Search Results (139)

Background: Posaconazole is an antifungal medication used to treat invasive fungal infections (IFI) in pediatric onco-hematological patients. Its approval for pediatric use was recent, and limitations still apply. Despite limited data, the safety and efficacy profile appear generally favorable in children. This study describes how posaconazole is used across centers affiliated with the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP). Methods: A national survey was conducted among physicians within the AIEOP network to evaluate current use of posaconazole in pediatric cancer patients, including those undergoing hematopoietic stem cell transplantation (HSCT). A 25-item web questionnaire was developed and distributed in June 2024. Data analysis involved descriptive statistics. Results: Twenty-one of thirty-one centers (68%) responded, reporting availability of various posaconazole formulations: oral suspension (76%), delayed-release tablets (95%), and intravenous solution (14%). Posaconazole was primarily used for prophylaxis in patients with acute lymphoblastic leukemia (ALL, 38%), acute myeloid leukemia (AML, 38%), and aplastic anemia (19%). It was also used as secondary prophylaxis against previous possible or probable IFI or as salvage therapy for probable or confirmed aspergillosis or mucormycosis, often combined with other treatments. Drug plasma level monitoring was common but varied in scheduling across centers. Most centers (74%) discontinued posaconazole if adverse events suspected drug–drug interactions, such as with vincristine. Conclusions: Posaconazole is widely used in AIEOP centers, though application varies significantly. This variability emphasizes the need for prospective studies to better define indications, dosing, and monitoring protocols for pediatric use of this antifungal. Full article

Background: Acute myeloid leukemia (AML) is an aggressive and biologically diverse hematologic cancer that disproportionately affects older individuals. Despite advances in molecular profiling and therapy, long-term outcomes remain unsatisfactory. This nationwide registry was established to provide real-world insights into clinical characteristics, treatment strategies, and survival among adult AML patients in Turkey. Methods: The Turkish AML Registry Project (ClinicalTrials.gov Identifier: NCT05979675) combines retrospective and prospective data from 23 tertiary hematology centers. Adult patients diagnosed between January 2008 and July 2023 were included. Baseline demographics, European LeukemiaNet (ELN) 2017 risk groups, Eastern Cooperative Oncology Group (ECOG) performance status, treatment intensity, and targeted therapy use were analyzed. Response and survival outcomes were assessed using Kaplan–Meier methods. Results: The interim dataset included 891 patients (median age 58 years, 45.5% ≥60). Intensive chemotherapy, most commonly 7 + 3, was applied in 74.1%, while 25.9% received lower-intensity regimens. Targeted agents, mainly venetoclax, were incorporated more frequently into low-intensity therapies (19.1% vs. 3.4%, p < 0.001). Complete remission occurred in 70.2% after intensive and 35.9% after low-intensity therapy, improving to 51.4% with targeted agents. Median overall survival (OS) was 27.2 months, with 1-year OS rates of 54.1%, 28.9%, and 17.6% for favorable, intermediate, and adverse ELN groups (p < 0.001). ECOG 0–1 predicted superior survival (1-year OS 70.3% vs. 47.0%). Conclusions: Nationwide real-world evidence underscores the prognostic relevance of ELN risk and functional status in AML. While intensive chemotherapy remains central, combining targeted agents with low-intensity regimens improves outcomes in less fit patients and supports personalized treatment approaches. Full article

