1. Plasminogen activation and plasmin activity are not required to prevent venous thrombosis/thromboembolism.
作者: Yaqiu Sang.;Marzia Menegatti.;Jennifer A Brody.;Kerri L Wiggins.;Brian C Cooley.;Katheryn N Kapfer.;Kadri Kangro.;Bas de Laat.;Flora Peyvandi.;Matthew J Flick.;Nicholas L Smith.;Amy D Shapiro.;Alisa S Wolberg.
来源: Blood. 2025年
Suppression of plasminogen activation and/or plasmin activity (PA) reduces blood loss and decreases hemorrhage-related death. However, whether the endogenous PA system is a biological mechanism to prevent intravascular thrombus formation is debated, and the potential that reduced PA may increase venous thrombosis/thromboembolism (VTE) risk cautions against the use of antifibrinolytic agents. We aimed to determine the contribution of PA to VTE. Type 1 plasminogen-deficient humans enrolled in the HISTORY registry (https://clinical trials.gov; NCT03797495) reported pathologic pseudomembrane formation, but not unprovoked VTE. When subjected to an experimental model of venous thrombosis, compared to Plg+/+ mice, neither partial (Plg+/-) nor complete (Plg-/-) deletion of plasminogen altered thrombus mass or thrombus nucleated cell, platelet, or fibrin(ogen) content at 24 or 6 hours after thrombus induction. Administration of tranexamic acid (TXA) to mouse plasma in vitro or healthy mice in vivo dose-dependently delayed and suppressed plasma plasmin generation for up to 3 hours. However, mice administered TXA did not have significantly altered thrombus mass or thrombus composition at 24 or 6 hours after thrombus induction, despite unexpectedly persistent TXA in plasma. In a genome-wide association study, variants in gene regions encoding PA pathway proteins were not significantly associated with VTE risk. In the UK Biobank repository, plasminogen protein levels were not significantly associated with VTE risk. These data from genetic, pharmacologic, and proteomic analyses of mice and humans indicate that perturbations in PA do not increase VTE risk. Collectively, these results suggest PA is not a molecular regulatory mechanism to protect against VTE.
2. Large B-cell lymphoma imprints a dysfunctional immune phenotype that persists years after treatment.
作者: Richard Pelzl.;Giulia Benintende.;Franziska Gsottberger.;Julia Katharina Scholz.;Matthias Ruebner.;Hao Yao.;Kerstin Wendland.;Kai Rejeski.;Heidi Altmann.;Srdjan Petkovic.;Lisa Mellenthin.;Sabrina Kübel.;Moritz Schmiedeberg.;Paulina Klein.;Agnese Petrera.;Rebecca Baur.;Sophie Eckstein.;Sandra Hoepffner-Grundy.;Christoph Röllig.;Marion Subklewe.;Hanna Huebner.;Georg Schett.;Andreas Mackensen.;Luca Laurenti.;Frederik Graw.;Simon Völkl.;Krystelle Nganou-Makamdop.;Fabian Müller.
来源: Blood. 2025年
Immunotherapy has become standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL). Changes in immunophenotypes observed at first diagnosis predict therapy outcome but little is known about the resolution of these alterations in remission. Comprehensive characterization of immune changes from fresh, peripheral whole blood revealed a functionally relevant increase of myeloid-derived suppressor cells, reduced naïve T-cells, and an increase of activated and terminally differentiated T-cells before treatment which aggravated after therapy. Suggesting causal relation, injection of lymphoma in mice induced similar changes in the murine T cells. Distinct immune imprints were found in breast cancer and AML survivors. Identified alterations persisted beyond five years of ongoing complete remission and in DLBCL correlated with increased pro-inflammatory markers such as IL-6, B2M, or sCD14. The chronic inflammation was associated with functionally blunted T-cell immunity against SARS-CoV-2-specific peptides and reduced responses correlated with reduced Tn-cells. Persisting inflammation was confirmed by deep sequencing and by cytokine profiles, together pointing towards a compensatory activation of innate immunity. The persisting, lymphoma-induced immune alterations in remission may explain long-term complications, have implications for vaccine strategies, and are likely relevant for immunotherapies.
3. Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.
作者: Martha L Arellano.;Michael J Thirman.;John F DiPersio.;Mael Heiblig.;Eytan M Stein.;Andre C Schuh.;Andrius Zucenka.;Stéphane De Botton.;Carolyn S Grove.;Gabriel N Mannis.;Cristina Papayannidis.;Alexander E Perl.;Ghayas C Issa.;Ibrahim Aldoss.;Ashish Bajel.;David S Dickens.;Michael W M Kühn.;Ioannis Mantzaris.;Emmanuel Raffoux.;Elie Traer.;Irina Amitai.;Hartmut Döhner.;Corinna Greco.;Tibor J Kovacsovics.;Christine M McMahon.;Pau Montesinos.;Arnaud Pigneux.;Paul J Shami.;Richard M Stone.;Ofir Wolach.;John G Harpel.;Yakov Chudnovsky.;Li Yu.;Rebecca G Bagley.;Angela R Smith.;James S Blachly.
来源: Blood. 2025年
The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary endpoints were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR+CRh), and safety and tolerability. Secondary endpoints included overall response rate (ORR) and duration of response. As of September 18, 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 prior lines of therapy, 35.9%; prior venetoclax, 75.0%). The CR+CRh rate was 23.4% (1-sided P=.0014); the ORR was 46.9%. Median duration of CR+CRh was 4.7 months. Five of 30 responders (16.7%) proceeded to hematopoietic stem cell transplant (HSCT); 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as NCT04065399.
4. Cryo-EM structure of coagulation factor Va bound to activated protein C.
Coagulation factor Va (FVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In addition, FVa is a target for proteolytic inactivation by activated protein C (APC). Like other protein-protein interactions in the coagulation cascade, the FVa-APC interaction has long posed a challenge to structural biology and its molecular underpinnings remain unknown. A recent cryogenic electron microscopy (cryo-EM) structure of FVa has revealed the arrangement of its A1-A2-A3-C1-C2 domains and the environment of the sites of APC cleavage at R306 and R506. Here, we report the cryo-EM structure of the FVa-APC complex at 3.15 Å resolution in which the protease domain of APC engages R506 in the A2 domain of FVa through electrostatic interactions between positively charged residues in the 30-loop and 70-loop of APC and an electronegative surface of FVa. The auxiliary γ-carboxyglutamic acid and epidermal growth factor domains of APC are highly dynamic and point to solvent, without making contacts with FVa. Binding of APC displaces a large portion of the A2 domain of FVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as a "latch," or exosite ligand, over the 70-loop of the enzyme. The latch induces a large conformational change of the autolysis loop of APC, which in turn promotes docking of R506 into the primary specificity pocket. The cryo-EM structure of the FVa-APC complex validates the bulk of existing biochemical data and offers molecular context for a key regulatory interaction of the coagulation cascade.
5. A Novel Mouse Model of Hemoglobin SC Disease Reveals Mechanisms Underlying Beneficial Effects of Hydroxyurea.
作者: Tahereh Setayesh.;Mengna Chi.;Zachery Oestreicher.;Masahide Sakabe.;Katie Giger Seu.;Zhenqi Zhu.;Harsimran Kaur.;Anifat Tijani.;Mei Xin.;Amy Shova.;Kenneth D Greis.;Tim M Townes.;Jozsef Balla.;Katherine VandenHeuvel.;Yueh-Chiang Hu.;Punam Malik.
来源: Blood. 2025年
Sickle cell hemoglobin-C (HbSC) disease results from compound heterozygosity of hemoglobin-S (HbS) and hemoglobin-C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces RBC dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, while HbSC patients are deprived of disease-modifying/transformative therapies due to lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation and organ damage were milder than HbSS mice, but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% versus 16.7%; p<0.05), like HbSC-SCD patients. While HbSC RBCs sickled at lower pO2 than HbSS RBCs (43mmHg versus 24mmHg; P<0.0001), they did not completely recover deformability after hypoxia-reoxygenation. Using the HbSC mice developed herein, we studied the mechanism by which hydroxyurea causes significant clinical benefit in HbSC-SCD patients, despite minimal/modest increases in fetal-hemoglobin (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice, but reduced RBC ROS, Ferryl-hemoglobin, Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before they switch off g-globin expression and continued postnatally, we could induce HbF in both HbSC/HbSS mice (higher HbF in HbSS versus HbSC mice). Minimal increases in HbF (~1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge-gap in mechanistic/therapeutic studies in this neglected disease.
