Search Results (504)

Background/Objectives. Recent evidence underscores the prognostic and classificatory relevance of somatic mutations in myelodysplastic neoplasms (MDSs) and acute myeloid leukemia (AML). Methods. This prospective study assessed gene mutation dynamics via next-generation sequencing (NGS) in 84 MDS/AML patients treated with intensive chemotherapy or hypomethylating agents plus venetoclax. Results. At diagnosis, 95% had somatic mutations detected by NGS, while only 29% had a measurable residual disease (MRD) marker with qPCRs. NGS at complete remission (CR) was performed in 56/71 patients who achieved CR; 59% had persisting mutations, mostly in DNMT3A, TET2, and ASXL1 (DTA mutations). Mutations’ persistence in CR was linked to a shorter relapse-free survival (RFS; median 8 months vs. not reached, HR 4.41, 95% CI 1.69–11.49; p = 0.002) and overall survival (OS; 2-year OS: 51.5% vs. 88%, HR 4.02, 95% CI 1.39–11.65; p = 0.001). Combining NGS and multiparameter flow cytometry (MFC) for MRD detection, we divided patients into three groups with distinct RFS (NGS−/MFC−, NGS−/MFC+, or NGS+/MFC− and NGS+/MFC+), with double-negative patients displaying the best RFS (p < 0.001). In the multivariate analysis, NGS and MFC MRD+ were independent predictors of RFS. Conclusions. This real-world study confirms the added prognostic role of NGS in MRD detection on RFS, particularly when combined with MFC. This approach may improve risk stratification and guide treatment decisions. Full article

Activation of TP53 signaling during ribosome biogenesis is an essential part of erythroid development, whereas the pathologic activation of TP53 in ribosomopathies such as Diamond-Blackfan anemia (DBA) and del (5q) myelodysplastic syndrome (MDS) prevents the normal expansion of erythroid precursors. TP53 can also be linked to the pathogenesis of DBA and MDS via ferroptosis, a form of iron-mediated cell death propagated by excess polyunsaturated fatty acid-containing oxidizable phospholipids and loss of lipid peroxide repair capacity. The primary objective of this work was to establish how overexpression and mutation of the TP53 gene influences lipid composition, erythroid differentiation, and ferroptosis sensitivity in K-562 cells, an in vitro model for studying erythropoiesis. Employing a reverse genetics approach, we generated four isogenic cell lines that either lacked functional TP53 expression, expressed wild-type (WT) TP53, or expressed one of the two most common TP53 mutation types, R175H or R282W. We then utilized non-targeted lipidomics to quantify and identify changes in specific lipid species that occur with induction of WT and mutant TP53 expression. We also analyzed differences in gene expression, ferroptosis sensitivity, and hemoglobinization by qPCR, CCK-8 cytotoxicity assay, and o-dianisidine staining, respectively. The abundance of 337 distinct lipid species was impacted by induction of WT TP53 expression compared to K-562 cells expressing a nonfunctional P53 protein. Yet only 17 lipid compounds were differentially impacted between cells expressing WT TP53 and either of the mutant TP53 genes tested. Similarly, while the TP53 null K-562 cells displayed modest sensitivity to ferroptosis, cells expressing both WT and mutant TP53 genes were remarkably resistant to ferroptosis. However, terminal differentiation and hemoglobinization were significantly impacted in R175H mutant TP53-expressing K-562 cells. Findings from this work provide novel insights into the role of TP53 in lipid metabolism and terminal erythropoiesis. Full article

