{"title":"Fast and furious: Changing gears on the road to cure with chimeric antigen receptor T cells in multiple myeloma","authors":"","doi":"10.1053/j.seminhematol.2024.07.002","DOIUrl":"10.1053/j.seminhematol.2024.07.002","url":null,"abstract":"<div><div>Based on the pivotal KarMMa-1 and CARTITUDE-1 studies, Idecabtagene vicleucel (Ide-cel) and Ciltacabtagene autoleucel (Cilta-cel) have been approved to treat multiple myeloma patients, who have been exposed to at least 1 proteasome inhibitor, immunomodulatory drug and anti-CD38 antibody after 4 or 3 lines of therapy, respectively. The unprecedented rates of deep and long-lasting remissions have been meanwhile confirmed in multiple real-world analyses and more recently, the KarMMa-3 and CARTITUDE-4 studies lead to the approval in earlier lines of therapy. It is currently believed that ultimately all patients with relapsed/refractory multiple myeloma experience relapse after anti-BCMA CAR T-cell therapies. There is a plethora of CAR T-cell therapies targeting novel antigens, with the aim to overcome current CAR T-cell resistance. In this review, we will summarize current evidence of novel antigens and their clinical potential. Together with current CAR T-cell therapy and T-cell engagers, these approaches might lead us to the next frontier in multiple myeloma: total immunotherapy and the road to chemotherapy-free cure.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141696986","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}
Sweta B Patel, Daniel R Moskop, Craig T Jordan, Eric M Pietras
{"title":"Understanding MDS stem cells: Advances and limitations.","authors":"Sweta B Patel, Daniel R Moskop, Craig T Jordan, Eric M Pietras","doi":"10.1053/j.seminhematol.2024.09.007","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.09.007","url":null,"abstract":"<p><p>In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression<sup>1</sup>. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547224","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 predisposition to myelodysplastic syndrome: Genetic counseling and transplant implications.","authors":"Yi Liu, Kathleen Calzone, Lisa J McReynolds","doi":"10.1053/j.seminhematol.2024.09.003","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.09.003","url":null,"abstract":"<p><p>The development of myelodysplastic syndromes (MDS) is influenced by various genetic predispositions. Several important genes contribute to disease susceptibility. This paper explores common genetic predisposition genes in MDS, including DDX41, CEBPA, and SAMD9/SAMD9L, which are linked to hereditary conditions presenting diagnostic and clinical challenges. It delves into hereditary conditions that affect platelet production and count, such as RUNX1, ETV6, and ANKRD26, detailing their clinical features and how they contribute to an increased risk of MDS. The discussion extends to additional genetic syndromes like GATA2 deficiency, telomere biology disorders, Fanconi anemia, and Li-Fraumeni syndrome, along with new findings on genes like ERG that offer new insights into disease etiology. The importance of genetic counseling in MDS is underscored, outlining its goals, methods for evaluating family history, risk assessment, and the ethical considerations involved. Furthermore, the role of hematopoietic cell transplantation in managing MDS, particularly in patients with germline syndromes, is reviewed, emphasizing the need for optimal donor selection and personalized treatment approaches. This comprehensive overview illustrates the critical role of genetic factors in MDS and highlights the need for continued research and tailored clinical practices to improve patient outcomes.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507134","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":"Inflammation in myelodysplastic syndrome pathogenesis.","authors":"Juan Jose Rodriguez-Sevilla, Simona Colla","doi":"10.1053/j.seminhematol.2024.09.005","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.09.005","url":null,"abstract":"<p><p>Inflammation is a key driver of the progression of preleukemic myeloid conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), to myelodysplastic syndromes (MDS). Inflammation is a critical mediator in the complex interplay of the genetic, epigenetic, and microenvironmental factors contributing to clonal evolution. Under inflammatory conditions, somatic mutations in TET2, DNMT3A, and ASXL1, the most frequently mutated genes in CHIP and CCUS, induce a competitive advantage to hematopoietic stem and progenitor cells, which leads to their clonal expansion in the bone marrow. Chronic inflammation also drives metabolic reprogramming and immune system deregulation, further promoting the expansion of malignant clones. This review underscores the urgent need to fully elucidate the role of inflammation in MDS initiation and highlights the potential of the therapeutical targeting of inflammatory pathways as an early intervention in MDS.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473900","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":"Cellular and immunotherapies for myelodysplastic syndromes.","authors":"Ryan J Stubbins, Hannah Cherniawsky, Aly Karsan","doi":"10.1053/j.seminhematol.2024.09.006","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.09.006","url":null,"abstract":"<p><p>In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473899","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":"Therapy-related myelodysplastic syndromes and acute myeloid leukemia.","authors":"Sangeetha Venugopal, Amy E DeZern","doi":"10.1053/j.seminhematol.2024.09.004","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.09.004","url":null,"abstract":"<p><p>Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy. T-MDS/AML is associated with adverse cytogenomic features and poor prognosis. While advances in the field of clonal hematopoiesis and germline variants has unraveled the molecular underpinnings of t-MDS/AML, we have miles to go in terms of t-MDS/AML directed therapy and improvement in outcomes. In this review, we discuss the epidemiology of t-MDS/AML, clinical and biological insights, evolution of t-MDS/AML and available treatment options.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473901","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}
