Seminars in hematology最新文献

{"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}

{"title":"MRD as an early endpoint in myeloma and other hematologic malignancies: Implication for ongoing and future study designs.","authors":"Elizabeth Hill, Dickran Kazandjian","doi":"10.1053/j.seminhematol.2026.02.002","DOIUrl":"10.1053/j.seminhematol.2026.02.002","url":null,"abstract":"<p><p>Advances in therapy have substantially improved survival across hematologic malignancies. Therefore, traditional clinical trial endpoints such as overall survival (OS) and progression-free survival (PFS) require long follow-up times delaying continued therapeutic advancement. Minimal (or measurable) residual disease (MRD) has emerged as a highly sensitive biomarker of treatment response particularly in multiple myeloma (MM). In 2024, the U.S. Food and Drug Administration (FDA) recognized MRD-negative complete responses in patients with MM as an early endpoint reasonably likely to predict clinical benefit, enabling its use to support accelerated approval for MM therapies-marking the first such acceptance in a hematologic malignancy. This review examines the scientific and regulatory pathway that led to this milestone. We summarize the extensive collaborative efforts, including large meta-analyses and regulatory engagement, that established MRD's prognostic validity. The article further explores the evolving role of MRD across other hematologic malignancies, using acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as examples, highlighting disease-specific challenges to broader regulatory adoption. Finally, we discuss innovative clinical trial designs utilizing MRD that may accelerate drug development and personalize therapy. The experience in MM provides a roadmap for integrating MRD into future regulatory and clinical trial paradigms across hematologic oncology.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"379-385"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494035","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":"Developing MRD as an early endpoint for accelerated approval in CLL.","authors":"Jacob D Soumerai, William G Wierda","doi":"10.1053/j.seminhematol.2026.03.008","DOIUrl":"10.1053/j.seminhematol.2026.03.008","url":null,"abstract":"<p><p>This review article focuses on measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL). Recent therapeutic advances in CLL have resulted in median progression-free survival (PFS) outcomes of ≥ 6 to 9 years, which threatens to slow further therapeutic progress, as it will take many years of follow-up for randomized trials to demonstrate improvements in PFS. Given growing evidence that undetectable MRD at < 10^-4 limit of detection (uMRD4) is strongly associated with PFS outcomes in patients with CLL receiving fixed-duration therapies, MRD warrants evaluation for use as an early endpoint in CLL. Herein, we summarize Food and Drug Administration guidance regarding surrogate endpoints and intermediate endpoints, describe currently utilized MRD assays in CLL, review clinical trials data evaluating the prognostic impact of uMRD4 on survival outcomes in CLL, address questions regarding its prognostic role across regimens with different mechanisms of action, and highlight an ongoing effort to develop end-of-treatment uMRD4 as an early endpoint for accelerated approval of fixed-duration therapies in treatment-naïve CLL.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"409-417"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692030","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":"Roadmap for developing MRD as an early endpoint for drug approval in lymphoma.","authors":"Jordan S Goldstein, Steven X Wang, Martine E D Chamuleau, Ash A Alizadeh","doi":"10.1053/j.seminhematol.2026.03.007","DOIUrl":"10.1053/j.seminhematol.2026.03.007","url":null,"abstract":"<p><p>Advances in lymphoma therapy have extended survival, but exposed limitations of traditional trial endpoints efficacy assessments. We propose two MRD-informed endpoints to accelerate drug development and improve regulatory decision-making: modified PFS (mPFS) and undetectable MRD (uMRD) rate. mPFS is a specific variant of event free survival (EFS) defined as the time from study enrollment until positive end-of-treatment MRD, clinical progression, or death and has potential as a validated surrogate endpoint for traditional approval. uMRD rate at a prespecified timepoint measures depth of response and can be useful in early phase and later-line studies for accelerated approval. Here, we outline the potential that can be slow, reliant on inconsistent imaging studies, and insensitive to molecular disease burden. Novel surrogate trial endpoints can expand and accelerate innovative therapies reaching patients. Advances in technology have led to ultrasensitive methods for detection of measurable residual disease (MRD) in peripheral blood, including circulating tumor DNA (ctDNA) and immunoglobulin clonotype sequencing. MRD methods have been studied with clear biologic rationale and prognostic ability across lymphomas including large B-cell, mantle cell, Hodgkin, and follicular lymphoma. Incorporating MRD into trial endpoints can lead to shorter trial times and perhaps more accurate treatment endpoints incorporating MRD, detail the current MRD data in lymphomas, and provide a practical roadmap towards regulatory use of MRD-based surrogate endpoints to speed drug development.