Search Results (344)

Endocrine therapy is the mainstay for estrogen receptor (ER) α-positive breast cancer (BC), yet many patients display acquired resistance. We then screened natural compounds using human ERα-positive BC cells and identified perillyl alcohol (POH), a monoterpene from perilla, that reduces ERα protein levels. Chemoproteome analysis using POH-immobilized nanomagnetic beads revealed adenine nucleotide translocase 2 (ANT2), a mitochondrial inner membrane protein, as a direct target of POH. Molecular dynamics (MD) simulations predicted POH binding to the central pore of ANT2, which functions in ATP transport. ANT2 depletion reduced ERα levels, and public datasets indicate that high ANT2 expression correlates with poor prognosis in ERα-positive BC. POH also inhibited the growth of Tamoxifen- and Fulvestrant-resistant BC cells. RNA sequencing showed that fatty acid elongation-related genes were upregulated in Fulvestrant-resistant cells but downregulated by ANT2 depletion. Both ANT2 depletion and POH treatment led to the accumulation of intracellular lipid droplets in Fulvestrant-resistant cells, consistent with impaired fatty acid elongation. Finally, in silico screening using MD simulations identified venetoclax and nystatin as potential ANT2 pore binders. Both compounds reduced ERα levels in ERα-positive BC cells and increased lipid droplet formation in Fulvestrant-resistant cells. These findings highlight ANT2 as a druggable target against endocrine-resistant BC. Full article

Background: Acute myeloid leukemia (AML) with monocytic differentiation poses significant clinical challenges, including high relapse rates and chemotherapy resistance. Current morphological assessment is limited by inter-observer variability, low sensitivity, and inefficiency, especially for detecting low-level residual disease. This creates an urgent need for automated, objective tools to improve diagnostic consistency and monitoring. Artificial intelligence, particularly deep learning, offers potential for extracting high-dimensional cytomorphological features to address these gaps. Methods: A retrospective cohort of 184 bone marrow smear slides from patients with monocytic leukemia was used. The core biomarker was the immature monocyte percentage (IMMP), defined as monoblasts plus promonocytes among nucleated cells, with a 2.0% clinical cutoff. An EfficientNet-based convolutional neural network was developed via transfer learning and trained to classify four cell types: monoblasts, promonocytes, monocytes, and other cells. Results: The model achieved robust cell-level classification, with F1 scores of 0.82 for monoblasts and 0.34 for promonocytes. At the slide level, using an optimized IMMP threshold of 0.045, it accurately assessed persistent leukemic cell burden with 78.9% Accuracy, 81.1% Recall, and 76.9% Specificity. Model-predicted IMMP values showed strong correlation with expert-derived values (Pearson r = 0.827), demonstrating reliable quantitative agreement. Conclusions: This deep learning model provides an automated, objective tool for quantifying immature monocytes, addressing key limitations in morphological assessment of monocytic AML. The IMMP metric shows promise for monitoring treatment response, predicting relapse, and potentially identifying patients at risk of venetoclax-based therapy resistance. While promising, prospective multicenter validation is needed to translate these findings into routine clinical practice. Full article

Backgroundand Objectives: Targeted therapies are increasingly used in the management of chronic lymphocytic leukemia (CLL); however, real-world data from routine clinical practice remain limited. Materials and Methods: We performed a retrospective analysis of 47 patients with CLL who received at least one targeted therapy at a tertiary university hospital. Clinical characteristics, treatment responses, and adverse events were assessed. A total of 58 treatment events were included. Results: Obinutuzumab, ibrutinib, and venetoclax were administered in 34.5%, 46.5%, and 19.0% of treatment events, respectively. Numerically higher response rates were observed in treatment events involving obinutuzumab compared with ibrutinib and venetoclax (92.9% vs. 54.5% and 55.6%, respectively); however, treatment allocation was not randomized and these findings should be interpreted descriptively. Median overall survival from initiation of the first targeted therapy was 30.9 months. Adverse events occurred in more than 80% of treatment events. Neutropenia was more frequent with obinutuzumab and venetoclax, whereas bleeding events were more common with ibrutinib. Conclusions: In this real-world cohort, targeted therapies showed response patterns and safety findings consistent with routine clinical practice. Obinutuzumab was more frequently prescribed in older and more comorbid patients, reflecting treatment patterns rather than comparative superiority. These findings should be considered descriptive and hypothesis-generating, given the retrospective and single-center design. Full article

