Pub Date : 2026-03-05DOI: 10.1182/blood.2025031100
Joanne I Hsu, Sarah Nikiforow, Nancy Berliner
Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.
{"title":"Hemophagocytic lymphohistiocytosis in adults.","authors":"Joanne I Hsu, Sarah Nikiforow, Nancy Berliner","doi":"10.1182/blood.2025031100","DOIUrl":"10.1182/blood.2025031100","url":null,"abstract":"<p><strong>Abstract: </strong>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1037-1047"},"PeriodicalIF":23.1,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145602085","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025031456
Robert H Lee,Francesca Ferraresso,Alexander Couzens,Angelica Taylor Jameson,Haley Elizabeth Hanes,Alessandro Casini,Marguerite Neerman-Arbez,Bernhard Nieswandt,Christian J Kastrup,Wolfgang Bergmeier,Matthew J Flick,Woosuk Steve Hur
Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19/264 (~7%) patients developed arterial thrombosis, including 4/41 (~10%) patients with hypofibrinogenemia. However, 0/8 patients with fibrinogen aC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen aC-region on arterial thrombosis, two mouse models were employed: 1) wildtype mice treated with lipid nanoparticles encapsulating siRNA against fibrinogen (siFga) and 2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated aC-region. While siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the aC-region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of aC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wildtype mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen aC-region promotes arterial thrombosis in hypofibrinogenemic conditions.
{"title":"The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.","authors":"Robert H Lee,Francesca Ferraresso,Alexander Couzens,Angelica Taylor Jameson,Haley Elizabeth Hanes,Alessandro Casini,Marguerite Neerman-Arbez,Bernhard Nieswandt,Christian J Kastrup,Wolfgang Bergmeier,Matthew J Flick,Woosuk Steve Hur","doi":"10.1182/blood.2025031456","DOIUrl":"https://doi.org/10.1182/blood.2025031456","url":null,"abstract":"Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19/264 (~7%) patients developed arterial thrombosis, including 4/41 (~10%) patients with hypofibrinogenemia. However, 0/8 patients with fibrinogen aC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen aC-region on arterial thrombosis, two mouse models were employed: 1) wildtype mice treated with lipid nanoparticles encapsulating siRNA against fibrinogen (siFga) and 2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated aC-region. While siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the aC-region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of aC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wildtype mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen aC-region promotes arterial thrombosis in hypofibrinogenemic conditions.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"32 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368255","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025032332
Betty S Pace,Xingguo Zhu
{"title":"IFN-γ/JAK/STAT axis awakens the delta force of hemoglobin.","authors":"Betty S Pace,Xingguo Zhu","doi":"10.1182/blood.2025032332","DOIUrl":"https://doi.org/10.1182/blood.2025032332","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"12 1","pages":"1014-1015"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350492","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025031366
Barbara Mora,Francesca Palandri,Paola Guglielmelli,Andrew T Kuykendall,Margherita Maffioli,Alessandra Iurlo,Valerio De Stefano,Silvia Salmoiraghi,Timothy Devos,Federico Itri,Francisco Cervantes,Jean-Jacques Kiladjian,Matteo G Della Porta,Francesco Albano,Jason Gotlib,Giulia Benevolo,Marianna Caramella,Marco Ruggeri,Elisa Rumi,David M Ross,Chiara Pessina,Ilaria Colugnat,Francesco Orsini,Giorgia Micucci,Giada Rotunno,Rami S Komrokji,Daniele Cattaneo,Patrizia Chiusolo,Marta Bortolotti,Tiziano Barbui,Daniela Cilloni,Massimo Breccia,Giuseppe A Palumbo,Filippo Branzanti,Ludovica Margotto,Matteo Franchi,Alessandro M Vannucchi,Francesco Passamonti
Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera and essential thrombocythemia, with overall survival (OS) currently defined by the MYelofibrosis SECondary to PV and ET (MYSEC) Prognostic Model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) subjects reported at least one CGV, with ASXL1, TET2 and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (p < .001): U2AF1, TP53 or SRSF2 variants (UTS, 9.3% of cases, median OS 4.1 years) and ASXL1 without UTS (25.3%, median OS 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (p from < .0001 to .02) and weighted: hemoglobin <11 g/dl (1 point), circulating blasts ⩾3% (2), platelets <150 × 109/l (2), age (0.21 points/year), ASXL1 without UTS mutations (1) and any UTS mutations (3). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 SMF patients into four categories with different OS (p < .001): low (median OS 18.0 years, 95%CI: 14.2-not reached; score <14), intermediate-1 (8.8. years, 95%CI: 7.7-9.7; score 14-16), intermediate-2 (4.6 years, 95%CI: 3.1-7.2; score 17-18), and high risk (1.9 years, 95%CI: 1.2-2.5; score ⩾19). Additionally, in 381 SMF with available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improve survival prediction in SMF, outperforming the MYSEC-PM.