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"370-378"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692028","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":"Role of MRD testing in acute myeloid leukemias. What is the status and how to get there?","authors":"Christopher S Hourigan","doi":"10.1053/j.seminhematol.2026.03.009","DOIUrl":"10.1053/j.seminhematol.2026.03.009","url":null,"abstract":"<p><p>Measurable residual disease (MRD) testing, high-sensitivity methods to estimate persistent leukemia below the threshold of conventional cytomorphological assessment, has the potential to transform the evaluation of treatment response, relapse prediction, and therapy development and selection for patients with acute myeloid leukemia (AML). Evidence accumulated over more than four decades demonstrates that patients testing MRD positive after treatment have substantially higher rates of relapse and inferior survival compared with those testing negative, but the heterogenous nature of the collection of diseases labeled as AML has resulted in slower clinical application and impact of such testing compared with other hematological malignancies. No single optimal universal AML MRD assay currently exists. The choice between imperfect AML MRD testing options requires explicit consideration of the evidence supporting a specific clinical context of use. Emerging technologies offer the prospect of improved sensitivity, specificity, and standardization, but most lack the prospective clinical validation required to guide practice change. Critically, beyond prognostication, it remains unproven in which clinical setting(s) therapeutic intervention guided by AML MRD results can improve overall survival. Updated clinical response criteria now recognize complete remission with MRD negativity as the optimal treatment response, and MRD status is increasingly integrated into clinical trial design, transplant decision-making, and drug development. Several large collaborative efforts, including prospective studies, are now generating the evidence needed to resolve fundamental questions in AML MRD regarding optimal assay selection, testing intervals, clinically meaningful thresholds, and surrogate endpoint validity. The coming years will determine whether AML MRD-guided therapy delivers measurable, patient-meaningful benefit.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"431-437"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699673","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":"Blood-based MRD testing in multiple myeloma: Update on mass spectrometry methods for detecting the monoclonal immunoglobulin.","authors":"Katie L Thoren","doi":"10.1053/j.seminhematol.2026.03.006","DOIUrl":"10.1053/j.seminhematol.2026.03.006","url":null,"abstract":"<p><p>Mass spectrometry provides a highly sensitive and specific way to detect low level monoclonal proteins in multiple myeloma. Two main approaches-the intact light chain approach and the clonotypic peptide approach-have been developed and several assays are now commercially available, with some moving into clinical use for routine M-protein testing. Multiple studies have compared the performance of mass spectrometry to established bone marrow-based minimal residual disease (MRD) tests and have provided early insights into its clinical utility in the setting of MRD. This review summarizes the different mass spectrometry methods for M-protein detection, discusses our current understanding of their clinical utility for MRD testing, and describes what the next steps might look like for these promising techniques.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"386-391"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623675","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":"MRD-driven treatment strategies in CLL: Current practice, limitations, and emerging paradigms.","authors":"Nathalie Javidi-Sharifi, Jennifer R Brown","doi":"10.1053/j.seminhematol.2026.03.010","DOIUrl":"10.1053/j.seminhematol.2026.03.010","url":null,"abstract":"<p><p>Measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) has evolved from a research tool to a central endpoint in modern clinical trials and is increasingly shaping treatment individualization. During the chemoimmunotherapy era, a strong association between MRD status and long-term outcomes positioned MRD as a surrogate marker for remission durability in selected contexts. With the widespread adoption of targeted therapies, however, the clinical meaning of MRD has become treatment-class and biology dependent. In time-limited venetoclax-based regimens, achieving undetectable MRD (uMRD) strongly predicts durable off-treatment remission. In contrast, in continuous BTK inhibitor-based therapy, conventional MRD thresholds are less prognostic, and durable disease control can occur despite persistent low-level disease. This review summarizes the current technical landscape of MRD assessment, including major testing platforms, sensitivity thresholds, and specimen considerations, and highlights practical factors that influence interpretation in routine practice and clinical trials. The role of MRD across contemporary therapeutic classes is examined, with particular emphasis on emerging combination strategies. Results from MRD-guided combination trials demonstrate that tailoring treatment duration to depth and trajectory of MRD clearance is feasible, safe, and capable of producing outstanding long-term outcomes, including survival rates exceeding those achieved with prior standards. These data provide the strongest prospective evidence to date that MRD can function not merely as a prognostic marker, but as a therapeutic guide when applied within regimens capable of deep disease eradication. Interpretation of MRD in biologically defined subgroups, including TP53-disrupted and IGHV-unmutated disease, as well as its evolving role following immune-based therapies, is also considered. We address the principal barriers to routine clinical implementation, along with the key questions being addressed by ongoing randomized studies that will determine whether MRD fully transitions from a prognostic biomarker to a practical therapeutic guide in CLL.