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by chromosomal translocation forming the fusion protein that blocks the differentiation of myeloid progenitors and increases the self-renewal of leukemia cells. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved outcomes in APL, making it a leading example of successful treatment through differentiation of cancer cells. However, life-threatening side effects and treatment resistance may develop; therefore, modulation of the safety and efficacy of these drugs may contribute to further improving treatment results. Recently, zinc, involved in the structure and function of transcription factors, has received special attention for its potential role in the development and treatment response of cancer. Zinc homeostasis is disrupted in APL, with intracellular accumulation stabilizing oncogenic proteins. Zinc depletion promotes degradation of PML–RARA and induces apoptosis, while supplementation enhances genotoxic stress in leukemic cells but protects normal hematopoiesis. Zinc also regulates key transcription factors involved in differentiation and proliferation, including RUNX2, KLF4, GFI1, and CREB. In this review, we examine how zinc may impact zinc-finger (ZnF) and non-ZnF transcription factors and differentiation therapy in APL, thereby identifying potential strategies to enhance treatment efficacy and minimize side effects. Full article

Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are urgently needed. γδ T cells are a promising candidate owing to their good safety profile and cytotoxic effects in various types of cancers but are mostly unstudied in AML. Methods: Here we used flow cytometry to profile the subtype and memory phenotype of peripheral blood γδ T cells in AML patients and investigate the feasibility of using donor-derived Vγ9Vδ2 T cells to treat AML as both a single agent and in combination with venetoclax. Additionally, we used bioluminescence imaging to examine the effect of donor-derived Vγ9Vδ2 T cells on AML xenograft models alone and in combination with venetoclax. Results: We observed that Vδ2 T cells were less abundant and the TEMRA (terminally differentiated effector memory) phenotype was more prevalent as compared with that of healthy donors, suggesting that replenishing patients with Vδ2 T cells may be an effective treatment option. We found that donor-derived Vγ9Vδ2 T cells that Vγ9Vδ2 T cells efficiently induced apoptosis in AML cells from eight cell lines and three primary cultures in an effector-to-target cell ratio-dependent manner. Moreover, Vγ9Vδ2 T cells showed potent cytotoxicity against the venetoclax-resistant OCI-AML3 cell line and remained potent in the presence of venetoclax. Treatment with Vγ9Vδ2 T cells significantly extended survival in two AML xenograft models established with the aggressive Molm-13 and the venetoclax-resistant OCI-AML3 cell lines. An additive effect of venetoclax and Vγ9Vδ2 T cells was observed in the latter model. Conclusions: Overall, these findings suggest Vγ9Vδ2 T cells as a promising “off-the-shelf” immunotherapy approach for AML patients, especially for patients with venetoclax-resistant disease. Full article

Acute myeloid leukemia (AML) is a highly heterogeneous disease, with significantly higher incidence and fatality rates in the elderly. Even with recent decades of research progress in AML, the exact etiology of this deadly disease is still not fully understood, with recent advancements in sequencing technologies highlighting the role of a growing number of non-coding RNAs (ncRNAs) that are intimately associated with AML leukemogenesis. These ncRNAs have been found to have a significant role in leukemia-related cellular processes such as cell division, proliferation, and death. A few of these non-coding RNAs exhibit potential as prognostic biomarkers. The three main groups of ncRNAs that contribute unique activities, especially in cancer, are microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Their existence or altered expression levels frequently offer vital information on the diagnosis, course of treatment, and follow-up of cancer patients. The identification of ncRNAs has opened up new avenues for the diagnosis, prognosis, and therapy of acute myeloid leukemia. In order to provide a clear understanding of the significant influence that lncRNAs have on prognostic predictions and diagnostic accuracy in AML, this review aims to provide a comprehensive and insightful understanding of how these molecules actively participate in the complex landscape of the disease. Full article