{"title":"Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis.","authors":"Barbara Mora,Francesca Palandri,Paola Guglielmelli,Andrew T Kuykendall,Margherita Maffioli,Alessandra Iurlo,Valerio De Stefano,Silvia Salmoiraghi,Timothy Devos,Federico Itri,Francisco Cervantes,Jean-Jacques Kiladjian,Matteo G Della Porta,Francesco Albano,Jason Gotlib,Giulia Benevolo,Marianna Caramella,Marco Ruggeri,Elisa Rumi,David M Ross,Chiara Pessina,Ilaria Colugnat,Francesco Orsini,Giorgia Micucci,Giada Rotunno,Rami S Komrokji,Daniele Cattaneo,Patrizia Chiusolo,Marta Bortolotti,Tiziano Barbui,Daniela Cilloni,Massimo Breccia,Giuseppe A Palumbo,Filippo Branzanti,Ludovica Margotto,Matteo Franchi,Alessandro M Vannucchi,Francesco Passamonti","doi":"10.1182/blood.2025031366","DOIUrl":"https://doi.org/10.1182/blood.2025031366","url":null,"abstract":"Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera and essential thrombocythemia, with overall survival (OS) currently defined by the MYelofibrosis SECondary to PV and ET (MYSEC) Prognostic Model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) subjects reported at least one CGV, with ASXL1, TET2 and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (p < .001): U2AF1, TP53 or SRSF2 variants (UTS, 9.3% of cases, median OS 4.1 years) and ASXL1 without UTS (25.3%, median OS 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (p from < .0001 to .02) and weighted: hemoglobin <11 g/dl (1 point), circulating blasts ⩾3% (2), platelets <150 × 109/l (2), age (0.21 points/year), ASXL1 without UTS mutations (1) and any UTS mutations (3). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 SMF patients into four categories with different OS (p < .001): low (median OS 18.0 years, 95%CI: 14.2-not reached; score <14), intermediate-1 (8.8. years, 95%CI: 7.7-9.7; score 14-16), intermediate-2 (4.6 years, 95%CI: 3.1-7.2; score 17-18), and high risk (1.9 years, 95%CI: 1.2-2.5; score ⩾19). Additionally, in 381 SMF with available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improve survival prediction in SMF, outperforming the MYSEC-PM.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"11 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359442","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025032152
Ozgur Can Eren,Sergej Konoplev
{"title":"Focal MPN-associated JAK2-mutated skeletal lesion with normal blood counts and bone marrow.","authors":"Ozgur Can Eren,Sergej Konoplev","doi":"10.1182/blood.2025032152","DOIUrl":"https://doi.org/10.1182/blood.2025032152","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"28 1","pages":"1135"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350821","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025031858
Lori S Muffly,Catherine J Lee,Arpita Gandhi,Ankur Varma,Bart L Scott,Sagar S Patel,Parveen Shiraz,Minyoung Youn,Chikako Yanagiba,Jeyakavitha Arulprakasam,Anne Le,Hye-Sook Kwon,Janel R Long-Boyle,Judith A Shizuru,Wendy Pang,Andrew S Artz
Briquilimab is a monoclonal antibody inhibiting stem cell factor (SCF) binding to CD117 (c-Kit). Based on preclinical data demonstrating the antibody clears hematopoietic stem and progenitor cells (HSPC) and myeloid malignant cells, we conducted a phase 1 trial examining briquilimab plus non-myeloablative fludarabine (flu) and total body irradiation (TBI) as conditioning for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing matched donor allogeneic hematopoietic cell transplantation (HCT). Briquilimab was infused 10-14 days before transplant day (TD) 0; fludarabine 30mg/m2 and TBI 2-3 Gy were administered on TD -4 to -2 and TD0, respectively. Graft-versus-host disease prophylaxis consisted of tacrolimus, sirolimus, and mycophenolate mofetil. Thirty-two patients enrolled (n=13 AML in complete remission [CR], n=3 AML in relapse, n=16 MDS). Median age was 70 years and most had detectable measurable residual disease at screening. There were no briquilimab infusion reactions, dose limiting toxicities, or primary graft failure events; briquilimab clearance was predictable across patients. Among the AML in CR cohort, 1-year EFS was 69.2% (95% CI, 37.3, 87.2); 1-year OS was 75% (95% CI, 40.8, 91.2). Among the MDS cohort, 1-year EFS was 53.8% (26.8, 74.8); 1-year OS was 76.4% (42.7, 91.8). One of 3 AML patients in relapse experienced a transient response. Marrow samples obtained before and after briquilimab and prior to flu/TBI demonstrated AML/MDS HSPC depletion (mean 62.4±22.7%) with resultant 3-fold increase in serum SCF. In summary, we demonstrate the feasibility, safety, and proof of concept of CD117 targeting with briquilimab as HCT conditioning for AML/MDS. The trial is registered at clinicaltrials.gov; using identifier: NCT04429191.
