Pub Date : 2025-11-17DOI: 10.1016/j.blre.2025.101353
Yesim Dargaud, Gabriela G Yamaguti-Hayakawa, Jéssica O Frade-Guanaes, Alexandre Leuci, Margareth C Ozelo
For decades, the management of hemophilia A and B has relied on frequent intravenous infusions of factor VIII (FVIII) or factor IX (FIX), a regimen that imposes substantial physical and emotional burdens on patients, and carries significant long-term costs despite advances in treatment. Although the advent of non-factor therapies has improved prophylaxis, these approaches still require regular administration and do not fully address the underlying factor deficiency. Adeno-associated virus (AAV)-mediated gene therapy represents a potentially transformative, one-time therapeutic alternative by enabling sustained, hepatocyte-driven production of FVIII or FIX. Approved therapies-valoctocogene roxaparvovec for hemophilia A and etranacogene dezaparvovec for hemophilia B-have demonstrated significant reductions in bleeding frequency and factor replacement requirements. Clinical experience indicates that FIX expression is generally stable over time, whereas FVIII levels often decline, highlighting ongoing challenges in achieving durable expression. These limitations are influenced by both immunological factors, including vector- and transgene-directed immune responses, and non-immunological factors such as hepatocyte turnover and epigenetic regulation of transgene expression. Pre-existing immunity and vector-induced immune responses may restrict the possibility of repeat administration. Long-term follow-up from pivotal trials has documented sustained factor expression for over 10 years in hemophilia B and up to 5 years in hemophilia A, though inter-individual variability remains substantial. Emerging strategies to enhance durability include next-generation vector design, codon optimization, gene editing technologies, and alternative delivery platforms. This review synthesizes current clinical evidence, biological understanding, and translational challenges, with an emphasis on strategies to optimize long-term efficacy of AAV-mediated gene therapy for hemophilia.
{"title":"Long-term durability of rAAV gene therapy in hemophilia: Factor expression, clinical outcomes and underlying molecular mechanisms.","authors":"Yesim Dargaud, Gabriela G Yamaguti-Hayakawa, Jéssica O Frade-Guanaes, Alexandre Leuci, Margareth C Ozelo","doi":"10.1016/j.blre.2025.101353","DOIUrl":"https://doi.org/10.1016/j.blre.2025.101353","url":null,"abstract":"<p><p>For decades, the management of hemophilia A and B has relied on frequent intravenous infusions of factor VIII (FVIII) or factor IX (FIX), a regimen that imposes substantial physical and emotional burdens on patients, and carries significant long-term costs despite advances in treatment. Although the advent of non-factor therapies has improved prophylaxis, these approaches still require regular administration and do not fully address the underlying factor deficiency. Adeno-associated virus (AAV)-mediated gene therapy represents a potentially transformative, one-time therapeutic alternative by enabling sustained, hepatocyte-driven production of FVIII or FIX. Approved therapies-valoctocogene roxaparvovec for hemophilia A and etranacogene dezaparvovec for hemophilia B-have demonstrated significant reductions in bleeding frequency and factor replacement requirements. Clinical experience indicates that FIX expression is generally stable over time, whereas FVIII levels often decline, highlighting ongoing challenges in achieving durable expression. These limitations are influenced by both immunological factors, including vector- and transgene-directed immune responses, and non-immunological factors such as hepatocyte turnover and epigenetic regulation of transgene expression. Pre-existing immunity and vector-induced immune responses may restrict the possibility of repeat administration. Long-term follow-up from pivotal trials has documented sustained factor expression for over 10 years in hemophilia B and up to 5 years in hemophilia A, though inter-individual variability remains substantial. Emerging strategies to enhance durability include next-generation vector design, codon optimization, gene editing technologies, and alternative delivery platforms. This review synthesizes current clinical evidence, biological understanding, and translational challenges, with an emphasis on strategies to optimize long-term efficacy of AAV-mediated gene therapy for hemophilia.</p>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":" ","pages":"101353"},"PeriodicalIF":5.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.blre.2025.101352
