IF 20.3 1区医学

Blood Pub Date : 2025-04-25 DOI: 10.1182/blood.2024027873

Sarah A Holstein,Shebli Atrash,Hira Mian,Meletios Athanasios Dimopoulos,Fredrik Schjesvold,Rakesh Popat,Nishi Shah,Moshe E Gatt,Christian B Gocke,Laurent Frenzel,Cyrille Touzeau,Meral Beksac,Salomon Manier,Hila Magen,Patrick Travis,Omar Nadeem,Kaveri Suryanarayan,Cheryl Li,Shuli Li,Allison Nelson,Dasha Cherepanov,Xavier Parot,Dan T Vogl

{"title":"A phase 2 randomized study of modakafusp alfa as a single agent in patients with relapsed/refractory multiple myeloma.","authors":"Sarah A Holstein,Shebli Atrash,Hira Mian,Meletios Athanasios Dimopoulos,Fredrik Schjesvold,Rakesh Popat,Nishi Shah,Moshe E Gatt,Christian B Gocke,Laurent Frenzel,Cyrille Touzeau,Meral Beksac,Salomon Manier,Hila Magen,Patrick Travis,Omar Nadeem,Kaveri Suryanarayan,Cheryl Li,Shuli Li,Allison Nelson,Dasha Cherepanov,Xavier Parot,Dan T Vogl","doi":"10.1182/blood.2024027873","DOIUrl":"https://doi.org/10.1182/blood.2024027873","url":null,"abstract":"Modakafusp alfa is a first-in-class immunocytokine directing interferon-α to CD38-positive cells. Our previous phase 1/2 trial identified two potential phase 2 doses of modakafusp alfa in patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks (Q4W). The overall response rate (ORR) among 30 patients treated at 1.5 mg/kg was 43%. This phase 2 dose optimization study (NCT03215030) randomized 147 patients with triple-class refractory disease and ≥3 prior lines of therapy 1:1 to modakafusp alfa 120 mg (n = 71) or 240 mg (n = 75) Q4W (fixed-dose equivalents of 1.5 and 3 mg/kg Q4W). Patients had received a median of 6 prior lines of therapy; 66% were penta-exposed and 45% anti-BCMA-exposed. Modakafusp alfa development was discontinued for strategic reasons by the sponsor and the study was terminated early. At median follow-ups of 7.3 and 7.6 months in the 120 and 240 mg arms, ORRs were 32% and 41%; median progression-free survival was 4.1 and 5.3 months, respectively. ORRs were higher in patients who had not received prior-BCMA therapy (46% vs 29%). The most common treatment-related adverse events (TEAEs) in the 120 and 240 mg arms were thrombocytopenia (75% and 84%; grade ≥3, 55% and 61%) and neutropenia (68% and 73%; grade ≥3, 56% and 68%); 90% and 96% of patients experienced grade ≥3 TEAEs; 39% and 44% experienced serious TEAEs. Pharmacokinetic studies showed a ~2-fold greater exposure with 240 vs 120 mg. Our results confirm the efficacy of single-agent modakafusp alfa in patients with RRMM.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"17 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880179","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}

引用次数: 0

Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD. 循环质母细胞扩增产生互助性IgA抗体是慢性GVHD的预测因子。

IF 21 1区医学

Blood Pub Date : 2025-04-25 DOI: 10.1182/blood.2024027301

Katharina Marie Habenicht, Jana Wanzek, Anna Bootz, Simon Schäfer, Lara Vollmer, Andreas Hiergeist, Matthias Alexander Fante, Jakob Thomas Hasenbank, Andrea Schneider, Ingrid Vasova, Silvia Spoerl, Anna Brandt, Michael Rehli, Petra Hoffmann, Stefan Wirtz, Jesika Kotorri, Roman G Gerlach, André Gessner, Andreas Mackensen, Julia Winkler, Daniel Wolff, Thomas H Winkler

