Seminars in hematology最新文献

{"title":"Solid malignancies in telomere biology disorders.","authors":"Sharon A Savage","doi":"10.1053/j.seminhematol.2026.03.004","DOIUrl":"10.1053/j.seminhematol.2026.03.004","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are caused by pathogenic germline variants in genes essential for telomere maintenance and function, including at least 17 different genes with X-linked recessive (XLR), autosomal dominant (AD) and/or autosomal recessive (AR) inheritance as well as de novo occurrence. Individuals with TBDs have short and/or dysfunctional telomeres and high rates of bone marrow failure, pulmonary fibrosis, liver disease, certain immunodeficiencies, and many other problems. TBDs are cancer predisposition syndromes with an approximately 3-fold increased risk of any cancer and an overall cancer-free survival in the mid-40s. Head/neck squamous cell carcinoma (HNSCC), the most common TBD-associated solid malignancy, is notable for a 43-fold increased risk in AD TBDs and 276-fold in AR/XLR disease compared with the general population. The limited data on cancer treatment in TBDs suggests poor tolerance of standard chemotherapy and radiation regimens and dismal outcomes. Cancer surveillance modalities have not been prospectively studied in TBDs and are currently based on expert opinion. The mechanisms by which cancer develops in TBDs are proposed to include chromosomal instability and DNA damage accumulation due to abnormal telomere function and an underlying T cell immunodeficiency with suboptimal immune surveillance. Clonal hematopoiesis (CH) is relatively common in TBDs, including reversion or compensation of the germline variant and recurrent clonal hematopoiesis mutations modulating the TP53 pathway associated with cancer development. This review highlights recent advances in understanding solid malignancies in TBDs and underscores the urgent need for prospective studies to develop the evidence base for cancer surveillance and treatment in these complex disorders.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"486-492"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13075653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomere biology disorders as an example of rare disease advocacy.","authors":"Katie Barrett Stevens, Hannah A Raj, Jane K Paxton, Hilary J Longhurst","doi":"10.1053/j.seminhematol.2026.04.002","DOIUrl":"10.1053/j.seminhematol.2026.04.002","url":null,"abstract":"<p><p>Patient advocacy has emerged as a transformative force within the rare disease landscape. Few rare diseases illustrate this dynamic as clearly as telomere biology disorders (TBDs). Once regarded primarily as rare pediatric bone marrow failure syndromes, TBDs are now understood as multisystem, lifelong conditions affecting individuals across the age spectrum. In this review, we examine TBDs as a case study in rare disease advocacy, highlighting how advocacy has functioned not only as a support mechanism but as an organizing architecture underpinning progress across diagnosis, management, research, and community engagement. We describe how advocacy efforts have advanced diagnostic awareness and access to validated testing, informed the development and dissemination of clinical management guidelines, enabled multidisciplinary models of care, and fostered robust research ecosystems through funding, registries, and collaborative convenings. We further explore the essential role of advocacy in addressing psychosocial needs, sustaining patient engagement, and confronting persistent inequities in access, representation, and care delivery. The TBD experience demonstrates that advocacy is not ancillary to science, but integral to its progress and impact. As the field enters a new era characterized by expanding diagnoses and emerging therapies, the TBD community offers a scalable framework for integrating advocacy as a core component of rare disease ecosystems.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"532-538"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975155","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":"Rare somatic manifestations of telomere biology disorders.","authors":"Nora M Gibson, Timothy S Olson","doi":"10.1053/j.seminhematol.2026.03.003","DOIUrl":"10.1053/j.seminhematol.2026.03.003","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are characterized by numerous somatic features across multiple organ systems, which contribute significantly to the morbidity and mortality of these conditions. In many cases, rare somatic manifestations may represent the earliest symptoms of a TBD and the first presentation to subspecialty care, and thus a high index of suspicion is necessary for timely diagnosis. Hoyeraal-Hriedarsson Syndrome, Revesz Syndrome, and Coats Plus Syndrome represent severe phenotypes with characteristic somatic features often diagnosed in early childhood. However, all patients with TBDs may exhibit these varied symptoms throughout the lifespan. Of note, patients continue to experience disease-related complications across multiple organ systems even after hematopoietic stem cell transplant, reinforcing the need for lifelong multidisciplinary care for patients with TBDs. In this chapter, we describe neurological, immunologic, gastrointestinal, ophthalmic, and endocrinologic manifestations of TBDs, among others.