Mold-active prophylaxis has reduced the incidence of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies (HMs), but breakthrough IPA (Bt-IPA) is increasingly encountered. Therefore, we studied determinants of Bt-IPA risk and its prognostic significance. We retrospectively reviewed culture-positive proven/probable IPA cases in HM patients at MD Anderson Cancer Center (2016–2021). Bt-IPA and non-Bt-IPA cases were compared to characterize risk factors, clinical presentation, and outcomes. Independent predictors of 42-day all-cause mortality were assessed using propensity score-adjusted Cox regression. Among 118 IPA cases, 50 (42.4%) were Bt-IPA. Bt-IPA was associated with acute leukemia/myelodysplastic syndrome, active HM, severe neutropenia (<100/mm³), and graft-versus-host diseases. Uncommon Aspergillus species (non-fumigatus, flavus, terreus, or niger) were more frequent in Bt-IPA than non-Bt-IPA (20.4% vs. 4.8%, p = 0.010). Forty-two-day mortality was higher in Bt-IPA (65.3% vs. 37.3%, p = 0.003), but Bt-IPA itself was not an independent predictor or mortality (p = 0.064), which was instead driven by neutropenia (p = 0.020) and hypoalbuminemia (p = 0.002). In conclusion, Bt-IPA accounted for nearly half of contemporary IPA cases and was linked to host-related risk factors and the recovery of uncommon Aspergillus species. Although not an independent prognostic predictor, Bt-IPA reflected poor host status. Thus, early diagnosis, immune enhancement strategies, and effective first-in-class antifungals may improve outcomes. Full article

Background and Clinical Significance: Acute megakaryoblastic leukemia (AMKL) is a rare and aggressive hematologic malignancy. The presence of genetic abnormalities often increases the complexity of AMKL. Among these, patients with monosomy 7 constitute a high-risk group associated with a poorer prognosis and greater chemoresistance. We report the case of a 10-year-old boy who had AMKL along with monosomy 7 and familial GATA2 deficiency. The case highlights the diagnostic and therapeutic challenges faced, as well as the critical importance of early genetic screening and timely hematopoietic stem cell transplantation (HSCT). Case Presentation: A 10-year-old boy presented with easy bruising and pancytopenia. AMKL was diagnosed with the help of a bone marrow biopsy and immunophenotyping. Genetic testing showed a GATA2 mutation and monosomy 7. Two induction cycles with daunorubicin and cytarabine were administered but failed to eliminate residual disease. The patient also developed pneumonia of a fungal origin. HSCT was delayed due to liver toxicity and elevated minimal residual disease (MRD). Azacitidine and venetoclax stabilized the disease, thereby allowing for successful haploidentical HSCT. The patient achieved complete remission with full donor chimerism. Conclusions: This case emphasizes the importance of early molecular diagnostics in pediatric AMKL. Identifying GATA2 mutations and monosomy 7 early can help guide risk stratification and the timing of HSCT. Multimodal therapy, which includes the use of infection control and targeted agents, is important for improving the outcomes in high-risk patients. Full article

Background/Objectives: This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. Methods: A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing. Patients were stratified into NPM1mut and NPM1wt cohorts, and genomic differences were systematically compared between the two groups. Results: Among 4206 cases, 633 (15.1%) featured NPM1 GA, with over 99% exhibiting short variant mutations. NPM1mut AML was more common in females (53.4% vs. 41.5%) and associated with a slightly higher median age (62 vs. 60 years). GA was more frequent in NPM1mut AML compared to the NPM1wt and included DNMT3A (39.2% vs. 12.6%; p < 0.0001), PTPN11 (18.3% vs. 7.5%; p < 0.0001), FLT3 (54.5% vs. 14.7%; p < 0.0001), IDH1 (16.1% vs. 5.6%; p < 0.0001), IDH2 (19.0% vs. 9.0%; p < 0.0001), TET2 (23.4% vs. 13.5%; p < 0.0001), and WT1 (12.5% vs. 9.4%; p = 0.02). GA was more frequent in NPM1wt AML and included ASXL1 (17.1% vs. 3.6%; p 0.0001), BCOR (7.5% vs. 1.6%; p < 0.0001), KMT2A (14.7% vs. 0.2%; p < 0.0001), RUNX1 (22.5% vs. 1.9%; p 0.0001), STAG2 (6.9% vs. 1.6%; p < 0.0001) and TP53 (19.1% vs. 4.1%; p < 0.0001). Conclusions: Mutations linked to therapy targets in AML, such as (FLT3 and IDH1/2), PTPN11, and DNMT3A (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas KMT2A, TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML. Full article