Chimeric antigen receptor (CAR) T-cell therapy directed to CD19 and B-cell maturation antigen has revolutionized treatment of B-cell leukemia and lymphoma, and multiple myeloma. However, identifying suitable targets for acute myeloid leukemia (AML) remains challenging due to concurrent expression of potential target antigens on normal hematopoietic stem cells or tissues. As the stress-induced B7H6 molecule is rarely found on normal tissues but expressed on many cancers including AML and melanoma, the NKp30-ligand B7H6 emerges as a promising target for NKp30-based CAR T therapy for these tumors. In this study, we report a comprehensive B7H6 expression analysis on primary AML and melanoma as well as on different tumor cell-lines examined by RT-qPCR and flow cytometry, and efficient anti-tumor reactivity of NKp30-CAR T cells to AML and melanoma. To overcome limitations of autologous CAR T-cell fitness-dependent efficacy and patient-tailored production, we generated CRISPR/Cas9-mediated TCR-knockout (TCR^KO) NKp30-CAR T cells as an off-the-shelf approach for CAR T therapy. Functional studies comparing NKp30-CD28 CAR or NKp30-CD137 CAR TCR⁺ and TCR^KO T lymphocytes revealed superior anti-tumoral immunity of NKp30-CD28 CAR TCR^KO T cells to AML and melanoma cell lines in vitro, and effective control of tumor burden in an NSG melanoma-xenograft mouse model. In conclusion, these findings highlight the therapeutic potential of NKp30 CAR TCR^KO T cells for adoptive T-cell therapy to B7H6-expressing cancers, including melanoma and AML. Full article

Autologous stem cell transplantation (ASCT) after high-dose chemo-therapy (HDCT) is an option of consolidation therapy in patients with AML, lymphoma, or myeloma. Clonal hematopoiesis (CH) is a premalignant state, associated with an increased risk of hematological cancer. The incidence of CH in patients with AML, myeloma, and lymphoma and its effect on the outcome after HDCT/ASCT remain poorly studied. Here we screened 142 patients treated with HDCT/ASCT between 2002 and 2021 at Bern University Hospital for somatic gene mutations in ASXL1, DNMT3A, JAK2, TET2, and TP53. CH-associated somatic gene mutations were detected in 14/31 AML patients (45%), 13/64 myeloma patients (20%), and 9/47 lymphoma patients (19%). Clinical characteristics, treatment modalities, and responses to treatment were similar in patients with and without CH. Patients with CH-associated gene mutations had higher relapse rates and reduced progression free survival, most evident in lymphoma patients (p = 0.007). Overall survival tended to be shorter in lymphoma patients with CH-associated mutations (p = 0.078), whereas this was not observed in AML and myeloma patients. Survival in lymphoma patients with CH was inferior, which may have an impact on post-transplant surveillance strategies in the future. In contrast, survival outcomes were not associated significantly with CH in AML and myeloma patients in our study. Longer follow-ups and larger cohorts will be needed to validate our observations. Full article

Background: Programmed cell death-related genes (PCDRGs) have been reported to play an important role in diagnosis, treatment and immunity regarding cancer, but their prognostic value and therapeutic potential in acute myeloid leukemia (AML) patients still need to be fully explored. Methods: Cox regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) analysis were used to identify PCDRGs significantly associated with the prognosis of AML patients. Furthermore, a prognostic risk model for AML patients was constructed based on the selected PCDRGs, and their immune microenvironment and biological pathways were analyzed. Cell experiments ultimately confirmed the potential role of PCDRGs in AML. Results: The results yielded four PCDRGs that were used to develop a prognostic risk model, and the prognostic significance of this model was confirmed using an independent external AML patient cohort. This prognostic risk model provides an independent prognostic risk factor for AML patients. This prognostic feature is related to immune cell infiltration in AML patients. The inhibition of solute carrier family 39 member 14 (SLC39A14) expression enhanced apoptosis and inhibited cell cycle progression in AML cells. Conclusions: This study integrates bioinformatics analysis and cellular experiments to reveal potential gene therapy targets and prognostic gene markers in AML. Full article

