Blood advances最新文献

{"title":"Genome-wide association study of somatic GATA1s mutations in newborns with Down Syndrome.","authors":"Yunqi Li, Natalina Elliott, Patricia Lein, Paresh Vyas, Irene Roberts, Adam J de Smith","doi":"10.1182/bloodadvances.2025016282","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016282","url":null,"abstract":"<p><p>Myeloid Leukemia of Down Syndrome (ML-DS) is preceded by a transient neonatal preleukemia driven by somatic mutations in the chromosome X gene GATA1, resulting in a shorter protein isoform (GATA1s). GATA1s mutations occur at high frequency in DS but beyond trisomy 21, risk factors for this preleukemia are unknown. We investigated whether germline genetic variation influences development of GATA1s mutations in DS. Whole-genome sequencing was performed on 434 DS children from the Oxford DS Study previously screened for GATA1s mutations. Following quality control, association tests were conducted separately for disomic autosomes, trisomic chromosome 21, and chromosome X. Regression tests were performed for mutation variant allele frequency or the binary trait (103 GATA1s-positive cases, 326 controls), adjusting for sex and ancestry-related principal components. Genetic ancestry of each subject was inferred and tested for association with GATA1s mutations. We identified three genome-wide significant (P<5x10-8) loci associated with GATA1s mutations. However, these may be false positives as few linked variants showed evidence of association at each locus. No significant associations were detected on chromosome 21 or the GATA1 region on chromosome X. Increasing proportions of South Asian genetic ancestry were associated with an increased risk of GATA1s mutations, with each 10% increase in ancestry associated with a 1.11-fold higher risk of developing GATA1s mutations (P=0.031). Our genetic epidemiology study of somatic GATA1s mutations in DS did not identify strong germline genetic effects. The association with genetic ancestry may relate to unmeasured genetic or nongenetic effects, such as fetal exposures, and warrants further investigation.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970599","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":"LNS-8801 as a therapeutic agent for aggressive lymphomas: ROS-induced cytotoxicity and synergy with existing therapies.","authors":"Yang Li, Corinna Kosnopfel, Daniela Schwammbach, Ling Jin, Michael Grau, Georg Lenz, Stephan Hailfinger","doi":"10.1182/bloodadvances.2025016199","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016199","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963957","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":"Atezolizumab Consolidation in Patients with High Risk Diffuse Large B-cell Lymphoma in Complete Remission after R-CHOP.","authors":"Marcel Nijland, Djamila E Issa, Johanna A A Bult, Dries Deeren, Gerjo A Velders, Marten R Nijziel, Yorick Sandberg, Vibeke Kj Vergote, Margriet Oosterveld, Rob Fijnheer, Rolf Brouwer, Rinske Boersma, Kalung Wu, Laurens Nieuwenhuizen, Joost Sp Vermaat, Roel J W van Kampen, Wim E Terpstra, Sylvia Snauwaert, Marjolein Wm van der Poel, Eva de Jongh, Marc Durian, Leonie Strobbe, Aart Beeker, Alain Pa Gadisseur, Roos Van Rijn, Otto J Visser, Jeanette Doorduijn, Tjeerd J F Snijders, Matthijs H Silbermann, Daphne de Jong, Martine E D Chamuleau, Rogier Mous, Mathilde Jalving, Heleen Visser-Wisselaar, Sonja Jansen van den Bergh, Gerben Jc Zwezerijnen, Edwin Bremer, Mirian Brink, Arjan Diepstra, Dana A Chitu, Harry R Koene, Josée M Zijlstra","doi":"10.1182/bloodadvances.2024015226","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015226","url":null,"abstract":"<p><p>The risk of relapse among high-risk diffuse large B-cell lymphoma (DLBCL) patients in complete metabolic remission (CMR) following R-CHOP therapy is 20-25%. Here, we evaluated whether consolidation with the PDL-1 checkpoint inhibitor atezolizumab could reduce the relapse risk. In this phase II, open-label trial (NCT03463057) DLBCL patients with an international prognostic index (IPI) score of ≥ 3 and CMR after R-CHOP received 1200mg atezolizumab every 3 weeks