Blood advances最新文献

{"title":"Immunophenotyping challenges in the diagnosis of NK-LGLL.","authors":"Aaron J Wilk, Jean S Oak, Erik Ames","doi":"10.1182/bloodadvances.2026020111","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026020111","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855936","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":"Gilteritinib + chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.","authors":"Philip Connor, Raul C Ribeiro, Albert Catala, Alice Norton, Michael M Schündeln, Nahla Hasabou, David Delgado, Alexandra Natalie Heinloth, Jason E Hill, Stanley C Gill, Theophile Bigirumurame, Sarah K Tasian, Franco Locatelli","doi":"10.1182/bloodadvances.2026020144","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026020144","url":null,"abstract":"<p><p>Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) occurs in ~15% of pediatric patients with acute myeloid leukemia (AML) and is associated with high relapse risk with conventional chemotherapy. Gilteritinib is a selective, next-generation FLT3 inhibitor (FLT3i) approved for adults with relapsed/refractory FLT3‑mutated AML, but pediatric-specific data remain limited. The multi-national phase 1/2 SKIPPER study evaluated gilteritinib combined with fludarabine and cytarabine chemotherapy and granulocyte colony‑stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3‑ITD AML. Nine patients, aged 8-15 years, were enrolled in phase 1 of the study between 2020 and 2023. Recruitment challenges, including disease rarity, off‑label FLT3i availability, and competing trials, led to study termination after phase 1. The composite complete remission rate in the study population was 66.7% (95% confidence interval: 29.9%-92.5%). Two‑year event‑free and overall survival probability was 41.7% and 55.6%, respectively. Treatment‑emergent adverse events, most commonly reversible hepatic enzyme elevations and cytopenias, were consistent with known toxicity profiles of gilteritinib and FLAG. Pharmacokinetic parameters were comparable to those of adults, and pharmacodynamic plasma inhibitory activity assays confirmed sustained FLT3 inhibition. No dose‑limiting toxicities were observed, and the recommended phase 2 dose of gilteritinib was established at 2 mg/kg/day for patients ≥2 years old. The gilteritinib and FLAG regimen had manageable safety, induced high remission rates, and enabled allogeneic hematopoietic stem cell transplant for several patients. Although limited by a small sample size, these findings support further evaluation of gilteritinib in pediatric patients with FLT3-mutated AML, particularly in frontline settings (ClinicalTrials.gov Identifier: NCT04240002).</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855975","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":"Disease Extent, Not Lesion Location, Determines Relapse Risk in Single-System Skeletal Langerhans Cell Histiocytosis.","authors":"Itziar Astigarraga, Helga Björk Arnardóttir, Oussama Abla, Maurizio Aricó, Jorge Luis Braier, Jean Donadieu, Nicole Grois, Jan-Inge Henter, Stephan Ladisch, Thomas Lehrnbecher, Kenneth L McClain, Vasanta Nanduri, Carlos Rodriguez-Galindo, Elena Sieni, Sheila Weitzman, Ulrike Pötschger, Milen Minkov","doi":"10.1182/bloodadvances.2026020075","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026020075","url":null,"abstract":"<p><p>Langerhans cell histiocytosis (LCH) confined to the skeleton has excellent survival, yet optimal management of multifocal bone disease and lesions at traditionally defined \"special sites\" remains uncertain due to limited prospective data. We report prospective results from an international pilot trial embedded within the Histiocyte Society LCH-III study (2001-2008; NCT00276757) evaluating six months of vinblastine-prednisolone in children with single-system skeletal LCH. Among 455 enrolled patients, 381 were evaluable. Early response at week 6 was achieved in 83% of cases. Five-year overall survival was 100%, and event-free survival (EFS) was 71%. Multifocal bone lesions (MFB) were the dominant predictor of relapse (5-year EFS: 63% vs 87% without MFB; p<0.001), whereas isolated CNS-risk skeletal lesions did not independently affect EFS. In contrast, the cumulative incidence of central diabetes insipidus at 5 years was 5% overall but was significantly higher in patients with CNS-risk lesions, particularly when combined with MFB. These prospective data demonstrate that in single-system skeletal LCH, disease extent and lesion location confer distinct risks, with skeletal multiplicity determining relapse propensity and anatomic location determining the risk of permanent endocrine sequelae. This study provides a prospective international benchmark for systemic therapy and supports risk-adapted treatment strategies that minimize long-term morbidity while avoiding unnecessary treatment escalation.