6. Clinical phenotype and pathophysiological mechanisms underlying qualitative Low VWF.
作者: Ferdows Atiq.;Robin Blok.;Calvin van Kwawegen.;Anne-Marije Hulshof.;Dearbhla Doherty.;Michelle Lavin.;Johanna G van der Bom.;Niamh M O'Connell.;Joke de Meris.;Kevin Ryan.;Saskia E M Schols.;Waander L van Heerde.;Mairead M Doyle.;Mary B Byrne.;Floor C J I Heubel-Moenen.;Karin P M van Galen.;Roger J S Preston.;Marjon H Cnossen.;Karin Fijnvandraat.;Ross Ian Baker.;Karina Meijer.;Paula D James.;Jorge Di Paola.;Jeroen C J Eikenboom.;Frank W G Leebeek.;James S O'Donnell.
来源: Blood. 2025年
Previous reports have highlighted that some low VWF patients with significant bleeding were diagnosed based upon an isolated but persistent reduction in plasma VWF activity levels in the 30-50 IU/dL range. These patients had plasma VWF:Ag levels > 50 IU/dL and thus had 'qualitative' rather than 'quantitative' low VWF. Although the clinical importance of functional VWF defects in type 2 VWD is well recognized, the translational implications of mild functional defects in patients with qualitative low VWF (low VWF-QL) have not been defined. To address this clinically important question, we combined low VWF datasets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for approximately 50% of our combined low VWF cohort. Importantly, our findings demonstrate that many of these patients with mild isolated functional VWF defects in the 30-50 IU/dl range had significant bleeding phenotypes, even though their plasma VWF:Ag levels were within the normal range. In addition, we further show that low VWF-QL is a distinct clinic-pathological entity compared to type 2 VWD. Finally, our studies highlight that low VWF-QL is predominantly due to abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.
7. Rapid ADAMTS13 activity assays for thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.
作者: Saarang R Deshpande.;Hemza Tarawneh.;Chloe Cate Deitelzweig.;Jiayi Tong.;Ting Zhou.;Yong Chen.;Adam Cuker.
来源: Blood. 2025年
Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal thrombotic microangiopathy caused by severe ADAMTS13 deficiency. Prompt treatment improves survival; however, reference standard ELISA and FRETS-VWF73 ADAMTS13 activity assays have long turnaround times that necessitate empiric treatment of many patients who ultimately are found not to have TTP. Rapid assays with analytical turnaround times within one hour have recently become available. We conducted a systematic review and meta-analysis of the performance characteristics of rapid assays relative to reference standard assays for ADAMTS13 activity for patients with suspected or confirmed TTP. Nineteen studies representing three rapid ADAMTS13 assays and 4,207 patient samples were included. The HemosIL AcuStar CLIA demonstrated high sensitivity (0.98, 95% CI 0.94 - 1.00), specificity (0.99, 0.97 - 1.00), and positive (0.96, 0.90 - 0.98) and negative predictive value (0.99, 0.99 - 1.00). The Technofluor FRET and Technoscreen assays had sensitivity of 0.93 (0.86 - 0.96) and 0.98 (0.42 - 1.00), specificity of 0.98 (0.95 - 0.99) and 0.87 (0.76 - 0.94), PPV of 0.97 (0.85 - 1.00) and 0.71 (0.59 - 0.80), and NPV of 0.96 (0.93 - 0.98) and 0.99 (0.72 - 1.00), respectively. The proportion of discrepant results (relative to reference standard assays) was 0.04 (0.03 - 0.05) for HemosIL AcuStar, 0.04 (0.02 - 0.06) for Technofluor FRET, and 0.11 (0.07 - 0.16) for the Technoscreen assay. With rapid turnaround time and high sensitivity, the HemosIL AcuStar CLIA appears able to reliably avert empiric plasma exchange, corticosteroids, and caplacizumab in patients without TTP.
