Blood最新文献

{"title":"Adult hematopoietic stem cells activate a normally fetal-restricted program to functionally expand ex vivo","authors":"Kyomi J Igarashi,Matthew Nicholls,Leonid Olender,Apapist Panichewa,Toshiya Nishimura,Paul K Mack,Shady Saad,Wesley Huang,Alia MN Welsh,Dean C Pask,Ryo Yamamoto,Stefan A Muljo,Hiromitsu Nakauchi,Adam C. Wilkinson","doi":"10.1182/blood.2025030268","DOIUrl":"https://doi.org/10.1182/blood.2025030268","url":null,"abstract":"The ability to robustly expand transplantable hematopoietic stem cells (HSCs) ex vivo enables basic science and clinical therapies otherwise hindered by the scarcity of these self-renewing multipotent cells. Despite recent improvements in long-term ex vivo HSC expansion conditions, the molecular mechanisms required for successful ex vivo expansion of functional HSCs remain unknown. Here we characterized the ex vivo expansion potential of HSCs from mouse fetal liver, young bone marrow, and aged bone marrow at the functional and molecular levels. We find that Lin28b, the in vivo fetal-restricted gene, contributes to the mechanism of both fetal and adult ex vivo HSC expansion. The expression of Lin28b correlates with reconstitution potential, with higher levels observed in HSCs expanded from the fetal liver and young adults. By contrast, expanded aged HSCs fail to robustly express Lin28b and also fail to stably reconstitute the hematopoietic system following transplantation. Consistent with a functional role for this fetal program in ex vivo expanded HSCs, Lin28b-deficient HSCs display aging-associated molecular and functional features following ex vivo expansion cultures. Importantly, Lin28b overexpression during ex vivo expansion was sufficient to enhance reconstitution potential of aged HSCs. In summary, we identify Lin28b as an important regulator of functional HSC expansion ex vivo, suggesting novel opportunities for HSC rejuvenation and clinical applications.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"5 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088466","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 new reporter strategy reveals a subset of nonmigratory hematopoietic stem cells located in a dynamic bone marrow niche.","authors":"Marine A Secchi, Cera Mai, Qi Liu, Aya M F E Elmeligy, Sara Gonzalez Anton, Aisha Jibril, Thorsten Richter, Jiarui Xu, Dónal O'Carroll, Nicola K Wilson, Konstantinos Kokkaliaris, Kamil R Kranc, Berthold Gottgens, Cristina Lo Celso, Tiago C Luis","doi":"10.1182/blood.2025031114","DOIUrl":"https://doi.org/10.1182/blood.2025031114","url":null,"abstract":"<p><p>Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and ageing. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC localization and migratory behavior. Here we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters, that are stably expressed in homeostasis, stress and ageing. Hoxb5+Vwf+ cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation, that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5+Vwf+ cells to be non-migratory in homeostasis, ageing, or following acute thrombocytopenia when these cells are actively proliferating, indicating that this non-migratory behavior is independent of cell cycle status. We found Hoxb5+Vwf+ HSCs in perivascular niches with a higher coverage by LepR+ mesenchymal cells but not preferentially located closer to megakaryocytes, when compared to Hoxb5+Vwf- cells. Nevertheless, stress-induced megakaryopoiesis following acute thrombocytopenia bring megakaryocytes into closer proximity of Hoxb5+Vwf+ HSCs, revealing previously unrecognized niche dynamics in HSC regulation during regeneration.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223192","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 randomized phase 2 study combining midostaurin, low-dose cytarabine and venetoclax in newly diagnosed AML ≥60 years.","authors":"Chong Chyn Chua, Wei-Hsun Hsun Hsu, Anoop K Enjeti, Ashish Bajel, Paula Marlton, Shaun A Fleming, Devendra K Hiwase, Chun-Kei-Kris Kris Ma, Peter J Browett, Carolyn S Grove, ShuhYing Tan, Travis Perera, Jad Othman, Hannah Rose, Julian P Cooney, Edward S Morris, Derek McCulloch, Kate Mason, Rachel M Koldej, Amanda Johnston, Stephen B Ting, David Ritchie, Natasha S Anstee, John Reynolds, Andrew H Wei","doi":"10.1182/blood.2026035389","DOIUrl":"https://doi.org/10.1182/blood.2026035389","url":null,"abstract":"<p><p>In randomized studies, addition of FLT3 inhibitors failed to improve survival in older patients with FLT3-ITD AML unfit for intensive chemotherapy. Although hypomethylating agents or low-dose cytarabine combined with venetoclax is standard, FLT3-ITD is an important mechanism of resistance and a barrier to improved survival. Recent studies show promise for the addition of gilteritinib or quizartinib to less intensive venetoclax-based therapy, however resulting marrow toxicity requires substantial reductions to administered treatment. The INTERVENE study (Investigating Novel Triplets to Extend Remission with VENetoclax in Elderly AML) (ACTRN12619001655134) examined the role of midostaurin (M) administered sequentially after low-dose cytarabine (L) combined with venetoclax (V) in patients with newly diagnosed AML ≥60 years with non-adverse karyotype. After a run-in phase (n=18) established that LDAC combined with venetoclax from days 1-28 and midostaurin from days 11-28 was tolerable, 120 patients were randomized 2:1 to receive either LVM or LV. For the primary endpoint, LVM did not improve composite complete remission (CRc), compared to LV (72% vs 68%). Combining midostaurin with LV enhanced CRc among the sub-group of patients (n=29) with FLT3-ITD (82% vs 57%, difference = 25%, 0.85 posterior probability true difference > 5%, 95% CrI: -10 to 59%) and improved FLT3-ITD clearance as measured by ultrasensitive NGS (65% vs 0%), resulting in longer OS (median 24.2 vs 8.8 months, HR=0.34, 95% CrI: 0.071 to 0.960), compared to LV. In conclusion, midostaurin combined with low-dose cytarabine and venetoclax is well-tolerated and may have a role in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223157","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":"Genomic and clinical landscape of RAS mutations in acute myeloid leukemia.","authors":"Eduardo Rodríguez-Arbolí, Elena Soria-Saldise, Eva Barragan, Rosa Ayala, Joaquin Sánchez-García, Cristina Bilbao-Sieyro, M Carmen Chillon, María José Larrayoz, Paulina Hillebrand, Teresa Bernal Del Castillo, Juan Miguel Bergua Burgues, Carmen Botella, Mar Tormo, Lorenzo Algarra, Rafael Colmenares, Josefina Serrano, María García-Fortes, Amaia Balerdi, Juan Manuel Alonso-Domínguez, Carlos Rodríguez-Medina, Maria Jose García Perez, Lourdes Hermosín, Irene Sanchez Vadillo, Rosa Fernández Martín, Ana Oliva Hernandez, Raimundo García-Boyero, Francisco Ibañez-Alis, Mercedes Colorado, José-Ángel Raposo-Puglia, Carolina Lacalzada Higueras, Víctor Noriega, Pilar Herrera, Aitor Abuin Blanco, María Solé-Rodríguez, María-Belén Vidriales, Jorge Labrador, Lara María Gómez-García, María Del Carmen García Garay, Juan A Lopez-Lopez, Olga Arce-Fernández, Teresa Olave, Esther Pérez Santaolalla, Claudia Sargas, Joaquin Martínez-López, Esther Prados de la Torre, Maria Teresa Gomez Casares, Norma C Gutierrez, Maria José Calasanz, José Antonio Pérez-Simón, Pau Montesinos","doi":"10.1182/blood.2026033409","DOIUrl":"https://doi.org/10.1182/blood.2026033409","url":null,"abstract":"<p><p>RAS mutations are recurrent in acute myeloid leukemia (AML); yet, their genomic and clinical landscape remain poorly characterized. We analyzed centralized molecular profiling data in 8,553 patients with newly diagnosed AML. Of these, 1,775 (21%) harbored RAS mutations: NRAS in 1,103 (13%), KRAS in 445 (5%), and both in 227 (3%). RAS mutations primarily clustered in P-loop hotspots (G12/G13, 70%), with NRAS showing higher Q61 mutation prevalence (24% vs. 9%) and KRAS showing additional K117/A146 hotspots. Multiple RAS mutations occurred in 23% of patients. Convergent evolution of RAS signaling mutations emerged as a key feature of RASmut AML. RTK/RAS pathway mutations were non-uniformly enriched: PTPN11, KIT and FLT3-TKD mutations were positively associated, CBL mutations showed no association, and FLT3-ITD mutations were negatively associated. The prognostic impact of RAS mutations was dependent on the genomic background and treatment. In multivariate analyses in intensively treated patients, NRAS mutations showed opposing associations with overall survival (OS): adverse in patients with AML, myelodysplasia-related (HR=1.32, p=0.036) and favorable in those with NPM1 (HR=0.61, p=0.036) or FLT3-ITD (HR=0.63, p=0.048) mutations, among others. KRAS mutations predicted inferior OS (HR=1.41; p=0.003). In patients treated with non-intensive, venetoclax-based regimens, RAS mutations were associated with markedly inferior OS in patients with NPM1 (HR=2.98, p=0.007) or IDH1/2 mutations (HR=4.06, p<0.001). These data inform risk stratification and development of RAS-targeting strategies in AML.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206688","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":"Cases of High-Titer Inhibitor Formation After AAV Gene Therapy for Hemophilia A.","authors":"Shelley E Crary, Divyaswathi Citla-Sridhar, C D'Ann Pierce, Guy Young","doi":"10.1182/blood.2026035372","DOIUrl":"https://doi.org/10.1182/blood.2026035372","url":null,"abstract":"<p><p>Gene therapy for hemophilia A (HA) aims to provide durable hemostatic control and reduce treatment burden, but AAV-based products to date have limitations: inconsistent peak expression, declining factor levels, and immunogenicity causing transaminitis and expression loss. ASC618 (ASC Therapeutics, Milpitas, CA, USA) was developed as a second-generation gene therapy product to overcome some of these limitations, using ET3, a bioengineered chimeric human/porcine B-domain-deleted FVIII transgene, paired