSCs; Group 2 (6/60; 10%) – Positive only for HSCs; Group 3 (11/60; 18%) – Double positive for both HSCs and LSCs; Group 4 (25/60; 42%) – Positive only for LSCs; notably, 6/25 (24%) pts in this group progressed to AML. To date, Next-Generation Sequencing (NGS) has been performed in 20/60 (33%) cases, revealing mutations in genes involved in RNA splicing (SRSF2, SF3B1, U2AF1), DNA methylation (IDH2, TET2, DNMT3A), transcription regulation (KRAS, RUNX1), histone modification (EZH2), and chromatid cohesion (STAG2). Interestingly, Groups 1 and 2 predominantly harbored initiating MDS-associated mutations, whereas Groups 3 and 4 already displayed AML-like molecular alterations. Conclusions: We developed a flow cytometry–based approach to stratify MDS pts by their stem cell compartment, identifying a subset (Groups 3 and 4) with AML-like LSCs and higher risk of leukemic transformation, distinct from those with an MDS-like phenotype and only initiating mutations (Groups 1 and 2). Combining flow cytometry, cytogenetic, and NGS data offers new insight into MDS clonal evolution, emphasizing mutated MDS-SCs as key drivers of progression. Ongoing work aims to expand the cohort and validate findings against normal BM, to establish this strategy as a predictive tool for early detection and monitoring of high-risk MDS pts.

Introduction: High risk MDS (HR-MDS) outcome significantly improved after the introduction of hypomethylating treatment, especially 5’-azacitidine (AZA). Despite AZA is now the standard treatment for HR-MDS, only 30-50% of patients respond to treatment. The identification of response/resistance biomarkers is essential to prevent prolonged exposure and toxicities in unresponsive patients.Methods: We used a comprehensive t-NGS, epigenetic (mERBBS), and transcriptomic (RNA-seq) approach to study 10 HR-MDS, prior and post 4-AZA cycles (5 responders, R, with complete remission; 5 non-responders, NR, with progressive disease). Healthy donor’s (HD) BM samples were used as controls (n=5). 55 BM samples, from the GROM-L multicenter study (n=12) and Gimema MDS0205 study (n=43), were used as independent validation cohort.Results: Age, gender, hematological and genetic features at diagnosis (T0) did not differ in the two subgroups. We identified a mean of 2 mutations (range=0–6, VAF>1%), in 8/10 patients at baseline, with TP53 (40%), DNMT3A (30%), TET2 (30%), ASXL1 (20%) and SETBP1 (20%) as the most frequently mutated genes. After AZA (T4), TP53 mutations became undetectable in 2/5 R patients (40%), while remained unchanged in NR. RNA-seq analysis at T0 (R vs HD, NR vs HD, R vs NR) and at T4 (R vs HD, NR vs HD, R vs NR) collectively showed different baseline transcriptional profiles in the two response-groups, particularly involving immune-related genes.Unsupervised analysis of DNA methylation separated the 2 subgroups, with one branch including all R (at T0 and T4) and HD, while the second all NR (at T0 and T4). mERRBS highlighted a DNA methylation gradient at diagnosis, in accordance with response. Indeed, NR was the most perturbed group, and the most hypermethylated. Within the hypermethylated promoters in NR at T0, BCL9L displayed the highest number of DMRs on its 5’-region. Pyrosequencing and qRT-PCR, were used to validate its hypermethylation and downregulation.Treatment with AZA induced a strong epigenetic shift only in R, with a reduction of DMRs (740 at T4 vs 2.732 at T0) and shift into a hypomethylated pattern (84.4%). By contrast, NR maintained at T4 a comparable number of DMRs (13.281 at T4 vs 13.231 at T0) and confirmed the hypermethylation seen at diagnosis (67.7%). Specifically, the methylation level at homeobox genes backed down to normal levels at T4 only in R. Within these DMRs, PRRX2 gene showed the stronger correlation with response. Hypermethylation in NR was confirmed in an independent validation cohort (n=5 R vs 5 NR, p<0.005).Conclusions: Overall, our results identified a different transcriptional and epigenetic profile according to AZA response, including differential expression of immune-related genes and significant hypermethylation of NR at diagnosis, and a marked epigenetic shift after AZA in R. Of note, hypermethylation at BCL9L promoter and at the PRRX2 gene emerged as candidate predictive markers of AZA-response.