8. T-ICAHT: Grading and Prognostic Impact of Thrombocytopenia After CAR T-cell Therapy.
作者: Kai Rejeski.;Jaime Sanz.;Teng Fei.;Monica S Nair.;Hamza Hashmi.;Abraham Avigdor.;Ofrat Beyar-Katz.;Veit L Bücklein.;Kevin J Curran.;Sigrun Einarsdottir.;Jonathan H Esensten.;Netta Glaubach.;Noa Golan-Accav.;Marina Gomez-Llobell.;Iris Halamis.;Orit Itzhaki.;Frederick L Locke.;Sham Mailankody.;Ronit Marcus.;Marcela V Maus.;M Lia Palomba.;Jae H Park.;Marcelo C Pasquini.;Sandeep S Raj.;Sridevi Rajeeve.;Gilles A Salles.;Michael Scordo.;Gunjan L Shah.;Avichai Shimoni.;Marion Subklewe.;Tobias Tix.;Saad Z Usmani.;Ori Ben Valid.;Yannis K Valtis.;Tsila Zuckerman.;Nirali N Shah.;Miguel-Angel Perales.;Roni Shouval.
来源: Blood. 2025年
Immune effector cell-associated hematotoxicity (ICAHT) was recently introduced as a distinct toxicity category of CAR-T therapy. While a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remains poorly defined. In this multicenter observational study, we systematically examined patterns of thrombocytopenia in 744 patients treated with commercial CD19 CAR-T for B-cell Non-Hodgkin Lymphoma (B-NHL). We developed a grading system termed T-ICAHT with thresholds that closely aligned with N-ICAHT - based on depth, duration and timing of thrombocytopenia. In the core NHL dataset, 43% of patients developed any-grade early T-ICAHT (day 0-30), with 23% developing severe (G3+) manifestations. Late T-ICAHT (day 31-100) was observed in 42% (G3+: 13%). While T-ICAHT and N-ICAHT gradings showed some correlation, considerable discordance was noted. On multivariate analysis, bridging therapy, poor performance status, and high Hematotox scores were associated with increased risk of severe early T-ICAHT. Patients with higher T-ICAHT grades showed increased platelet and red blood cell transfusion burden (p<0.001) and more bleeding events (p=0.01). T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (G0), to 48% (G1-2) and 35% (G3+). In multivariable Cox regression analysis, the independent prognostic capacity of T-ICAHT for OS was confirmed. Finally, we validated T-ICAHT's clinical and prognostic utility in 3 external cohorts spanning an additional 599 pediatric and adult patients (NHL, MM, B-ALL), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.
9. Genotype-specific immune responses at the intestinal barrier predispose to colitis in mouse models of chronic granulomatous disease.
作者: Emma Darbinian.;Kodjovi D Mlaga.;Prabha Chandrasekaran.;Yu Han.;Ágnes Donkó.;Aléhandra Desjardins.;Thomas L Leto.;Steven M Holland.;Johanne Poudrier.;Emilia Liana Falcone.
来源: Blood. 2025年145卷26期3153-3165页
Chronic granulomatous disease (CGD) is an inborn error of immunity that is caused by defects in any 1 of the 5 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox) that form the NAD phosphate oxidase complex 2 (NOX2) or in the chaperone protein essential for reactive oxygen species (ROS) that supports its assembly. These defects lead to severely reduced phagocyte-derived ROS production. Almost 50% of patients with CGD have inflammatory bowel disease (IBD) associated with dysbiosis, and the age of IBD onset may vary according to the CGD genotype. Although we previously demonstrated that the intestinal microbiota determines colitis susceptibility in CGD mice, the underlying mechanisms remain unknown. We hypothesized that NOX2 defects are associated with distinct intestinal microbiome signatures and immune responses, which impact colitis severity. Chemical colitis susceptibility was evaluated in 2 strains of CGD mice (gp91phox-/- and p47phox-/-) with distinct microbiotas from 2 different animal facilities, while also evaluating the impact of microbiota standardization and colitogenic microbiota transfer on mucosal immune responses at the intestinal barrier. Although p47phox-/- and gp91phox-/- mice that harbored a colitogenic microbiota had increased colitis severity, the intestinal epithelial cells from p47phox-/- mice produced more ROS, which was associated with increased NOX isoform gene expression. In contrast, gp91phox-/- mice had decreased mucin production and a mucosal immune response profile suggestive of increased inflammasome activation at the intestinal barrier when compared with control and p47phox-/- mice. Our findings suggest that the microbiota impacts colitis susceptibility in a CGD genotype-specific manner, thereby potentially explaining differences in the timing of IBD onset in patients with different CGD genotypes and identifying potential novel and personalized therapeutic targets.