for 18 cycles. The primary endpoint was disease-free survival (DFS) at 2 years with the aim of improving it to 89% compared to historical 79%. Secondary endpoints included overall survival (OS) and safety (CTCAE version 4.0). Analyses were intention-to-treat. Of 109 patients, 65% completed treatment. The cohort was 59% males, with 63% having high-intermediate risk IPI scores. At a median follow-up of 36.4 months, 15 relapses occurred (median time 8.2 months). The 2-year DFS was 87.9% (90% confidence interval (CI) 81.5-92.1%) and 2-year OS was 96.3% (90% CI 91.7-98.3%) meeting the primary objective. Treatment with salvage chemotherapy resulted in 10/13 patients achieving a second CMR. Compared to a population-based matched control cohort from the Netherlands Cancer Registry, OS was significantly better among atezolizumab-treated patients. Adverse events (AE) affected 79% of patients, with 18% developing immune-related AEs, including 4.5% grade 3-4. Atezolizumab consolidation significantly improved DFS in high-risk DLBCL patients compared to historical cohorts. OS was significantly better compared to a population-based control cohort. These findings warrant further validation and assessment of immune checkpoint inhibitors as consolidation strategy in DLBCL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979008","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":"Prognostic Significance of Monocytic-like Phenotype in AML patients treated with Venetoclax and Azacytidine.","authors":"Lin-Pierre Zhao, Typhaine Dumas-Rivero, Lauren Barette, Lorea Aguinaga, Arij Cheffai, Clementine Chauvel, Reinaldo Dal Bello, Emmanuel Raffoux, Emmanuelle Clappier, Matthieu Duchmann, Pierre Fenaux, Pierre Lemaire, Stephanie Mathis, Marie Sébert, Lionel Adès, Raphael A Itzykson","doi":"10.1182/bloodadvances.2024015734","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015734","url":null,"abstract":"<p><p>The prognostic impact of monocytic differentiation in AML patients receiving Venetoclax (Ven) and azacitidine (Aza) remains unclear. In a prospective cohort of 86 newly diagnosed AML patients treated with Ven-Aza, we used multiparametric flow cytometry (MFC) to define mono-blasts as AML blasts co-expressing ≥2 monocytic markers (CD4, CD36, CD64) per ELN guidelines. Patients with higher mono-blasts/CD45+ proportions had lower complete response rates (OR=0.24, p=0.005) and significantly shorter overall survival (OS, 4.0 versus 14.9 months, p=0.003). A ≥10% mono-blasts/CD45+ threshold, identified via maximally selected rank statistics, stratified patients into mono-blasthigh (≥10%) and mono-blastlow (<10%) groups. MFC reclassified 20% of FAB non-M4/5 and 15% of FAB M4/5 cases into mono-blasthigh and mono-blastlow groups, respectively. Multivariable analysis confirmed mono-blasthigh status as an independent adverse prognostic factor for OS (HR=1.95, p=0.023), with a particularly strong impact in ELN 2024 favorable-risk patients (HR=2.81, p=0.024). Our findings highlight monocytic differentiation, assessed via MFC, as a key predictor of Ven-Aza resistance and poor survival, independent of genetic classification. Given its availability in routine diagnostics, MFC-based monocytic assessment could improve AML risk stratification and treatment decisions in patients eligible for less intensive therapies.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981522","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":"Red blood cell aggregation within a blood clot causes platelet-independent clot shrinkage.","authors":"Alina D Peshkova, Ekaterina K Rednikova, Rafael R Khismatullin, Oleg V Kim, Vladimir R Muzykantov, Prashant K Purohit, Rustem I Litvinov, John W Weisel","doi":"10.1182/bloodadvances.2024015533","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015533","url":null,"abstract":"<p><p>Platelet-driven blood clot contraction (retraction) is important for hemostasis and thrombosis. RBCs occupy about half of the clot volume, but their possible active contribution to contraction is unknown. The work was aimed at elucidating the ability of RBCs to promote clot shrinkage. To distinguish effects of