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"513-520"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147646472","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":"Clonal hematopoiesis in telomere biology disorders.","authors":"Christopher M Sande, Daria V Babushok","doi":"10.1053/j.seminhematol.2026.02.004","DOIUrl":"10.1053/j.seminhematol.2026.02.004","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are a group of genetic conditions of varying severity caused by defects in telomere maintenance. Patients with TBDs can experience dysfunction in nearly all organ systems, including the bone marrow, with increased risk for bone marrow failure and myeloid neoplasms. Over the past decade, several groups have identified higher rates and earlier onset of clonal hematopoiesis (CH) in TBDs patients, with a distinct profile of somatic variants compared to the general population. While TBDs patients sometimes develop variants seen in age-related CH, these are proportionally much less prevalent in TBDs. Instead, TBDs patients develop recurrent gene variants that overcome cell growth constraints caused by telomere shortening or dysfunction. These variants include those that enhance telomere maintenance through reversion of the underlying TBD-causing germline variant or through compensatory mutations in other telomere maintenance machinery, mutations in spliceosome genes, and mutations that disrupt components of the DNA damage response. Early links between specific types of variants and subsequent progression to myeloid malignancies have been reported. In this manuscript, we critically review the existing literature, highlighting open questions in the field, and discuss clinical tools for detecting and monitoring CH in patients with TBDs.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"461-472"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147532382","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":"Stem cell transplantation and gene therapy for telomere biology disorders: Historical perspective, current approaches, and emerging strategies.","authors":"Jane Koo, Helen D Reed, Kasiani C Myers, Suneet Agarwal","doi":"10.1053/j.seminhematol.2026.03.001","DOIUrl":"10.1053/j.seminhematol.2026.03.001","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are inherited conditions characterized by defective telomere maintenance, leading to critically short telomeres and multisystem disease, with hematologic complications representing a major cause of morbidity and mortality. Bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia occur at markedly increased rates in affected individuals, and hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for these hematologic manifestations. Historically, outcomes following HSCT in TBDs were poor, largely due to heightened sensitivity to myeloablative conditioning regimens, resulting in excessive early mortality, graft failure, graft-versus-host disease, and severe pulmonary and hepatic toxicity. Advances in disease recognition, donor selection, conditioning regimens, and supportive care have substantially improved transplant outcomes over the last several decades. Contemporary strategies emphasize reduced-intensity or reduced-toxicity approaches, with growing experience in the use of alkylator- and radiation-free platforms. Despite improved early survival, long-term outcomes remain limited by progressive non-hematologic organ dysfunction, vascular complications, and secondary malignancies inherent to telomere-mediated disease and potentially accelerated by transplantation. Optimal management of patients with TBDs undergoing HSCT requires careful patient selection, thorough pre-transplant evaluation, exclusion of occult TBDs in related donors, preference for bone marrow grafts, and aggressive strategies to prevent graft-versus-host disease. Lifelong, multidisciplinary posttransplant surveillance focused on multiorgan complications is essential. Emerging gene and cellular therapies, including autologous telomere-elongation approaches, offer promising alternatives for select patients and may further expand the therapeutic landscape. Continued progress will depend on disease-specific, multi-institutional prospective studies aimed at optimizing transplant strategies, minimizing long-term toxicity, and improving survival and quality of life for patients with TBDs.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"493-502"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147594276","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":"Genetic aspects of telomere biology disorders.","authors":"Sophie de Tocqueville, Helene Morel, Ibrahima Ba, Patrick Revy, Caroline Kannengiesser","doi":"10.1053/j.seminhematol.2026.03.011","DOIUrl":"10.1053/j.seminhematol.2026.03.011","url":null,"abstract":"<p><p>The presence of germline pathogenic variants (GPVs) in genes involved in telomere length regulation or protection has been demonstrated to be a causative factor for telomere biology disorders (TBDs). TBDs are a group of rare diseases characterized by premature ageing, which exhibit remarkable clinical heterogeneity, with manifestations ranging from pulmonary fibrosis and liver disease in adulthood to bone marrow failure and mucocutaneous anomalies in infancy. To date, pathogenic variants in over 20 telomere-related genes (TRGs) have been implicated, each affecting telomere length or integrity through diverse molecular pathways. This review summarizes the genetic and clinical complexity of TBDs, highlighting challenges in diagnosis and genetic counselling.