10. The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy.
作者: Naval G Daver.;Paresh Vyas.;Gerwin A Huls.;Hartmut Döhner.;Sebastien Maury.;Jan Novak.;Cristina Papayannidis.;Carmen Martinez Chamorro.;Pau Montesinos.;Rabin Niroula.;Pierre Fenaux.;Jordi Esteve.;Shang-Ju Wu.;Adrien De Voeght.;Jiri Mayer.;Peter J M Valk.;Lisa Johnson.;Mei Dong.;Ke Liu.;Sowmya Banda Kuwahara.;Kenneth Caldwell.;Guru Subramanian Guru Murthy.
来源: Blood. 2025年
Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary endpoint was overall survival (OS); key secondary endpoints included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis due to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (HR, 1.178 [95% CI, 0.848-1.637]). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.
11. Maternal Tmprss6 is required for hepcidin suppression and fetal health.
作者: Katherine L Fielding.;Cavan Bennett.;Anne Pettikiriarachchi.;Naomi Jones.;Rebecca Harding.;Alistair R D McLean.;Louise Randall.;Ute Schaeper.;Alberto Martinez.;Ricardo Ataíde.;Sant-Rayn Pasricha.
来源: Blood. 2025年145卷25期3056-3059页
The antenatal role of the hepcidin-regulating protease Tmprss6 has never been elucidated because knockout dams are infertile. Using an in vivo knockdown approach, we confirm Tmprsss6 is critical for hepcidin suppression in pregnancy, and Tmprss6 inhibition drives deleterious fetal outcomes.
12. Project EVOLVE: An international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.
作者: Sara K Silbert.;Alexander W Rankin.;Chloe N Hoang.;Alexandra Semchenkova.;Regina M Myers.;Elena Zerkalenkova.;Hao-Wei Wang.;Alexandra E Kovach.;Constance M Yuan.;Dana Delgado Colon.;Loic Vasseur.;Alex Bataller.;Samuel John.;Kaylyn Utley Lyons.;Barbara D Friedes.;Anna Alonso-Saladrigues.;Hisham Abdel-Azim.;Estelle Balducci.;Ahmed Aljudi.;Marie Balsat.;D Nathan Biery.;Aghiad Chamdin.;Bill H Chang.;Raymund S Cuevo.;Barbara De Moerloose.;David S Dickens.;Ulrich A Duffner.;Nicolas Duployez.;Firas El Chaer.;Michelle Ann Elliott.;Gabriele Escherich.;Sneha Fernandes.;Mandi R Fitzjohn.;Zhubin J Gahvari.;Stephan A Grupp.;Rui Rochelle He.;Cynthia Harrison.;Christopher Bruce Hergott.;Emily M Hsieh.;Annette S Kim.;Dennis John Kuo.;Daniel P Larson.;Benjamin J Lee.;Thibaut Tl Leguay.;R Coleman Lindsley.;Abhishek A Mangaonkar.;Kerstin Mezger.;Holly L Pacenta.;Jing Pan.;Marlie R M Provost.;Latika Puri.;Sunil Sudhir Raikar.;Armando Jose Martinez.;Isabella Quijada Bristol.;Kyle Daniel Murphy.;Lauren Reiman.;Michele S Redell.;Kelly Reed.;Gabrielle Roth Guepin.;Jeremy D Rubinstein.;Süreyya Savaşan.;Kristian T Schafernak.;Alexandra McLean Stevens.;Aimee C Talleur.;Naomi Torres Carapia.;Jacques Vargaftig.;Anant Vatsayan.;Matthias Wölfl.;Lipng Zhao.;Susana Rives.;Vanessa A Fabrizio.;Koji Sasaki.;Ibrahim Aldoss.;Nicolas Boissel.;Susan R Rheingold.;Kara L Davis.;Sara Ghorashian.;Elad Jacoby.;Alexander Popov.;Adam Joseph Lamble.;Nirali N Shah.
