HemaSphere最新文献

{"title":"Preclinical evaluation of the ROR1-targeting antibody–drug conjugates zilovertamab vedotin and VLS-211 against B-cell ALL patient-derived xenografts","authors":"Christopher M. Smith,&nbsp;Ben Watts,&nbsp;Kathryn Evans,&nbsp;Hansen Kosasih,&nbsp;Chelsea Mayoh,&nbsp;Stephen W. Erickson,&nbsp;Eric J. Earley,&nbsp;Steven Neuhauser,&nbsp;Timothy M. Stearns,&nbsp;Vivek M. Philip,&nbsp;Jeffrey H. Chuang,&nbsp;Charles E. de Bock,&nbsp;Edward P. Bowman,&nbsp;Katti A. Jessen,&nbsp;Emily L. Jocoy,&nbsp;Carol J. Bult,&nbsp;Beverly A. Teicher,&nbsp;Malcolm A. Smith,&nbsp;Richard B. Lock","doi":"10.1002/hem3.70438","DOIUrl":"10.1002/hem3.70438","url":null,"abstract":"<p>Although survival rates for acute lymphoblastic leukemia (ALL) have improved dramatically over the past 60 years, outcomes vary across different molecular subtypes and risk categories, and a significant number of patients remain difficult to treat. ROR1 is a receptor tyrosine kinase expressed in B-cell ALL, particularly in patients with <i>TCF3</i>::<i>PBX1</i> gene rearrangements. ROR1 has served as the target of several immune-based therapies including antibody–drug conjugates (ADCs), bispecific T-cell engagers, and CAR T-cell therapies. Here, we evaluated the ROR1-targeting ADCs zilovertamab vedotin (ZV, previously known as MK-2140 or VLS-101) and VLS-211 in vivo against a panel of ALL patient-derived xenografts with variable ROR1 expression. Both agents showed modest activity, which was dependent on ROR1 expression. Notably, we identified pediatric patients with <i>TCF3</i>::<i>HLF</i> gene fusions, which is a highly chemoresistant ALL subtype, as having some of the highest ROR1 expression in pediatric ALL and show that this subtype is susceptible to targeting ROR1 via ADC-based therapy. Given that ZV has a favorable toxicity profile in patients with hematological malignancies, it may have some utility in the treatment of very high-risk pediatric B-ALL, particularly cases with <i>TCF3</i>::<i>HLF</i> gene fusions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tale of a transposition error","authors":"Stephen P. Hibbs","doi":"10.1002/hem3.70415","DOIUrl":"10.1002/hem3.70415","url":null,"abstract":"&lt;p&gt;The fear hit me with a wave of nausea. I was preparing to give a talk for a group of students about a research project I had co-led, which highlighted how cancer clinical trials and therapies structurally discriminate against people with the Duffy null variant, common in people of African and Middle Eastern ancestry. By accounting for Duffy-related variation in absolute neutrophil count, clinical trial eligibility criteria could exclude fewer people, and prescription guidance could result in fewer unnecessary dose interruptions or reductions. Our paper had been published 2 months earlier.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;I returned to the study datasheet to pick out a couple of examples of trials to show to the students. This should have been a straightforward task. Instead, I came across something surprising—a trial that one column of my datasheet categorized as “UK- or US-based” only listed locations in China. What had gone on?&lt;/p&gt;&lt;p&gt;With a knot in my stomach, I gave a half-hearted talk to the students and went home. Lying awake, my thoughts swirled. If the location of this trial was miscategorized, was this the case for others too? Or even worse—were other fields of the dataset wrong? How deep did the problem go?&lt;/p&gt;&lt;p&gt;I felt the significance of this paper. Our findings illuminated a significant aspect of cancer health inequity. We planned to use these results to influence clinical practice, and an accompanying discussion paper with policy recommendations was in press.