Journal of Hematology & Oncology最新文献

{"title":"Chinese guidelines for HER2-targeted therapy in gastric and gastroesophageal junction adenocarcinoma (2025 Edition).","authors":"Xiaotian Zhang, Yakun Wang, Muyan Cai, Fenghua Wang, Tong Xie, Jianming Ying, Weiqi Sheng, Xiangshan Fan, Xiujuan Qu, Chang Wang, Zhi Peng, Jie'er Ying, Miaozhen Qiu, Tianshu Liu, Yueping Liu, Dongmei Lin, Xiaohong Yao, Ziyu Li, Wenlong Guan, Ruihua Xu, Jin Li, Hong Bu, Lin Shen","doi":"10.1186/s13045-026-01804-8","DOIUrl":"https://doi.org/10.1186/s13045-026-01804-8","url":null,"abstract":"<p><p>Gastric and gastroesophageal junction adenocarcinoma (GC/GEJC) poses a substantial clinical burden in China. This updated guideline introduces a refined human epidermal growth factor receptor 2 (HER2) classification system (high, intermediate, low, absent) to redefine patient stratification for targeted therapy. It integrates cutting-edge evidence on standardized detection-including immunohistochemistry, in situ hybridization, and liquid biopsy-to overcome spatial-temporal heterogeneity. Recent progress in the use of HER2-targeted agents, including monoclonal antibodies, antibody-drug conjugates, tyrosine kinase inhibitors, and bispecific antibodies, is systematically reviewed and presented to inform evidence-based clinical practice. These updates aim to optimize personalized HER2-targeted therapy and improve outcomes in GC/GEJC patients.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":40.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-enhanced CAR-T therapy strategies in cancer, aging, and autoimmune diseases.","authors":"Hongjia Li, Jinxin Li, Xiting Liu, Xueju Wei, Xin Zeng, Qiwei Wang, Yingli Han, He Huang, Pengxu Qian","doi":"10.1186/s13045-026-01805-7","DOIUrl":"https://doi.org/10.1186/s13045-026-01805-7","url":null,"abstract":"<p><p>Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a transformative immunotherapy, which achieves remarkable success in hematological malignancies. However, broader application of CAR-T therapy is hindered by multiple challenges, including limited efficacy in solid tumors, antigen escape, severe toxicities, and complex, costly manufacturing. Recent studies have emerged that nanotechnology offers innovative solutions to overcome barriers. In this review, we summarized how nanotechnology enhances CAR-T therapy across six dimensions: CAR design, transfection, expansion, modification, monitoring, and combination with other therapies. We discussed the applications of various nanomaterials to improve CAR-T cell function, including lipid nanoparticles, nanogels, and nanobodies. Specifically, we recapitulate that nanotechnology facilitates the generation of CAR-T cells in vivo, enables spatiotemporal control of T cells, remodels the immunosuppressive microenvironment in solid tumors, and enables dual-targeting strategies to mitigate antigen escape. Finally, we outlined the clinical application of nanotechnology in hematological malignancies and solid tumors, as well as non-malignant senescence and autoimmune diseases. Collectively, we believe the integration of nanotechnology enhances the safety and efficacy and broadens therapeutic scope, which will open a new era of precision medicine.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":40.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokines and cancer-associated fibroblasts.","authors":"Yidu Hu, Jiaqi Liang, Lewei Duan, Junkan Zhu, Guangyao Shan, Tao Cheng, Yingting Wu, Lijie Tan, Cheng Zhan","doi":"10.1186/s13045-026-01801-x","DOIUrl":"https://doi.org/10.1186/s13045-026-01801-x","url":null,"abstract":"<p><p>Cancer-associated fibroblast (CAF) is the dominant stromal component within the tumor microenvironment (TME), driving tumor malignancy through complex cell-to-cell communication, with cytokines serving as the fundamental communication medium. In this review, we systematically categorize cytokines into several major families-including interleukins, chemokines, growth factors, tumor necrosis factors, interferons, colony-stimulating factors, and complement system-to delineate their distinct roles in the reciprocal interactions around CAFs, tumor cells, and immune infiltrates. We explore how