with a minimal liver promoter and liver codon optimization. In a phase 1/2 trial (NCT04676048), two patients received ASC618. Despite initial factor expression, both developed high-titer FVIII inhibitors and are now maintained on emicizumab prophylaxis. Although inhibitor titers have declined, both remain high-titer nearly two years after a single infusion. The best explanation for inhibitor formation is that the novel FVIII with the human-porcine hybrid construct (ET3) contained epitopes for which these patients had not developed tolerance despite both having more than 1000 exposure days to exogenous FVIII in the past. Although this trial has been halted, these cases provide important lessons for the development of future hemophilia gene therapies. They highlight the need for careful immunogenicity assessment when using bioengineered transgenes, even in previously treated patients with extensive factor VIII exposure.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206685","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":"Erythroblast-derived lipid mediators program neutrophil development and function.","authors":"Duco S Koenis, Roberta de Matteis, Esteban A Gomez, Vishaka Gorur, Paul Telfer, Antal Rot, Jesmond Dalli","doi":"10.1182/blood.2026033170","DOIUrl":"10.1182/blood.2026033170","url":null,"abstract":"<p><strong>Abstract: </strong>Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defense. The mechanisms that maintain balanced regulation of neutrophil effector functions during this process remain incompletely understood. In this study, we identified bone marrow-resident erythroblasts as a key source of specialized proresolving mediators (SPMs) and also showed that they imprint neutrophil development and function. Maturing erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes, including augmented release of reactive oxygen species and neutrophil extracellular traps, as well as increased migration toward chemotactic stimuli. This was accompanied by increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in dextran sodium sulfate-induced colitis. Aberrant neutrophil phenotypes were rectified by reconstitution with RvD5n-3DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting that the involvement of the macrophage niche mediates the SPM effects on granulopoiesis. Thus, our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2043-2058"},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599122","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":"TRANSFORM-1 phase 3 study: efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis.","authors":"Naveen Pemmaraju, Adam J Mead, Tim C P Somervaille, Francesca Palandri, Steffen Koschmieder, Robert Delage, Jean-Jacques Kiladjian, Christopher Benton, Srinivas K Tantravahi, Noa Lavi, Su-Peng Yeh, Maria Teresa Gomez Casares, Emanuele Ammatuna, Andrew McDonald, Sung-Soo Yoon, Keita Kirito, Timothy Devos, Andrew Perkins, Atanas Radinoff, Omur Gokmen Sevindik, Andrija Bogdanovic, Rastislav Moskal, Jason G Harb, Bryan Murray, Qi Jiang, Avijeet S Chopra, Elektra J Papadopoulos, Jalaja Potluri, Francesco Passamonti","doi":"10.1182/blood.2025032360","DOIUrl":"10.1182/blood.2025032360","url":null,"abstract":"<p><strong>Abstract: </strong>The phase 3 TRANSFORM-1 study evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus kinase inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status of ≤2. Patients were randomized 1:1 to NAV (200 mg/d starting dose, or 100 mg escalated to 200 mg/d) or PBO, with RUX dosed per label. The primary end point was ≥35% spleen volume reduction (SVR) at week 24 (SVR35W24). Secondary end points included change from baseline in total symptom score (TSS) at week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n = 125; PBO+RUX, n = 127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk, and ∼50% had high-molecular risk disease. SVR35W24 was achieved by 63.2% with NAV+RUX vs 31.5% with PBO+RUX (P< .0001). Mean change in TSS at week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P = .2852). SVR35 at any time was achieved in 76.8% with NAV+RUX vs 44.1% with PBO+RUX (nominal P< .0001). A ≥20% variant allele frequency reduction (exploratory end point) occurred in 58.5% (95% confidence interval [CI], 49.0-67.5) with NAV+RUX and 45.5% (95% CI, 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity vs PBO+RUX (grade 3/4 thrombocytopenia, 54.0% vs 19.2%; grade 3/4 neutropenia, 40.3% vs 8.8%); diarrhea (any grade, 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments. This trial was registered at www.clinicaltrials.gov as NCT04472598.