Background/Objectives: In recent years there has been a consistent development of clinical studies surrounding the incorporation of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) into the treatment of acute myeloid leukemia (AML) Methods: A search of the literature showed a tremendous development of experimental and clinical studies evaluating the impact of VEN-based regimens in the treatment of AML patients. This review comprehensively analyzes the available scientific evidence—including prospective clinical trials, retrospective cohorts, and real-world studies—to summarize current knowledge on the efficacy and safety of venetoclax-based regimens in AML patients. Results: Recent studies have evaluated VEN-based regimens in newly diagnosed (ND) and refractory/relapsed (R/R) AML patients, showing the efficacy of these treatments. VEN with hypomethylating agents (HMAs) became the standard-of-care for elderly/unfit AML patients. Recent studies strongly support the effectiveness of VEN-based regimens in frontline treatment of adult AML patients eligible for intensive treatments. VEN-based therapies were also used in combination with targeted therapies, thus generating triplet therapeutic regimens that are under evaluation for the treatment of some AML subtypes. However, the response to VEN+HMAs is highly variable and in part depends on tumor genetics; some patients are resistant or relapse following VEN-based treatments and future studies will be required to develop therapeutic strategies able to circumvent resistance and to identify patients at high risk of relapse. Prospective randomized trials are required to establish the real efficacy of VEN in various clinical settings and to refine maintenance and discontinuation strategies, aiming to improve long-term outcomes and to make more safe treatments based on VEN. Full article

Background: The clinical efficacy of the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is significantly undermined by the frequent emergence of drug resistance, which precipitates disease progression and poor patient outcomes. However, the molecular landscape of this resistance remains insufficiently understood. Methods: To address this, we developed venetoclax-resistant AML cell models and utilized transcriptomic profiling integrated with comprehensive in vitro and in vivo functional assays. Results: Resistant cells demonstrated sustained proliferation even under the suppression of BCL-2, MCL-1, and key intrinsic apoptotic markers, including cleaved PARP and caspase-9, indicating a bypass mechanism independent of classical BCL-2 signaling. Compared to their sensitive counterparts, resistant Kasumi-1 (VENK) and MV4-11 (VENM) cells exhibit aggressive growth phenotypes in vitro and in vivo, characterized by larger, more numerous spheroids and colonies, alongside heightened tumorigenicity in murine models. Transcriptomic profiling and KEGG analysis identified the neuroactive ligand–receptor interaction (NLRI) pathway as a significant signaling node shared between these resistant lines. While multiple NLRI-associated genes were altered, CHRNB4 was consistently and significantly downregulated in both VENK and VENM cells and tumors. Re-expression of CHRNB4 in resistant cells, a primary gain-of-function approach, significantly impaired colony formation, and tumor growth in vivo. Clinically, CHRNB4 downregulation correlates with shortened overall survival and diminished response to venetoclax. Conclusions: Our findings implicate the NLRI pathway in venetoclax resistance and identify CHRNB4 as a robust prognostic indicator and a promising therapeutic target for developing next-generation AML strategies. Full article