cytokines function as upstream signals that guide CAF activation and lineage commitment, as well as downstream effectors secreted by CAFs to promote tumor cell malignancy and reprogram the TME. Furthermore, we evaluate therapeutic strategies that target this network by reprogramming CAF functions through blockade of upstream activators or downstream mediators, and by harnessing CAFs for local cytokine delivery. Finally, we address key challenges impeding clinical translation-arising from the pleiotropy, functional redundancy, compensatory feedback loops and spatiotemporal heterogeneity that characterize cytokine signaling networks, as well as from the inherent limitations of current preclinical models-and we outline a theoretical framework for optimizing cytokine-targeted therapies in precision oncology.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":40.4,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current and future immunotherapies for NSCLC.","authors":"Chu-Yu Zhou, Yi-Fan Qi, Hong-Ji Li, Chao Zhang, Bai-Xin Lin, Jun-Tao Lin, Yi-Long Wu, Mei-Mei Zheng, Wen-Zhao Zhong","doi":"10.1186/s13045-026-01791-w","DOIUrl":"10.1186/s13045-026-01791-w","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 axes have fundamentally transformed its treatment landscape. This narrative review traces the evolution of NSCLC immunotherapy, from advanced-stage monotherapy and chemoimmunotherapy to its critical expansion into early-stage disease, highlighting the paradigm shift brought by neoadjuvant, adjuvant, and perioperative strategies. We examine essential clinical challenges, including optimal treatment duration, management of brain metastases, immune-related adverse events, and mechanisms of primary and acquired resistance, with a focus on genomic alterations like KRAS co-mutations with STK11 and KEAP1. Furthermore, we critically evaluate the evolving biomarker landscape, moving beyond PD-L1 to encompass circulating tumour DNA, microbiome composition, and multiparametric approaches like T-cell receptor clonality. Finally, we provide an in-depth exploration of next-generation strategies, including bispecific antibodies, novel checkpoint targets, mRNA vaccines, antibody-drug conjugates, and advanced cellular therapies. While significant progress has been made, refining biomarker-driven selection and optimizing combination sequencing remain paramount. This thorough synthesis highlights promising future directions to overcome these hurdles and improve long-term survival in NSCLC.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":40.4,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolving antibody-drug conjugates in breast cancer from precision delivery to tumor microenvironment reprogramming.","authors":"Na Lu,Bin Yan,Yu-Qiang Li,Jing-Lei Wan","doi":"10.1186/s13045-026-01799-2","DOIUrl":"https://doi.org/10.1186/s13045-026-01799-2","url":null,"abstract":"Antibody-drug conjugates (ADCs) have emerged as an important therapeutic strategy for breast cancer, particularly in the context of its molecular heterogeneity. Initially developed as targeted cytotoxic delivery systems, ADCs are increasingly being explored as multifunctional platforms that may also influence the tumor microenvironment (TME). The expansion of ADC targets beyond human epidermal growth factor receptor 2 (HER2) to include molecules such as trophoblast cell surface antigen 2 (TROP-2) and human epidermal growth factor receptor 3 (HER3) has broadened the therapeutic landscape, offering new options for subtypes with limited targeted therapies, including triple-negative breast cancer (TNBC).Accumulating evidence suggests that the tumor microenvironment plays a critical role in modulating ADC efficacy and resistance. Physical barriers, immunosuppressive signaling, and stromal interactions may limit drug penetration and therapeutic response. In parallel, ADC-induced cytotoxicity has been associated with immunogenic cell death and potential remodeling of the tumor immune milieu. These insights have prompted the development of improved ADC designs, including environment-responsive linkers, optimized payloads, and rational combination strategies with immunotherapy.In this review, we summarize the evolving landscape of ADC development in breast cancer, focusing on target expansion, structural optimization, resistance mechanisms, and interactions with the tumor microenvironment. We also discuss emerging strategies aimed at enhancing therapeutic efficacy and overcoming resistance, highlighting growing interest in integrating targeted cytotoxicity with modulation of the tumor microenvironment.