Myelodysplastic/myeloproliferative neoplasm with neutrophilia (MDS/MPN-N) is a rare and heterogeneous hematologic malignancy characterized by overlapping myelodysplastic and myeloproliferative features and recurrent mutations in ASXL1, SETBP1, and ETNK1. Current therapeutic options remain limited, with hydroxyurea providing only transient benefit and allogeneic transplantation being feasible in only few cases. The hypomethylating agent azacitidine (aza) has shown efficacy in high-risk myelodysplastic syndromes, but its molecular effects in MDS/MPN-N are poorly understood. This study aimed to characterize clinical responses and molecular mechanisms of aza in MDS/MPN-N through integrated clinical and single-cell transcriptome analyses.Three patients with MDS/MPN-N received subcutaneous aza (75 mg/m², days 1–7, every 28 days) for up to nine cycles. Longitudinal hematologic, morphologic, and targeted NGS analyses were performed at baseline and after cycles 3, 6, and 9. Bone marrow CD34⁺ cells collected at diagnosis and after three cycles underwent single-cell RNA sequencing to assess transcriptional and lineage changes. Complementary in vivo studies were conducted in a conditional SETBP1-G870S murine model treated with aza (5 mg/kg × 5 days).Aza was well tolerated and achieved hematologic improvement in all patients, including normalization of leukocyte counts (A) and reduction in transfusion dependence (B). Bone marrow analyses revealed restored granulocytic maturation without disease acceleration. NGS monitoring showed heterogeneous clonal dynamics, indicating that clinical benefit was not strictly linked to clonal eradication.Single-cell transcriptomics (C) demonstrated that aza profoundly remodels bone marrow architecture, reducing hematopoietic stem and early progenitor populations while expanding differentiating progenitors (D). Treated samples showed activation of cell cycle and differentiation programs (E) and repression of self-renewal drivers such as MECOM, EYA1, and FLT3 (F). Gene ontology and GSEA analyses revealed enrichment of pathways related to chromatin remodeling, histone modification, and hematopoietic differentiation. In the erythroid compartment, aza promoted reactivation of GATA1-dependent transcriptional programs and downmodulation of SPI1/PU.1 regulon activity (G), restoring the GATA2-to-GATA1 switch (H-I) and enhancing heme biosynthesis and proliferation of erythroid precursors. Consistent with human data, SETBP1-driven leukemic mice treated with aza showed expansion of early erythroid progenitors.Aza promotes extensive epigenetic and transcriptional remodeling in MDS/MPN-N, promoting differentiation and erythropoietic recovery while limiting aberrant stem cell self-renewal. Collectively, these data position aza as a rational therapeutic approach capable of modulating hematopoietic stem cell fate and achieving durable hematologic improvement in MDS/MPN-N patients who are not eligible for transplantation.

Background. Imetelstat is a first-in-class human telomerase (hTERT) inhibitor, decreasing the upregulated telomerase activity of neoplastic hematopoietic stem and progenitor cells (HSPCs). By suppressing hTERT, Imetelstat selectively eliminates dysplastic clones, enabling restoration of normal hematopoiesis. Recently approved by the FDA for the treatment of red blood cell transfusion–dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) patients after erythropoiesis-stimulating agent (ESA) failure, its precise mechanism of action remains unclear. We provide the first in vivo evidence that Imetelstat enhances erythroid maturation by alleviating ineffective erythropoiesis and reducing bone marrow (BM) clonal burden in responding LR-MDS patients.Methods. Comprehensive erythroid flow cytometry (FC) and targeted next-generation sequencing (t-NGS) analyses were performed on BM samples from LR-MDS patients enrolled in the phase III IMerge trial (. NCT02598661). FC analysis included total CD71⁺ erythroid cells (Erytot), early CD34+/CD117⁺, and late CD117⁻ erythroid precursors. The erythroid ratio (ER) was defined as the ratio of late to early precursors. BM erythroid indices and variant allele frequency (VAF) of driver somatic mutations were longitudinally assessed at baseline, +6 and +12 months after Imetelstat initiation; extended FC data were available at +24 months for one ongoing responder.Results. Four representative cases were analyzed: (a) a long responder (>1 year RBC transfusion independence), (b) a transient responder (<1 year RBC-TI), (c) a non-responder, and (d) a placebo-treated patient. The sustained responder displayed marked and persistent decreases in Erytot population (29%→11% at 24 months) accompanied by increased ER (2.36→7.33), consistent with enhanced erythroid maturation (Figure 1a). The transient responder exhibited a similar pattern during response (Erytot 17%→2%, ER 3→6.14 at 6 months) but relapsed by 12 months, with Erytot expansion (30%) and ER reduction (2.22). No significant changes were observed in non-responder or placebo cases. Clonal dynamics mirrored erythroid trends: BM VAFs of driver mutations decreased during hematologic response (22%→4.7% in the ongoing responder at 12 months, 32.9% →4.3% in the short responder at 6 months) and re-expanded at relapse (4.3%→22.6% in the transient responder at 12 months, Figure 1b). As for erythroid populations, BM VAF did not change significantly over time in both the non-responder and the placebo-treated patient. Conclusions. Imetelstat treatment in LR-MDS promotes erythroid maturation and reduces BM clonal burden during clinical response, supporting a dual mechanism of action that combines telomerase-mediated clonal suppression with restoration of effective erythropoiesis. These findings provide in vivo mechanistic insight into how telomerase inhibition reverses ineffective erythropoiesis in MDS and underpin the durable clinical responses observed in the IMerge trial.