{"title":"Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD.","authors":"Katharina Marie Habenicht, Jana Wanzek, Anna Bootz, Simon Schäfer, Lara Vollmer, Andreas Hiergeist, Matthias Alexander Fante, Jakob Thomas Hasenbank, Andrea Schneider, Ingrid Vasova, Silvia Spoerl, Anna Brandt, Michael Rehli, Petra Hoffmann, Stefan Wirtz, Jesika Kotorri, Roman G Gerlach, André Gessner, Andreas Mackensen, Julia Winkler, Daniel Wolff, Thomas H Winkler","doi":"10.1182/blood.2024027301","DOIUrl":"https://doi.org/10.1182/blood.2024027301","url":null,"abstract":"Chronic graft-versus-host disease (cGVHD) is characterized by a dysregulation of the adaptive immune system including an aberrant B cell homeostasis after allogeneic hematopoietic stem cell transplantation (allo-SCT). It is uncertain, however, whether this B cell dysregulation is a result of manifest cGVHD or develops as a sign of aberrant B lymphopoiesis after allo-SCT before cGVHD becomes apparent. To gain insight into the development of B cell dysregulation before the onset of cGVHD, we analyzed B cell subpopulations by multiparameter flow cytometry on day 90, day 180 and day 356 post allo-SCT in a prospective study design. After completion of follow-up, patients were assigned retrospectively to three groups according to onset of GVHD: 1) no GVHD (n=17), 2) acute GVHD (aGVHD) without subsequent cGVHD (n=32) and 3) cGVHD (n=59). Whereas CD21low CD11c+ B cells were increased in all groups, the frequency of CD20neg CD38hi plasmablasts was significantly elevated already 90 days after allo-SCT in those patients subsequently developing cGVHD, as compared to patients without GVHD or aGVHD only (median 5.9% vs 2.2% vs 2.2% of CD19+ cells; p=0.0016 and p=0.0304, respectively). Detailed molecular analysis of expanded plasmablasts revealed a dominance of the IgA isotype with molecular evidence for recent generation in mucosal sites and markers for intestinal homing. A large fraction of the clonally expanded plasmablasts produced antibodies binding to subgroups of commensals which are known to produce short-chain fatty acids. In summary, our data suggests that dysregulated intestinal antibody responses against commensals contribute to the pathophysiology of cGVHD.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975272","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}

引用次数: 0

STINGing leukemia stem cells through PSTK inhibition. 通过PSTK抑制刺痛性白血病干细胞。

IF 20.3 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2024028046

Sylvain Garciaz

引用次数: 0

Prognostic and therapeutic implications of measurable residual disease levels during remission induction of childhood ALL. 儿童急性淋巴细胞白血病缓解诱导期间可测量的残留疾病水平的预后和治疗意义。

IF 21 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2024026381

Weina Zhang, Jiaoyang Cai, Xiang Wang, Yani Ma, Xiaofan Zhu, Jie Yu, Peifang Xiao, Ju Gao, Yongjun Fang, Changda Liang, Xue Li, Fen Zhou, Xiaowen Zhai, Xiaoxiao Xu, Xin Tian, Aiguo Liu, Ningling Wang, Jiashi Zhu, Lingzhen Wang, Frankie Wai-Tsoi Cheng, Liangchun Yang, Ge Zhang, Cheng Cheng, Jun J Yang, Shuhong Shen, Chi-Kong Li, Benshang Li, Hua Jiang, Ching-Hon Pui

{"title":"Prognostic and therapeutic implications of measurable residual disease levels during remission induction of childhood ALL.","authors":"Weina Zhang, Jiaoyang Cai, Xiang Wang, Yani Ma, Xiaofan Zhu, Jie Yu, Peifang Xiao, Ju Gao, Yongjun Fang, Changda Liang, Xue Li, Fen Zhou, Xiaowen Zhai, Xiaoxiao Xu, Xin Tian, Aiguo Liu, Ningling Wang, Jiashi Zhu, Lingzhen Wang, Frankie Wai-Tsoi Cheng, Liangchun Yang, Ge Zhang, Cheng Cheng, Jun J Yang, Shuhong Shen, Chi-Kong Li, Benshang Li, Hua Jiang, Ching-Hon Pui","doi":"10.1182/blood.2024026381","DOIUrl":"10.1182/blood.2024026381","url":null,"abstract":"Abstract: We evaluated the prognostic and therapeutic significance of measurable residual disease (MRD) during remission induction in pediatric patients with acute lymphoblastic leukemia (ALL). In the Chinese Children Cancer Group ALL 2015 protocol, 7640 patients were categorized into low-, intermediate-, or high-risk groups based on clinical and genetic features. Final risk classification was determined by assessing MRD using flow cytometry on days 19 and 46 of remission induction with additional intensified chemotherapy for day 19 MRD ≥1%. Patients with B-ALL with negative MRD (<0.01%) on day 19 or day 46 had significantly better 5-year event-free survival (EFS) than those with MRD of between 0.01% and 0.99% who, in turn, had better EFS than patients with MRD of ≥1%. Provisional low-risk patients with day 19 MRD ≥1% but negative day 46 MRD who were reclassified as intermediate risk had a 5-year EFS that was comparable with that of low-risk patients with day 19 MRD of 0.3% to 0.99% and negative day 46 MRD (82.5% vs 83.0%) and better EFS than provisional low-risk patients with MRD on both days (83.0% vs 72.6%; P < .001). Similarly, patients with provisional intermediate-risk B-ALL with day 19 MRD ≥1% but negative day 46 MRD who received additional therapy had better 5-year EFS than those with day 19 MRD between 0.3% and 0.99% (70.7% vs 53.0%; P < .001). Among low-risk patients with negative day 46 MRD, those with negative day 19 MRD had superior EFS than those with positive day 19 MRD (91.7% vs 86.1%; P < .001). Optimal use of day 19 MRD could improve individualized treatment and outcomes. This trial was registered at www.chictr.org.cn as #ChiCTR-IPR-14005706.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1890-1902"},"PeriodicalIF":21.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944563","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}