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"418-430"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147780117","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":"Emerging technologies for minimal residual disease detection in hematologic malignancies.","authors":"Daniel J Groso, David G Coffey","doi":"10.1053/j.seminhematol.2026.02.001","DOIUrl":"10.1053/j.seminhematol.2026.02.001","url":null,"abstract":"<p><p>Minimal residual disease (MRD) detection plays a critical role in determining prognosis, guiding therapy, and monitoring relapse in hematologic malignancies. Current gold-standard assays rely on flow cytometry, polymerase chain reaction (PCR), and next-generation sequencing (NGS) performed on bone marrow aspirates. While highly sensitive, these methods rely on invasive bone marrow sampling, which limits assessment frequency and restricts evaluation to a single anatomic site, potentially missing spatially heterogeneous or extramedullary disease. Emerging plasma-based and imaging approaches promise broader, more frequent, and less invasive surveillance. This review discusses the principles and clinical readiness of both conventional and emerging MRD assays, describing how these approaches can improve disease monitoring and therapeutic decision-making.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"392-399"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348989","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":"T-cell engaging antibodies for B-cell lymphomas.","authors":"Dong Hyun Kim, Tae Min Kim","doi":"10.1053/j.seminhematol.2025.12.002","DOIUrl":"10.1053/j.seminhematol.2025.12.002","url":null,"abstract":"<p><p>T-cell engaging bispecific antibodies (BsAbs) have transformed the treatment paradigms for B-cell non-Hodgkin lymphomas. This review focused on 4 CD20 × CD3 BsAbs, as well as surovatamig, a CD19 × CD3 BsAb currently under investigation that has demonstrated promising efficacy against relapsed/refractory B-cell lymphomas. All 4 CD20 × CD3 BsAbs are approved as third-line and beyond therapies: mosunetuzumab for follicular lymphoma (FL), glofitamab for diffuse large B-cell lymphoma (DLBCL), and epcoritamab and odronextamab for both FL and DLBCL (the latter in European Union only). Although all are T-cell-directed immunotherapies, they differ in their development platforms, structural configurations, and routes of administration. The safety profile is characterized by T-cell overactivation-related events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS was observed in nearly half of patients and mostly low grade with different mitigation strategies across BsAbs. The incidence of ICANS was mostly below 10%, with grade ≥ 3 events being rare. Multiple studies are currently evaluating these agents in both the relapsed/refractory and frontline settings, either as monotherapy or in combination with other agents. This review summarizes the efficacy and safety of each agent across B-cell lymphoma subtypes, along with their dosing schedules and CRS mitigation strategies.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"255-266"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990685","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":"Chemical evolution of antibody-drug conjugates focused on linker design and conjugation strategies in hematology.","authors":"Seungbin Park, Geetanjali B Gone, Dohee Ahn, Sang J Chung","doi":"10.1053/j.seminhematol.2025.11.004","DOIUrl":"10.1053/j.seminhematol.2025.11.004","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have transformed the treatment of hematologic malignancies by coupling antibody selectivity with potent cytotoxic payloads. Their clinical performance depends largely on chemical design, particularly linker stability and conjugation strategy. Advances in site-specific and site-selective platforms, such as ThioMab, GlycoConnect, AJICAP, and AbClick, enable homogeneous ADCs with controlled drug-to-antibody ratio (DAR) and improved safety. Cleavable linkers-protease-sensitive, acid-labile, and redox-responsive-facilitate intracellular drug release, while non-cleavable and solubility-enhancing designs improve stability and pharmacokinetics (PK). Case studies of FDA-approved ADCs, including brentuximab vedotin, polatuzumab vedotin, inotuzumab ozogamicin, and loncastuximab tesirine, demonstrate how these innovations translate into therapeutic benefit. Nonetheless, challenges such as antigen heterogeneity, resistance mechanisms, and off-target toxicities persist. By integrating advances in conjugation chemistry, linker engineering, and payload selection, next-generation ADCs are poised to expand efficacy and safety in hematologic oncology and further refine targeted therapy in blood cancers.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"289-304"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828026","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}