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Would finding and reporting a data error jeopardize the core message we were trying to communicate, delaying progress in the real world? And how would others in the research team respond to any error I had made? These were people I respected, but within our trans-Atlantic collaboration, I knew few of them personally.&lt;/p&gt;&lt;p&gt;As these questions swirled, another thought skulked across my mind—perhaps I could allow myself to forget what I saw? After all, had I not been preparing this teaching session, I might never have known that there were any problems in the data. It seemed unlikely that anyone else would ever notice.&lt;/p&gt;&lt;p&gt;I slept restlessly, but by the morning, I decided that I could not “unsee” this. I needed to look back at the dataset, understand the extent of the problem, and follow through with the consequences, however exposing they might be. I sat down at my desk with a strong cup of coffee, took a deep breath, and opened my computer. Within a few minutes, the problem was clear—I had made a transposition error where all location assignments were mismatched by two rows, resulting in the location status of each trial being taken from an unrelated study.&lt;/p&gt;&lt;p&gt;Looking through the dataset, I was relieved to find that other elements of data were not affected by my transposition error. Location was used for a sensitivity analysis rather than our main results. The consequences were real, but limited: the sensitivity analysis and its corresponding supple","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148602379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death in TP53-deficient ALL","authors":"Kari J. T. Grünewald,&nbsp;Marjolein M. G. Kes,&nbsp;Gawin R. Stoll,&nbsp;Willem P. J. Cox,&nbsp;Dorette S. van Ingen Schenau,&nbsp;Enzo M. Scutigliani,&nbsp;Emmely M. Wagener,&nbsp;Ziqin Tang,&nbsp;Senna Visser,&nbsp;Jolanda Kooiman,&nbsp;Jessica Buijs-Gladdines,&nbsp;Maria Rodionova,&nbsp;Esther A. Zaal,&nbsp;Jeroen W. A. Jansen,&nbsp;Jeroen F. van Velzen,&nbsp;Jarno Drost,&nbsp;Laurens T. van der Meer,&nbsp;Celia R. Berkers,&nbsp;Frank N. van Leeuwen","doi":"10.1002/hem3.70439","DOIUrl":"10.1002/hem3.70439","url":null,"abstract":"<p>Mutations or deletions affecting the <i>TP53</i> gene predict a dismal outcome in relapsed acute lymphoblastic leukemia (ALL). Loss of p53 function compromises the response to many anti-leukemic therapies, underscoring the need for agents that are effective in <i>TP53-</i>deficient cells. Leukemic blasts depend on de novo pyrimidine synthesis to sustain proliferation, and the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) is essential for this pathway. While DHODH inhibitors (DHODHis) show preclinical anti-leukemic activity, the efficacy in <i>TP53</i>-deficient contexts has not been tested. Using both isogenic <i>TP53</i>-wildtype and knock-out cell line models and patient-derived xenografts (PDXs), we show that dual inhibition of DHODH and Ataxia Telangiectasia and Rad3-related (ATR) produces pronounced anti-leukemic effects, irrespective of the <i>TP53</i> status. Through integrated transcriptomic and metabolomic analyses, we show that combined inhibition of DHODH and ATR leads to a reduced flux of glucose into the TCA cycle, accompanied by an increase in oxidative stress. This metabolic phenotype triggers cell death through a mechanism converging on Activating Transcription Factor 4 (ATF4), a key integrator of cellular responses to metabolic and oxidative stress, which operates largely independently of p53. Taken together, our findings identify ATF4-mediated cell death as a previously unrecognized vulnerability in <i>TP53</i>-deficient ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148602399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemophagocytic lymphohistiocytosis-like syndrome after CD19-directed CAR T-cells for B-cell lymphoma and B-cell acute lymphoblastic leukemia: A LYSA, SFCE, and GRAALL study from the DESCAR-T registry","authors":"Nicolas