Nadir Ullah, Marco Muccio, Claudia Bartalucci, Elisa Balletto, Chiara Sepulcri, Matteo Cerchiaro, Matteo Bassetti, Malgorzata Mikulska
Adenovirus (AdV) infection in adult patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) is associated with poor outcomes but management strategies differ among the centers. Data on incidence and risk factors for AdV infections in adult allo-HCT recipients are limited. Recommendations for routine monitoring for AdV are mainly based on data from pediatric cohorts, in which the incidence of AdV infection is much higher than in adults. The primary aim of this study was to report pooled incidence of AdV infections in adult allo-HCT recipients. Secondary aims were to report the incidence of AdV viremia, AdV high-level viremia (>1000 copies/ml), and AdV related mortality. The PRISMA system was used for systematic search. The Science Direct, and Scopus databases were searched for studies published between January 2000 and January 2025. In total, the meta-analysis included 25 studies reporting data on 61,832 patients, with 12 of them reporting regular AdV screening. The pooled incidence of any AdV infection was 7.3 % (95 % confidence interval CI, 6.2-8.4), the pooled incidence of AdV viremia was 7.2 % (95 % CI, 5.5-9.0), and the pooled incidence of high-level viremia was 3.4 % (95 % CI, 2.2-4.5). The overall mortality due to any AdV infection was 16.7 % (95 % CI, 12.1-21.3), mortality due to AdV in patients with viremia was 11.5 % (95 % CI, 7.3-15.7), and mortality due to AdV in patients with high-level viremia was 24.0 % (95 % CI, 11.1-36.9). The pooled incidence of AdV infection after HCT from different donors was: matched related donor 4.9 % (95 % CI, 3.0-6.9), matched unrelated donor 5.6 % (95 % CI, 2.9-8.2), and haploidentical donor 7.4 % (95 %CI, 5.3-9.5), with no statistically significant differences for donor type. When the incidence of AdV based on donor type was compared within the same study, in 3 among 7 studies, the incidence was higher in case of haploidentical donor (all 3 studies with post-transplant cyclophosphamide platform), while no difference in incidence was found in 4 studies. High AdV incidence was reported in 3 studies after transplant from cord blood (13-30 %). The subgroup analyses revealed that incidence of AdV infection and AdV viremia were higher in studies performing PCR screening and in studies with lower number of patients. No factors influencing AdV attributable mortality were identified. In conclusion, this meta-analysis identified the rate of AdV infection or viremia in adult allo-HCT recipients of over 7 %, and AdV-related mortality lower than previously reported, but as high as 24 % in patients with high level viremia. The role of routine screening and optimal pre-emptive management of AdV in adult patients require further studies.
{"title":"Adenovirus infection in adult allogeneic hematopoietic stem cell transplant recipients: Systematic review and meta-analysis.","authors":"Nadir Ullah, Marco Muccio, Claudia Bartalucci, Elisa Balletto, Chiara Sepulcri, Matteo Cerchiaro, Matteo Bassetti, Malgorzata Mikulska","doi":"10.1016/j.blre.2025.101352","DOIUrl":"https://doi.org/10.1016/j.blre.2025.101352","url":null,"abstract":"<p><p>Adenovirus (AdV) infection in adult patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) is associated with poor outcomes but management strategies differ among the centers. Data on incidence and risk factors for AdV infections in adult allo-HCT recipients are limited. Recommendations for routine monitoring for AdV are mainly based on data from pediatric cohorts, in which the incidence of AdV infection is much higher than in adults. The primary aim of this study was to report pooled incidence of AdV infections in adult