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855916","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":"Long-term Follow-up of a Pediatric Regimen for AYA with Ph-negative ALL: 10-year Survival of CALGB 10403 (Alliance).","authors":"Wellington F Silva, Jun Yin, Michaela Liedtke, David Claxton, Noreen Fulton, Sharmila Giri, Gregory Malnassy, Krzysztof Mrózek, Elisabeth Paietta, Charles G Mullighan, Ilene A Galinsky, Jeffrey Bogart, John C Grecula, LeAnne Kennedy, Richard A Larson, Richard M Stone, Geoffrey L Uy, Selina M Luger, Anjali S Advani, Wendy Stock","doi":"10.1182/bloodadvances.2026019616","DOIUrl":"10.1182/bloodadvances.2026019616","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855969","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":"A long first intron of PROS1 modulates protein S expression across tissues in mice and humans.","authors":"Keiko Maruyama, Sheng Ye, Yuka Eura, Akihiro Tsuji, Yoshitaka Fujihara, Koichi Kokame","doi":"10.1182/bloodadvances.2026019759","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026019759","url":null,"abstract":"<p><p>Introns can modulate gene expression through enhancer- or silencer-like elements, as well as intron-mediated enhancement. Protein S (PS), encoded by PROS1, is an anticoagulant cofactor for activated protein C and tissue factor pathway inhibitor. PROS1 spans ~100 kb and harbors an unusually long first intron (~46 kb). We asked whether intron 1 contributes to PS regulation. Reporter assays in HepG2 cells identified discrete intron-1 regions that enhanced or repressed PROS1 promoter activity. CRISPR/Cas9-mediated deletion of most of intron 1 in HepG2 cells reduced endogenous PS mRNA and secreted PS. Mice carrying large intron-1 deletions were viable but showed markedly reduced PS antigen in plasma and platelets versus wild type. Tissue profiling revealed variable decreases in PS mRNA across organs, indicating tissue-dependent regulation. In a patient with congenital PS deficiency who was initially negative by conventional coding-region sequencing, long-read sequencing uncovered rare intron-1 variants that reduced reporter activity. These data show that regulatory sequences within PROS1 intron 1 are necessary to maintain PS expression in vivo and suggest that noncoding intronic variants may contribute to congenital PS deficiency. Our findings support incorporating PROS1 intron 1 and other noncoding PROS1 regions into genetic testing for PS deficiency.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856008","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":"Revisiting KIR Restriction and CD94 Expression in Diagnostic Criteria for NK-Large Granular Lymphocytic Leukemia.","authors":"Jansen N Seheult, Gregory E Otteson, Dragan Jevremovic, William W Morice, Michael M Timm, Eric D Hsi, Horatiu Olteanu, Pedro Horna, Min Shi","doi":"10.1182/bloodadvances.2026020572","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026020572","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855986","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":"Single cell long read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-MPN AML.","authors":"Julian Grabek, Jasmin M Straube, Leanne Cooper, Rohit Halder, Ranran Zhang, Inken Dulige, Matthew A Barker, Will Gatehouse, Helen Christensen, Gerlinda Amor, Victoria Y Ling, Caroline McNamara, David M Ross, Andrew C Perkins, Megan J Bywater, Steven W Lane","doi":"10.1182/bloodadvances.2025018902","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025018902","url":null,"abstract":"<p><p>Myeloproliferative neoplasms (MPNs) are caused by acquired mutations in hematopoietic stem and progenitor cells (HSPCs). The acquisition of additional mutations like TP53 and the overall mutational burden influence a patient's risk of disease progression toward lethal post-MPN acute myeloid leukemia (AML). Recent technological advancements in linking single-cell gene expression with genotype have improved our understanding of tumor heterogeneity. However, current methodologies have limitations in simultaneously genotyping low-expression genes (such as JAK2) alongside other pathogenic loci. To address this, we developed a novel long read genotyping pipeline of cDNA transcripts called LOTR-Seq, which can genotype the full length of expressed transcripts of 30 genes at once. Using LOTR-Seq, we genotyped HSPCs at the JAK2V617 locus in 9,075 single cells from eight patients with chronic phase MPN (CP-MPN) and in 5,016 cells from four patients with post-MPN AML. We then linked the mutations to the single cell transcriptome of 29,712 JAK2V617F-driven CP-MPN cells and 16,895 post-MPN AML cells. In our analysis of post-MPN AMLs, we identified nine mutated loci across six genes (JAK2, IDH1/2, TP53, SRSF2, U2AF1) and linked these mutations to specific transcriptional phenotypes. Overall, LOTR-Seq provides novel insights into the evolution of post-MPN AML.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833925","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":"Metabolic Profiling and Perturbations of Human CD34+ Hematopoietic Stem and Progenitors to Regulate HSPC Function.","authors":"Kai Yuan, Mingfang Xiong, Rong Yang, Keyu Sun, Zheng Zhang, Shiwei Zhang, Yanyu Xiu, Bo Cai, Jing Yang, Yan Ju, Hongyu Yin, Fei Liang, Yuying Sun, Guangyu Zhao, Yang Zeng","doi":"10.1182/bloodadvances.2025018876","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025018876","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) possess self-renewal and multilineage differentiation abilities to generate blood cells and sustain hematopoiesis. Recent studies indicate that HSC metabolism is crucial for regulating their function and cell fate determination in mammals. However, a comprehensive understanding of the metabolic landscape of human HSCs across distinct developmental stages remains