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"449-460"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147780103","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":"Targeted immunoPET imaging of multiple myeloma.","authors":"Gary A Ulaner, Ola Landgren","doi":"10.1053/j.seminhematol.2026.03.005","DOIUrl":"10.1053/j.seminhematol.2026.03.005","url":null,"abstract":"<p><p>Current standard of care methods of imaging multiple myeloma disease burden are suboptimal. For example, fluorodeoxyglucose-(FDG)-PET/CT may fail to detect up to 50% of myeloma lesions. Immunologically based positron emission tomography (immunoPET) is an imaging modality allowing detecting of multiple myeloma by targeting specific tumor antigens using antibodies, antibody fragments, or antibody mimics labelled with position emitting radioisotopes. ImmunoPET agents for multiple myeloma have targeted CD38, CD46, CD138, BCMA, CS1, VLA-4, and CXCR4, which are all highly expressed on the majority of myeloma cells. As opposed to biopsies, immunoPET allows noninvasive, whole-body assessment of multiple myeloma tumor burden. Clinical applications of immunoPET for patients with multiple myeloma currently under investigation include disease detection, localization, quantification, biopsy targeting, and evaluation of residual disease following therapy. In addition, targeted immunoPET is under investigation for its ability to predict response to subsequent targeting therapies. For instance, immunoPET agents targeting CD38 are being used to predict response to subsequent CD38-targeted therapies using uptake on pretherapy immunoPET studies as a predictive biomarker. When the positron emitting radioisotope can be exchanged for an isotope emitting a high energy beta or alpha particle, the construct may be utilized for radioligand therapy of multiple myeloma. This review introduces the concept of immunoPET, summarizes the current immunoPET agents in development, and discusses potential clinical applications of immunoPET agents.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"400-408"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minimal residual disease testing in hematologic malignancies: From early endpoint to precision clinical decision making.","authors":"Ola Landgren","doi":"10.1053/j.seminhematol.2026.04.005","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2026.04.005","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 5","pages":"357-359"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942889","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":"Minimal residual disease guided treatment approaches in non-Hodgkin lymphoma-Where we are and where we're headed.","authors":"Rahul Lakhotia, Mark Roschewski","doi":"10.1053/j.seminhematol.2026.02.003","DOIUrl":"10.1053/j.seminhematol.2026.02.003","url":null,"abstract":"<p><p>Minimal residual disease (MRD) assessment, particularly through circulating tumor DNA (ctDNA), offers highly tumor-specific and quantitative measurement of treatment response across subtypes of B-cell non-Hodgkin lymphoma (NHL). Conventional imaging, including positron emission tomography (PET) scans, remains central to the NHL response criteria but lacks the analytical sensitivity to detect molecular disease. In contrast, ultrasensitive ctDNA can detect variants at frequencies as low as 1 part per million and allows more precise quantification of tumor burden throughout therapy. In large B-cell lymphoma, ctDNA kinetics predict clinical outcomes more accurately after frontline therapy than PET and retain prognostic value with targeted agents and chimeric antigen receptor T-cell therapy. In mantle cell lymphoma, undetectable MRD after induction identifies patients who can safely omit high-dose chemotherapy consolidation. Prospective clinical trials across NHL subtypes now routinely embed MRD assessment to test its utility in clinical decision-making, including timing and selection of therapy. Barriers to widespread adoption of MRD in NHL include a lack of standardized specimen collection and analysis, assay availability, and definitive evidence that treating molecular-only disease improves outcomes. Ongoing clinical trials are addressing this information gap and will guide how MRD can be integrated into routine clinical care.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"360-369"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13077458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147594290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRD in multiple myeloma: From an early endpoint for accelerated approval to MRD driven treatment and clinical management.","authors":"Ola Landgren, Rafat Abonour, Dickran Kazandjian","doi":"10.1053/j.seminhematol.2026.01.002","DOIUrl":"10.1053/j.seminhematol.2026.01.002","url":null,"abstract":"<p><p>The integration of minimal residual disease (MRD) assessment into multiple myeloma research and care has transformed the therapeutic and regulatory landscape. Building upon decades of progress in genomics, immunophenotyping, and high-sensitivity assays, MRD has now progressed from a prognostic biomarker to a U.S. Food and Drug Administration (FDA)-recognized early endpoint suitable for accelerated approval. This shift was catalyzed by the EVIDENCE meta-analysis and the I²TEAMM study, which together formed the evidentiary backbone presented at the April 2024 Oncologic Drugs Advisory Committee (ODAC) meeting. Simultaneously, prospective trials-such as PERSEUS, MIDAS, and ADVANCE-have already established the feasibility of MRD-guided treatment intensification or de-escalation. Looking ahead, the development of sensitive and reliable blood-based MRD technologies promises to expand real-time disease monitoring, streamline clinical pathways, and enable precision-based care for patients with multiple myeloma.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"438-443"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147285055","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}