Myeloid Sarcoma (MS) constitutes a rare extramedullary manifestation characterised by the clonal proliferation of myeloid precursor cells. It may present in association with Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS), or Myeloproliferative Neoplasms (MPN), or as an isolated entity. Its variable morphology and frequent absence of a prior haematological history present a significant diagnostic challenge. This report delineates five cases of MS diagnosed at our tertiary care centre between July 2023 and June 2025. All patients were male, with a median age of 36 years. Affected anatomical sites included soft tissue (n=2), bone (n=1), lymph node (n=1), and testis (n=1). Two patients had an underlying diagnosis of Chronic Myeloid Leukaemia (CML). Histopathological evaluation consistently revealed blastic morphology, often closely mimicking lymphoma or small round cell tumours. Immunohistochemistry (IHC) proved indispensable for definitive diagnosis, with all cases demonstrating positivity for CD34 and Myeloperoxidase (MPO). Notably, one case also exhibited CD99 and FLI-1 expression, thereby creating diagnostic overlap with Ewing sarcoma. This case series highlights the diverse presentations and inherent diagnostic pitfalls of MS, emphasising the importance of considering MS in the differential diagnosis of extramedullary masses and employing judicious IHC, particularly MPO and CD34, to ensure accurate diagnosis.

Beyond Sweet Syndrome: Untangling the Threads of Histiocytoid Sweet Syndrome and Cutaneous Myeloid Neoplasia.

Impact of donor characteristics on the outcomes following haplo-HSCT in patients aged 55 years and older.

Myelodysplastic syndromes (MDSs) are clonal hematopoietic disorders characterized by ineffective hematopoiesis and their diagnosis remains challenging, requiring integration of clinical, morphological, and genetic data. MicroRNAs (miRNAs) have emerged as potential biomarkers in MDS, offering insights into disease mechanisms and patient stratification. This study aimed to evaluate the diagnostic and prognostic significance of five plasma microRNAs (miR-22-3p, miR-144-3p, miR-16-5p, let-7a-5p, and miR-451a) in 40 patients with MDS, diagnosed according to WHO 2016 criteria and stratified by R-IPSS, and ten healthy controls. Plasma miRNA levels were measured by RT-qPCR. Expression profiles were compared between patients and controls, and further assessed in relation to disease subtypes, risk categories, and clinicopathological features. Expression analysis showed that miR-144-3p, miR-16-5p, let-7a-5p, and miR-451a were significantly lower in MDS patients compared to controls. MiR-451a demonstrated the highest diagnostic predictive value (p = 0.0022), followed by miR-16-5p (p = 0.0055), miR-144-3p (p = 0.0074), and let-7a-5p (p = 0.0092). Let-7a-5p was higher in MDS with excess blasts and both let-7a-5p and miR-451a were lower in the low-risk R-IPSS group. Strong correlations between miR-16-5p, miR-144-3p, and miR-451a were observed, probably reflecting their function in erythropoiesis. None of the investigated microRNAs showed independent prognostic significance for overall survival. In conclusion, circulating microRNAs, particularly miR-451a and let-7a-5p, show promise as supportive biomarkers that may complement existing diagnostic and risk assessment tools in MDS. Further studies are needed to validate their clinical applicability.

MDM4 HAPLOINSUFFICIENCY LEADS TO P53-MEDIATED BONE MARROW FAILURE.