Background/Objectives: Minimal residual disease (MRD) negativity is associated with improved outcomes in acute myeloid leukemia (AML) patients. In this retrospective observational real-life case series study, we investigated the efficacy and safety of venetoclax dose adjustment in unfit AML patients and the role of WT1 expression levels as a surrogate marker of MRD monitoring. Methods: A total of 24 consecutive unfit AML patients treated with azacytidine and venetoclax were enrolled in this study, and MRD monitoring was performed by flow cytometry as per international guidelines and by WT1 expression levels assessed by RT-qPCR. Dose adjustment of venetoclax was decided based on MRD status and the onset of grade > 2 neutropenia. Results: The overall response rate was 87.5%, and 16 patients achieved a response already at the first re-evaluation (66.7%). No statistically significant differences were observed between patients who received the standard dose and those with venetoclax dose adjustment in terms of overall survival (19.6 months vs. 30.1 months, respectively; p = 0.9428) and progression-free survival (not reached vs. 22.1 months, respectively; p = 0.3865), although a numerical trend toward lower relapse rates was observed in subjects with late (33.3%) or early and late dose reduction (37.5%) compared to those who had dose adjustment only at the first re-evaluation (75%) (p = 0.3014). The toxicity rate was 33.3% in patients who had early and late dose adjustments, which was lower than that observed with early adjustment (58.3%) and than that reported in the VIALE-A study (84%). Conclusions: Reduced-dose venetoclax regimens (from 28 to 21 days per cycle) in unfit AML patients do not affect response rates or survival and are associated with comparable rates of neutropenia and infectious events, supporting flexible dosing strategies based on patient response and side effects. In addition, WT1 expression could serve as a reliable marker for MRD monitoring. Full article

Introduction: PMBCL is an aggressive type of lymphoma characterized by high heterogeneity in clinical, molecular, and genetic features. In PMBCL, disturbances in the NFkB pathway and deregulation of BCL-2 and mTOR family proteins are observed, which may contribute to impaired apoptosis. Therefore, many strategies have been established to target the functioning of these pathways. Early clinical trials of mTOR, NFkB and Bcl-2 inhibitors suggest their activity in many hematological cancers, but their activity as monotherapy agents may still be insufficient; therefore, combinations of these compounds with other molecules acting on those active in a given cancer subtype are being sought. Materials and Methods: In vitro studies were conducted on a single PMBCL cell line, Karpas 1106P. We administered three novel drugs: AZD2014 (vistusertib), an inhibitor of the serine-threonine kinase mTOR; IMD-0354, an NFκB inhibitor; and ABT-199 (venetoclax), a highly selective inhibitor for BCL-2. Drugs were administered alone, in pairs and in combination of all three agents. Results: Based on the results of our own research, for the Karpas cell line individually, ABT-199 had the strongest pro-apoptotic effect on cancer cells, while in pairs the most potent induction of apoptosis occurred following treatment with AZD2014+ABT-199. The combination of three drugs did not have a stronger effect than either a single drug used alone or any two-drug combination. Conclusions: These results provide preliminary in vitro evidence that targeting the BCL-2 and mTOR pathways may enhance pro-apoptotic activity in a PMBCL cell model; however, further validation in additional cell lines and in vivo models is needed before translational implications can be considered. Full article

For decades, induction treatment of acute myeloid leukemia consisted of intensive chemotherapy for induction. High relapse rates and severe toxicity resulted in a five-year overall survival of ~30%. In patients ineligible for intensive treatment, hypomethylating agents (HMA) could be administered but generally failed to induce durable remissions. These limitations have driven the development of targeted drugs and less toxic therapeutic regimens. In the past decade, fourteen new agents have gained FDA and/or EMA approval, including small-molecule inhibitors targeting FLT3, IDH1, IDH2, BCL-2, menin, and the hedgehog pathway, as well as a CD33-directed antibody-drug conjugate. The combination of targeted drugs with intensive chemotherapy or HMA has resulted in improved remission rates and prolonged survival in certain patient subpopulations. However, many promising combinations are currently being evaluated in randomized trials and are not yet available in clinical routine. A combination that has become standard of care is HMA plus venetoclax for patients unfit for intensive chemotherapy, achieving high remission rates with relatively manageable toxicity. Moreover, targeted drugs directed against FLT3 and IDH1 have been approved in combination with intensive chemotherapy and HMA, respectively. Clinical decision-making requires rapid molecular diagnostic testing, assessment of a patient’s fitness for intensive chemotherapy, and management of toxicities and drug interactions. This narrative review, illustrated with patient vignettes, summarizes currently available therapies, guides through the latest trials on frontline combinations in AML, and provides a preview of how the therapeutic landscape may evolve in the near future. Full article