platelets and RBCs, we formed thrombin-induced clots from reconstituted human samples containing platelet-free plasma and platelet-depleted RBCs, followed by tracking the clot size. The clots before and after RBC-induced shrinkage were analyzed using histology and scanning electron microscopy. Tension developed in the RBC-containing plasma clots was measured with rheometry and theoretical modeling was used to elucidate the clot shrinkage mechanisms. Platelet-depleted clots formed in the presence of RBCs exhibited >20% volume shrinkage within one hour. This process was insensitive to blebbistatin, latrunculin A, and abciximab. At a higher RBC count clot shrinkage increased, whereas in the absence of RBCs no plasma clot shrinkage was observed. At low platelet counts RBCs stimulated clot contraction proportionately to the platelet level. Inside the shrunken clots, RBCs formed aggregates. The average tensile force per one RBC was ~120±100 pN. Clots from purified fibrinogen formed in the presence of RBCs did not change in size, but underwent shrinkage in the presence of osmotically active dextran. Blood clot shrinkage can be caused by RBCs alone and this effect is due to the RBC aggregation driven mainly by osmotic depletion. The RBC-induced clot shrinkage may reinforce platelet-driven blood clot contraction and promote clot compaction when there are few and/or dysfunctional platelets.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973561","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":"Expression and treatment of ROR1+ cells with bispecific T cell engagers in pediatric acute lymphoblastic leukemia.","authors":"Paraskevi Diamanti, Bethan K Bailey, Obinna E Iheanacho, John P Moppett, Amit C Nathwani, Allison Blair","doi":"10.1182/bloodadvances.2024013814","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013814","url":null,"abstract":"<p><p>Receptor tyrosine-like orphan receptor (ROR)1 is overexpressed in some hematological cancers but has low expression in normal tissues, making it a potential therapeutic target. We investigated this therapeutic potential in childhood B cell precursor (BCP) and T cell acute lymphoblastic leukemia (ALL) cases. The proportion of ROR1+ cells was significantly higher in T-ALL (median 13.8%, range 2.9-87%) than BCP-ALL (6%, 0.3-83%, P=0.02). Antigen density was also lower in BCP-ALL (median 1027, range 876-2588) compared to T-ALL (1089, 865-1527). In leukemia propagating cells (LPC), ROR1 levels were highest in CD34-/CD19+ and CD34-/CD7+ subpopulations. Notably, ROR1+ LPC, in both BCP- and T-ALL, survived induction therapy and their numbers increased post treatment. Subsequently, ROR1 bispecific T cell engagers (Teng) were tested on primary cases in vitro and in vivo. Addition of ROR1 Teng in vitro reduced ALL survival to 44% in BCP- and 58% in T-ALL, compared to T cells alone (94% and 84%, respectively P≤0.01). When NOD.Cg-PrkdcscidIl2rγtm1Wjl/SzJ mice engrafted with primary leukemia were treated with ROR1 Teng, disease burden was reduced by up to 520-fold (from 15.6% to 0.03%) in ROR1+ cells and 68-fold (58% to 0.9%) in CD19+ cells in BCP-ALL. In T-ALL cases, there was a 4-fold reduction (1.2% to 0.3%) in ROR1+ and 2.3-fold (83.7% to 36.7%) in CD7+ levels. This resistance of ROR1+ cells to current therapies makes it an important target. Moreover, as ROR1 Teng were at least comparable to CD19 Teng in vivo, they could be considered for the treatment of refractory BCP-ALL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983882","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":"Molecular inflammatory expression profiles associated with the frequency of pain in individuals with sickle cell disease.","authors":"Lana Mucalo Katunaric, Shuang Jia, Ashima Singh, Mark F Roethle, Julie A Panepinto, David Brousseau, Martin Hessner, Amanda M Brandow","doi":"10.1182/bloodadvances.2024015085","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015085","url":null,"abstract":"<p><p>Pain is the most common complication of sickle cell disease (SCD). The underlying biology of SCD pain is not well understood, which is a barrier to novel, effective analgesic