Background: Myeloid sarcoma (MS) is a malignant extramedullary tumor that occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). The standard first-line treatment for MS is intensive chemotherapy according to the AML protocol, regardless of bone marrow involvement. The role of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of pediatric patients with MS requires further investigation. The aim of the study was to evaluate treatment outcomes for MS in pediatric patients with a focus on assessing the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on treatment efficacy. Material and Methods: The study included 64 patients aged 0 to 19 years from 15 pediatric oncology centers in Poland who were diagnosed with MS between 1998 and 2024. An Excel database was created to collect data on clinical features and treatment methods and outcomes. Results: The probability of 5-year overall survival (pOS) for the entire cohort was 0.63 ± 0.07, while the 5-year event-free survival (pEFS) and 5-year relapse-free survival (pRFS) were 0.62 ± 0.07 and 0.72 ± 0.07, respectively. Treatment outcomes were compared between patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (ICR) (n1 = 17/64; 27%) and those who did not receive alloHSCT (n2 = 47/64; 73%). In the alloHSCT group (n1), the estimated survival probabilities were pOS = 0.49 ± 0.13, pEFS = 0.44 ± 0.14, and pRFS = 0.40 ± 0.14. In the non-alloHSCT group (n2), these values were pOS = 0.68 ± 0.08, pEFS = 0.68 ± 0.08, and pRFS = 0.84 ± 0.06. The difference in pRFS between groups n1 and n2 was statistically significant (p = 0.0049). Extramedullary relapses were more frequently observed in patients who had undergone allogeneic hematopoietic stem cell transplantation (alloHSCT) (p = 0.0001). Conclusions: Allogeneic hematopoietic stem cell transplantation (alloHSCT) does not improve the outcome of patients with MS. Further research is needed to identify effective strategies for sustaining remission in patients with MS after alloHSCT.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy often characterized by poor response to conventional therapies and frequent relapse. Ponatinib, a third-generation tyrosine kinase inhibitor, has demonstrated efficacy in various leukemias but remains underexplored in AML. Vitamin K2 (VK2), a fat-soluble vitamin, has recently been implicated in inducing apoptosis in leukemia cells. This study aimed to evaluate the therapeutic potential of ponatinib and VK2, alone and in combination, across five AML cell lines. SKM-1 (myelodysplastic syndrome cell line) and AML cell lines MOLM-14, Kasumi-1, THP-1, and MV4-11 were tested. Cells were plated in 96-well plates and exposed to ponatinib or VK2, and cell viability and cytotoxicity were assessed. After 48 or 72 h of incubation, luminescence or absorbance was recorded, and cell numbers were quantified. Cells were plated in MethoCult medium supplemented with the indicated drug concentrations and incubated for 10 days at 37°C in a humidified 5% CO2 atmosphere. Colonies containing more than 50 cells were enumerated, and representative images were captured. Caspase-3/7 activity was measured after 48 h of drug exposure, and luminescence signals were detected. Cells were stained with the JC-1 MitoMP Detection Kit and analyzed using a fluorescence microplate reader. Mitochondrial membrane potential was determined by calculating the ratio of red to green fluorescence intensity. Intracellular adenosine triphosphate levels were quantified. Ponatinib exhibited cell line-dependent cytotoxic effects, with MOLM-14 and MV4-11 being the most sensitive. VK2 suppressed cell viability in all tested lines, with synergistic enhancement when combined with ponatinib. The combination treatment significantly increased apoptosis, reduced colony formation, and disrupted mitochondrial membrane potential. The combined ponatinib and VK2 treatment synergistically impairs AML cell survival by enhancing apoptosis, suppressing clonogenic growth, and disrupting mitochondrial function. This dual targeting of oncogenic kinase signaling and metabolic integrity supports the ponatinib-VK2 combination as a promising therapeutic strategy for AML.