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm of hematopoietic stem and progenitor cells. The advent of high-resolution genomic sequencing has uncovered several genetic drivers of AML which spurred a surge of therapies that target the disease at a mutational, clonal, or epigenetic level. Currently, the molecular profiling of AML patients before treatment is commonplace and crucial for ensuring that patients receive the most optimal therapy for any driver mutations they may have. Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them. Full article

Background: BH3 mimetics (such as venetoclax and navitoclax) are increasingly investigated in the context of the “one-two punch” anticancer strategy, wherein senescence-inducing therapies are combined with senolytic clearance. However, real-world pharmacovigilance evidence describing hematologic adverse event (AE) patterns and serious outcomes for venetoclax versus navitoclax in such combination settings remains limited. This study aims at providing an expectation based on the current reporting of the safety implications of senolytics combined with senescence-inducing therapy in clinical practice. Methods: We analyzed de-duplicated U.S. FDA Adverse Event Reporting System (FAERS) reports retrieved on 1 August 2025. Venetoclax reports (Q2 2016–Q2 2025) were categorized as monotherapy or combination with senescence-inducing chemotherapy (predefined based on published evidence of therapy-induced senescence [TIS]). Hematologic AEs were grouped into three categories (isolated low WBC, isolated low platelet count, and multi-lineage cytopenia). Disproportionality analyses were conducted using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) with 95% CIs and chi-squared testing. Navitoclax reports were analyzed descriptively due to limited volume. Results: A total of 47,508 venetoclax reports were included (34,485 monotherapy; 13,023 combination). Compared with monotherapy, combination therapy showed disproportionate reporting signals (ROR/PRR; reflecting reporting disproportionality rather than incidence or causal risk) for low WBC (ROR 2.87, PRR 2.59) and multi-lineage cytopenias (ROR 3.54, PRR 2.94), while isolated low platelet count was under-represented (ROR 0.31, PRR 0.32). For outcomes, combination therapy demonstrated higher reporting signals for life-threatening outcomes (ROR 7.06, PRR 6.56), hospitalization (ROR 1.74, PRR 1.39), and other outcomes (ROR 2.36, PRR 1.57), while death (ROR 0.55, PRR 0.65) and non-serious outcomes (ROR 0.26, PRR 0.29) were proportionally less reported (all p < 0.001). Navitoclax had 172 reports; hematologic cytopenias and serious outcomes were frequent, but analyses were descriptive only. Conclusions: In FAERS, venetoclax combined with senescence-inducing chemotherapy shows stronger reporting signals for leukopenia and multi-lineage cytopenias and for several serious outcome categories compared with monotherapy. These reporting patterns highlight the need for further care in terms of clinical implementation of the currently investigated senolytics prior to the consideration of the “one-two punch” strategy. Full article

The development of targeted treatments, including inhibitors of BCL-2, FLT3, IDH1/2, and menin, has significantly expanded the therapeutic landscape of acute myeloid leukemia (AML), offering more personalized and molecularly driven treatment approaches. Despite these advances, achieving durable responses represents a major challenge, limited by the emergence of intrinsic and acquired resistance to targeted agents. This review summarizes the current understanding of the cellular and molecular mechanisms underlying resistance to targeted therapies in AML. Key mechanisms include acquired mutations that alter the drug target, other co-occurring genetic and epigenetic alterations, activation of bypass signaling pathways, and metabolic reprogramming. Furthermore, the role of clonal heterogeneity and the bone marrow microenvironment in the development of resistance is increasingly recognized. In addition, we discuss emerging strategies aiming at overcoming resistance, such as combination treatments and novel inhibitors designed to target resistant clones. Finally, this review highlights the critical need for mechanism-driven therapeutic design in order to achieve sustained responses and improve long-term outcomes in patients with AML. Full article

