381. Venetoclax plus daunorubicin and cytarabine for newly diagnosed acute myeloid leukemia: results of a phase 1b study.
作者: Ioannis Mantzaris.;Mendel Goldfinger.;Matan Uriel.;Aditi Shastri.;Nishi Shah.;Kira Gritsman.;Noah S Kornblum.;Lauren Shapiro.;Roberto Alejandro Sica.;Anne Munoz.;Nicole Chambers.;Aradhika Dhawan.;Jhannine Alyssa Verceles.;Karen Fehn.;Balda Tirone.;Lamisha Shah.;Shaunmonique Clark.;Chenxin Zhang.;Mimi Kim.;Dennis L Cooper.;Amit Verma.;Marina Konopleva.;Eric J Feldman.
来源: Blood. 2025年145卷17期1870-1875页
Venetoclax (Ven), when combined with intensive chemotherapy, shows promise for untreated acute myeloid leukemia (AML), but its integration with the 7+3 regimen remains underexplored. In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total of 34 patients (median age, 59 years; 62% non-White) received Ven at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), but there were no induction deaths. The median recovery times for neutrophils (>1.0 × 103/μL) and platelets (>100 × 103/μL) were less than 30 days. Composite complete remission was achieved in 85.3% of patients, and 86.2% were negative for measurable residual disease (MRD). Responses spanned all European Leukemia Net 2022 risk categories. With a median follow-up of 9.6 (2-20) months, the median duration of response, event-free survival, and overall survival were not reached. Ven (400 mg), when combined with 7+3 chemotherapy, was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings. This trial was registered at clinicaltrials.gov as #NCT05342584.
382. The JAK2 46/1 haplotype influences PD-L1 expression.
作者: Gonzalo Carreño-Tarragona.;María Tiana.;Raquel Rouco.;Alejandra Leivas.;Jesús Victorino.;Roberto García-Vicente.;Andrew J Chase.;Andrea Maidana.;William J Tapper.;Rosa Ayala.;Nicholas C P Cross.;Joaquín Martínez-López.;Miguel Manzanares.
来源: Blood. 2025年145卷19期2196-2201页
Although described more than a decade ago, the mechanism by which the JAK2 46/1 haplotype increases the risk of developing JAK2-mutated myeloproliferative neoplasms (MPNs) remains unexplained. Inflammation and immunity are linked to MPN development and thus could be relevant to the mechanism by which 46/1 mediates its effect. Here, we show that programmed death-1 receptor ligand (PD-L1) expression is elevated in 46/1 haplotype, both in healthy carriers and in CD34+ cells from patients with MPN. Using circular chromosome conformation capture, we observed that PD-L1 and the neighboring PD-L2 loci physically interact with JAK2 in a manner that differs between 46/1 and nonrisk haplotypes. CRISPR/Cas9 genome editing identified a region within JAK2 intron 2 that influences both JAK2 and PD-L1 expression. We suggest that increased PD-L1 expression may be relevant to the mechanism by which 46/1 leads to an increased inherited risk of developing MPN.
383. Targeting cell-surface VISTA expression on allospecific naïve T cells promotes tolerance.
作者: Brent H Koehn.;Elizabeth C Nowak.;Sladjana Skopelja-Gardner.;Asim Saha.;Michael C Zaiken.;Jeremy Allred.;Yiyung Peng.;Wilson L Davis.;Isabelle Le Mercier.;Nicholas Schwertner.;Michael J Molloy.;Jay Rothstein.;Catherine Carriere.;Megan J Riddle.;Cindy R Eide.;Jakub Tolar.;Angela Panoskaltsis-Mortari.;Kyle D Smith.;Keli L Hippen.;Tae Kon Kim.;Randolph J Noelle.;Bruce R Blazar.