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"26 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-year follow-up of patients with relapsed/refractory mantle cell lymphoma treated with anti-CD19 CAR T-cell therapy in ZUMA-2, Cohorts 1 and 2.","authors":"Javier Muñoz,Frederick L Locke,Patrick M Reagan,Andre Goy,Caron A Jacobson,Brian T Hill,John M Timmerman,Ian W Flinn,David B Miklos,John M Pagel,Marie José Kersten,Edouard Forcade,Max S Topp,Roch Houot,Amer Beitinjaneh,Dan Zheng,Mengru Chang,Wangshu Zhang,Rhine R Shen,Rita Damico Khalid,Ioana Kloos,Michael L Wang","doi":"10.1186/s13045-026-01797-4","DOIUrl":"https://doi.org/10.1186/s13045-026-01797-4","url":null,"abstract":"BACKGROUNDTreatment with brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated a high objective response rate (93%) and complete response rate (67%) in 60 patients with relapsed/refractory mantle cell lymphoma (R/R MCL) treated in the pivotal ZUMA-2 Cohort 1 study. Subsequently, brexu-cel was approved in the United States and European Union for the treatment of adults with R/R MCL (after ≥ 2 prior therapies in the European Union). Here we report 5-year outcomes from the pivotal ZUMA-2 Cohort 1 study (N = 68), as well as two previously unpublished ZUMA-2 data sets, long-term outcomes in 10 patients who received axi-cel in Cohort 1 and in 14 patients who received a lower dose of brexu-cel in Cohort 2.METHODSThe primary endpoint for all cohorts of ZUMA-2 was objective response rate. Key secondary endpoints included duration of response (DOR), overall survival (OS), and safety. Patients could transition to a long-term follow-up study after 24 months for monitoring of survival and select adverse events possibly related to brexu-cel. Patients in Cohort 1 received a single infusion of 2 × 106 anti-CD19 CAR T cells/kg (axi-cel or brexu-cel). Patients in Cohort 2 received 0.5 × 106 anti-CD19 CAR T cells/kg (brexu-cel).RESULTSMedian follow-up for the pivotal cohort (N = 68) was 67.8 months (range, 58.2-88.6) with a median DOR of 36.5 months (n = 60), per investigator review. Median OS was 46.5 months (95% CI, 24.5-60.2; N = 68) and was 60.2 months (95% CI, 42.8-not estimable) in patients with complete response (n = 46). The 5-year incidence of cumulative relapse-related and non-relapse-related mortality was 40% (24/60) and 22% (13/60) in responders, respectively. Descriptive outcomes for axi-cel-treated patients (N = 10) and Cohort 2 (N = 14) are reported herein. No Grade 5 cytokine-release syndrome or neurologic events, subsequent T-cell malignancies, or new safety signals were reported in any patient.CONCLUSIONSPatients in ZUMA-2 continued to have durable responses after 5 years of follow-up with predictable long-term safety, supporting the continued use of brexu-cel in R/R MCL. Interpretations of outcomes in axi-cel-treated patients and Cohort 2 are not feasible due to small patient numbers and unmatched baseline characteristics.TRIAL REGISTRATIONNCT02601313 and NCT05041309.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"144 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Claudin18.2 positive gastric cancer: biology, tumor microenvironment, and therapeutic strategies.","authors":"Yi Xie,Pengfei Guan,Dan Liu,Zhi Peng,Xiaotian Zhang,Lin Shen,Yang Chen","doi":"10.1186/s13045-026-01803-9","DOIUrl":"https://doi.org/10.1186/s13045-026-01803-9","url":null,"abstract":"Claudin18.2 (CLDN18.2) is primarily expressed in gastric epithelial cells, where it plays a crucial role in maintaining the integrity of the gastric mucosal barrier. Its aberrant expression is closely associated with the initiation, progression, and tumor microenvironment (TME) remodeling of gastric cancer(GC). Clinical evidence indicates that CLDN18.2 is highly expressed in a substantial proportion of GC. Notably, its expression