Gower,&nbsp;Roch Houot,&nbsp;Cécile Pizot,&nbsp;André Baruchel,&nbsp;Marie-Emilie Dourthe,&nbsp;David Beauvais,&nbsp;Thomas Gastinne,&nbsp;Gabriel Brisou,&nbsp;Rémy Dulery,&nbsp;Stéphanie Guidez,&nbsp;Jean-Jacques Tudesq,&nbsp;Adrien Chauchet,&nbsp;Laura Herbreteau,&nbsp;Arnaud Campidelli,&nbsp;Jacques-Olivier Bay,&nbsp;Pierre Sesques,&nbsp;Edmond Chiche,&nbsp;François-Xavier Gros,&nbsp;Amandine Durand,&nbsp;Marion Lubnau,&nbsp;Arthur Sterin,&nbsp;Roberta Di Blasi,&nbsp;Alexandra Marquet,&nbsp;Elodie Gat,&nbsp;Florence Rabian,&nbsp;Thibaut Leguay,&nbsp;Gabrielle Roth-Guépin,&nbsp;Nicolas Boissel,&nbsp;Franck Morschhauser,&nbsp;Jérôme Paillassa","doi":"10.1002/hem3.70425","DOIUrl":"https://doi.org/10.1002/hem3.70425","url":null,"abstract":"<p>While cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are well-recognized toxicities of CAR T-cell therapy, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) remains poorly characterized. We aimed to describe the incidence, clinical features, management, and outcomes of IEC-HS using real-world data from the DESCAR-T registry (NCT04328298). We conducted a multicenter retrospective study of patients registered in DESCAR-T who received standard-of-care CD19 CAR T-cell therapy for relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or B-cell acute lymphoblastic leukemia (B-ALL) and fulfilled ASTCT criteria for IEC-HS. We analyzed 42 patients who developed IEC-HS. Most had a high CAR-HEMATOTOX score (≥2, <i>n</i> = 36) and prior high-grade CRS (grade ≥3, <i>n</i> = 20). IEC-HS was characterized by marked hyperinflammation, with high median ferritin (18,561 µg/L), lactate dehydrogenase (825 IU/L), and triglycerides (4.5 g/L), and low fibrinogen (0.9 g/L). Median time to IEC-HS onset was 9 days (IQR 6–21). Patients received a median of two treatment lines. Observed response rates were 77% with etoposide, 70% with corticosteroids, 70% with corticosteroids plus anakinra, and 50% with tocilizumab, with combination therapy more frequently used in severe cases. After a median follow-up of 24.1 months, overall mortality was 81%. One-year overall survival was 15.6% for B-NHL and 47.1% for B-ALL. In this real-world cohort, IEC-HS was a rare but life-threatening complication of CD19 CAR T-cell therapy, often occurring after severe CRS and associated with poor outcomes. Despite initial inflammatory control, mortality remained high, underscoring the need for improved risk stratification and management strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoimmunity and peginterferon therapy for polycythemia vera","authors":"Etienne Rivière,&nbsp;Alexandre Guy,&nbsp;Olivier Mansier,&nbsp;Clémence Mediavilla,&nbsp;Jean-Jacques Kiladjian,&nbsp;Chloé James,&nbsp;Patrick Blanco,&nbsp;Estibaliz Lazaro,&nbsp;Jean-François Viallard","doi":"10.1002/hem3.70432","DOIUrl":"https://doi.org/10.1002/hem3.70432","url":null,"abstract":"<p>Peginterferon‑α is useful to treat myeloproliferative neoplasms (MPNs) but can precipitate broad autoimmunity. By promoting beta-cell, thyroid, and systemic immune injury, it can lead to Type 1 diabetes, autoimmune thyroiditis, systemic lupus erythematosus, or Sjögren's syndrome. Onset typically occurs within the first months but may be delayed until after treatment cessation. Type 1 diabetes is usually irreversible and requires lifelong therapy, whereas thyroiditis and lupus more often improve after interferon withdrawal, though autoantibodies frequently persist. In this narrative review, we provide an overview of how peginterferon can induce autoimmunity in genetically susceptible individuals with pre-existing subclinical autoimmunity. Pre-treatment risk assessment, including personal/family history of autoimmune disease and consideration of baseline thyroid function and anti-GAD antibodies in high-risk patients, may identify those at elevated risk for irreversible complications, particularly Type 1 diabetes. Targeted clinical and laboratory monitoring throughout therapy and for 12–24 months post-cessation can enable early detection and appropriate intervention.