引用次数: 0

Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis. 出血和血栓患者血栓调节蛋白基因变异的功能评估。

IF 21 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2024026454

Christine Van Laer, Renaud Lavend'homme, Sarissa Baert, Koenraad De Wispelaere, Chantal Thys, Cyrielle Kint, Sam Noppen, Kathelijne Peerlinck, Chris Van Geet, Dominique Schols, Thomas Vanassche, Veerle Labarque, Peter Verhamme, Marc Jacquemin, Kathleen Freson

{"title":"Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis.","authors":"Christine Van Laer, Renaud Lavend'homme, Sarissa Baert, Koenraad De Wispelaere, Chantal Thys, Cyrielle Kint, Sam Noppen, Kathelijne Peerlinck, Chris Van Geet, Dominique Schols, Thomas Vanassche, Veerle Labarque, Peter Verhamme, Marc Jacquemin, Kathleen Freson","doi":"10.1182/blood.2024026454","DOIUrl":"10.1182/blood.2024026454","url":null,"abstract":"Abstract: Thrombomodulin (TM) expressed on endothelial cells regulates coagulation. Specific nonsense variants in the TM gene, THBD, result in high soluble TM levels causing rare bleeding disorders. In contrast, although THBD variants have been associated with venous thromboembolism, this association remains controversial. A multigene panel was used to diagnose 601 patients with inherited bleeding or thrombotic disorders. This resulted in the identification of 8 THBD variants for 6 patients with a thrombotic (C175S, A282P, L433P, P501L, G502R, and P508L) and 2 patients with a bleeding (P260A and T478I) phenotype. These were all classified as variants of uncertain significance, and we here aimed to assess their functional role in coagulation. For this purpose, soluble and cell membrane-bound recombinant TM were produced in Expi293F cells. L433P TM showed a marked decrease in the inhibition of thrombin generation and complete inhibition of protein C and thrombin activatable fibrinolysis inhibitor (TAFI) activation. Soluble C175S TM showed decreased inhibition of thrombin generation and protein C activation, whereas no effect was observed for cell membrane-bound recombinant TM. For the other TM variants, no effect on thrombin generation, protein C, or TAFI activation could be observed. Surface plasmon resonance analysis showed no thrombin-TM binding in the presence of L433P because this residue is located at their interaction site. In conclusion, our study shows the functional effects of L433P TM and potentially C175S TM, which are compatible with an increased thrombosis risk. THBD variants are rare but can be relevant to both bleeding and thrombosis. Functional assays for these variants are critical to understand their roles.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1929-1942"},"PeriodicalIF":21.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999693","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}

引用次数: 0

Recycling is "bad to the bone" in patients with myeloma. 对骨髓瘤患者来说，回收利用“对骨骼有害”。

IF 20.3 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2024027940

Kevin C Miller,Alexander M Lesokhin

引用次数: 0

CAR T cells in autoimmunity: game changer or stepping stone? CAR - t细胞在自身免疫中的作用：游戏规则改变者还是垫脚石？

IF 21 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2024025413

Dimitrios Mougiakakos, Everett H Meyer, Georg Schett

{"title":"CAR T cells in autoimmunity: game changer or stepping stone?","authors":"Dimitrios Mougiakakos, Everett H Meyer, Georg Schett","doi":"10.1182/blood.2024025413","DOIUrl":"10.1182/blood.2024025413","url":null,"abstract":"Abstract: The advent of chimeric antigen receptor (CAR) T cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article evaluates the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus, have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called \"reset\" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymphoid structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared with malignancies. Technological advances in cell therapy, such as next-generation CAR T cells, allogeneic off-the-shelf products, and alternative cell types, such as regulatory CAR T cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion, and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1841-1849"},"PeriodicalIF":21.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863345","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}

引用次数: 0

17(R)-Resolvin D1: a novel approach for SCD cardiomyopathy. 17(R)-Resolvin D1：一种治疗SCD心肌病的新方法。

IF 20.3 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2025028490

Thilina U Jayawardena,Gavin Y Oudit

引用次数: 0

Seeing is believing: a histology textbook's dream case of sarcoidosis. 眼见为实：组织学教科书上的梦幻结节病病例。

IF 20.3 1区医学

Blood Pub Date : 2025-04-24 DOI: 10.1182/blood.2025028699

Pravin Patel,Olga Pozdnyakova

引用次数: 0

Beyond conVENtional 7+3 in acute myeloid leukemia. 在急性髓性白血病中超越常规的7+3