allo-HCT recipients. Secondary aims were to report the incidence of AdV viremia, AdV high-level viremia (>1000 copies/ml), and AdV related mortality. The PRISMA system was used for systematic search. The Science Direct, and Scopus databases were searched for studies published between January 2000 and January 2025. In total, the meta-analysis included 25 studies reporting data on 61,832 patients, with 12 of them reporting regular AdV screening. The pooled incidence of any AdV infection was 7.3 % (95 % confidence interval CI, 6.2-8.4), the pooled incidence of AdV viremia was 7.2 % (95 % CI, 5.5-9.0), and the pooled incidence of high-level viremia was 3.4 % (95 % CI, 2.2-4.5). The overall mortality due to any AdV infection was 16.7 % (95 % CI, 12.1-21.3), mortality due to AdV in patients with viremia was 11.5 % (95 % CI, 7.3-15.7), and mortality due to AdV in patients with high-level viremia was 24.0 % (95 % CI, 11.1-36.9). The pooled incidence of AdV infection after HCT from different donors was: matched related donor 4.9 % (95 % CI, 3.0-6.9), matched unrelated donor 5.6 % (95 % CI, 2.9-8.2), and haploidentical donor 7.4 % (95 %CI, 5.3-9.5), with no statistically significant differences for donor type. When the incidence of AdV based on donor type was compared within the same study, in 3 among 7 studies, the incidence was higher in case of haploidentical donor (all 3 studies with post-transplant cyclophosphamide platform), while no difference in incidence was found in 4 studies. High AdV incidence was reported in 3 studies after transplant from cord blood (13-30 %). The subgroup analyses revealed that incidence of AdV infection and AdV viremia were higher in studies performing PCR screening and in studies with lower number of patients. No factors influencing AdV attributable mortality were identified. In conclusion, this meta-analysis identified the rate of AdV infection or viremia in adult allo-HCT recipients of over 7 %, and AdV-related mortality lower than previously reported, but as high as 24 % in patients with high level viremia. The role of routine screening and optimal pre-emptive management of AdV in adult patients require further studies.</p>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":" ","pages":"101352"},"PeriodicalIF":5.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145642979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101323
Ayman Mohammad , John Mascarenhas , Bridget K. Marcellino , Daniel I. Nathan
Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.
{"title":"Target practice: Opportunities for therapeutic intervention in CHIP and CCUS","authors":"Ayman Mohammad , John Mascarenhas , Bridget K. Marcellino , Daniel I. Nathan","doi":"10.1016/j.blre.2025.101323","DOIUrl":"10.1016/j.blre.2025.101323","url":null,"abstract":"<div><div>Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101323"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101340
Jowan Al-Nusair , Luca Lanino , Arda Durmaz , Matteo Giovanni Della Porta , Amer M. Zeidan , Tariq Kewan
This review summarizes applications of machine learning (ML) in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), spanning diagnosis, prognostication, treatment prediction, and research tools. In diagnostics, deep learning applied to bone marrow smears, peripheral blood films, and flow cytometry has shown high sensitivity and specificity, outperforming conventional methods. ML-driven unsupervised clustering and consensus classification have refined disease taxonomies, identifying genomic subtypes with prognostic value. Prognostic models and neural networks enable dynamic, personalized survival predictions. In treatment, ML assists in predicting responses to hypomethylating agents and venetoclax-based regimens, supporting clinical decision-making. In research, generative approaches create privacy-preserving synthetic cohorts and digital twins, facilitating trial design and overcoming data limitations. Future integration into clinical practice will require rigorous validation, explainable algorithms, seamless workflow incorporation, and regulatory oversight to ensure trust, equity, and safety. ML has potential to enhance multiple aspects of AML and MDS management.