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article

Background: The AML60+ score has been proposed for risk stratification in intensively treated elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic neoplasms (MDS). Its prognostic impact in patients treated with hypomethylating agents (HMA) is unknown. Methods: Patients ≥ 60 years of age diagnosed with AML or MDS/AML according to ICC2022 were eligible for this retrospective and multicenter chart review if they had received at least one cycle of HMA-based treatment. Results: A cohort of 142 patients was analyzed. During follow-up (median 8 months), 114 patients died. The molecular Prognostic Score (mPRS) was available for 121 patients, the European Leukemia Net (ELN) 2022 classification for 117 patients, and the AML60+ for 105 patients. According to AML60+, 33 patients (31.4%) were classified as very poor risk, 36 (34.3%) as poor risk, and 34 (32.4%) as intermediate risk. Two patients (1.9%) were classified as favorable. Median overall survival (OS) was 21.7 months (mo) for the combined intermediate/favorable group, 7 mo for the poor risk group and 3 mo for the very poor risk group (p < 0.0001). Cox regression analysis (reference category: very poor) showed a significantly lower risk of death for both intermediate/favorable risk patients (HR 0.17, 95% CI 0.10–0.31, p < 0.001) and poor risk patients (HR 0.47, 95% CI 0.28–0.78, p = 0.004). The concordance score was 0.67 for AML60+, 0.60 for mPRS, and 0.58 for ELN2022. Conclusions: The AML60+ may represent a useful prognostic tool for elderly AML patients treated with HMA-based therapies. In particular, it could help to identify a group with a relatively favorable prognosis that is not clearly identified by the ELN2022 or the mPRS risk classification. However, analyses of larger cohorts are necessary to confirm our findings. Full article

Background: Myelodysplastic syndromes are clonal hematopoietic disorders characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia. Accurate prognostic stratification is essential to guide treatment, with several scoring systems in clinical use: IPSS, IPSS-R, and WPSS. Objective: We aimed to evaluate the prognostic accuracy of IPSS, IPSS-R, and WPSS in a real-world Romanian MDS cohort by comparing risk classifications with observed overall survival and progression-free survival. Methods: We conducted a retrospective analysis of 117 patients diagnosed with MDS treated in our clinic between 2018 and 2022. All patients had confirmed diagnoses based on bone marrow biopsy and cytogenetic testing. Data were used to assign risk categories based on IPSS, IPSS-R, and WPSS. Survival outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Results: The median age of the cohort was 70 years; gender distribution was balanced. Transfusion dependence was present in 73.5%, and 49.6% had cytogenetic abnormalities. Overall, low-risk classification was assigned in 58.1% (IPSS), 38.5% (IPSS-R), and 38.5% (WPSS) of patients. Median OS was 20 months, and median PFS was 35 months. Although no statistically significant overall survival differences were observed across scoring systems, IPSS-R demonstrated a trend toward stronger prognostic discrimination in multivariable analysis. Reclassification of patients initially categorized as IPSS intermediate-1 revealed a significant survival impact: patients reclassified as lower-risk by IPSS-R and WPSS had a median OS of 67.5 months versus 15 months for those reclassified as higher-risk (IPSS-R: HR = 0.24; p = 0.0017; WPSS: HR = 0.26; p = 0.0031). Similarly, leukemic transformation occurred in 13.6% of reclassified lower-risk patients vs. 52.2% in higher-risk patients (IPSS-R: HR = 0.13; p = 0.0021; WPSS: HR = 0.12; p = 0.002), with a median PFS of 21 months in the higher-risk group. In multivariable Cox regression analysis, IPSS-R stratification remained a strong independent predictor for both OS (HR = 3.22; p = 0.000003) and PFS (HR = 4.77; p < 0.00001), while azacitidine treatment was associated with significantly improved survival (OS: HR = 0.43; p = 0.00002) and reduced risk of progression (PFS: HR = 0.36; p = 0.013). Full article