Background/Objectives: Cancer research aims to understand the cellular and molecular mechanisms involved, in order to identify new therapeutic targets and provide patients with more effective therapies that generate fewer side undesirable and toxic effects. Previous studies have demonstrated the role of small nucleolar RNAs (snoRNAs) in many physiological and pathological cellular processes, including cancers. SnoRNAs are a group of non-coding RNAs involved in different post-transcriptional modifications of ribosomal RNAs. Recently, we identified a new snoRNA (jouvence), first in Drosophila, and thereafter, by homology, in humans. Methods: Here, we characterize the effect of the knockdown of jouvence by a sh-lentivirus on human primary patient-derived glioblastoma cells. Results: The sh-lentivirus anti-jouvence induces a significant decrease in cell proliferation and leads to cell death. EdU staining confirmed this decrease, while TUNEL also showed the presence of apoptotic cells. An RNA-Seq analysis revealed a decrease, in particular, in the level of BAALC, a gene known to potentiate the oncogenic ERK pathway and deregulating p21, leading to cell cycle blockage. Conclusions: Altogether, these results allow the hypothesis that the knockdown of jouvence could potentially be used as a new anti-cancer treatment (sno-Therapy), especially against glioblastoma and also, potentially, against acute myeloid leukemia (AML) due to the BAALC deregulation. Full article

The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely 5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that 5-3 potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of 5-3 depends highly on FLT3-ITD expression. Mechanically, 5-3 significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound 5-3 is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that 5-3 might be a drug candidate for the treatment of FLT3-ITD-positive AML. Full article

Background/Objectives: Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models—AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). Methods: After PDX model establishment, mice were assigned to treatment groups hulgG4 (VC, vehicle control for Magro), Magro, Ara-C + VC, Aza + VC, Ara-C + Magro, and Aza + Magro, and then followed for survival. Mice that met humane euthanasia endpoints and at the culmination of experimental timelines had tissues harvested to measure disease burden. Results: Magro alone significantly improved survival in AML006 (p < 0.0001) and AML013 (p = 0.003) and decreased bone marrow (BM) disease burden in AML006 (p = 0.009) and AML013 (p = 0.002). Ara-C + Magro therapy led to significantly improved survival in all three models and significantly decreased BM disease burden in AML006 (p < 0.0001) and AML013 (p = 0.048). Aza + Magro therapy led to significantly improved survival in AML013 (p = 0.047) and AML010 (p = 0.017) and significantly lower BM disease burden in AML010 (p = 0.001). Conclusions: Interestingly, the two models that demonstrated improvement in survival with Magro harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is being evaluated for use in other malignancies, future studies may focus on investigating the importance of biomarker-based patient selection. Full article

Background: The precise diagnosis and classification of acute myeloid leukemia (AML) has important implications for clinical management and medical research. Methods: We investigated the expression of protein-coding genes in blood samples from AML patients and controls using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Subsequently, we applied the feature selection method of the least absolute shrinkage and selection operator (LASSO) to select the optimal gene subset for classifying AML patients and controls as well as between a particular FAB subtype and other subtypes of AML. Results: Using LASSO method, we identified a subset of 101 genes that could effectively distinguish between AML patients and control individuals; these genes included 70 up-regulated and 31 down-regulated genes in AML. Functional annotation and pathway analysis indicated the involvement of these genes in RNA-related pathways, which was also consistent with the epigenetic changes observed in AML. Results from survival analysis revealed that several genes are correlated with the overall survival in AML patients. Additionally, LASSO-based gene subset analysis successfully revealed differences between certain AML subtypes, providing valuable insights into subtype-specific molecular mechanisms and differentiation therapy. Conclusions: This study demonstrated the application of machine learning in genomic data analysis for identifying gene subsets relevant to AML diagnosis and classification, which could aid in improving the understanding of the molecular landscape of AML. The identification of survival-related genes and subtype-specific markers may lead to the identification of novel targets for personalized medicine in the treatment of AML. Full article