BACKGROUND GATA-binding protein 2 (GATA2) is a critical transcription factor that plays an essential role in maintaining the stemness of hematopoietic stem cells. Mutations in GATA2 are recognized as disease-causing mutations for aplastic anemia (AA) and myelodysplastic syndromes; however, the mechanisms linking these mutations to chronic liver injury (CLI) (e.g. , cirrhosis) remain elusive. AIM To investigate the molecular mechanisms through which GATA2 deficiency promotes CLI. METHODS Whole genome sequencing was performed to identify loss-of-function mutations in GATA2 in a 55-year-old female patient who was suspected of and later diagnosed with AA and developed cirrhosis one year post-diagnosis. After establishing the genetic association between GATA2 mutations and cirrhosis through clinical case analysis, liver injury murine and hepatocyte models were developed to characterize GATA2 expression in response to liver injury. rAAV8-TBG-Gata2- shRNA-mediated liver-specific Gata2 knockdown was employed to elucidate the role of GATA2 in exacerbating liver injury. RESULTS The patient presented with a three-year medical history of dizziness, fatigue, and thrombocytopenia. Following conventional treatment, she developed severe fatigue, abdominal distension, and jaundice, indicative of liver disease. Multimodal evaluations, including bone marrow biopsy, flow cytometry, liver biopsy, and genetic testing, confirmed GATA2 mutation-associated AA complicated by cirrhosis. Experimental studies in cellular and animal models demonstrated compensatory upregulation of hepatocyte GATA2 in response to endoplasmic reticulum stress and oxidative stress. Mechanistically, liver-specific Gata2 knockdown exacerbated hepatocyte apoptosis, necroptosis, ferroptosis, and impaired regeneration. Furthermore, Gata2 knockdown suppressed the adaptive unfolded protein response, attenuated the antioxidant response, and inhibited fatty acid β-oxidation. CONCLUSION GATA2 deficiency drives the CLI by disrupting the hepatocyte death-regeneration balance.

Not available.

High-throughput cloning reveals diverse properties of T-cell receptors targeting minor histocompatibility antigens.

Background: An decrease in all three blood components; leukopenia, thrombocytopenia, and anemia below the normal level is known as pancytopenia. This study is an attempt to fill the lacunae regarding the information about pancytopenia in pediatric patients. The study aimed to study the clinical and etiopathological profile of pancytopenia in children aged 1–18 years. Methods: This cross-sectional observational study was to find out more about the etiopathological profile, clinical characteristics, and demographics of pediatric pancytopenia. The study was conducted from June 2025 to November 2025 with 65 patients who fulfilled the inclusion criteria and were admitted to the pediatric department of Sri Krishna Medical College and Hospital in Muzaffarpur, Bihar, and were between the ages of 1 and 18. IBM’s Statistical Package for the Social Sciences version 23 was used for the statistical study. Results: The majority of cases (55%) out of 65 patients were in the 1–6 years age group. Our study revealed male predominance over females with male-to-female ratio of 2.09:1, mostly belonging to rural areas. The most common presenting complaint was easy fatigue in (90%) of patients followed by fever (54%). The most common physical finding was pallor (100%), followed by splenomegaly and pedal edema (38%) and (18%), respectively. Bone marrow cellularity shows hypocellular marrow (62%), hypercellular (31%), and normocellular (7%). Peripheral smears of most of the patients showed normocytic normochromic (34%), followed by macrocytic hypochromic (30%). Regarding etiology megaloblastic anemia (30%) was reported as the most common cause of pancytopenia followed by malignancies (30%) including myelodysplastic syndrome (9%), multiple myeloma (3%), acute lymphocytic leukemia (9%), and acute myeloid leukemia (9%) followed by aplastic anemia (14%) and sepsis (8%). The study also shows other rare causes of pancytopenia such as disseminated tuberculosis (6%), malaria (9%), and dengue (3%). Conclusion: According to the present study, megaloblastic anemia, malignancies, and aplastic anemia are the most frequent nutritional causes of pancytopenia.

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have been established as a first-line maintenance therapy in advanced epithelial ovarian cancer (EOC) following platinum-based chemotherapy. While phase III trials have demonstrated significant progression-free survival (PFS) benefits with olaparib and niraparib, real-world data remain limited. Methods: This retrospective, multicenter real-world study included 179 patients with newly diagnosed epithelial ovarian treated with first-line maintenance olaparib or niraparib across 33 centers in Türkiye between January 2014 and March 2025. Clinical, pathological, and molecular data-including BRCA (Breast Cancer Susceptibility Gene) mutation status, origin, and variant classification-was collected. The primary endpoint was PFS, and secondary endpoints included overall survival (OS) and safety. Survival outcomes were analyzed using Kaplan-Meier methods. Results: Of 179 patients, 110 received olaparib and 69 received niraparib. BRCA mutations were present in 88.3% of patients, while 11.7% had unknown HRD status. Median follow-up was 16.5 months, and median PFS was not reached. Estimated PFS rates for the overall cohort were 91.0% at 6 months, 83.0% at 12 months, and 64.0% at 24 months. In the olaparib cohort, BRCA-mutant patients demonstrated PFS rates of 89%, 78%, 73%, and 64% at 6, 12, 18, and 24 months, respectively. In the niraparib cohort, corresponding PFS rates among BRCA-mutant patients were 87% at 6 months and 75% at 12 months. Patients harboring pathogenic BRCA variants experienced longer PFS compared with those with likely pathogenic variants. Any-grade adverse events occurred in 73.7% of patients, and grade 3-4 events in 29.6%, with hematologic toxicities predominating. Dose interruptions were more frequent with niraparib, while treatment discontinuation rates were low in both groups. No cases of myelodysplastic syndrome or acute myeloid leukemia were observed. Conclusions: In this large multicenter real-world cohort, first-line maintenance therapy with olaparib and niraparib provided durable PFS benefit in patients with advanced EOC, particularly among those with pathogenic BRCA mutations, confirming their effectiveness and manageable safety profiles in routine clinical practice.