appears to be largely independent of established biomarkers such as human epidermal growth factor receptor 2 (HER2) and programmed death-ligand 1 (PD-L1). These features collectively suggest CLDN18.2 as a viable candidate for therapeutic intervention in GC. Increasing evidence suggests that CLDN18.2 positivity is associated with patient prognosis and may indicate a distinctive TME characterized by increased infiltration of CD4⁺ and CD8⁺ T cells, macrophages, and cancer-associated fibroblasts. This review systematically summarizes the biological characteristics of CLDN18.2 and the features of CLDN18.2-positive TME, and provides an overview of emerging therapeutic strategies targeting CLDN18.2. The aim is to elucidate the biological and clinical significance of CLDN18.2 in GC and to provide insights for optimizing future precision therapies.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"68 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in multiple myeloma: key updates from the ASH 2025 meeting.","authors":"Phyu Thin Naing,Muhamed Baljevic","doi":"10.1186/s13045-026-01802-w","DOIUrl":"https://doi.org/10.1186/s13045-026-01802-w","url":null,"abstract":"The therapeutic landscape of multiple myeloma (MM) is undergoing rapid transformation with the expansion of immune-based strategies. This editorial summarizes key MM abstracts presented at the American Society of Hematology (ASH) 2025 meeting, highlighting how bispecific antibodies (BsAbs), minimal residual disease (MRD)-adaptive approaches, and next-generation immune platforms are reshaping treatment across all MM disease stages. In newly diagnosed MM (NDMM), minimal residual disease (MRD)-adaptive consolidation with linvoseltamab in IMMUNOPLANT converted persistent MRD positivity to MRD negativity in all evaluable patients, supporting biologically guided treatment intensification. In transplant-ineligible (TIE) NDMM patients, TecLille showed that antibody-only therapy achieved deep responses with manageable infection risks. In early relapsed/refractory MM (RRMM), the pioneering phase III MajesTEC-3 trial demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits with BsAb teclistamab plus daratumumab compared to other standard triplets, with response rates approaching those historically observed with chimeric antigen receptor (CAR) T cell therapy. A novel rational BsAb combination of BsAb elranatamab anda cereblon E3 ligase modulatory drug (CELMoD) iberdomide in MagnetisMM-30 showed promising synergy despite cytopenias and updates to combination BsAb targeting in RedirecTT-1 demonstrated major activity in difficult to treat extramedullary myeloma (EMM). First-in-human inMMyCAR data showcased the forefront of engineered immune strategies, by introducing an in vivo CAR-T product as a proof-of-concept platform, with tremendous potential to streamline the access to therapy. Collectively, these studies signal a shift toward earlier and adaptive immunotherapy in all phases of MM disease, while underscoring the importance of infection mitigation and long-term safety evaluation.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"21 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved outcomes of the refined risk-stratification and risk-adapted therapy in children with acute myeloid leukemia: final results of the AIEOP AML 2013.","authors":"Franco Locatelli,Barbara Buldini,Martina Pigazzi,Carmelo Rizzari,Giuseppe Menna,Franca Fagioli,Manuela Tumino,Luca Lo Nigro,Paolo D'Angelo,Maria Giuseppina Cefalo,Valeria Paganelli,Luisa Strocchio,Marco Becilli,Marco Spinelli,Giovanna Giagnuolo,Francesco Saglio,Nicola Santoro,Concetta Micalizzi,Marco Zecca,Riccardo Masetti,Pietro Merli","doi":"10.1186/s13045-026-01798-3","DOIUrl":"https://doi.org/10.1186/s13045-026-01798-3","url":null,"abstract":"BACKGROUNDThe previous Italian national trial (AIEOP-AML-2002/01) on children with acute myeloid leukemia (AML) achieved a 3-year overall (OS) and event-free survival (EFS) of 72.3% and 59.1%, respectively. In this study (AIEOP-AML-2013), we evaluated if refined patient's stratification in 3 groups and a second induction with randomization could improve outcomes.METHODSIn the new AIEOP-AML-2013, patients were stratified