Seminars in hematology最新文献

{"title":"The immunotherapy landscape in AML: Defining knowledge gaps toward rational combinatorial strategies.","authors":"Marion Subklewe, Sergio Rutella, Antonio Curti","doi":"10.1053/j.seminhematol.2025.08.003","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.08.003","url":null,"abstract":"<p><p>Immunotherapy has dramatically improved outcomes in lymphoid malignancies. In B cell cancers, CD19-directed CAR T cells and T-cell engagers have produced high remission rates and durable responses, now forming the cornerstone of treatment in many relapsed or refractory settings. In contrast, acute myeloid leukemia (AML) has not experienced a comparable breakthrough. To date, only antibody-drug conjugates have reached regulatory approval, with gemtuzumab ozogamicin approved in combination with intensive induction and consolidation therapy for newly diagnosed CD33-positive AML. This divergence is rooted in the biological and immunologic complexity of AML. Unlike B-cell malignancies with lineage-restricted surface markers such as CD19, AML lacks leukemia-specific antigens. Most targets are shared with normal hematopoietic progenitors, leading to on-target/off-leukemia toxicity. Moreover, AML exerts local and systemic immunosuppression through both tumor-intrinsic and microenvironmental mechanisms, limiting T-cell persistence and function. This review will introduce the current immunotherapy platforms under investigation in AML, starting with antibody-based approaches, followed by T-cell redirecting therapies, and culminating in an overview of immune resistance, the bone marrow microenvironment, and strategies toward personalized combinatorial immunotherapy. By synthesizing recent clinical data and mechanistic insights, including those from early CAR and T-cell engager trials, we aim to provide a translational framework for how immunotherapy might still reshape AML care-through integration of immune contexture of the bone marrow environment aiming for rational combinatorial approaches.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of anti-CD3 antibodies in clinically available bispecific T cell engagers.","authors":"Hyeonmin Lee, Yonghee Lee, Junho Chung","doi":"10.1053/j.seminhematol.2025.08.004","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.08.004","url":null,"abstract":"<p><p>Bispecific T cell engagers (bispecific TCEs) are engineered antibodies that redirect T cells to mediate tumor cell killing by simultaneously binding to CD3 on T cells and tumor-associated antigens. As of July 2025, ten bispecific TCEs are clinically available. The CD3-binding antibodies in these bispecific TCEs can be classified into 6 groups based on the amino acid sequence similarity across their 6 complementarity-determining regions (CDRs). Specifically, antibodies were assigned to the same family if their six CDRs-HCDR1-3 and LCDR1-3-exhibited ≥80% pairwise sequence identity upon multiple sequence alignment. Family 1, derived from OKT3-a mouse hybridoma generated by immunizing BALB/c mice with human T cells-includes only blinatumomab; Family 2, derived from SP34-a rhesus monkey (Macaca mulatta) derived hybridoma specific for human T cells-comprises 5 antibodies; and Family 6, derived from UCHT1-a mouse hybridoma generated by immunizing mice with human T cells-contains only tebentafusp. The origin of the remaining 3 antibodies has not been disclosed and they possess unique CD3-binding sequences. We classified them into their own distinct families (Families 3, 4, and 5). Interestingly, mosunetuzumab (Family 4) showed remarkably lower incidence of adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infection compared to other bispecific TCEs even though its affinity for CD3ε was not significantly different. The epitopes of 4 antibodies in Family 2, teclistamab, talquetamab, glofitamab, and tarlatamab were previously defined to be located at the N-terminal region of CD3ε via hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis. In our in silico epitope prediction analysis, the N-terminal region was included in the epitope region of all bispecific TCEs regardless of their family. Blinatumomab (Family 1) and tebentafusp (Family 6) did not bind to the CD3ε homolog of the cynomolgus monkey, whereas the other 8 bispecific TCEs did. This lack of cross-reactivity poses clear disadvantages in their preclinical development, particularly for toxicity and safety evaluation in nonhuman primate models.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline predispositions to myeloid malignancies: Across the lifespan.","authors":"Himachandana Atluri, Alok Swaroop, Lucy A Godley","doi":"10.1053/j.seminhematol.2025.08.002","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.08.002","url":null,"abstract":"<p><p>Germline predisposition syndromes to myeloid malignancies have been recognized increasingly over the last decade. Although many of these genetic syndromes present early in life, the age at which a hematopoietic malignancy develops can vary widely depending on the specific gene involved and its role in hematopoiesis. Herein, we aim to review age-related penetrance and phenotype of key germline predisposition syndromes including: SAMD9/9L, GATA2, inherited bone marrow failure syndromes, RUNX1, CEBPA, TP53, and DDX41. We describe optimal diagnostic strategies for these patients, and explain how recognition of germline predisposition allows for the development of optimal treatment plan for the affected individual and counseling of at-risk family members.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menin inhibition for the treatment of acute leukemia.","authors":"Daniela V Wenge, Scott A Armstrong","doi":"10.1053/j.seminhematol.2025.08.