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Switching between complement inhibitors in paroxysmal nocturnal hemoglobinuria: Analysis of strategy, efficacy, and safety","authors":"Morag Griffin,&nbsp;Bruno Fattizzo,&nbsp;Jong Wook Lee,&nbsp;Richard J. Kelly,&nbsp;Roochi Trikha,&nbsp;Yasutaka Ueda,&nbsp;Jun-ichi Nishimura,&nbsp;Christopher J. Patriquin,&nbsp;Alexander Röth,&nbsp;Petra Muus,&nbsp;Jens Panse,&nbsp;Miguel Gómez Álvarez,&nbsp;Alexandra Pike,&nbsp;Talha Munir,&nbsp;Shreyans Gandhi,&nbsp;Austin Kulasekararaj","doi":"10.1002/hem3.70427","DOIUrl":"10.1002/hem3.70427","url":null,"abstract":"<p>Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan disease. In 2026, approved complement inhibitors (CIs) for PNH include three C5 inhibitors (C5i) and three proximal inhibitors (PIs). Clinical trials for the approved PI pegcetacoplan, iptacopan, and C5i + danicopan had clear protocols for changing from terminal to PI, extrapolated into real-world practice. There is no guidance for patients changing from a PI to a different CI. We present the largest international cohort to date. The inclusion criteria were as follows: patients established on a PI, who have changed treatment to a different CI. Sixty-five patients with a median age at PNH diagnosis of 40 years were included. Indications for CI switch were as follows: hemolysis (extravascular/recurrent breakthrough/not specified), side effects, trial termination, patient choice, and other. CI changes (149) were classified as (1) terminal-to-proximal (75/149), 6 hemolytic events reported within 14 days of CI change; (2) proximal-to-proximal (45/149), 2 hemolytic events reported within 14 days of CI change; and (3) proximal-to-terminal (29/149), 13 hemolytic events within 14 days of CI change. This is the largest cohort of PNH patients facing multiple CI changes. With the increasing availability of different CI classes, patients may experience several treatment changes over their disease course. CI should not be interrupted. The cohort would suggest that overlapping treatment for patients changing from PI to another CI is not required. Tapering of treatment does not seem to be effective at preventing hemolysis complications. Patients should be monitored closely for hemolysis, especially when changing from proximal-to-terminal inhibition. Prospective clinical/laboratory analysis is recommended for further clarification management for this patient group.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148446061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of thrombosis and bleeding following CAR T-cell therapy: Insights from the Dutch “Follow that CAR!” registry","authors":"Amica K. Ko,&nbsp;Pim G. N. J. Mutsaers,&nbsp;Lukas M. van Kleij,&nbsp;Amária Vledder,&nbsp;Elise R. A. Pennings,&nbsp;Anne M. Spanjaart,&nbsp;Janneke W. de Boer,&nbsp;Kylie Keijzer,&nbsp;Astrid M. P. Demandt,&nbsp;Jaap A. van Doesum,&nbsp;Suzanne van Dorp,&nbsp;Margot Jak,&nbsp;Maria T. Kuipers,&nbsp;Tom van Meerten,&nbsp;Marjolein W. M. van der Poel,&nbsp;Joost S. P. Vermaat,&nbsp;Frank W. G. Leebeek,&nbsp;Marie J. Kersten,&nbsp;Mandy N. Lauw","doi":"10.1002/hem3.70433","DOIUrl":"10.1002/hem3.70433","url":null,"abstract":"<p>Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes in patients with relapsed/refractory aggressive large B-cell lymphoma (R/R LBCL). Although thrombosis and bleeding complications have been increasingly reported, their clinical relevance and risk factors remain unclear, also due to heterogeneity between reporting studies. We investigated the incidence of thrombosis and bleeding in a more homogeneous real-world multicenter cohort by analyzing 250 adults with R/R LBCL who were included in the Dutch “Follow that CAR!” multicenter