{"title":"Artificial intelligence in myeloid malignancies: Clinical applications of machine learning in myelodysplastic syndromes and acute myeloid Leukemia","authors":"Jowan Al-Nusair , Luca Lanino , Arda Durmaz , Matteo Giovanni Della Porta , Amer M. Zeidan , Tariq Kewan","doi":"10.1016/j.blre.2025.101340","DOIUrl":"10.1016/j.blre.2025.101340","url":null,"abstract":"<div><div>This review summarizes applications of machine learning (ML) in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), spanning diagnosis, prognostication, treatment prediction, and research tools. In diagnostics, deep learning applied to bone marrow smears, peripheral blood films, and flow cytometry has shown high sensitivity and specificity, outperforming conventional methods. ML-driven unsupervised clustering and consensus classification have refined disease taxonomies, identifying genomic subtypes with prognostic value. Prognostic models and neural networks enable dynamic, personalized survival predictions. In treatment, ML assists in predicting responses to hypomethylating agents and venetoclax-based regimens, supporting clinical decision-making. In research, generative approaches create privacy-preserving synthetic cohorts and digital twins, facilitating trial design and overcoming data limitations. Future integration into clinical practice will require rigorous validation, explainable algorithms, seamless workflow incorporation, and regulatory oversight to ensure trust, equity, and safety. ML has potential to enhance multiple aspects of AML and MDS management.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101340"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101318
Xenia Bubnova, Lauren Hope, Helen Wheadon
Leukaemia is caused by genetic mutations within haematopoietic stem and progenitor cells, leading to the production of immature blasts. While mouse models have been instrumental in studying disease mechanisms and testing therapies, their limitations contribute to 90 % failure rate of new therapies in clinical trials. This is often attributed to the choice of model utilised, and failure of mouse models to accurately replicate the complexity of the human disease. This review examines different leukaemia mouse models, including transgenic, syngeneic and xenografts, discussing their phenotype, advantages and limitations. Finally, we describe advanced technologies for in vitro modelling of haematopoiesis and leukaemia. These models provide a promising platform for tumour microenvironment research, and a robust human-relevant pipeline for drug screening, reducing our reliance on in vivo testing. The information in this review will enable researchers to make informed decisions on the most appropriate models to carry out pre-clinical testing in the future.
{"title":"Evaluation of current mouse in vivo models and advanced in vitro models for leukaemia research","authors":"Xenia Bubnova, Lauren Hope, Helen Wheadon","doi":"10.1016/j.blre.2025.101318","DOIUrl":"10.1016/j.blre.2025.101318","url":null,"abstract":"<div><div>Leukaemia is caused by genetic mutations within haematopoietic stem and progenitor cells, leading to the production of immature blasts. While mouse models have been instrumental in studying disease mechanisms and testing therapies, their limitations contribute to 90 % failure rate of new therapies in clinical trials. This is often attributed to the choice of model utilised, and failure of mouse models to accurately replicate the complexity of the human disease. This review examines different leukaemia mouse models, including transgenic, syngeneic and xenografts, discussing their phenotype, advantages and limitations. Finally, we describe advanced technologies for <u><em>in vitro</em></u> modelling of haematopoiesis and leukaemia. These models provide a promising platform for tumour microenvironment research, and a robust human-relevant pipeline for drug screening, reducing our reliance on <u><em>in vivo</em></u> testing. The information in this review will enable researchers to make informed decisions on the most appropriate models to carry out pre-clinical testing in the future.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101318"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101324
Subodh Selukar , Vivien Yin , Megan Othus
Clinical trialists have been debating the use of data external to the study for decades. In this review, we develop concepts for interested readers to consider the use of external data in clinical trials, and we provide perspectives on the real-world usage of external data in phase 2 and 3 clinical trials for hematological malignancies across US academic cancer clinical trial networks. Only a minority of these studies have included external data (beyond use in establishing outcome benchmarks) in recent years, but improvements in data sharing and advances in methodologies may lead to more sources of potentially high-quality data for the broader clinical trials community. Identifying appropriate external data specific to the clinical trial and developing plans to adequately address differences between study and external data will remain key considerations for including external data in clinical trials.