来源: Blood. 2025年145卷15期1687-1700页
The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by coinhibitory signals such as the checkpoint molecule VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation)/programmed death-1 homolog that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA monoclonal antibody (mAb) prevents acute GVHD lethality in multiple models. Naïve donor T cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with T-cell receptor signaling, leading to heightened susceptibility to anti-VISTA mAb-mediated depletion, in contrast to donor T cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peritransplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8+ T cells was not protective against GVHD lethality. Instead, anti-VISTA mAb-mediated deletion of alloreactive donor T cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via Fc receptor (FcR)-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma (GVL) effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4+ T cells, and was delayed but mostly retained when unseparated donor T cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.
391. Targeting caseinolytic mitochondrial matrix peptidase, a novel contributor to the pathobiology of high-risk multiple myeloma.
作者: Li Qin.;Luz Yurany Moreno Rueda.;Upasana Ray.;Iqbal Mahmud.;Lin Tan.;Philip L Lorenzi.;Suyu Liu.;Heather Lin.;David E Mery.;Fenghuang Zhan.;John D Shaughnessy.;Qing Yi.;Maria Jose Acevedo Calado.;Hua Wang.;Elisabet E Manasanch.;Hans C Lee.;Krina K Patel.;Isere Kuiatse.;David E Symer.;Robert Z Orlowski.
来源: Blood. 2025年145卷22期2614-2629页
Plasma cell dyscrasias encompass a spectrum from the precursors monoclonal gammopathy of undetermined significance and smoldering myeloma to symptomatic myeloma, but the genes that enable progression and confer poor prognosis are incompletely understood. Using single-cell transcriptomics, we identified the caseinolytic protease proteolytic subunit (CLPP), a key component of the mitochondrial caseinolytic protease (CLP) serine endopeptidase, as being overexpressed in CD138+ neoplastic vs normal and in symptomatic vs precursor plasma cells. Its high expression was associated with an adverse prognosis across multiple molecularly defined subgroups in the newly diagnosed and relapsed/refractory settings and with extramedullary disease. Pharmacologic CLPP inhibition and genetic suppression reduced organoid growth, cell viability, and cell cycle progression, and triggering an unfolded protein response and apoptosis. This occurred in association with mitochondrial transmembrane potential loss and caspase and proteasome activation in a reactive oxygen species-dependent manner. Downstream consequences included autophagy and mitophagy induction and reductions in oxidative phosphorylation and glycolysis with consequent compromise of mitochondrial and cytoplasmic adenosine triphosphate (ATP) production. CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes.
392. Impact of new medications on the treatment of immune TTP.
The last decade has seen the introduction of 2 new licensed therapies for thrombotic thrombocytopenic purpura (TTP), caplacizumab and recombinant ADAMTS13 (rADAMTS13), for immune and congenital TTP (cTTP), respectively. They improve acute TTP outcomes, and reduce the need for plasma therapy, time to clinical response, and treatment burden. Future pathways need to replace plasma exchange in acute TTP and optimize/personalize rADAMTS13 in cTTP. Future emphasis should focus on additional monoclonals/treatments to tackle ADAMTS13 antibodies.
393. PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.
作者: Lingli He.;Ting Zhao.;Wei Zhong Leong.;Azeem Sharda.;Christina Mayerhofer.;Shenglin Mei.;Gracia M Bonilla.;Juan Bautista Menendez-Gonzalez.;Karin Gustafsson.;Tsuyoshi Fukushima.;Trine A Kristiansen.;Ji-Won Lee.;Yanxin Xu.;Lei Chen.;Jun Xia.;Luis Angel Orozco.;Bogdan Budnik.;Ruslan Sadreyev.;Zhixun Dou.;David B Sykes.;David T Scadden.
来源: Blood. 2025年145卷17期1903-1914页
Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AMLs). A phenotypic CRISPR-CRISPR-associated protein 9 screen in AML identified dependence on phosphoseryl-transfer RNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemotherapy-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cyclic GMP-AMP Synthase-Stimulator of interferon genes (cGAS-STING). This activation, in turn, disrupted iron metabolism, augmenting ROS generation, and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop, culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. These data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemotherapy-persisting cells and thereby impede disease relapse.