registry, and all received axicabtagene ciloleucel (axi-cel) CAR T-cell therapy. We assessed the impact of thrombosis and bleeding, incorporated as time-dependent covariates on overall survival and explored associations with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), anticoagulant therapy, and laboratory parameters. One-year cumulative incidences of thrombosis and bleeding were 6.3% and 11.0%, respectively. Median time to thrombosis or bleeding was 28 days after infusion for both events. Bleeding was associated with poorer overall survival (hazard ratio [HR] 3.77, 95% CI 1.96–7.27). Patients with a CAR-HEMATOTOX score ≥2 before CAR T-cell therapy (HR 3.62, 95% CI 1.23–10.69), therapeutic anticoagulation at time of infusion (HR 3.74, 95% CI 1.33–10.49), or thrombocytopenia grade ≥3 (platelet count &lt; 50 × 10⁹/L) at time of infusion (HR 3.55, 95% CI 1.12–11.26, P = 0.03) had a significantly higher risk of bleeding. Our study confirms the high risk and clinical relevance of bleeding in patients receiving CAR T-cell therapy. Prospective studies are necessary to confirm these results and to guide recommendations regarding modifiable risk factors such as the use of anticoagulation or transfusion thresholds during CAR T-cell therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148446092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short BRAF+MEK coinhibition, alone and combined with anti-CD20 immunotherapy, in relapsed or refractory hairy cell leukemia: An investigator-sponsored multi-center phase 2 clinical trial","authors":"Luca De Carolis,&nbsp;Monia Capponi,&nbsp;Alessandro Mancini,&nbsp;Flavio Falcinelli,&nbsp;Caterina Stelitano,&nbsp;Alessandro Pulsoni,&nbsp;Edoardo Simonetti,&nbsp;Alessandra Romano,&nbsp;Gianna Maria D'Elia,&nbsp;Jacopo Olivieri,&nbsp;Maria Paola Martelli,&nbsp;Alessandra Pucciarini,&nbsp;Alessia Santi,&nbsp;Marta Naccari,&nbsp;Alessandra Venanzi,&nbsp;Antonio Bennati,&nbsp;Pier Luigi Zinzani,&nbsp;Marzia Varettoni,&nbsp;Simone Ferrero,&nbsp;Massimo Pini,&nbsp;Robin Foà,&nbsp;Elisa Lucchini,&nbsp;Maurizio Frezzato,&nbsp;Brunangelo Falini,&nbsp;Enrico Tiacci","doi":"10.1002/hem3.70431","DOIUrl":"10.1002/hem3.70431","url":null,"abstract":"&lt;p&gt;Hairy cell leukemia (HCL) is a rare chronic mature B-cell neoplasm caused by the BRAF V600E kinase-activating mutation in &gt;95% of cases, and usually presents with cytopenia(s) and splenomegaly.&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; Although purine analogs (PNAs) ± rituximab yield frequent and durable remissions, up to 58% of patients relapse.&lt;span&gt;&lt;sup&gt;4-7&lt;/sup&gt;&lt;/span&gt; In phase 2 trials, monotherapy with the oral BRAF inhibitors vemurafenib and dabrafenib showed good activity when given for a few months to relapsed/refractory (R/R) HCL patients (30%–35% of complete remissions [CRs]).&lt;span&gt;&lt;sup&gt;8-12&lt;/sup&gt;&lt;/span&gt; Still, minimal residual disease (MRD) persisted in the bone marrow (BM) even in CR patients, resulting in a median duration of response of up to 1.5 years overall. Interestingly, in our trial, we observed frequent ERK phosphorylation (pERK+) in residual BM HCL cells despite ongoing BRAF inhibition by vemurafenib. This finding correlated with a greater burden of leukemic residue and a shorter progression-free survival (PFS),&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; indicating MEK/ERK re-activation bypassing BRAF as a potential resistance mechanism.&lt;/p&gt;&lt;p&gt;In a subsequent phase 2 trial of continuous BRAF+MEK coinhibition with dabrafenib+trametinib given for a median of ~3 years to R/R HCL patients, CRs were more frequent (66%), but MRD clearance was still rare (16%). Such continuous therapy sustained a high PFS at 2 years (94%), but led to frequent treatment-related serious adverse events (SAEs; 35% of patients).