{"title":"Synthetic control arms and other uses of external data in clinical trials for hematological malignancies","authors":"Subodh Selukar , Vivien Yin , Megan Othus","doi":"10.1016/j.blre.2025.101324","DOIUrl":"10.1016/j.blre.2025.101324","url":null,"abstract":"<div><div>Clinical trialists have been debating the use of data external to the study for decades. In this review, we develop concepts for interested readers to consider the use of external data in clinical trials, and we provide perspectives on the real-world usage of external data in phase 2 and 3 clinical trials for hematological malignancies across US academic cancer clinical trial networks. Only a minority of these studies have included external data (beyond use in establishing outcome benchmarks) in recent years, but improvements in data sharing and advances in methodologies may lead to more sources of potentially high-quality data for the broader clinical trials community. Identifying appropriate external data specific to the clinical trial and developing plans to adequately address differences between study and external data will remain key considerations for including external data in clinical trials.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101324"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101321
Mostafa Mohammed Saleh , Walid Rasheed , Saud Alhayli , Alfadel Alshaibani , Mahmoud Aljurf , Riad El Fakih
Checkpoint inhibitors emerged as a promising therapeutic approach in the management of central nervous system lymphomas, particularly primary and secondary B-cell CNS lymphomas. These are aggressive malignancies and carry a poor prognosis with limited treatment options. Advances in tumor immunology highlighted the role of immune checkpoint pathways, especially PD-1/PD-L1 axis, in facilitating immune evasion in CNS lymphomas. Preclinical studies demonstrated a suppressive tumor microenvironment, often with expression of checkpoint ligands and infiltration by exhausted T cells, suggesting potential sensitivity to immune checkpoint blockade. Clinical experience, including early phase studies, showed encouraging response rates and durable remissions in patients treated with PD-1 inhibitors. Combination strategies incorporating checkpoint inhibitors with targeted therapies are under investigation and may enhance treatment efficacy while maintaining manageable toxicity profiles. As evidence accumulates, checkpoint blockade is increasingly viewed as a potential treatment strategy in CNS lymphomas, warranting further exploration in prospective trials and biomarker-driven studies.
{"title":"Programmed death inhibitors in CNS B-cell lymphoma: A literature review","authors":"Mostafa Mohammed Saleh , Walid Rasheed , Saud Alhayli , Alfadel Alshaibani , Mahmoud Aljurf , Riad El Fakih","doi":"10.1016/j.blre.2025.101321","DOIUrl":"10.1016/j.blre.2025.101321","url":null,"abstract":"<div><div>Checkpoint inhibitors emerged as a promising therapeutic approach in the management of central nervous system lymphomas, particularly primary and secondary B-cell CNS lymphomas. These are aggressive malignancies and carry a poor prognosis with limited treatment options. Advances in tumor immunology highlighted the role of immune checkpoint pathways, especially PD-1/PD-L1 axis, in facilitating immune evasion in CNS lymphomas. Preclinical studies demonstrated a suppressive tumor microenvironment, often with expression of checkpoint ligands and infiltration by exhausted T cells, suggesting potential sensitivity to immune checkpoint blockade. Clinical experience, including early phase studies, showed encouraging response rates and durable remissions in patients treated with PD-1 inhibitors. Combination strategies incorporating checkpoint inhibitors with targeted therapies are under investigation and may enhance treatment efficacy while maintaining manageable toxicity profiles. As evidence accumulates, checkpoint blockade is increasingly viewed as a potential treatment strategy in CNS lymphomas, warranting further exploration in prospective trials and biomarker-driven studies.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101321"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101322
Debbie Jiang, David J. Kuter
Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia. At an incidence of approximately 10 to 30 times lower than AIHA and ITP, respectively, ES has been historically overlooked and our understanding of the pathogenesis, clinical characteristics, and optimal management strategies for ES lags behind. Observational studies suggest that although initial response rates to standard therapies are similar, long-term outcomes and mortality in ES are worse than in AIHA and ITP. A panoply of novel therapies is now available or in development for ITP and to a lesser extent, AIHA. In this review, we revisit our understanding of the pathophysiology and clinical features of adult ES and discuss the potential novel therapeutics that might hold promise for patients with Evans syndrome.