into 3 groups [standard-(SR), intermediate-(IR) and high-risk (HR)] mainly according to genetic criteria and centralized assessment of multiparametric flow-cytometry measurable residual disease (MFC-MRD). The 1st induction course was common for all patients [idarubicin-cytarabine-etoposide (ICE)]. IR and HR patients were then randomized to receive either a 2nd ICE or the fludarabine-cytarabine- liposomal-doxorubicin (FLA-My) scheme as second induction. IR patients with HLA-compatible sibling, and all HR patients were consolidated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), while the remaining IR and SR patients were consolidated with chemotherapy only. Data cut-off was February 1, 2024.RESULTSFrom June/2015 to June/2022, 371 patients were enrolled in the trial. Twenty-six children (7%) experienced primary induction failure, while only 3 patients died during the 2 induction courses. The cumulative incidence of 3-year non-relapse mortality in continuous complete remission was 6.8%. The proportion of patients allocated to the SR, IR, and HR groups were 19.5%, 22%, and 58.5%, respectively. Three-year cumulative incidence of relapse was 18.9%. The 3-year probabilities of OS and EFS were 83.9% and 68.5%, respectively, both values being significantly better (p = 0.001) than those of the AIEOP-AML-2002/01 study. The 3-year OS of SR, IR, and HR patients were 97.0%, 84.2%, and 79.4%, respectively, (p = 0.01). The probability of EFS did not differ in IR and HR randomized to receive either a 2nd ICE or the FLA-My scheme course. Levels of MRD after the 1st and 2nd induction course strongly influenced the EFS probability.CONCLUSIONSA significant improvement in the outcomes of children with de novo AML was obtained with refined risk-stratification and risk-adapted therapy. FLA-My did not offer any advantage over repeating a 2nd ICE as 2nd induction course.TRIAL REGISTRATIONThis study was registered in the European Clinical Trials Database (EudraCT 2014-000652-28).","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"135 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncoupling toxicity from efficacy in donor selection for allogeneic hematopoietic cell transplantation: a retrospective cohort study using double machine learning.","authors":"Rohtesh S Mehta,Yosra M Aljawai,Warren Fingrut,Portia Smallbone,Gabriela Rondon,Amanda Olson,Betul Oran,Partow Kebriaei,Richard E Champlin,Elizabeth J Shpall","doi":"10.1186/s13045-026-01800-y","DOIUrl":"https://doi.org/10.1186/s13045-026-01800-y","url":null,"abstract":"Haploidentical hematopoietic cell transplantation (HCT) offers potent graft-versus-tumor effects but is historically limited by higher non-relapse mortality (NRM) compared to matched unrelated (MUD) or related donors (MRD). To algorithmically decouple the competing risks of NRM and relapse, we analyzed 1,713 adult patients (MD Anderson discovery cohort) and 6,829 patients (registry replication cohorts) using a double machine-learning framework of Causal Survival Forests to estimate individualized treatment effects, while Random Survival Forests defined absolute prognostic risk. We found biological uncoupling of relapse and NRM: relapse was driven by disease biology, while NRM was governed by physiological reserve. Specifically, cardiovascular or cerebrovascular comorbidities acted as selective amplifiers of haploidentical toxicity-a \"vascular penalty\" that doubled mortality risk in the bootstrapped model (sub-distribution hazard ratio 2.09, 95% confidence interval 1.26-3.35). We developed a 3-factor nomogram (recipient age, vascular comorbidity, B-leader matching status) to identify an \"Optimized Haploidentical\" phenotype. Exploratory multivariable modeling suggested MUD consistently maximized predicted disease-free survival across all subgroups. Among haploidentical versus MRD comparisons, B-leader mismatch appeared to favor MRD across ages, while B-leader matched haploidentical donors in older patients (≥ 60 years) modeled near-equivalent DFS to MRD, representing a hypothesis-generating \"zone of equivalence\" requiring prospective validation.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"37 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}