Blood最新文献

{"title":"Zanubrutinib, venetoclax, and obinutuzumab in R/R CLL.","authors":"","doi":"10.1182/blood.2025028638","DOIUrl":"https://doi.org/10.1182/blood.2025028638","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 12","pages":"1334"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662453","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":"Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes.","authors":"Marta Lionetti, Margherita Scopetti, Antonio Matera, Akihiro Maeda, Alessio Marella, Francesca Lazzaroni, Giancarlo Castellano, Sonia Fabris, Stefania Pioggia, Silvia Lonati, Alfredo Marchetti, Alessandra Cattaneo, Marta Tornese, Antonino Neri, Claudia Leoni, Loredana Pettine, Valentina Traini, Ilaria Silvestris, Marzia Barbieri, Giuseppina Fabbiano, Domenica Ronchetti, Elisa Taiana, Claudio De Magistris, Matteo Claudio Da Via', Francesco Passamonti, Niccolò Bolli","doi":"10.1182/blood.2024026236","DOIUrl":"https://doi.org/10.1182/blood.2024026236","url":null,"abstract":"<p><p>Multiple myeloma (MM) initiation is dictated by genomic events. However, its progression from asymptomatic stages to an aggressive disease that ultimately fails to respond to treatments is also dependent on changes of the tumor microenvironment (TME). Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent clonal condition of the hematopoietic stem cell whose presence is causally linked to a more inflamed microenvironment. Here, we show in 106 patients with MM that CHIP is frequently co-existing with MM at diagnosis, associates with a more advanced R-ISS stage, higher age and shows a non-significant trend towards lower median hemoglobin. In our cohort the two conditions do not share a clonal origin. Single cell RNA-sequencing in 16 MM patients highlights significant TME changes when CHIP is present: decreased naïve T cells, a pro-inflammatory TME, decreased antigen-presenting function by dendritic cells and expression of exhaustion markers in CD8 cells. Inferred interactions between cell types in CHIP-positive TME suggested that especially monocytes, T cells and clonal plasma cells may have a prominent role in mediating inflammation, immune evasion and pro-survival signals in favor of MM cells. Altogether, our data show that, in the presence of CHIP, the TME of MM at diagnosis is significantly disrupted in line with what usually seen in more advanced disease, with potential translational implications. Our data highlight the relevance of this association and prompt for further studies on the modifier role of CHIP in the MM TME.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668949","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":"How I treat secondary acute myeloid leukemia.","authors":"Steven D Green, Eunice S Wang","doi":"10.1182/blood.2024024011","DOIUrl":"10.1182/blood.2024024011","url":null,"abstract":"<p><strong>Abstract: </strong>Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or after prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML, myelodysplastic related; myeloproliferative neoplasm-blast phase; and AML post-cytotoxic therapy. These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased life span of individuals receiving DNA-damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise ∼25% to 30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many either are not applicable to sAML (ie, lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are underrepresented in clinical trials, and novel therapeutic options are critically needed. Here, we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1260-1272"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364349","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":"Potentiating CD20 monoclonal antibody therapy by targeting complement C3 fragments covalently deposited on lymphoma cells.","authors":"Sivasubramanian Baskar, Haiyong Peng, Erika M Gaglione, Elizabeth J Carstens, Margaret A Lindorfer, Inhye E Ahn, Sarah E M Herman, Martin Skarzynski, Jing Chang, Keyvan Keyvanfar, Vicent Butera, Amy Blackburn, Bérengère Vire, Irina Maric, Maryalice Stetler-Stevenson, Constance M Yuan, Michael A Eckhaus, Susan Soto, Mohammed Z H Farooqui, Ronald P Taylor, Christoph Rader, Adrian Wiestner","doi":"10.1182/blood.2024024846","DOIUrl":"10.1182/blood.2024024846","url":null,"abstract":"<p><strong>Abstract: </strong>Monoclonal antibodies (mAbs) improve survival of patients with mature B-cell malignancies. Fcγ receptor-dependent effector mechanisms kill tumor cells but can promote antigen loss through trogocytosis, contributing to treatment failures. Cell-bound mAbs trigger the complement cascade to deposit C3 activation fragments and lyse cells. Within 24 hours after ofatumumab administration to patients with chronic lymphocytic leukemia (CLL), circulating tumor cells had lost CD20 and were opsonized with C3d, the terminal covalently bound form of complement protein C3. We hypothesized that C3d provides a target to eliminate residual CD20- tumor cells. To test this hypothesis, we generated C8xi, a mouse/human chimeric immunoglobulin G1 (IgG1) that reacts with human but not mouse C3d. C8xi was effective in a patient-derived xenograft model against CD20-, C3d opsonized CLL cells from patients treated with ofatumumab. We also generated rabbit mAbs, 2 of which were chosen because they bound mouse and human C3d with low nanomolar affinity but were minimally cross-reactive with full-length C3. Anti-C3d rabbit/human chimeric IgG1 in combination with ofatumumab or rituximab prolonged survival of xenografted mice that model 3 different types of non-Hodgkin lymphoma (NHL). For example, in a diffuse large B-cell lymphoma model (SU-DHL-6), median survival with single-agent CD20 mAb was 114 days but was not reached for mAb combination treatment (P = .008). In another NHL model (SU-DHL-4), single-agent and combination mAb therapy eradicated lymphoma in most mice. In long-term survivors from both cohorts, there was no evidence of adverse effects. We propose that C3d mAbs combined with complement-fixing CD20 mAbs can overcome antigen-loss escape and increase efficacy of mAb-based therapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1309-1320"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944603","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":"How I treat acute myeloid leukemia with differentiation therapy.","authors":"Ghayas C Issa, Eytan M Stein, Courtney D