{"title":"Nonmyeloablative Conditioning Combined with Anti-CD117 Antibody Briquilimab in Older Adults with High-Risk AML and MDS.","authors":"Lori S Muffly,Catherine J Lee,Arpita Gandhi,Ankur Varma,Bart L Scott,Sagar S Patel,Parveen Shiraz,Minyoung Youn,Chikako Yanagiba,Jeyakavitha Arulprakasam,Anne Le,Hye-Sook Kwon,Janel R Long-Boyle,Judith A Shizuru,Wendy Pang,Andrew S Artz","doi":"10.1182/blood.2025031858","DOIUrl":"https://doi.org/10.1182/blood.2025031858","url":null,"abstract":"Briquilimab is a monoclonal antibody inhibiting stem cell factor (SCF) binding to CD117 (c-Kit). Based on preclinical data demonstrating the antibody clears hematopoietic stem and progenitor cells (HSPC) and myeloid malignant cells, we conducted a phase 1 trial examining briquilimab plus non-myeloablative fludarabine (flu) and total body irradiation (TBI) as conditioning for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing matched donor allogeneic hematopoietic cell transplantation (HCT). Briquilimab was infused 10-14 days before transplant day (TD) 0; fludarabine 30mg/m2 and TBI 2-3 Gy were administered on TD -4 to -2 and TD0, respectively. Graft-versus-host disease prophylaxis consisted of tacrolimus, sirolimus, and mycophenolate mofetil. Thirty-two patients enrolled (n=13 AML in complete remission [CR], n=3 AML in relapse, n=16 MDS). Median age was 70 years and most had detectable measurable residual disease at screening. There were no briquilimab infusion reactions, dose limiting toxicities, or primary graft failure events; briquilimab clearance was predictable across patients. Among the AML in CR cohort, 1-year EFS was 69.2% (95% CI, 37.3, 87.2); 1-year OS was 75% (95% CI, 40.8, 91.2). Among the MDS cohort, 1-year EFS was 53.8% (26.8, 74.8); 1-year OS was 76.4% (42.7, 91.8). One of 3 AML patients in relapse experienced a transient response. Marrow samples obtained before and after briquilimab and prior to flu/TBI demonstrated AML/MDS HSPC depletion (mean 62.4±22.7%) with resultant 3-fold increase in serum SCF. In summary, we demonstrate the feasibility, safety, and proof of concept of CD117 targeting with briquilimab as HCT conditioning for AML/MDS. The trial is registered at clinicaltrials.gov; using identifier: NCT04429191.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359441","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2024027753
Laura Polcik,Abhishek Pethe,Driti Ashok,Erika Tissino,Adrián Fernández-Rego,Federico Pozzo,Danielle-Justine Danner,Manuel Holst,Claudio Martines,Karin Hofmann,Aleksandar J Dimovski,Sandra Kissel,Andrea Härzschel,Lixia Li,Tamara Bittolo,Geoffroy Andrieux,Theresa Haslauer,Jan Philip Höpner,Nadja Zaborsky,Richard Greil,Cornelius Miething,Jesus Duque-Afonso,Natalie Köhler,Melanie Boerries,Riccardo Bomben,Justus Duyster,Robert Grosse,Gianluca Gaidano,Alberto Zamò,Antonella Zucchetto,Yolanda R Carrasco,Dimitar G Efremov,Valter Gattei,Tanja Nicole Hartmann
B cell receptor (BCR) signaling is a key determinant of chronic lymphocytic leukemia (CLL) pathophysiology. CD49d, the alpha4 subunit of the very late antigen-4 (VLA-4) integrin, can be activated by BCR signals; however, its role in modulating BCR functionality remains unknown. We used knockout mouse models and primary human CLL stratified by CD49d expression to address this aspect. CD49d was required for bone marrow infiltration and shaped bone marrow infiltration patterns and patient outcomes in human CLL. In TCL1 transplantation models, loss of CD49d abrogated bone marrow homing and leukemic cell positioning within splenic niches. At the cellular level, CD49d-deficient murine TCL1 transgenic cells and human CD49d-low CLL cells failed to form efficient immune synapses with antigen-presenting membranes. Transcriptome analyses identified CD49d-dependent regulation of actin-associated pathways and distinct signatures of BCR responsiveness in human and mouse. Consistently, CD49d-low human CLL cells displayed aberrant actin remodeling following BCR stimulation, and a second aggressive murine CLL model reproduced the actin and engraftment