and preventative therapies. A wide variability in the phenotypic expression of pain exists among individuals with SCD, despite the inheritance of a similar defective hemoglobin gene. This interindividual pain variability further complicates the ability to understand the biology and effectively treat pain. We sought to discover a biological signature comprised of differentially expressed genes unique to SCD that could differentiate between individuals with varied pain frequency. We conducted plasma-induced transcription analysis from 149 individuals with SCD and 60 Black individuals without SCD from multiple sites. We discovered 3028 differentially expressed genes that underwent Weighted Gene Co-Expression Network Analysis (WGCNA) to distinguish gene modules significantly associated with pain frequency. We identified 524 genes, significantly associated with pain frequency (≥|0.3| and p<0.05), that were further analyzed using The Database for Annotation, Visualization and Integrated Discovery (DAVID) tool to delineate the biological pathways associated with these genes. The highest ranked gene ontology process from DAVID was inflammatory response (p=1.67E-12) and many related pathways were enriched (e.g., response to lipopolysaccharide, chemokine and cytokine signaling). The top 10 hub genes identified within our biologic signature were TNF, CCL2, ITGAM, ITGAX, ICAM1, CCR5, CXCL2, IFNG, CCR1, CXCL3. Future work should focus on further validating this signature and investigating the potential targets uncovered for their mechanistic and potentially therapeutic role in SCD pain.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987582","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":"Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma.","authors":"Bo Zhang, Yaping Xie, Minmin Shen, Jianai Sun, Yue Li, Jing Zhang, Qi Li, Chuanghua Chen, Zhenzhen Chen, Wei Wang, Jingcheng Wu, Zhan Zhou, Jianhua Fang, Youyou Yan, Shenxian Qian, Xiangmin Tong, Nengming Lin, Hongyan Tong","doi":"10.1182/bloodadvances.2024015469","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015469","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by distinct morphological, genetic, and clinical features. DLBCL with Myc/Bcl-2 double-expression (DE) has been positively correlated with poor prognosis and a low response rate to chemotherapy. However, molecular mechanisms underlying the malignant progression of DE DLBCL, and the tumor microenvironment of DE DLBCL has not been fully elucidated. In this study, we assessed protein expression in 18 DLBCL patient samples using imaging mass cytometry with a panel of 26 metal-tagged antibodies, identifying eight cell types within the tumor microenvironment. Although the ratio of immune cells did not significantly differ between DE and non-DE tissues, a strong interaction between fibroblasts and exhausted CD8+ T cells was specifically observed in DE tissues. By comparing protein expression ratios between DE and non-DE tissues, we found that p-S6 levels were significantly higher in B cells and fibroblasts of DE samples compared to non-DE samples. In our retrospective study, p-S6 independently predicted an inferior prognosis in DLBCL patients (n=71, HR = 5.758; 95% CI: 1.297-25.558; p=0.021). Additionally, co-culture with fibroblasts accelerated the in vitro and in vivo growth of DLBCL cells, and enrichment of the mTOR/S6 pathways was identified using bulk RNA sequencing. Conversely, specific inhibition of p-S6 suppressed DLBCL cell proliferation and exhibited synergistic effects with chemotherapy in vivo. In summary, our findings elucidated the specific tumor microenvironment in DE DLBCL tissues and identified p-S6 as a promising therapeutic target to enhance the efficacy of chemotherapy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959147","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":"Canagliflozin May Increase Thromboembolic Events in Males With Erythrocytosis but Not in Females.","authors":"Yohei Doi, Takayuki Hamano, Osamu Yamaguchi, Yoshitaka Isaka","doi":"10.1182/bloodadvances.2025016320","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016320","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly recognized as a common cause of drug-induced erythrocytosis. SGLT2 inhibitor-induced erythropoiesis may increase blood viscosity and precipitate thromboembolism, particularly in patients with pre-existing erythrocytosis. We conducted a post hoc, pooled analysis of patient-level data from the randomized, double-blind, placebo-controlled CANVAS Program and CREDENCE trials, which assessed the safety and efficacy of canagliflozin in patients with type 2 diabetes. The primary outcome, a composite of myocardial infarction (MI), stroke, and any thromboembolism, was evaluated using sex-specific Cox models, with baseline hematocrit as an effect modifier. Among participants with available baseline hematocrit values (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased hematocrit levels compared to placebo even in patients with erythrocytosis (males >49%, females >48%) and raised the proportion of individuals with erythrocytosis at 1 year (males: 16.9% vs. 5.5%; females: 5.2% vs. 1.0%). Overall, canagliflozin did not alter the risk of the primary outcome in either males (hazard ratio [HR] 0.97; 95% CI, 0.86-1.10) or females (HR 0.95; 95% CI, 0.78-1.15). However, in males, baseline hematocrit levels modified the treatment effect on the primary outcome, whether assessed categorically (anemia, normal, erythrocytosis) or continuously with fractional polynomial (FP) analysis (P interaction <0.05). FP analysis showed treatment benefits in anemic males but harm in those with erythrocytosis, primarily driven by an increased risk of MI. Meanwhile, no heterogeneity was seen in females for these outcomes. In conclusion, canagliflozin may pose a safety concern for thromboembolism in males with erythrocytosis at baseline, warranting further investigations. NCT01032629, NCT01989754, and NCT02065791.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962978","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":"Evaluating the Long-Term Benefits of Hydroxyurea in Pediatric Sickle Cell Anemia.","authors":"Paul E George, Grace Gardiner Kalmus, Peter A Lane, Wilbur A Lam, Joseph Lipscomb, David Howard","doi":"10.1182/bloodadvances.2024015564","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015564","url":null,"abstract":"<p><p>Hydroxyurea is the primary disease-modifying medication for sickle cell anemia (SCA), but its long-term effects, particularly how these effects change over time, are not well understood. This study aimed to quantify the effects of hydroxyurea on clinical and laboratory outcomes in children with SCA over a prolonged period of use. We conducted a quasi-experimental study using contemporary difference-in-differences and dynamic event study analyses on a longitudinal cohort of 2,147 children with SCA (HbSS/HbSβ0) from 2010-2021. Primary outcomes included emergency department (ED) visits per year, hospital days per year, and annual average hemoglobin concentration. Hydroxyurea use was associated with fewer ED visits per year (average treatment effect on the treated [ATT] -0.36 visits/year, 95% CI -0.57, -0.16) and fewer hospital days per year (ATT -0.84 days/year, 95% CI -1.51, -0.17), with sustained effects over time. On average, hemoglobin concentration increased with hydroxyurea use (ATT 0.56 g/dL, 95% CI 0.39, 0.73) but the sustained effect was observed only among the subgroup with laboratory markers of good adherence. This study demonstrates that hydroxyurea has sustained clinical benefits in reducing ED visits and hospital days across years of use in children with SCA. These findings provide perspective for clinicians and families regarding the long-term efficacy of hydroxyurea in pediatric SCA management and underscore the importance of ongoing adherence counseling to optimize clinical benefit. Furthermore, this study design provides a methodological framework for rigorously and causally evaluating other SCA-specific treatments, such as stem cell transplant and gene therapy, in real-world settings.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970597","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}