&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; Furthermore, therapeutic strategies of fixed and short duration would be desirable in a chronic disease like HCL that allows for an almost normal life expectancy in most cases.&lt;span&gt;&lt;sup&gt;14, 15&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In another phase 2 trial on R/R HCL, we showed that adding anti-CD20 immunotherapy with rituximab (eight doses) to a short 8-week course of vemurafenib yielded 87% CR, frequent MRD clearance (60%), and 78% PFS at ~3 years of median follow-up.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt; Such results were largely reproduced in a subsequent real-life study of the same treatment regimen.&lt;span&gt;&lt;sup&gt;17&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Here, we tested in R/R HCL a short course of BRAF+MEK coinhibition with vemurafenib+cobimetinib first alone, and then combined with obinutuzumab (an anti-CD20 agent potentially more active than rituximab&lt;span&gt;&lt;sup&gt;18&lt;/sup&gt;&lt;/span&gt;) in patients not responding to, or relapsing after, vemurafenib+cobimetinib.&lt;/p&gt;&lt;p&gt;From 8/2017 to 6/2019, 19 patients with R/R HCL needing treatment were enrolled across 7 Italian centers in a phase 2 investigator-sponsored trial (EudraCT-2017-001836-20) of 2–3 cycles (cycle = 28 days) of vemurafenib (960 mg b.i.d.; Days 1–28 of each cycle) and cobimetinib (60 mg daily; Days 1–21 of each cycle). Cycle-3 was delivered only if no CR was obtained after cycle 2. Patient not responding to, or relapsing after, vemurafenib+cobimetinib, could receive up to three additional cycles of vemurafenib+cobimetinib co","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of high-frequency low-dose rituximab and acalabrutinib in chronic lymphocytic leukemia","authors":"Charles C. Chu,&nbsp;Clare B. Heffernan,&nbsp;Nydia C. Jaimes-Delgadillo,&nbsp;Christine A. Herne,&nbsp;Jennifer E. Bruno,&nbsp;Andrea M. Baran,&nbsp;John M. Ashton,&nbsp;Timothy R. Mosmann,&nbsp;Paul M. Barr,&nbsp;Ronald P. Taylor,&nbsp;Michael R. Elliott,&nbsp;Clive S. Zent","doi":"10.1002/hem3.70430","DOIUrl":"10.1002/hem3.70430","url":null,"abstract":"<p>Anti-CD20 monoclonal antibodies (mAbs) are effective but not curative treatment for chronic lymphocytic leukemia (CLL). To study rituximab efficacy, we examined serial blood samples from CLL patients receiving initial monotherapy with high-frequency low-dose (HFLD) rituximab for 1 week followed by the addition of acalabrutinib. Low-dose rituximab (intravenous infusion of 25 mg over 1 h) decreased the circulating CLL cell count by 85% with no additional changes during infusion of the next 25 mg of rituximab. Limited clearance of CLL cells was not attributable to low concentrations of rituximab or complement and was most likely caused by exhaustion of innate immune cytotoxicity as previously described for larger rituximab doses. Circulating CLL counts and CD20 levels rebounded by 48 h when subcutaneous administration of 50 mg of rituximab caused a small but significant decrease in CLL cell counts. Administration of 100 mg of rituximab in the first week of therapy decreased palpable lymphadenopathy by 66%. Addition of acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor (BTKi), on Day 8 of treatment was followed by decreases in CLL cell expression of <i>MS4A1</i> coding for CD20, CD20 levels, and CLL cell sensitivity to rituximab-induced antibody-dependent cellular phagocytosis. Based on these data and previous reports, we propose that rituximab therapy in CLL patients is optimized by HFLD regimens, which achieve maximum CLL cell clearance at dosing intervals sufficient for recovery of immune cytotoxicity. Our data also suggest that the efficacy of rituximab, and possibly other CD20-targeting mAbs, could be decreased by the addition of acalabrutinib or other BTKi.