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2029-2042"},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359135","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":"Optical genome mapping reveals a MYC-amplified ring chromosome arising through chromoanagenesis in AML.","authors":"Guilin Tang, Ying S Zou","doi":"10.1182/blood.2026035550","DOIUrl":"https://doi.org/10.1182/blood.2026035550","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"148 16","pages":"2083"},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190997","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":"Arterial iron regulates vasodilation during anemia via endothelial holo-α-globin.","authors":"Luke S Dunaway, Shruthi Nyshadham, Skylar A Loeb, Brooke L O'Donnell, Nasim Abib, Wyatt J Schug, Zuzanna J Juśkiewicz, Melissa A Luse, Macy E Stahl, Timothy M Sveeggen, Pooneh Bagher, Jason D Allen, Stefano Toldo, Adam N Goldfarb, Brant E Isakson","doi":"10.1182/blood.2025032905","DOIUrl":"10.1182/blood.2025032905","url":null,"abstract":"<p><strong>Abstract: </strong>Iron deficiency is a highly prevalent nutrient deficiency and the most common cause of anemia. Although iron deficiency exacerbates cardiovascular disease, the direct impact of iron deficiency on the vasculature remains unstudied. We assessed iron levels across the vascular endothelium in mouse and human endothelial cells and found that resistance artery endothelial cells have the lowest iron stores, suggesting they may be especially affected by iron deficiency. Anemia has previously been shown to increase arterial nitric oxide (NO) signaling in patients, and we have previously shown endothelial α-globin scavenges NO in the resistance artery endothelium. We hypothesized that iron regulates vascular function through regulation of endothelial α-globin. To test this, we used a mouse model of iron deficiency anemia (IDA). In female mice, IDA increased NO signaling, which was rescued to control levels by repletion of vascular iron with iron dextran. Despite being similarly anemic and having a similar reduction in α-globin protein, there were no changes in NO signaling across groups in male mice. We further measured whether α-globin was in its heme-bound (holo-α-globin) or heme-free (apo-α-globin) state and found males did not fully lose its functional, heme-bound α-globin. Using endothelial-specific α-globin knockout mice, we show loss of endothelial α-globin is necessary for increased NO signaling in IDA and for the rescue of NO signaling by iron dextran in female mice. Altogether, the data presented here demonstrate iron is a determinant of endothelial identity and modulates endothelial NO signaling through the regulation of α-globin.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2072-2082"},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350582","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":"A phase 2 trial of daratumumab monotherapy for patients with newly diagnosed cardiac stage IIIb AL amyloidosis.","authors":"Efstathios Kastritis, Monique C Minnema, Meletios A Dimopoulos, Giampaolo Merlini, Foteini Theodorakakou, Despina Fotiou, Antoine Huart, Giorgos Psarros, Helen Vassalou, Pieter Sonneveld, Giovanni Palladini","doi":"10.1182/blood.2025032897","DOIUrl":"10.1182/blood.2025032897","url":null,"abstract":"<p><strong>Abstract: </strong>Treatment options for patients with immunoglobulin light chain (AL) amyloidosis and advanced cardiac involvement remain limited. The prospective phase 2 European Myeloma Network 22 trial included patients with previously untreated AL amyloidosis, measurable hematologic disease, and Mayo2004/European cardiac stage IIIB disease to receive daratumumab monotherapy at the standard dose and schedule for up to 2 years (28-day cycles); patients with inadequate response after 3 cycles could additionally receive weekly bortezomib and dexamethasone. The primary end point was 6-month overall survival (OS) rate. Of 40 patients enrolled, 10 (25.0%) received additional treatment with bortezomib and dexamethasone. The 6-month OS rate was 65% (95% confidence interval, 48.2-77.6), and median OS was 10.4 months. The best hematologic response rate (partial response or better) up to 6 months was 75% (very good partial response or better, 47.5%; complete response, 12.5%), with the median time to first and best hematologic response being 1 week and 2.3 months, respectively. Cardiac response rate at 6 months was 30%. Common serious adverse events were cardiac failure (25%), sudden cardiac death (10%), and acute kidney injury (7.5%). The patients' quality of life remained stable throughout the trial treatment and observation. In patients with high-risk, advanced (stage IIIB) AL amyloidosis, daratumumab monotherapy was feasible and well tolerated, achieving rapid hematologic responses and associated with prolonged survival relative to historical cohorts. Cardiac response rates at 6 months were significant, considering advanced cardiac disease. These findings support daratumumab as the backbone of anticlonal therapy in advanced cardiac AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT04131309.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1973-1983"},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257349","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}