defects. Kinome profiling linked impaired antigen-induced BCR responses in CD49d-deficient murine cells to altered kinase activity, and pharmacological actin perturbation phenocopied CD49d loss. In human CD49d-low CLL cells, a desynchronization of BCR-related downstream Syk and PLCɣ activation was found. Mechanistically, the CD49d-BCR interplay involved their co-localization, and CD49d converged with BCR signaling on a focal adhesion kinase-actin axis. In summary, our findings establish CD49d as a key regulator of BCR functionality in CLL, linking integrins to cytoskeletal dynamics and antigen responsiveness.
{"title":"CD49d governs immune synapse formation through actin rearrangements and synchronizes BCR signaling in CLL.","authors":"Laura Polcik,Abhishek Pethe,Driti Ashok,Erika Tissino,Adrián Fernández-Rego,Federico Pozzo,Danielle-Justine Danner,Manuel Holst,Claudio Martines,Karin Hofmann,Aleksandar J Dimovski,Sandra Kissel,Andrea Härzschel,Lixia Li,Tamara Bittolo,Geoffroy Andrieux,Theresa Haslauer,Jan Philip Höpner,Nadja Zaborsky,Richard Greil,Cornelius Miething,Jesus Duque-Afonso,Natalie Köhler,Melanie Boerries,Riccardo Bomben,Justus Duyster,Robert Grosse,Gianluca Gaidano,Alberto Zamò,Antonella Zucchetto,Yolanda R Carrasco,Dimitar G Efremov,Valter Gattei,Tanja Nicole Hartmann","doi":"10.1182/blood.2024027753","DOIUrl":"https://doi.org/10.1182/blood.2024027753","url":null,"abstract":"B cell receptor (BCR) signaling is a key determinant of chronic lymphocytic leukemia (CLL) pathophysiology. CD49d, the alpha4 subunit of the very late antigen-4 (VLA-4) integrin, can be activated by BCR signals; however, its role in modulating BCR functionality remains unknown. We used knockout mouse models and primary human CLL stratified by CD49d expression to address this aspect. CD49d was required for bone marrow infiltration and shaped bone marrow infiltration patterns and patient outcomes in human CLL. In TCL1 transplantation models, loss of CD49d abrogated bone marrow homing and leukemic cell positioning within splenic niches. At the cellular level, CD49d-deficient murine TCL1 transgenic cells and human CD49d-low CLL cells failed to form efficient immune synapses with antigen-presenting membranes. Transcriptome analyses identified CD49d-dependent regulation of actin-associated pathways and distinct signatures of BCR responsiveness in human and mouse. Consistently, CD49d-low human CLL cells displayed aberrant actin remodeling following BCR stimulation, and a second aggressive murine CLL model reproduced the actin and engraftment defects. Kinome profiling linked impaired antigen-induced BCR responses in CD49d-deficient murine cells to altered kinase activity, and pharmacological actin perturbation phenocopied CD49d loss. In human CD49d-low CLL cells, a desynchronization of BCR-related downstream Syk and PLCɣ activation was found. Mechanistically, the CD49d-BCR interplay involved their co-localization, and CD49d converged with BCR signaling on a focal adhesion kinase-actin axis. In summary, our findings establish CD49d as a key regulator of BCR functionality in CLL, linking integrins to cytoskeletal dynamics and antigen responsiveness.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"62 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368258","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}
Pub Date : 2026-03-04DOI: 10.1182/blood.2025031651
Rajshekhar Chakraborty,Yevgeniy Brailovsky,Mazen Hanna,Ronald Witteles,Joban Vaishnav,James E Hoffman,Jan Marie Griffin,Pablo Garcia-Pavia,David Wolinsky,Chafic Karam,Helen J Lachmann,Morie A Gertz,Brian C Boursiquot,Dimitrios Bampatsias,Kristen Hsu,Phaedra Theodora Johnson,Jamie L Zigterman,Ana Carolina Kazemzadeh,Mathew S Maurer,Ashutosh D Wechalekar
The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% five-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyses prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains (dFLC) and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify high-risk patients who may benefit from interventions beyond anti-plasma cell therapy.