lacking. In this study, we performed untargeted metabolomics of Lin-CD34+ hematopoietic stem and progenitor cells (HSPCs) from human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM), revealing different developmentally associated metabolic signatures that shape HSPC function across ontogeny. Metabolomic analysis identified D-glutamine and arachidonic acid (AA) as metabolites exhibiting distinct abundance during HSPC development, suggesting their potential roles in modulating HSPC function. Transcriptomic profiling after specific metabolic treatment further revealed distinct gene expression programs associated with lineage commitment, stemness maintenance, and metabolic regulation. Functional assays demonstrated that the inhibition of glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) induced HSPCs into quiescent cell states, improving the engraftment of HSPCs and myeloid differentiation. Conversely, exogenous AA supplementation in HSPC culture promoted proliferation and significantly enhanced megakaryocytic differentiation both in vitro and in vivo. Collectively, our study profiled the metabolic landscape of human HSPCs from embryonic to adult period through the newborn stages, suggesting that metabolic modulation could regulate HSPC function. These findings provide novel mechanistic insights and potential strategies for metabolite-based interventions to promote and enhance human HSPC function, with broad implications for basic research and regenerative medicine.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833932","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":"Toxicity from asparaginase during acute lymphoblastic leukemia induction: A report from the Children's Oncology Group.","authors":"Etan Orgel, Luke D Maese, Meenakshi Devidas, Olga Militano, Rachel E Rau, Anne Angiolillo, Jennifer McNeer, Reuven J Schore, Michael J Borowitz, Brent L Wood, Elizabeth A Raetz, Lewis B Silverman, Naomi J Winick, Eric C Larsen, William L Carroll, Stuart Sheldon Winter, Kimberly P Dunsmore, Stephen P Hunger, Mignon L Loh","doi":"10.1182/bloodadvances.2026019870","DOIUrl":"https://doi.org/10.1182/bloodadvances.2026019870","url":null,"abstract":"<p><p>Asparaginase-associated toxicities (AAT) often compromise therapy for acute lymphoblastic leukemia (ALL), impacting relapse risk and survival. There are conflicting data on the contributions of older age, obesity by body mass index (BMI), and/or large body surface area (BSA) to AAT. We examined the association of these risk factors with AAT and the impact of AAT on disease response. Induction data were examined from 4,925 patients ages 1-30 years enrolled in the Children's Oncology Group ALL trials AALL0232 and AALL0434, which included a single dose of pegaspargase (2,500 IU/m2) without a maximum dose. The associations of age, BMI, and BSA with hyperbilirubinemia, elevated alanine aminotransferase (ALT), thrombosis, and pancreatitis were evaluated. The impact of AAT on minimal residual disease (MRD) positivity (≥0.01%) at the end of induction (EOI) was assessed. Increased risk for developing at least one AAT was observed in patients ≥10 years (p=0.002) and in those with obesity and high BSA (p<0.0001), but not with high BSA alone. Risks for hyperbilirubinemia, ALT elevations, and thrombosis were all increased in patients with obesity and high BSA (Odds ratio [OR] 3.5 [95% confidence interval [CI] 2.2-5.7], OR 3.3 [95%CI 1.7-6.6], and OR 3.1 [95%CI 1.5-6.5], respectively). AATs were not associated with EOI MRD positivity. To our knowledge, we report the largest dataset of AAT in children, adolescents, and young adults. Preventive strategies are indicated for older patients and for those with obesity and high BSA but not with high BSA alone. NCT00075725, NCT00408005.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833863","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":"Infections in Patients Receiving Daratumumab for Newly Diagnosed Multiple Myeloma: A Pooled Analysis of MAIA and ALCYONE.","authors":"Nizar J Bahlis, Thierry Facon, Jesús F San-Miguel, Saad Z Usmani, Meletios-Athanasios A Dimopoulos, Philippe Moreau, Sonja Zweegman, Aurore Perrot, Salomon Manier, Ajai Chari, Noopur S Raje, Robert Z Orlowski, Hartmut Goldschmidt, Supratik Basu, Cyrille Hulin, Katja C Weisel, Mohamad Mohty, Xavier Leleu, Torben Plesner, Andrzej J Jakubowiak, Gordon Cook, Hang Quach, Christopher P Venner, Michele Cavo, Mai Ngo, Kasey Bolyard, Robin Carson, Fredrik Borgsten, Maria-Victoria Mateos, Shaji K Kumar","doi":"10.1182/bloodadvances.2025019323","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025019323","url":null,"abstract":"<p><p>Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care lenalidomide and dexamethasone (D-Rd) or bortezomib, melphalan, and prednisone (D-VMP), respectively, versus Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP versus Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any grade infections led to discontinuation of study treatment in approximately 2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in D-Rd/D-VMP and Rd/VMP groups, respectively. While rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. ClinicalTrials.gov Identifiers NCT02252172 (MAIA) and NCT02195479 (ALCYONE).</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833946","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}