Sweet syndrome (SS) is a rare neutrophilic dermatosis often associated with hematologic malignancies, particularly myelodysplastic syndromes (MDSs). We report a case of SS-like dermatosis in a patient with MDS who subsequently developed peripheral T-cell non-Hodgkin lymphoma (NHL). We review the literature on Sweet syndrome to contextualize this atypical presentation Methods: We present a case report of a 77-year-old male with leukopenia and known MDS, admitted for a persistent, infiltrated erythematous eruption. The patient underwent repeated dermatologic assessments, and serial skin and bone marrow biopsies with histopathologic and immunohistochemical analysis. A literature review was also conducted, focusing on SS in association with hematologic malignancies, including T-cell NHL. Results: Initial skin biopsies were inconclusive, and SS was diagnosed clinically based on lesion morphology and a prompt response to corticosteroids, despite the absence of definitive neutrophilic infiltrates. During follow-up, the patient’s condition progressed with worsening cytopenias and recurrent febrile episodes. Repeat biopsies eventually confirmed the diagnosis of peripheral T-cell NHL with secondary hemophagocytic lymphohistiocytosis (HLH). Conclusions: This case illustrates the diagnostic uncertainty of SS-like eruptions in hematologic patients when histopathological findings are atypical or absent. Corticosteroid responsiveness may guide early diagnosis. Full article

Background: Coronavirus disease 2019 (COVID-19) has led to the expansion of the spectrum of invasive fungal infections beyond traditional immunocompromised populations. Although COVID-19-associated pulmonary aspergillosis is increasingly being recognised, COVID-19-associated mucormycosis remains rare, particularly in non-endemic regions. Concurrent COVID-19-associated invasive tracheobronchial aspergillosis and pulmonary mucormycosis with histopathological confirmation is exceedingly uncommon and poses significant diagnostic and therapeutic challenges. Case presentation: We report the case of a 57-year-old female with myelodysplastic syndrome who underwent haploidentical allogeneic haematopoietic stem cell transplantation. During post-transplant recovery, she developed COVID-19 pneumonia, complicated by respiratory deterioration and radiological findings, including a reverse halo sign. Bronchoscopy revealed multiple whitish plaques in the right main bronchus. Despite negative serum and bronchoalveolar lavage fluid galactomannan assay results, cytopathological examination revealed septate hyphae and Aspergillus fumigatus was subsequently identified. Given the patient’s risk factors and clinical features, liposomal amphotericin B therapy was initiated. Subsequent surgical resection and histopathological analysis confirmed the presence of Rhizopus microsporus. Following antifungal therapy and surgical intervention, the patient recovered and was discharged in stable condition. Conclusions: This case highlights the critical need for heightened clinical suspicion of combined invasive fungal infections in severely immunocompromised patients with COVID-19, even in non-endemic regions for mucormycosis. Early tissue-based diagnostic interventions and prompt initiation of optimal antifungal therapy are essential for obtaining ideal outcomes when co-infection is suspected. Full article

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and examine translation into precision therapeutic approaches. Methods: We reviewed breakthrough discoveries from the past three years, analyzing single-cell multi-omics technologies, epitranscriptomics, stem cell architecture analysis, and precision medicine approaches. We examined cell-type-specific splicing aberrations, distinct stem cell architectures, epitranscriptomic modifications, and microenvironmental alterations in MDS pathogenesis. Results: Four interconnected mechanisms drive MDS: genetic alterations (splicing factor mutations), aberrant stem cell architecture (CMP-pattern vs. GMP-pattern), epitranscriptomic dysregulation involving pseudouridine-modified tRNA-derived fragments, and microenvironmental changes. Splicing aberrations show cell-type specificity, with SF3B1 mutations preferentially affecting erythroid lineages. Stem cell architectures predict therapeutic responses, with CMP-pattern MDS achieving superior venetoclax response rates (>70%) versus GMP-pattern MDS (<30%). Epitranscriptomic alterations provide independent prognostic information, while microenvironmental changes mediate treatment resistance. Conclusions: These advances represent a paradigm shift toward personalized MDS medicine, moving from single-biomarker to comprehensive molecular profiling guiding multi-target strategies. While challenges remain in standardizing molecular profiling and developing clinical decision algorithms, this systems-level understanding provides a foundation for precision oncology implementation and overcoming current therapeutic limitations. Full article