Introduction: Front-line therapy with Azacitidine (AZA) + Venetoclax (Ven) improved overall survival (OS) and remissions in acute myeloid leukemia (AML) patients ineligible for standard induction. Less is known about the outcome of AML treated with AZA + Ven in the “real world”. Methods: We assessed the comparative pattern of administration, tolerability, efficacy and safety of AZA vs. AZA + Ven administered at our cancer centre. We retrospectively reviewed all patients treated with AZA alone or AZA + Ven. Patients who received less than one cycle or proceeded with consolidative stem cell transplant were excluded. Results: A total of 53 patients, median age 77 years, received AZA, and 23 patients, median age 73 years, received AZA + Ven. Among those, 69% and 47.8% were ≥75 years old, respectively. Only 52% received Ven doses above 200 mg. Mean time on therapy was 13.1 months in AZA vs. 5.9 months in AZA + Ven. Treatment delays occurred in 22.6% of AZA and 34.8% of AZA + Ven patients, primarily due to infections and cytopenias. Neutropenia grade 3/4 occurred in 28.3% of AZA vs. 56.5% of AZA + Ven patients. Thrombocytopenia grade 3/4 occurred in 15.1% of AZA and 51.2% of AZA + Ven patients. Anemia grade 3/4 occurred in 5.7% of AZA vs. 30.4% of AZA + Ven patients. Moreover, 69.8% of AZA and 69.5% AZA + Ven patients reached stable disease/partial and complete remission. Median overall survival (OS) was similar: 18 months in AZA vs. 14 months in the AZA + Ven group, p = 0.905. Conclusions: In a community setting, the addition of Venetoclax to AZA did not improve overall survival or disease control, mainly due to low tolerability and higher toxicity. However, these results should be interpreted cautiously due to a significant imbalance in the cytogenetic risk profiles and lower tolerability in the combined group. This suggests the need for a larger study with adjusted analyses. Full article

Background/Objectives: The emergence of FLT3 inhibitors (FLT3i) has radically transformed the prognostic and therapeutic landscape for FLT3-mutated Acute Myeloid Leukemia, stimulating the need for comprehensive and structured clinical guidance. Methods: We aimed to develop evidence-based recommendations spanning the entire disease continuum of FLT3-mutated AML from leading Italian experts through a modified Delphi consensus process. Results: The panel achieved a high degree of agreement on specific interventions covering diagnostic testing, upfront FLT3i integration, role of allogeneic hematopoietic cell transplantation (allo-HSCT), Minimal Residual Disease (MRD) monitoring, and relapsed/refractory (R/R) strategies. Key recommendations mandate that analysis for both FLT3-ITD and FLT3-TKD mutations is required at diagnosis, with capillary electrophoresis or NGS as preferred methods. All fit patients with FLT3m-AML must receive intensive chemotherapy plus a FLT3i (midostaurin or quizartinib) and be evaluated for allo-HSCT. For unfit patients, the current standard of HMA + venetoclax is considered suboptimal, making the search for alternative strategies imperative. MRD monitoring using available molecular or flow cytometry markers is recommended to assess relapse risk and to optimize the allo-HSCT strategy. In the R/R setting, retesting the FLT3 status is mandatory, and gilteritinib is the standard treatment, serving as a bridge-to-transplant and for post-HSCT maintenance. Conclusions: The integration of FLT3i has shifted FLT3m-AML into a more favorable intermediate prognostic category, enhancing the role of curative strategies like allo-HSCT. This consensus paper provides a structured evidence-based comprehensive guide, translating complex data into clear actionable clinical recommendations that minimize practice variability and ultimately optimize management for this high-risk population. Full article