{"title":"Evans syndrome revisited","authors":"Debbie Jiang, David J. Kuter","doi":"10.1016/j.blre.2025.101322","DOIUrl":"10.1016/j.blre.2025.101322","url":null,"abstract":"<div><div>Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia. At an incidence of approximately 10 to 30 times lower than AIHA and ITP, respectively, ES has been historically overlooked and our understanding of the pathogenesis, clinical characteristics, and optimal management strategies for ES lags behind. Observational studies suggest that although initial response rates to standard therapies are similar, long-term outcomes and mortality in ES are worse than in AIHA and ITP. A panoply of novel therapies is now available or in development for ITP and to a lesser extent, AIHA. In this review, we revisit our understanding of the pathophysiology and clinical features of adult ES and discuss the potential novel therapeutics that might hold promise for patients with Evans syndrome.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101322"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144735586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101343
Ian Landry , Adam F. Binder , Marc Yorker , Sarah Ramirez
Background
Central nervous system involvement in multiple myeloma (CNS-MM) is considered a rare but devastating manifestation of extra-medullary disease (EMD) associated with aggressive biology and dismal outcomes. Treatment advances over the past few decades have improved survival in patients with MM, however, it has not translated into a similar survival benefit for those with CNS-MM. Early recognition and targeted management of CNS-MM remain major clinical challenges.
Objective
This literature review summarizes the current literature on epidemiology, risk factors, clinical features, diagnostic modalities, and therapeutic approaches to CNS-MM. It focuses on emerging biomarkers and new treatment options that may affect the natural course of the disease. This review hypothesizes that CNS involvement may represent a distinct biologic entity characterized by unique patterns of tropism, resistance, and microenvironmental adaptation.
Findings
CNS-MM typically arises in the context of relapsed or refractory disease and is associated with high-risk cytogenetics, plasmablastic morphology, circulating plasma cells, elevated lactate dehydrogenase, and other sites of EMD. Survival remains poor, with most cohorts reporting a median overall survival of less than 6 months from CNS involvement. Effective therapeutic options in systemic treatment have a limited effect in CNS-MM due to the poor penetration of the blood-brain barrier. Novel therapeutics such as CAR-T cells, bispecific antibodies, and intrathecal chemotherapy have shown isolated activity, but data remains limited.
Future directions
Emerging diagnostic tools such as CSF-based circulating tumor DNA (ctDNA) and soluble BCMA (sBCMA) may enable earlier detection and dynamic monitoring. While sBCMA has been correlated with systemic disease activity, its role in CSF-based testing for CNS-MM has not been validated. Screening high risk patients may increase the predictive value of these tests. Advances in immune and cellular therapy could expand treatment options but need direction on sequencing of therapies and consideration of maintenance therapy.
Conclusion
In conclusion, this review supports the hypothesis that CNS-MM may represent an underdiagnosed, biologically distinct entity, requiring dedicated diagnostic and therapeutic strategies. Integrating novel diagnostics with CNS-penetrant therapies offers a path forward in managing this ultra-high-risk population. Clinicians should consider screening high risk patients for this entity to affect survival.