来源: Blood. 2025年
Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse following antigen-targeted immunotherapy which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS following a host of antigen-targeted therapies (e.g., CD19, CD22, CD38 and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of post-immunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-ALL to AML, 17 (22.7%) cases of B-ALL to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (i.e., T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as "lineage drift" were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5 months) post-immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. While the majority involved KMT2A rearrangements (n=45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor with < 40% remission rates. The median overall survival following LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or "lineage drift." This global initiative robustly categorizes lineage changes post-immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.
13. Blood-based proteomic profiling identifies OSMR as a novel biomarker of AML outcomes.
作者: Patrick K Reville.;Bofei Wang.;Jennifer Marvin-Peek.;Bin Yuan.;Yu-An Kuo.;Araceli Garza.;Jessica Root.;Wei Qiao.;Andrea Arruda.;Ivo Veletic.;Yiwei Liu.;Nicholas J Short.;Courtney D DiNardo.;Tapan M Kadia.;Naval G Daver.;Philip L Lorenzi.;Koji Sasaki.;Steven Kornblau.;Mark D Minden.;Farhad Ravandi.;Hagop M Kantarjian.;Hussein A Abbas.
来源: Blood. 2025年145卷25期3015-3029页
Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 patients with newly diagnosed AML. Using a machine learning model, we derived an 8-protein prognostic score termed the leukemia inflammatory risk score (LIRS). Individual proteins were evaluated in multivariable Cox models, and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across 2 institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular prognostic factors. Oncostatin M receptor was uniquely identified as the strongest independent predictor of survival, early mortality, and induction chemotherapy response, and further validated in an independent assay. These blood-based biomarkers could have significant clinical implications for risk stratification and prognostication in patients with newly diagnosed AML.
14. Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma.
作者: Adrian Gottschlich.;Ruth Grünmeier.;Gordon Victor Hoffmann.;Sayantan Nandi.;Vladyslav Kavaka.;Philipp Jie Müller.;Jakob Jobst.;Arman Oner.;Rainer Kaiser.;Jan Gärtig.;Ignazio Piseddu.;Stephanie Frenz-Wiessner.;Savannah D Fairley.;Heiko Schulz.;Veronika Igl.;Thomas Alexander Janert.;Lea Di Fina.;Maité Mulkers.;Moritz Thomas.;Daria Briukhovetska.;Donjetë Simnica.;Emanuele Carlini.;Christina Angeliki Tsiverioti.;Marcel P Trefny.;Theo Lorenzini.;Florian Märkl.;Pedro Mesquita.;Ruben Brabenec.;Thaddäus Strzalkowski.;Sophia Stock.;Stefanos Michaelides.;Johannes Hellmuth.;Martin Thelen.;Sarah Reinke.;Wolfram Klapper.;Pascal Francois Gelebart.;Leo Nicolai.;Carsten Marr.;Eduardo Beltrán.;Remco T A Megens.;Christoph Klein.;Fanny Baran-Marszak.;Andreas Rosenwald.;Michael von Bergwelt-Baildon.;Paul J Bröckelmann.;Stefan Endres.;Sebastian Kobold.
来源: Blood. 2025年145卷14期1536-1552页
The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.
15. Efficacy of a Novel BCL-xL Degrader, DT2216, in Preclinical Models of JAK2-mutated Post-MPN AML.
作者: Zhe Wang.;Anna Skwarska.;Gowri Poigaialwar.;Sovira Chaudhry.;Alba Rodriguez-Meira.;Pinpin Sui.;Emmanuel Olivier.;Yannan Jia.;Varun Gupta.;Warren Fiskus.;Cassandra L Ramage.;Guangrong Zheng.;Alexandra Schurer.;Kira Gritsman.;Eirini P Papapetrou.;Kapil N Bhalla.;Daohong Zhou.;Adam J Mead.;Raajit K Rampal.;Jeffrey W Tyner.;Hussein A Abbas.;Naveen Pemmaraju.;Qi Zhang Tatarata.;Marina Y Konopleva.