Background. One of the key pathogenetic mechanisms in myelodysplastic syndrome (MDS) is a disruption of the hematopoietic stem cell microenvironment, which is accompanied by changes in the secretion of pro-inflammatory cytokines, in particular tumor necrosis factor alpha (TNF). Given the immunoinflammatory nature of MDS pathogenesis, the use of immunomodulatory drugs, in particular lenalidomide, has shown clinical efficacy in low-risk patients. Objective: to assess the clinical and hematological status and colony-forming activity of bone marrow cells in patients with MDS and refractory anemia with excess blasts 1 (RANB-1) depen­ding on the concentration of TNF in the blood serum. Materials and methods. Twenty-seven patients receiving lenalidomide were examined. Serum TNF level was determined with enzyme-linked immunosorbent assay using standard production kits. The analysis was performed on an enzyme immunoassay analyzer Multiskan EX ( = 430 nm). Plasma from healthy donors served as a control. ­Results. It was found that a decrease in TNF is accompanied by clinical improvement, increased erythropoiesis and increased co­lony formation in vitro. Serum TNF concentration significantly decreases in patients with MDS and RANB-1 when achieving a complete or partial response to lenalidomide therapy. TNF level demonstrates high predictive accuracy (AUC = 1.00) for differentiating response to treatment. Functional activity of progenitor cells (CFU-GM) and the level of CD34+/CD117+ in the bone marrow are inversely related to TNF. It is noteworthy that in the group of patients with MDS and RANB-1 who did not respond to lenalidomide therapy, a deterioration in the general condition was noted due to worsening anemia, which can be assessed as a clinical situation for correction of the therapeutic route in order to prevent emergencies. Conclusions. The obtained results confirm the feasibility of including TNF and colony formation in the set of diagnostic markers for risk stratification and predicting the course of MDS.

Myelodysplastic syndromes are clonal bone marrow failure disorders demonstrating variable degrees of cytopenias, morphologic dysplasia, and risk of progression to acute myeloid leukemia. We hypothesized that MDS with a normal karyotype (NK) would exhibit a unique mutational or morphologic signature. We investigated the morphologic features and genetic profiles of 89 patients with myelodysplastic syndrome (MDS), including 42 with a NK and 47 with an abnormal karyotype (non-NK). We used next-generation sequencing (NGS) to detect pathogenic variants and performed morphologic review by two independent hematopathologists in a blinded manner with a nested set of 43 control cases. NK and non-NK cases showed similar levels of dysplasia in granulocytes and erythroids, but non-NK cases showed significantly more dysplasia in megakaryocytes (P = 0.037). The mutational burden was similar between NK and non-NK cases. TET2 and SF3B1 mutations were more frequent in NK cases (P = 0.029 and P = 0.013, respectively), and TP53 mutations were more frequent in non-NK cases (P = 0.007). Overall, higher mutational burden was associated with higher levels of megakaryocyte dysplasia (P = 0.003), but there was no association with granulocytic or erythroid dysplasia. Cases with STAG2 mutations were associated with higher overall megakaryocyte dysplasia (P = 0.0016) and proportion of megakaryocytes with separate nuclear lobes (P < 0.0001). The megakaryocyte lineage is the most expressive in terms of reflecting morphologic dysplasia due to cytogenetic or molecular abnormalities. MDS with NK shows similar morphologic features to non-NK cases, but our findings suggest that non-NK cases exhibit higher levels of megakaryocytic dysplasia.