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.08.001","url":null,"abstract":"<p><p>Menin inhibitors are emerging as targeted therapies for acute leukemias with high HOXA gene expression. These leukemias harbor mutations including KMT2A-rearrangements, NPM1c mutations, NUP98-fusions, UBTF tandem duplications and potentially others. Mechanistically, each of these oncoproteins depend on the KMT2A:Menin interaction to maintain critical gene expression. Several Menin inhibitors have entered clinical trials and have shown impressive efficacy in heavily pretreated patients with acute myeloid leukemia (AML). Revumenib received FDA approval for patients with relapsed or refractory acute myeloid leukemia with KMT2A-rearrangements in November 2024. Despite the success of Menin inhibitors, leukemia progression due to therapeutic resistance is a common occurrence with monotherapy. Hence, current clinical trials focus on Menin inhibition in combination with chemotherapy and/or standard-of-care targeted therapies to potentially overcome or prevent resistance. Menin inhibitors are also being investigated in patients with newly diagnosed acute leukemia or as a maintenance therapy post allogeneic stem cell transplantation. This review provides an overview of the mechanism of action of Menin inhibitors and the disease subsets that show sensitivity. We explain the current understanding of genetic resistance, mediated by Menin mutations that reduce drug binding affinity, and the emerging understanding of other types of resistance. Ongoing clinical trials are summarized, and we discuss the future role of Menin inhibition as a potentially practice-changing treatment for up to 50% of patients with AML.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resolving leukemic stem cell heterogeneity and plasticity with single-cell multiomics.","authors":"Frank Y Huang, Andreas Trumpp, Patrick Stelmach","doi":"10.1053/j.seminhematol.2025.07.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.07.001","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is an aggressive blood cancer in which disease initiation and relapse are driven by leukemic cells with stem-like properties, known as leukemic stem cells (LSCs). The LSC compartment is highly heterogenous and this contributes to differences in therapy response. This heterogeneity is determined by genetic and nongenetic factors including somatic mutations, the cell of origin, transcriptional and epigenetic states as well as phenotypic plasticity. While this complicates the identification and eradication of LSCs, it also presents an opportunity to tailor therapeutic strategies to the phenotypic and functional states of LSCs present in a patient, exploiting their specific vulnerabilities. The emergence of single-cell multiomics technologies has transformed our ability to dissect cellular heterogeneity in AML, enabling simultaneous interrogation of genomic, transcriptomic, epigenomic and proteomic layers and providing high-resolution molecular snapshots of individual cells. In this review, we discuss causes and consequences of LSC heterogeneity, highlight advances in single-cell multiomics technologies to resolve it and outline how they can address shortcomings in our understanding of LSC heterogeneity and plasticity to revolutionize diagnostics and disease monitoring of AML.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary and therapy-related acute myeloid leukemias: Overlapping features, distinct trajectories.","authors":"Luca Guarnera, Emiliano Fabiani, Giorgia Silvestrini, Enrico Attardi, Maria Teresa Voso","doi":"10.1053/j.seminhematol.2025.06.005","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.06.005","url":null,"abstract":"<p><p>Therapy-related acute myeloid leukemia (tAML) and AML arising from previous hematologic disorders (secondary AML, sAML) share similar biological features, including karyotype abnormalities and gene specific mutations, patient-related risk factors. Older age and lower performance status also contribute to dimal prognosis, and dismal prognosis, both in terms of response rate and overall survival. However, these 2 entities significantly differ in leukemogenic trajectories. In this line, recent advances allowed for a better understanding of differential clonal progression processes in the broad landscape of sAMLs. Thus, in this manuscript, we reviewed clinical and biological characteristics of tAML and sAML, highlighting commonalities and divergent features and discussed classification aspects. We also gathered the newest evidence of leukemogenic trajectories leading from bone marrow failure syndromes, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and MDS/MPN overlap syndromes to sAML, as well as leukemias arising from donors' cells in the setting of allogenic transplantation. Furthermore, we reviewed germline and acquired predisposition to leukemias and discussed the therapeutic landscape and future directions.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic dysregulation in acute myeloid leukemia.","authors":"Jens Schrezenmeier, B J P Huntly","doi":"10.1053/j.seminhematol.2025.06.003","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.06.003","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the clonal expansion of undifferentiated myeloid blasts with a block in differentiation and aberrant self-renewal. While recurrent genomic mutations are well-documented in AML, epigenetic dysregulation has emerged as an equally pivotal driver of leukemogenesis, a notion corroborated by the frequent recurrence of mutations in epigenetic regulators. Leukemic cells exhibit pervasive epigenetic alterations-including abnormal DNA methylation patterns, dysregulated histone modification, disrupted chromatin architecture and RNA-based regulatory mechanisms -which collectively rewire gene expression programs. These changes silence key differentiation genes and sustain self-renewal pathways, enforcing the developmental arrest and hyper-proliferation that are the hallmarks of AML. Importantly, epigenetic aberrations in AML are not merely downstream consequences of genetic lesions but actively contribute to the malignant phenotype. Somatic mutations frequently target epigenetic regulators (for example, DNA methyltransferases or histone modifiers), and these lesions cooperate with other genetic alterations to initiate and maintain the leukemic clone. Together, these insights highlight epigenetic dysregulation as a central mechanism in AML pathogenesis.