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13345710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion and safety profile of CD28-costimulated anti-CD19 CAR T cells in B-cell lymphoma versus autoimmune disease","authors":"Mirjeta Berisha,&nbsp;Denise Walther,&nbsp;Martin Böttcher,&nbsp;Lea Reemts,&nbsp;Martin Mikuško,&nbsp;Enrico Schalk,&nbsp;Achim J. Kaasch,&nbsp;Romy Böttcher-Loschinski,&nbsp;Ondrej Lukac,&nbsp;Tobias Hegelmaier,&nbsp;Stefanie Schreiber,&nbsp;Heiko Bruns,&nbsp;Stephan Fricke,&nbsp;Karolin Trautmann-Grill,&nbsp;Verena Keitel,&nbsp;Aiden Haghikia,&nbsp;Dimitrios Mougiakakos","doi":"10.1002/hem3.70426","DOIUrl":"10.1002/hem3.70426","url":null,"abstract":"&lt;p&gt;Autoimmune diseases (ADs) affect approximately 10% of the Western population, with an estimated 10%–15% of patients remaining refractory to standard-of-care therapies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In these individuals, disease manifestations are often associated with substantial impairment of quality of life and, in some cases, life-threatening organ involvement, underscoring a clear unmet need for innovative therapeutic approaches.&lt;/p&gt;&lt;p&gt;Across a broad spectrum of ADs, B cells represent a central pathogenic driver. Beyond their role as producers of autoantibodies, B cells critically contribute to disease pathogenesis through antigen presentation, including the presentation of self-peptides to autoreactive T cells, secretion of pro-inflammatory cytokines, and dysfunctional regulation of immune tolerance, including defects in regulatory B-cell subsets.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Therapeutic strategies aimed at B-cell depletion using monoclonal antibodies have therefore been extensively explored and have demonstrated clinical efficacy in selected indications, such as rheumatoid arthritis.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, these approaches have generally failed durable immune reset, limiting their transformative potential.&lt;/p&gt;&lt;p&gt;Cellular therapies targeting B cells, particularly chimeric antigen receptor (CAR) T cells, offer a fundamentally different strategy by inducing profound and sustained B-cell depletion. In hematologic malignancies, anti-CD19 CAR T cells are associated with deep and long-lasting B-cell aplasia,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; providing a strong biological rationale for their translation into ADs. Indeed, early case reports, case series, and more recently emerging clinical trial data have demonstrated striking clinical responses across multiple autoimmune indications, supporting the feasibility of this concept.&lt;span&gt;&lt;sup&gt;5-8&lt;/sup&gt;&lt;/span&gt; Similar signals have been reported in pediatric refractory AD, supporting broad applicability.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Initial concerns that CAR T-cell therapy might be associated with increased toxicity in autoimmune setting, given the presence of an inflammatory immune milieu, have so far not been substantiated. Instead, available evidence suggests a favorable tolerability profile in ADs, even superior to that observed in patients with hematologic malignancies.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Hypothesized explanations include lower antigen burden, resulting in attenuated CAR T-cell activation, although definitive mechanistic proof is currently lacking. Notably, in a recently published comparative analysis, patients with systemic lupus erythematosus (SLE) treated with second-generation anti-CD19 CAR T cells exhibited reduced toxicity compared with patients with lymphoma, who had received either CD28-based or 4-1BB-costimulated CAR T cells, supporting the concept of disease-context–dependent differences in tolerability.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In this single-center experience, we sought to exte","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13345674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}