Background: DNMT3B is frequently overexpressed in molecular subsets of acute myeloid leukemia (AML) and is associated with poor prognosis. Unlike DNMT3A, DNMT3B is rarely mutated, suggesting dysregulation through epigenetic mechanisms. The regulatory basis and downstream consequences of DNMT3B overexpression in AML remain incompletely defined. Methods: We integrated analyses of BeatAML, TCGA, and BLUEPRINT cohorts with multi-omic profiling (RNA-seq, DNA methylation, ATAC-seq, and proteomics) in DNMT3B-high AML models. Nanaomycin A (NanA) was used as a DNMT3B-directed functional probe to interrogate cis-regulatory remodeling, transcriptional circuitry, and apoptotic dependencies. Results: DNMT3B overexpression was linked to enhancer-associated chromatin activation rather than recurrent genetic mutation, particularly in CEBPA- and NPM1-mutant AML. NanA exposure produced focal epigenomic remodeling, including 6900 differentially methylated CpGs, with 268 CpGs located within regions of altered chromatin accessibility. These changes were accompanied by coordinated transcriptomic and proteomic reprogramming enriched for cell-cycle, checkpoint, and stress-response pathways. Functionally, DNMT3B perturbation induced redistribution of cell-cycle phases with increased S-phase fraction and progressive apoptosis. Transcriptional profiling demonstrated induction of BH3-only sensitizers (NOXA, PUMA), repression of BCL2, and compensatory upregulation of MCL1 and BCL-XL, collectively reshaping apoptotic dependency. Combined DNMT3B perturbation and BCL2 inhibition produced cooperative cytotoxicity in DNMT3B-high AML models. Conclusion: DNMT3B functions as a context-dependent epigenetic regulator linking enhancer-associated chromatin organization with proliferative control and apoptotic resistance in AML. DNMT3B-directed epigenetic perturbation remodels cis-regulatory circuitry and is associated with increased venetoclax responsiveness, supporting DNMT3B-governed networks as a candidate co-targeting axis in high-risk AML. Full article

DLBCLs constitute an aggressive type of lymphoma with varied clinical, molecular and genetic features. The cells are characterized by NFkB pathway disturbances and BCL-2 and mTOR protein deregulation, which significantly inhibit apoptosis. Hence, many treatment strategies have been established to target the functioning of these pathways. While early clinical trials have found mTOR, NFkB and Bcl-2 inhibitors to have activity in many hematological cancers, their activity as monotherapy agents may still be insufficient; therefore, combinations of these compounds with other molecules demonstrating activity in a given cancer subtype are under evaluation. In vitro studies were conducted on the Riva (ABC subtype) and Toledo (GCB subtype) cell lines. Three novel drugs were administered: AZD2014 (vistusertib)—an inhibitor of the serine–threonine kinase mTOR; IMD-0354—an NFκB inhibitor; and ABT-199 (venetoclax)—a highly selective inhibitor for BCL-2. Drugs were administered alone, in pairs and as a combination of all three agents. For the Riva cell line, ABT-199 had the strongest pro-apoptotic effect on cancer cells as monotherapy. As pairs, AZD2014+ABT-199 and ABT-199+IMD0354 demonstrated similar effects. The combination of the three drugs did not have a stronger effect than the drug pairs. For the Toledo cell line, no significant differences were noted between the drugs when used as monotherapy. In pairs, the strongest effect was observed for AZD2014+ABT-199; furthermore, this effect was not intensified by the combination of the three drugs. Our findings, including those for the BCL-2 and mTOR inhibitors, indicate that there is a need for further in vivo studies to evaluate these drugs as potentially effective treatments for DLBCL of the ABC and GCB subtypes. Full article