394. EMZL at various sites: learning from each other.
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) invariably develops from a background of chronic inflammatory disorder caused by a diverse chronic microbial infection and/or autoimmunity, depending on the site. These chronic inflammatory/autoimmunity disorders trigger innate and acquired immune responses, generating a unique microenvironment at each site that drives clonal evolution of B cells, their expansion, and eventual malignant transformation. At a molecular level, this involves temporal and spatial acquisition of cooperative oncogenic events by dysregulated immune responses and somatic genetic changes. Although these events are not yet fully characterized, EMZL at several sites shows distinct genetic profiles and molecular insights, bridging the pathologic process to lymphomagenesis. For example, gastric EMZL, particularly those lacking a BCL10 or MALT1 translocation, critically depends on T-helper cell signals produced by immune responses to Helicobacter pylori infection. Likewise, thyroid EMZL may also involve exaggerated T-cell help because of highly frequent inactivating mutations in TET2, CD274 (programmed cell death 1 ligand 1), and TNFRSF14, which impede the coinhibitory interactions between the neoplastic B- and T-helper cells, thus releasing T-cell help. Ocular adnexal EMZL shows frequent TNFAIP3 (A20) mutation/deletion that significantly associates with expression of autoreactive IGHV4-34 B-cell receptor, emphasizing its potential cooperation in NF-κB pathway activation. Finally, the genesis of salivary gland EMZL may be closely associated with GPR34 activation that is caused by mutation/t(X;14)(p11;q32) and/or paracrine stimulation mediated by ligand generated by lymphoepithelial lesions. This review will focus on these novel molecular insights and how these advances may provide a paradigm for future investigations.
395. X-linked sideroblastic anemia in females.
作者: Sarah Ducamp.;Dean R Campagna.;Anoop K Sendamarai.;Paul J Schmidt.;Harrison K Tsai.;Matthew M Heeney.;Sylvia S Bottomley.;Mark D Fleming.
来源: Blood. 2025年145卷14期1583-1587页
X-linked sideroblastic anemia (XLSA) in female carriers of 5-aminolevulinic acid synthase 2 mutations is not uncommon. We describe unique features and genotype/phenotype correlations in females with XLSA and evaluate the contributions of X-chromosome skewing and clonal hematopoiesis, emphasizing the importance of distinguishing it from myelodysplastic syndromes with ring sideroblasts.
396. Reactive oxygen species regulate early development of the intestinal macrophage-microbiome interface.
作者: Zohreh Mansoori Moghadam.;Bei Zhao.;Candice Raynaud.;Valentina Strohmeier.;Jana Neuber.;Anne Kathrin Lösslein.;Sabrina Qureshi.;Vitka Gres.;Tara Ziegelbauer.;Sebastian Baasch.;Christoph Schell.;Klaus Warnatz.;Naohiro Inohara.;Gabriel Nuñez.;Thomas Clavel.;Stephan P Rosshart.;Julia Kolter.;Philipp Henneke.
来源: Blood. 2025年145卷18期2025-2040页
The controlled development of cellular intestinal immunity in the face of dynamic microbiota emergence constitutes a major challenge in very early life and is a bottleneck for sustained growth and well-being. Early-onset inflammatory bowel disease (IBD) represents an extreme disturbance of intestinal immunity. It is a hallmark and often the first manifestation of chronic granulomatous disease (CGD), caused by inborn defects in the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) in phagocytes and thus the failure to produce reactive oxygen species (ROS). However, in contrast to the known role of ROS in antimicrobial defense, the mechanisms underlying intestinal immunopathology in CGD remain enigmatic. This is partly due to the incomplete recapitulation of the CGD-IBD phenotype in established mouse models. We found that mice deficient in the NOX2 subunits p47phox or gp91phox showed similar baseline disturbances in lamina propria macrophage differentiation but responded differently to chemically induced colitis. Although p47phox- and gp91phox-deficient mice differed markedly in microbiota composition, crossfostering failed to equalize discrepant IBD phenotypes and microbiota, pointing at extremely early and functionally important microbiota fixation under specific pathogen-free housing conditions. In contrast, neonatal acquisition of a complex wild-mouse microbiota triggered spontaneous IBD, granuloma formation, and secondary sepsis with intestinal pathogens in both NOX2-deficient mouse lines, which was in part dependent on NOX2 in intestinal macrophages. Thus, in experimental CGD, the aberrant development of tissue immunity and microbiota are closely intertwined immediately after birth.
397. Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.
作者: Michael C Zaiken.;Sujeong Jin.;Cameron S McDonald-Hyman.;Christina R Hartigan.;Peter T Sage.;Keli L Hippen.;Brent H Koehn.;Angela Panoskaltsis-Mortari.;Megan J Riddle.;Cindy R Eide.;Jakub Tolar.;Geoffrey R Hill.;Leo Luznik.;Corey S Cutler.;Jerome R Ritz.;Leslie S Kean.;Ageliki Tsagaratou.;Anjana Rao.;Bruce R Blazar.
来源: Blood. 2025年145卷24期2813-2827页
Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and nonrelapse-associated mortality after allogeneic hematopoietic cell transplantation. Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. In this study, we sought to investigate the DNA demethylase ten-eleven translocase (Tet) methylcytosine dioxygenases 2 (Tet2) and 3 (Tet3) in T follicular helper cell (TFH)-dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2-deleted donor T cells did not have improved pulmonary function tests in contrast with the markedly improved pulmonary function in Tet3-deleted donor T cells. Tet3 deleted donor T cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency led to elevated GATA3 (GATA-binding protein 3) expression in and interleukin-4 production by TFHs. TET3-deficient TFHs supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c, thereby enabling mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH-driven immunoglobulin class switching and suggest a new approach to mitigate cGVHD.
398. How I approach pharmacological thromboprophylaxis in children.
The incidence of venous thromboembolism in children continues to rise, with the most recent analysis from the Pediatric Hospital Information Systems database in the United States reporting a 200-fold increase in pediatric hospitalization-related venous thromboembolism diagnoses over the past 2 decades. In the past decade, several pediatric venous thromboembolism risk prediction models have been published, in some cases derived from multi-institutional data, and multicenter randomized clinical trials of thromboembolism prevention in specific pediatric subpopulations have been conducted. Yet, apart from children hospitalized for COVID-19, guidelines for thromboprophylaxis (TP) in children that address several distinct at-risk subpopulations and settings for venous thromboembolism are presently lacking. It is becoming increasingly apparent that approaches to pharmacological TP for hospitalized children should be risk-stratified regarding a priori risks of both venous thromboembolism and clinically relevant bleeding. In this manuscript, we present model cases of common inpatient clinical scenarios and review the evidence related to venous thromboembolism risk models and pharmacological TP clinical trials in children, describing a pragmatic approach to pharmacological TP for each scenario. We then conclude by describing our evidence-informed, subpopulation- and setting-specific approach to pharmacological TP for the clinical scenarios and reviewing critical knowledge gaps well-suited for future pediatric trials to inform TP in children.
399. IL-10 from tumoral B cells modulates the diffuse large B-cell lymphoma microenvironment and response to immunotherapy.
作者: Marcos Garcia-Lacarte.;Sara C Grijalba.;Javier Melchor.;Marién Pascual.;Enrique Goñi.;Iñigo Clemente-Larramendi.;Sandra Morales-Sánchez.;María A Burrell.;Oscar Blanco.;Adrián Arnaiz-Leché.;Blanca S Berrozpe.;Maria Amann.;Christian Klein.;Pablo Umaña.;Miguel Canales.;José Ángel Martínez-Climent.;Juan J Lasarte.;Pablo Sarobe.;Francisco J Novo.;Sergio Roa.
来源: Blood. 2025年145卷23期2746-2761页
The contribution of interleukin-10 (IL-10), secreted by tumoral B cells, to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell-like (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knockout of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T-cell depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell-exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, which is refractory to PD-1 immune checkpoint blockade. However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes the survival of malignant B cells, whereas the paracrine action of B-cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies targeting the lymphoma microenvironment. Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Thus, our work provides important functional and mechanistic insights into the role of B-cell-derived IL-10 in the biology of ABC-DLBCL.
400. MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial.
作者: 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.
来源: Blood. 2025年145卷12期1282-1292页
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.
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