{"title":"Prognostic Factors and Progression Biomarkers in AL Amyloidosis: Mapping Current Knowledge and Critical Gaps.","authors":"Rajshekhar Chakraborty,Yevgeniy Brailovsky,Mazen Hanna,Ronald Witteles,Joban Vaishnav,James E Hoffman,Jan Marie Griffin,Pablo Garcia-Pavia,David Wolinsky,Chafic Karam,Helen J Lachmann,Morie A Gertz,Brian C Boursiquot,Dimitrios Bampatsias,Kristen Hsu,Phaedra Theodora Johnson,Jamie L Zigterman,Ana Carolina Kazemzadeh,Mathew S Maurer,Ashutosh D Wechalekar","doi":"10.1182/blood.2025031651","DOIUrl":"https://doi.org/10.1182/blood.2025031651","url":null,"abstract":"The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% five-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyses prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains (dFLC) and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify high-risk patients who may benefit from interventions beyond anti-plasma cell therapy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"30 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350782","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}
Pub Date : 2026-03-04DOI: 10.1182/blood.2025032352
William T Johnson,Kevin O McNerney,Matthew J Frank,Nirali N Shah
Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities including checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engagers, amongst others. However, their distinct toxicity profiles have required clinicians across all specialties to rapidly adopt an immunologic perspective in management. Among them, therapy related hemophagocytic lymphohistiocytosis (HLH)-like toxicities are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined Immune effector cell-associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches and early intervention strategies may improve outcomes-preserving the potential benefit of the therapies patients are receiving. In this "How I Treat," we highlight our collective approach in managing two recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.
{"title":"How I Treat HLH-Like Toxicities Following Immune Effector Cell Therapy.","authors":"William T Johnson,Kevin O McNerney,Matthew J Frank,Nirali N Shah","doi":"10.1182/blood.2025032352","DOIUrl":"https://doi.org/10.1182/blood.2025032352","url":null,"abstract":"Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities including checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engagers, amongst others. However, their distinct toxicity profiles have required clinicians across all specialties to rapidly adopt an immunologic perspective in management. Among them, therapy related hemophagocytic lymphohistiocytosis (HLH)-like toxicities are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined Immune effector cell-associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches and early intervention strategies may improve outcomes-preserving the potential benefit of the therapies patients are receiving. In this \"How I Treat,\" we highlight our collective approach in managing two recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"198 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350647","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}
Pub Date : 2026-03-04DOI: 10.1182/blood.2025031016
Alessandro M Vannucchi,Jay L Patel,Jean-Jacques Kiladjian
Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (M/LN-FGFR1) are rare, heterogenous diseases due to fusion transcripts originated by translocations of FGFR1 with different partners, resulting in constitutive FGFR1-mediated signaling. Presentation varies from chronic myeloid neoplasms to acute leukemia or lymphoma and extramedullary localizations are common. Outside allogeneic stem cell transplantation (ASCT), survival with conventional therapy is dismal, representing an unmet clinical need. We summarize here the data that led to approval of pemigatinib, a FGFR1 inhibitor, showing unprecedented efficacy in M/LN-FGFR1.
{"title":"Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement and Pemigatinib.","authors":"Alessandro M Vannucchi,Jay L Patel,Jean-Jacques Kiladjian","doi":"10.1182/blood.2025031016","DOIUrl":"https://doi.org/10.1182/blood.2025031016","url":null,"abstract":"Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (M/LN-FGFR1) are rare, heterogenous diseases due to fusion transcripts originated by translocations of FGFR1 with different partners, resulting in constitutive FGFR1-mediated signaling. Presentation varies from chronic myeloid neoplasms to acute leukemia or lymphoma and extramedullary localizations are common. Outside allogeneic stem cell transplantation (ASCT), survival with conventional therapy is dismal, representing an unmet clinical need. We summarize here the data that led to approval of pemigatinib, a FGFR1 inhibitor, showing unprecedented efficacy in M/LN-FGFR1.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"86 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350510","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}
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