Continuous development of molecular and immunophenotypic techniques enables more precise diagnoses and more accurate assessment of prognosis in myelodysplastic syndromes (MDS). However, the relationship between genetic alterations and immunophenotype remains very poorly understood. The analysis included 30 patients diagnosed at a tertiary center who were eligible for azacitidine treatment. Next-generation sequencing (NGS) was performed at the start of the study to assess the mutation status of 40 genes associated with MDS pathogenesis. In addition, multiparametric flow cytometry (MFC) was performed to assess the ELN score (Ogata score) and, additionally, to detect an abnormal CD11b/HLA-DR and CD11b/CD13 expression pattern. In the studied patient population, higher ELN score results were found in patients with mutations in epigenetic modifiers and pathogenic mutations of the tumor suppressor genes. Signal pathway mutations were associated with lower platelet counts at diagnosis. The results of this study indicate a correlation between molecular abnormalities and deviations in cell immunophenotype. Investigating this correlation may, in the future, allow the development of new scales that allow a more sensitive and specific diagnosis of MDS and a more precise prediction of its course. Full article

ANKRD26-related thrombocytopenia (ANKRD26-RT) is characterized by lifelong mild to moderate thrombocytopenia. Patients suffer from an increased susceptibility to acute or chronic myeloid leukemia, myelodysplastic syndrome, or chronic lymphocytic leukemia. We described here a patient with inherited thrombocytopenia initially misdiagnosed as immune thrombocytopenic purpura. A chromosomal deletion involving the ANKRD26 gene was identified. Gene and protein expression analyses suggest an alternative pathogenic mechanism of altered megakaryopoiesis: the synthesis of a chimeric protein with aberrant expression due to the unregulated action of a promoter from a gene located upstream of ANKRD26. This study highlights the importance of advanced genetic testing and functional analysis of patients’ primary cells in the case of the detection of previously unrecognized structural variants in order to understand pathogenic mechanisms. These investigations provided a definitive diagnosis for the patient and facilitated the development of a tailored clinical management strategy, especially concerning the potential for myeloid transformation. Full article

Myelodysplastic syndromes/neoplasms (MDS) represent a biologically and clinically diverse group of myeloid malignancies marked by cytopenias, morphological dysplasia, and an inherent risk of progression to acute myeloid leukemia. Over the past two decades, the field has made significant advances in characterizing the molecular landscape of MDS, leading to refined classification systems to reflect the underlying genetic and biological diversity. In 2025, the treatment of MDS is increasingly individualized, guided by integrated clinical, cytogenetic, and molecular risk stratification tools. For lower-risk MDS, the treatment paradigm has evolved beyond erythropoiesis-stimulating agents (ESAs) with the introduction of novel effective agents such as luspatercept and imetelstat, as well as shortened schedules of hypomethylating agents (HMAs). For higher-risk disease, monotherapy with HMAs continue to be the standard of care as combination therapies of HMAs with novel agents have, to date, failed to redefine treatment paradigms. The recognition of precursor states like clonal hematopoiesis of indeterminate potential (CHIP) and the increasing use of molecular monitoring will hopefully enable earlier intervention/prevention strategies. This review provides a comprehensive overview of the current treatment approach for MDS, highlighting new classifications, prognostic tools, evolving therapeutic options, and ongoing challenges. We discuss evidence-based recommendations, treatment sequencing, and emerging clinical trials, with a focus on translating biological insights into improved outcomes for patients with MDS. Full article

Somatic and epigenetic alterations contribute to myeloid leukemogenesis and play an important role in risk stratification and the optimization of treatment for myeloid malignancies. The significance of rare genetic alterations, such B-cell lymphoma-6 corepressor (BCOR) and B-cell lymphoma-6 corepressor-like protein 1 (BCORL1) mutations, in pediatric acute myeloid leukemias (AML) and myelodysplastic syndrome (MDS) is unknown. We present a case series of pediatric and adolescent patients, with de novo AML, harboring BCOR/BCORL1 mutations. Studies involving larger cohorts of patients are needed to further elucidate the role of BCOR/BCORL1 mutations in pediatric AML and MDS. Full article