DiNardo","doi":"10.1182/blood.2024024008","DOIUrl":"10.1182/blood.2024024008","url":null,"abstract":"<p><strong>Abstract: </strong>An increasing number of acute myeloid leukemia (AML) therapeutics have been developed, not as cytotoxic therapies but rather as targeted agents able to restore the aberrant and leukemogenic \"block\" in normal differentiation. All-trans retinoic acid and arsenic trioxide are classic examples of differentiating agents for treatment of acute promyelocytic leukemia (APL); newer therapies functioning through differentiation include isocitrate dehydrogenase 1 and 2 inhibitors, FMS-like tyrosine kinase 3 inhibitors, and menin inhibitors. The terminal differentiation of leukemic blasts via differentiating-agent therapy can lead to a constellation of signs and symptoms, originally referred to as \"retinoic acid syndrome\" and now termed \"differentiation syndrome\" (DS), characterized predominantly by systemic inflammatory response system-like features of dyspnea, pulmonary infiltrates, pleural and pericardial effusions, unexplained fevers, hypotension, edema, and renal insufficiency. DS in patients with newly diagnosed APL is generally straightforward to identify; however, DS in patients with multiply relapsed AML can be more challenging to diagnose, due to nonspecific signs and symptoms that can be mistakenly attributed to infectious etiologies or the underlying refractory leukemia itself. Prompt consideration of DS, rapid initiation of systemic corticosteroids, and early cytoreduction in the setting of concomitant hyperleukocytosis are essential for optimal management.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1251-1259"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558005","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":"Math models expose myeloid bias mechanisms in hematopoiesis.","authors":"Artur C Fassoni, Ingmar Glauche","doi":"10.1182/blood.2024027777","DOIUrl":"https://doi.org/10.1182/blood.2024027777","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 12","pages":"1231-1232"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662498","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":"Development of the Lee Symptom Scale-Skin Sclerosis for chronic GVHD-associated sclerosis.","authors":"Emily Baumrin, Joseph Pidala, Sandra A Mitchell, Lynn Onstad, Stephanie J Lee","doi":"10.1182/blood.2024027334","DOIUrl":"10.1182/blood.2024027334","url":null,"abstract":"<p><strong>Abstract: </strong>Sclerosis is a highly morbid manifestation of chronic graft-versus-host disease (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome (PRO) measure for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults aged ≥18 years with cGVHD-associated sclerosis participated in semistructured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were used to evaluate content validity of the items, response options, recall period, and respondent instructions. Thirty-six open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (5) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n = 25). Phrasing changes were made to improve relevance and comprehension. One item was removed, and 2 items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important differences are underway in an external cohort to validate the PROs.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1321-1332"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982763","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":"Complementing CD20 antibodies' effector functions.","authors":"Jeanette Leusen, Thomas Valerius","doi":"10.1182/blood.2024027767","DOIUrl":"https://doi.org/10.1182/blood.2024027767","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 12","pages":"1232-1234"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662469","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":"Megakaryocyte mitotic figures in de novo AML, myelodysplasia related, with STAG2, SRSF2, and ASXL1 comutations.","authors":"Zhaodong Xu, Kristine Roland","doi":"10.1182/blood.2024027590","DOIUrl":"https://doi.org/10.1182/blood.2024027590","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 12","pages":"1333"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662504","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":"MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial.","authors":"Moritz Fürstenau, Sandra Robrecht, Christof Schneider, Eugen Tausch, Adam Giza, Matthias Ritgen, Jörg Bittenbring, Holger Hebart, Björn Schöttker, Anna Lena Illert, Ullrich Graeven, Andrea Stoltefuß, Bernhard Heinrich, Robert Eckert, Anna Fink, Janina Stumpf, Kirsten Fischer, Othman Al-Sawaf, Florian Simon, Fanni Kleinert, Jonathan Weiss, Karl-Anton Kreuzer, Anke Schilhabel, Monika Brüggemann, Petra Langerbeins, Stephan Stilgenbauer, Barbara Eichhorst, Michael Hallek, Paula Cramer","doi":"10.1182/blood.2024026685","DOIUrl":"10.1182/blood.2024026685","url":null,"abstract":"<p><strong>Abstract: </strong>The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)-guided combination treatment of zanubrutinib, venetoclax, and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In total, 42 patients were enrolled and 2 patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of 1 prior therapy (range, 1-5); 18 patients (45%) had already received a Bruton tyrosine kinase (BTK) inhibitor (BTKi); 7 patients (17.5%) venetoclax; and, of these, 5 (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion, and 31 (77.5%) had unmutated immunoglobulin heavy chain variable region gene. With a median observation time of 21.5 months (range, 8.0-35.3) the most common adverse events were COVID-19 (n = 26 patients), diarrhea (n = 15), infusion-related reactions (n = 15), thrombocytopenia (n = 14), nausea (n = 12), fatigue (n = 12), and neutropenia (n = 12). Two patients had fatal adverse events (COVID-19, and fungal pneumonia secondary to COVID-19). After 6 months of the triple combination, all patients responded, and 21 (52.5%; 95% confidence interval, 36.1-68.5) showed undetectable MRD (uMRD) in the peripheral blood. In many patients, remissions deepened over time, with a best uMRD rate of 85%. The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%, respectively. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04515238.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1282-1292"},"PeriodicalIF":21.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063650","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}