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AML diagnostics in the 21st century: Use of AI.","authors":"Torsten Haferlach, Jan-Niklas Eckardt, Wencke Walter, Sven Maschek, Jakob Nikolas Kather, Christian Pohlkamp, Jan Moritz Middeke","doi":"10.1053/j.seminhematol.2025.06.002","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.06.002","url":null,"abstract":"<p><p>The landscape of acute myeloid leukemia (AML) diagnostics is undergoing a pivotal shift towards a transformative era, driven by the integration of artificial intelligence (AI). This review delves into the pivotal role of AI in reshaping AML diagnostics in the 21st century, highlighting advancements, challenges, and future prospects. AML, marked by the immediate need for accurate diagnosis and treatment, requires precise analysis against the complexity of various diagnostic methods such as cytomorphology, immunophenotyping, cytogenetics, and molecular testing. The introduction of AI in this field promises to address the critical need for rapid and standardized diagnostics, thereby enhancing patient care. AI technologies, including deep learning (DL) and machine learning (ML), are revolutionizing the interpretation of complex diagnostic data. With the use of AI-based models such as deep learning (DL) classifiers or automated karyotyping, promising tools do already exist. When it comes to reporting and reasoning, large language models (LLM) show their potential in efficient data processing and better clinical decision-making. This includes the use of large language models (LLMs) for generating comprehensive diagnostic reports that integrate multi-layered diagnostic information. However, there is a critical need for transparency and interpretability in AI-driven diagnostics. Explainable AI (XAI) models address this need building trust among clinicians and patients. Moreover, this review addresses the growing field of synthetic data that are becoming increasingly accessible due to advances in AI and computational technology. While synthetic data present a promising avenue for augmenting clinical research and potentially optimizing clinical trials in fields such as AML, their application requires careful ethical, regulatory, and methodological considerations. There are several limitations and challenges to consider regarding not only synthetic data but also AI models in general. This includes regulatory hurdles due to the dynamic nature of AI, as well as data privacy concerns and interoperability between different systems. In conclusion, AI has the potential to completely change how we diagnose and treat AML by offering faster, more accurate, and more comprehensive diagnostic insights. This potential is especially crucial for preserving knowledge in times of shortages of human experts. However, realizing this potential will require overcoming significant challenges and fostering collaboration between technologists and clinicians. As we move forward, the synergy between AI and human expertise will undoubtedly redefine the landscape of AML diagnostics, leading in a new era of precision medicine in hematology.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurable residual disease monitoring in acute myeloid leukaemia: Techniques, timing and therapeutic implications.","authors":"Kasper J Croese, Jacqueline Cloos, Jesse M Tettero","doi":"10.1053/j.seminhematol.2025.06.004","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.06.004","url":null,"abstract":"<p><p>The detection of measurable residual disease (MRD) in acute myeloid leukaemia (AML) has emerged as one of the strongest prognostic indications of adverse outcomes across different treatment settings and disease stages, independent of baseline genetic risk classification. Multiple techniques for MRD-assessment have been developed and clinically validated, including multiparameter flow cytometry (MFC) and molecular assays such as quantitative PCR (qPCR) and next-generation sequencing (NGS). These approaches have been incorporated into routine clinical practice to evaluate treatment efficacy and refine disease risk stratification. Beyond the prognostic significance, MRD monitoring offers a powerful tool for monitoring subclinical disease, enabling early relapse detection and influencing therapeutic decisions, including consolidation strategies, transplant conditioning, and pre-emptive interventions. In non-intensive treatment settings, MRD may help tailor treatment duration and identify patients eligible for therapy cessation. As the therapeutic landscape of AML continues to evolve with novel agents and strategies, the role and clinical applications of MRD are becoming increasingly relevant. This review summarizes current MRD assessment techniques, optimal measurement timepoints, and clinical applications across different therapeutic settings. We also highlight ongoing innovations and future directions that aim to fully integrate MRD into precision management of patients with AML.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genomic landscape of acute myeloid leukemia: Redefining classifications, ontogeny, and therapeutic strategies.","authors":"Nicolas Duployez, Claude Preudhomme","doi":"10.1053/j.seminhematol.2025.06.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2025.06.001","url":null,"abstract":"<p><p>Over the past decades, the progressive identification of chromosomal abnormalities and gene mutations has transformed acute myeloid leukemia (AML) from a morphologically defined disease into a genetically stratified malignancy. The coexistence and competition of multiple mutations within leukemic clones underscore the complexity of AML and the need for therapeutic strategies that address clonal interference and mutational synergy. Molecular profiling now offers a more accurate definition of AML ontogeny, surpassing clinical history and revealing biologically and prognostically distinct subtypes. At the same time, new classifications focusing on genetic characteristics have enabled a more coherent and clinically meaningful categorization of the disease. These advances have contributed directly to risk stratification and treatment selection, and thus to more appropriate management.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}