来源: Blood. 2025年
Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments don't significantly extend survival beyond 12 months. BCL-xL has been found to be overexpressed in leucocytes from MPN patients, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera (PROTAC), in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in post-MPN AML patients compared to those with de novo AML. Single-cell multi-omics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression, elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells (iPSC-HPCs), primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from post-MPN AML patients. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.
16. Iron overload in HFE-related hemochromatosis severely impairs Vδ2 γδ T-cell homeostasis.
作者: Derya Erdogdu.;Ina Becoku.;Valerie Huber.;Yao Wang.;Matthias Eyrich.;Hisayoshi Hashimoto.;Michaela Döring.;Johannes H Schulte.;Karin Schilbach.
来源: Blood. 2025年
HFE-related hemochromatosis (HH) induces systemic iron overload. Although extensive studies indicate a pivotal role for iron homeostasis in αβ-T-cell immunity, its effect on γδ-T cells is unknown. Here we show a reversal of the Vδ2+/Vδ2- ratio in the γδ-T-cell compartment as a feature of hemochromatosis, which is associated with a Vδ2+ population that cannot be enriched by ZOL-stimulation, despite evidence of TCR-ligand formation and strong proliferative behavior. Already in vivo, ROS production and exhaustion marker expression are significantly increased on Vδ2+-T-cells in hemochromatosis compared with healthy individuals. Ex vivo, hemochromatosis-donor-derived Vδ2+-cells are hyporesponsive to TCR stimulation in terms of ROS production, but significantly increase their paramount expression of exhaustion markers further. Fas-Fas Ligand coexpression indicates their high susceptibility to activation-induced cell death. Consistent therewith FeSO4 alone induces Vδ2+ subset-specific proliferation in healthy PBMCs comparable to stimulation by ZOL, and blocking experiments identify FeSO4-induced proliferation as BTN3A1/TCR-mediated. Pyrophosphates are key for Vδ2+-TCR-ligand formation. Iron, by suppressing pyrophosphatase ALP promotes their stability. In light of this our data suggest that the transcriptional repression of pyrophosphatases - as under the conditions of iron overload in hemochromatosis in vivo - leads to the constitutive availability of stress-signaling Vδ2+-TCR ligand thus permanent TCR-triggering in Vδ2+-T-cells even under homeostatic conditions, ultimately leading to their subset-specific activation-induced cell death. A similar phenotype was observed in patients with iron overload due to inborn hemoglobinopathies, suggesting an inverted Vδ2+/Vδ2- ratio in the γδ-T-cell compartment as a hallmark of iron overload.
17. Reducing clinical trial eligibility barriers for patients with MDS: an icMDS position statement.
作者: Uma Borate.;Kelly Pugh.;Allyson Waller.;Rina Li Welkie.;Ying Huang.;Jan Philipp Bewersdorf.;Maximilian Stahl.;Amy E DeZern.;Uwe Platzbecker.;Mikkael A Sekeres.;Andrew H Wei.;Rena J Buckstein.;Gail J Roboz.;Michael R Savona.;Sanam Loghavi.;Robert P Hasserjian.;Pierre Fenaux.;David A Sallman.;Christopher S Hourigan.;Matteo Giovanni Della Porta.;Stephen Nimer.;Richard F Little.;Valeria Santini.;Fabio Efficace.;Justin Taylor.;Guillermo Garcia-Manero.;Olatoyosi Odenike.;Tae Kon Kim.;Stephanie Halene.;Rami S Komrokji.;Elizabeth A Griffiths.;Peter L Greenberg.;Mina L Xu.;Zhuoer Xie.;Rafael Bejar.;Guillermo F Sanz.;Mrinal M Patnaik.;Maria Figueroa.;Hetty E Carraway.;Omar Abdel-Wahab.;Daniel Starczynowski.;Eric Padron.;Jacqueline Boultwood.;Steven Gore.;Naval G Daver.;Jane E Churpek.;Ravindra Majeti.;John M Bennett.;Alan F List.;Andrew M Brunner.;Amer M Zeidan.