Acute myeloid leukemia (AML) corresponds to a heterogeneous group of clonal hematopoietic diseases, which are characterized by uncontrolled proliferation of malignant transformed myeloid precursors and their inability to differentiate into mature blood cells. The prognosis of AML depends on many variables, including the genetic features of the disease. Treatment outcomes, despite the introduction of new targeted therapies, are still unsatisfactory. Recently, there have been an increasing number of reports on enzymatic proteins of the sirtuin family and their potential importance in cancer in general. Sirtuins are a group of 7 (SIRT1-7) NAD+-dependent histone deacetylases with pleiotropic effects on metabolism, aging processes, and cell survival. They are not only responsible for post-translational modification of histones but also play various biochemical functions and interact with other proteins regulating cell survival, such as p53. Thus, their role in key mechanisms of tumorigenesis makes them a worthwhile topic in AML. Different sirtuins have been shown to act oppositely depending on the biological context, the mechanism of which requires further exploration. This review provides a comprehensive description of the significance and role of sirtuins in AML in light of the current state of knowledge. It focuses in particular on molecular mechanisms regulated by sirtuins and signaling pathways involved in leukemogenesis, as well as clinical aspects and potential therapeutic targets in AML. Full article

Background: Acute myeloid leukemia (AML) is an aggressive cancer with variable treatment responses. While clinical factors such as age and genetic mutations contribute to prognosis, recent studies suggest that CT attenuation scores may also predict treatment outcomes. This study aims to develop a nomogram combining clinical and CT-based factors to predict treatment response and guide personalized therapy for AML patients. Methods: This retrospective study included 74 newly diagnosed AML patients who underwent unenhanced abdominal CT scans within one week before receiving their first induction chemotherapy. Clinical biomarkers of tumor burden were also collected. Patients were classified into two groups based on treatment response: complete remission (CR; n = 24) and non-complete remission (NCR; n = 50). Multivariable logistic regression was used to identify independent predictors of treatment response. Predictive performance was evaluated using receiver operating characteristic (ROC) curves, and model consistency was assessed through calibration and decision curve analysis (DCA). Results: Significant differences in hemoglobin (Hb), platelets (Plt), and CT attenuation scores were observed between the CR and NCR groups (all p < 0.05). Multivariable logistic regression identified Hb, Plt, and CT attenuation scores as independent predictors of treatment response. A nomogram incorporating these factors demonstrated excellent predictive performance, with an area under the curve (AUC) of 0.912 (95% CI: 0.842–0.983), accuracy of 0.865 (95% CI: 0.765–0.933), sensitivity of 0.880 (95% CI: 0.790–0.970), and specificity of 0.833 (95% CI: 0.684–0.982). The CR nomogram displayed significant clinical value and excellent goodness of fit. Conclusions: The nomogram, which incorporates Hb, Plt, and CT attenuation scores, provides valuable insights into predicting treatment response in AML patients. This model offers strong discriminatory ability and could enhance personalized treatment planning and prognosis prediction for AML. Full article

Thrombosis is one of the most frequent complications of cancer, with a potential impact on morbidity and mortality, particularly those with acute myeloid leukemia (AML). Therefore, effective thrombosis prevention is a crucial aspect of cancer management. However, preventive measures against thrombosis may carry inherent risks and complications. Consequently, the application of thrombosis prevention should be limited to patients with a reasonable risk of developing thrombosis. This thesis explores the potential of data science (DS) methods for predicting venous thrombosis in patients with acute myeloid leukemia. In order to ascertain which patients are at risk, statistical and machine-learning (ML) algorithms were employed to predict which patients with leukemia will develop thrombosis. Multilayer Perceptron (MLP) was found to be the best fit among the models evaluated, achieving the C statistic of 0.749. We examined which attributes are significant and what role they play in prediction and found six significant parameters: sex of the patient, prior history of thrombotic event, type of therapy, international normalized ratio (INR), Eastern Cooperative Oncology Group (ECOG) performance status, and Hematopoietic Cell Transplantation-specific Comorbidity. These findings suggest that subtle DS techniques can improve the prediction of Thrombosis in AML patients, thereby aiding in individual treatment planning. Full article