Ted M Getz, Jan P Bewersdorf, Tariq Kewan, Jessica M Stempel, Aram Bidikian, Rory M Shallis, Maximilian Stahl, Amer M Zeidan
{"title":"Beyond HMAs: Novel Targets and Therapeutic Approaches.","authors":"Ted M Getz, Jan P Bewersdorf, Tariq Kewan, Jessica M Stempel, Aram Bidikian, Rory M Shallis, Maximilian Stahl, Amer M Zeidan","doi":"10.1053/j.seminhematol.2024.08.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.08.001","url":null,"abstract":"<p><p>Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401199","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}
Mary M Czech, Eduard Schulz, Alain Mina, Juan Gea-Banacloche
{"title":"Infections and antimicrobial prophylaxis in patients with myelodysplastic syndromes.","authors":"Mary M Czech, Eduard Schulz, Alain Mina, Juan Gea-Banacloche","doi":"10.1053/j.seminhematol.2024.07.004","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2024.07.004","url":null,"abstract":"<p><p>Infectious complications are an important cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS). Preventing infections could significantly improve both survival and quality of life. Unfortunately, both infections and antimicrobial prophylaxis in patients with MDS are incompletely assessed due to the heterogeneity of disorders included in each publication, changing definitions over time, and lack of standardized prophylaxis practices. Despite these limitations, some basic statements can be made. Infections in MDS are associated with neutropenia. Patients with lower-risk (LR) MDS tend to have fewer infections compared to patients with higher-risk (HR) MDS, which may be related to the different prevalence of neutropenia in the 2 groups. Pneumonia is the most common infection, and bacteria are the most common pathogens. Invasive fungal infections (IFI) are uncommon. Reactivation of latent viruses are rare. With the limited data available, we agree that antibacterial prophylaxis can be considered in patients with HR-MDS during severe neutropenia and early cycles of therapy when infections are most likely to occur. Given the low prevalence of IFI and viral reactivation, antimicrobial prophylaxis for these pathogens is less likely to be advantageous for most patients, although antifungal prophylaxis with activity against mold is commonly used in patients with persistent, profound neutropenia. Ultimately, improved data collection regarding infections and antimicrobial prophylaxis is needed to improve care for patients with MDS.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093712","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 pediatric approach to Hodgkin lymphoma","authors":"","doi":"10.1053/j.seminhematol.2024.05.003","DOIUrl":"10.1053/j.seminhematol.2024.05.003","url":null,"abstract":"<div><p><span>Hodgkin lymphoma (HL) occurs throughout the lifespan but is one of the most common </span>cancers in adolescents<span><span> and young adults (AYA; 15-39 years). HL has become a highly curable disease with survival rates surpassing 90%, including patients with high-risk and advanced stage disease. Unfortunately, intensive treatment carries a risk of short- and long-term toxicity. Given the decades pediatric HL survivors are expected to live after treatment, the pediatric approach to treatment has focused on improving the </span>therapeutic index<span> through response adapted treatment and more recently the incorporation of novel agents. The efforts of pediatric and medical oncologists in research and clinical trial<span> development have long occurred in parallel, but recent efforts have laid the foundation for collaboration with the goal of standardizing AYA care and allowing earlier incorporation of novel therapy for younger patients. This review focuses on the evolution of the management of pediatric HL including epidemiology, biology, and approaches to upfront and salvage treatment regimens.</span></span></span></p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141055924","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":"Molecular biomarkers in classic Hodgkin lymphoma","authors":"","doi":"10.1053/j.seminhematol.2024.05.005","DOIUrl":"10.1053/j.seminhematol.2024.05.005","url":null,"abstract":"<div><p><span><span>Classic Hodgkin lymphoma<span> is a unique B-cell derived malignancy<span> featuring rare malignant Hodgkin and Reed Sternberg (HRS) cells that are embedded in a quantitively dominant tumor microenvironment (TME). Treatment of classic Hodgkin lymphoma has significantly evolved in the past decade with improving treatment outcomes for newly diagnosed patients and the minority of patients suffering from </span></span></span>disease progression<span><span>. However, the burden of toxicity and treatment-related long-term sequelae remains high in a typically young patient population. This highlights the need for better molecular biomarkers aiding in risk-adapted treatment strategies and predicting response to an increasing number of available treatments that now prominently involve multiple </span>immunotherapy<span> options. Here, we review modern molecular biomarker approaches that reflect both the biology of the malignant HRS cells and cellular components in the TME, while holding the promise to improve diagnostic frameworks for clinical decision-making and be feasible in clinical trials and routine practice. In particular, technical advances in sequencing and analytic pipelines using </span></span></span>liquid biopsies, as well as deep phenotypic characterization of tissue architecture at single-cell resolution, have emerged as the new frontier of biomarker development awaiting further validation and implementation in routine diagnostic procedures.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538549","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}