来源: Blood. 2025年145卷13期1369-1381页
Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.
18. Use of machine learning techniques to predict poor survival after hematopoietic cell transplantation for myelofibrosis.
作者: Juan Carlos Hernández-Boluda.;Adrián Mosquera-Orgueira.;Luuk Gras.;Linda Koster.;Joe Tuffnell.;Nicolaus Kröger.;Massimiliano Gambella.;Thomas Schroeder.;Marie Robin.;Katja Sockel.;Jakob Passweg.;Igor Wolfgang Blau.;Ibrahim Yakoub-Agha.;Ruben Van Dijck.;Mattias Stelljes.;Henrik Sengeloev.;Jan Vydra.;Uwe Platzbecker.;Moniek de Witte.;Frédéric Baron.;Kristina Carlson.;Javier Rojas.;Carlos Pérez Míguez.;Davide Crucitti.;Kavita Raj.;Joanna Drozd-Sokolowska.;Giorgia Battipaglia.;Nicola Polverelli.;Tomasz Czerw.;Donal P McLornan.
来源: Blood. 2025年145卷26期3139-3152页
With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5183 patients with MF who underwent first allo-HCT between 2005 and 2020 at European Society for Blood and Marrow Transplantation centers, we examined different machine learning (ML) models to predict overall survival after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A random survival forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a 4-level Cox regression-based score and other ML-based models derived from the same data set, and with the Center for International Blood and Marrow Transplant Research score. The RSF outperformed all comparators, achieving better concordance indices across both primary and postessential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike information criterion and time-dependent receiver operating characteristic area under the curve metrics in both sets. Although all models were prognostic for nonrelapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in patients with MF undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.
19. NGS-based IG/TR rearrangement profiling in acute lymphoblastic leukemia: age dependence of immunogenetic maturation.
作者: Michaela Kotrova.;Constantin Proske.;Nikos Darzentas.;Anna Laqua.;Britta Kehden.;Jan Christian Kässens.;Sonja Bendig.;Saskia Kohlscheen.;Monika Szczepanowski.;Wiebke Wessels.;Željko Antić.;Christiane Pott.;Matthias Ritgen.;Jacques J M van Dongen.;Nicola Gökbuget.;Guranda Chitadze.;Anke Bergmann.;Lorenz Bastian.;Claudia D Baldus.;Gunnar Cario.;Martin Schrappe.;Stefan Schwartz.;Julia Alten.;Rolf Koehler.;Monika Brüggemann.
来源: Blood. 2025年
We comprehensively profiled the landscape of immunoglobulin (IG) and T-cell receptor (TR) rearrangements at diagnosis in 1212 acute lymphoblastic leukemia (ALL) patients (573 children, 639 adults) diagnosed in Germany between 2017 and 2022.Our findings indicate that immunogenetic maturity in ALL patients is age-dependent, with younger patients exhibiting more mature profiles. In fact, 68.7% of pediatric B-ALL and 85.7% T-ALL patients carried IGK, or complete TRB and/or TRD rearrangements, respectively; compared to 39.0% and 67.3% in adults (B-ALL: p<2.2e-16, T-ALL: p=6.7e-03). Additionally, children carried more IG/TR markers compared to adults (mean 6/patient versus 4/patient, respectively; p=2.5e-38). Only 0.5% of pediatric patients lacked markers, contrasted with 6.7% of adults.IGH clonal evolution was most pronounced among pro-B ALL cases (60.9%), with the V-to-DJ mechanism driving pro-B evolution (78.6%), while V-replacement dominated other immunophenotypes. Additionally, we observed that the presence of expanded accompanying T-cell clones of unknown significance in B-ALL patients increased with age.This next-generation sequencing (NGS)-based study offers an unprecedented characterization of IG/TR rearrangement patterns across ALL subtypes and age groups. It highlights the higher immunogenetic maturity in children, which may be explained by the infection-driven abnormal activity of the IG/TR recombination machinery in pediatric ALL.
20. Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes.
作者: 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.
来源: Blood. 2025年
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.
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