261. Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the life span.
作者: Shuhei Koide.;Motohiko Oshima.;Takahiro Kamiya.;Zhiqian Zheng.;Zhaoyi Liu.;Ola Rizq.;Akira Nishiyama.;Koichi Murakami.;Yuta Yamada.;Yaeko Nakajima-Takagi.;Bahityar Rahmutulla.;Atsushi Kaneda.;Kazuaki Yokoyama.;Nozomi Yusa.;Seiya Imoto.;Fumihito Miura.;Takashi Ito.;Tomohiko Tamura.;Claus Nerlov.;Masayuki Yamashita.;Atsushi Iwama.
来源: Blood. 2025年146卷1期62-75页
Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, using clusterin (Clu)-green fluorescent protein (GFP) reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behavior in the bone marrow, favoring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.
262. Daratumumab-Bortezomib-Thalidomide-Dexamethasone for Newly Diagnosed Myeloma: CASSIOPEIA Minimal Residual Disease Results.
作者: Jill Corre.;Laure Vincent.;Philippe Moreau.;Benjamin Hebraud.;Cyrille Hulin.;Marie-Christine Béné.;Annemiek Broijl.;Denis Caillot.;Michel Delforge.;Thomas Dejoie.;Thierry Facon.;Jerome Lambert.;Xavier Leleu.;Margaret Macro.;Aurore Perrot.;Sonja Zweegman.;Thomas Filleron.;Bastien Cabarrou.;Niels W C J van de Donk.;Sabrina Mahéo.;Winnie Hua.;Jianping Wang.;Maria Krevvata.;Véronique Vanquickelberghe.;Carla de Boer.;Alba Tuozzo.;Fredrik Borgsten.;Melissa Rowe.;Robin Carson.;Soraya Wuilleme.;Pieter Sonneveld.
来源: Blood. 2025年
Previous results from CASSIOPEIA (NCT02541383) demonstrated superior progression-free survival (PFS) and minimal residual disease (MRD) negativity with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (VTd) induction/consolidation and with daratumumab maintenance versus observation in transplant-eligible newly diagnosed multiple myeloma (NDMM). Here, we present long-term MRD status and PFS outcomes after an 80.1-month median follow-up. Patients were randomly assigned (1:1) to daratumumab plus VTd (D-VTd) or VTd induction/consolidation; patients remaining on study were re-randomized to daratumumab maintenance or observation for £2 years. MRD status was assessed at pre-defined timepoints during each study phase. D-VTd improved overall MRD-negativity rates (10-5) post-induction (34.6% vs 23.1%; P<0.0001) and post-consolidation (63.7% vs 43.7%; P<0.0001) and provided PFS benefit, regardless of post-induction MRD status, versus VTd alone. Daratumumab maintenance improved overall MRD-negativity rates over observation, regardless of induction/consolidation treatment (D-VTd/daratumumab vs D-VTd/observation: 10-5, 77.3% vs 70.7% [P=0.0417]; 10-6, 60.7% vs 52.0% [P=0.0365]; VTd/daratumumab vs VTd/observation: 10-5, 70.9% vs 51.2% [P<0.0001]; 10-6, 48.4% vs 30.7% [P<0.0001]), and improved MRD-negativity rates, regardless of risk status, as defined by cytogenetic abnormalities or revised International Staging System score. Further, daratumumab maintenance provided PFS benefit versus observation, regardless of induction/consolidation treatment and post-consolidation MRD status. D-VTd followed by daratumumab maintenance consistently produced the highest landmark, accumulative, and sustained MRD-negativity rates (10-5 and 10-6), translating to superior long-term PFS outcomes. These results demonstrate that daratumumab-based induction/consolidation followed by daratumumab maintenance resulted in the deepest and most durable MRD negativity, leading to superior PFS outcomes.
263. 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.
264. Diabetes mellitus and APOL1 genotype increase the risk for chronic kidney disease progression in sickle cell disease.
作者: Ryan Sun.;Anand Srivastava.;Joseph L Zapater.;Franklin Njoku.;Jin Han.;Zalaya Ivy.;Marwah Farooqui.;Insia Rizvi.;Brian Layden.;Robert E Molokie.;Victor R Gordeuk.;Santosh L Saraf.
来源: Blood. 2025年145卷24期2927-2930页
We observed diabetes mellitus (DM) in 9.3% of adults with sickle cell disease (SCD), and DM predicted a sevenfold greater risk of chronic kidney disease progression adjusting for high-risk APOL1. Our results emphasize the clinical significance of DM in SCD.
272. Role of allo-HCT in "nonclassical" MPNs and MDS/MPNs: recommendations from the PH&G Committee and the CMWP of the EBMT.