{"title":"Redefining central nervous system multiple myeloma: From rare phenomenon to emerging entity","authors":"Ian Landry , Adam F. Binder , Marc Yorker , Sarah Ramirez","doi":"10.1016/j.blre.2025.101343","DOIUrl":"10.1016/j.blre.2025.101343","url":null,"abstract":"<div><h3>Background</h3><div>Central nervous system involvement in multiple myeloma (CNS-MM) is considered a rare but devastating manifestation of extra-medullary disease (EMD) associated with aggressive biology and dismal outcomes. Treatment advances over the past few decades have improved survival in patients with MM, however, it has not translated into a similar survival benefit for those with CNS-MM. Early recognition and targeted management of CNS-MM remain major clinical challenges.</div></div><div><h3>Objective</h3><div>This literature review summarizes the current literature on epidemiology, risk factors, clinical features, diagnostic modalities, and therapeutic approaches to CNS-MM. It focuses on emerging biomarkers and new treatment options that may affect the natural course of the disease. This review hypothesizes that CNS involvement may represent a distinct biologic entity characterized by unique patterns of tropism, resistance, and microenvironmental adaptation.</div></div><div><h3>Findings</h3><div>CNS-MM typically arises in the context of relapsed or refractory disease and is associated with high-risk cytogenetics, plasmablastic morphology, circulating plasma cells, elevated lactate dehydrogenase, and other sites of EMD. Survival remains poor, with most cohorts reporting a median overall survival of less than 6 months from CNS involvement. Effective therapeutic options in systemic treatment have a limited effect in CNS-MM due to the poor penetration of the blood-brain barrier. Novel therapeutics such as CAR-T cells, bispecific antibodies, and intrathecal chemotherapy have shown isolated activity, but data remains limited.</div></div><div><h3>Future directions</h3><div>Emerging diagnostic tools such as CSF-based circulating tumor DNA (ctDNA) and soluble BCMA (sBCMA) may enable earlier detection and dynamic monitoring. While sBCMA has been correlated with systemic disease activity, its role in CSF-based testing for CNS-MM has not been validated. Screening high risk patients may increase the predictive value of these tests. Advances in immune and cellular therapy could expand treatment options but need direction on sequencing of therapies and consideration of maintenance therapy.</div></div><div><h3>Conclusion</h3><div>In conclusion, this review supports the hypothesis that CNS-MM may represent an underdiagnosed, biologically distinct entity, requiring dedicated diagnostic and therapeutic strategies. Integrating novel diagnostics with CNS-penetrant therapies offers a path forward in managing this ultra-high-risk population. Clinicians should consider screening high risk patients for this entity to affect survival.</div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101343"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.blre.2025.101304
Yesim Dargaud , Sebastien Lobet , Nathalie Roussel , Leonard A. Valentino
Hemophilia A and B are rare X-linked bleeding disorders caused by coagulation factor deficiencies, leading to joint bleeding, synovial hypertrophy and chronic hemophilic arthropathy marked by progressive cartilage and bone damage. Musculoskeletal issues remain the primary source of morbidity in people with hemophilia (PwH). Despite significant advances in prophylactic therapies, joint pain, functional limitations, and deterioration persist. The long-term impact of novel treatments on joint health and physical activity levels remains incompletely understood. Early detection and prevention of damage is challenging, highlighting the need for highly sensitive diagnostic tools to identify subclinical changes before irreversible damage occurs. Pain management, currently adapted from other conditions, does not fully meet the unique needs of PwH. Research into targeted pain relief, synovial hypertrophy management, and cartilage regeneration is crucial. Addressing unmet needs in diagnosis, treatment, and management requires collaboration between clinical and research communities to improve care effectiveness and enhance the quality of life for PwH.
{"title":"Unmet needs in hemophilic arthropathy","authors":"Yesim Dargaud , Sebastien Lobet , Nathalie Roussel , Leonard A. Valentino","doi":"10.1016/j.blre.2025.101304","DOIUrl":"10.1016/j.blre.2025.101304","url":null,"abstract":"<div><div><span><span>Hemophilia A and B are rare X-linked bleeding disorders caused by </span>coagulation factor<span> deficiencies, leading to joint bleeding, synovial hypertrophy and chronic </span></span>hemophilic arthropathy<span> marked by progressive cartilage and bone damage. Musculoskeletal issues remain the primary source of morbidity in people with hemophilia<span><span><span> (PwH). Despite significant advances in prophylactic therapies, joint pain, functional limitations, and deterioration persist. The long-term impact of novel treatments on joint health and </span>physical activity levels remains incompletely understood. Early detection and prevention of damage is challenging, highlighting the need for highly sensitive diagnostic tools to identify subclinical changes before irreversible damage occurs. Pain management, currently adapted from other conditions, does not fully meet the unique needs of PwH. Research into targeted pain relief, synovial hypertrophy management, and cartilage regeneration is crucial. Addressing unmet needs in diagnosis, treatment, and management requires collaboration between clinical and research communities to improve care effectiveness and enhance the </span>quality of life for PwH.</span></span></div></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":"74 ","pages":"Article 101304"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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