作者: Nicola Polverelli.;Juan Carlos Hernández-Boluda.;Francesco Onida.;Carmelo Gurnari.;Kavita Raj.;Tomasz Czerw.;Michelle Kenyon.;Marie Robin.;Katja Sockel.;Annalisa Ruggeri.;Isabel Sánchez-Ortega.;Daniel A Arber.;Luca Arcaini.;Fernando Barroso Duarte.;Giorgia Battipaglia.;Yves Chalandon.;Fabio Ciceri.;Nicholas C P Cross.;Joanna Drozd-Sokolowska.;Vaneuza Funke.;Nico Gagelmann.;Naseema Gangat.;Jason Gotlib.;Paola Guglielmelli.;Claire Harrison.;Gabriela Hobbs.;Tania Jain.;Joseph D Khoury.;Jean Jacques Kiladjian.;Nicolaus Kröger.;Luca Malcovati.;Massimo Martino.;Ruben Mesa.;Attilio Orazi.;Eric Padron.;Francesca Palandri.;Francesco Passamonti.;Mrinal M Patnaik.;Naveen Pemmaraju.;Deepti H Radia.;Andreas Reiter.;Domenico Russo.;Christof Scheid.;Ayalew Tefferi.;Alessandro M Vannucchi.;Daniel H Wiseman.;Ibrahim Yakoub-Agha.;Donal P McLornan.
来源: Blood. 2025年145卷22期2561-2573页
"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.
273. Low rates of chronic graft-versus-host disease with ruxolitinib maintenance following allogeneic HCT.
作者: Zachariah DeFilipp.;Haesook T Kim.;Laura W Knight.;Suzanne M O'Connor.;Shilton E Dhaver.;Meghan White.;Bhagirathbhai Dholaria.;Mark A Schroeder.;Sumithira Vasu.;Sameem Abedin.;Jooho Chung.;Areej El-Jawahri.;Matthew J Frigault.;Steven McAfee.;Richard A Newcomb.;Paul V O'Donnell.;Thomas R Spitzer.;Yi-Bin Chen.;Gabriela S Hobbs.
来源: Blood. 2025年145卷20期2312-2316页
Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD (cGVHD) remain of high importance. In this prospective, multicenter, phase 2 trial, ruxolitinib, an oral inhibitor of Janus kinase (JAK) 1 and 2, was administered as maintenance therapy after reduced-intensity allogeneic hematopoietic cell transplantation (HCT). GVHD prophylaxis consisted of tacrolimus and methotrexate. Ruxolitinib began between day +30 to 100 and was administered continuously in 28-day cycles for up to 24 cycles. Seventy-eight participants were enrolled before HCT; 63 participants received the intervention. The median start date of ruxolitinib after HCT was day +45. The most common grade ≥3 adverse events were neutropenia, thrombocytopenia, and anemia. Seven participants experienced grade ≥3 infectious events. GVHD-free, relapse-free survival at 1 year after HCT, the primary end point, was 70%. Grade 3 to 4 acute GVHD at 6 months was 4.8%, and moderate-severe cGVHD at 2 years was 16%. cGVHD requiring systemic therapy was 9.5% at 1 year and 13% at 2 years. Overall survival and progression-free survival at 2 years were 76% and 68%, respectively. Prolonged administration of ruxolitinib following HCT is associated with low rates of clinically significant cGVHD. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT03286530.
274. PI3Kγ in leukemia: class IB PI3 kinase reemerges as a cancer-intrinsic target.
Phosphoinositide 3-kinase gamma (PI3Kγ), the only class IB PI3 kinase, is a cell-extrinsic immunotherapy target in solid tumors. PI3Kγ inhibition reprograms immunosuppressive myeloid cells to acquire immunostimulatory phenotypes, which promote antitumor cytotoxic T-cell activity. Although PI3Kγ inhibition has no direct effect on solid tumor cells, several new studies have nominated PI3Kγ as a cell-intrinsic target in various leukemias, particularly acute myeloid leukemia. Intrinsic dependency on PI3Kγ is present at baseline in leukemias with specific pathological characteristics, is inducible by extrinsic inflammation in others, and may also be acquired with resistance to certain therapies. The discovery of leukemia PI3Kγ dependency has generated enthusiasm for immediate clinical trial evaluation of inhibitor monotherapy and combinations. Parallel laboratory evaluation is needed to develop an improved understanding of leukemia disease features associated with clinical inhibitor sensitivity that might suggest biomarker-directed patient enrichment strategies. In this review, we discuss recent progress credentialing PI3Kγ as a bona fide target in leukemia. We also highlight open questions, including a need to understand the mechanism of acquired resistance to PI3Kγ inhibition, how to optimally prioritize combination therapies to enhance PI3Kγ inhibitor utility, and how cell-extrinsic effects of PI3Kγ inhibition in the leukemia microenvironment might also contribute to clinical activity.
275. NKG2D-mediated cytotoxicity of CD4 cytotoxic T cells in multiple myeloma.
作者: Sojeong Kim.;Jeong-Eun Kwak.;June-Young Koh.;Ji Eun Lee.;Hye Won Kook.;Minchae Kim.;Haerim Chung.;Yuri Kim.;Soo Jeong Kim.;Jin Seok Kim.;June-Won Cheong.;Min Goo Lee.;Hoyoung Lee.;Su-Hyung Park.;Eui-Cheol Shin.;Saeam Shin.;Sun Och Yoon.;Il-Kyu Choi.;Jeong Seok Lee.;Hyunsoo Cho.
来源: Blood. 2025年
Emerging evidence indicates that CD4+ T cells contribute to antitumor immunity beyond their traditional roles as helpers or regulators. However, the specific subset of CD4+ T cells mediating beneficial outcomes in patients with multiple myeloma remains unclear. Here, we performed single-cell RNA sequencing and T cell receptor sequencing on CD4+ T cells sorted from the bone marrow of patients across the stages of myeloma progression. We identified several distinct states of CD4+ cytotoxic T lymphocytes (CTLs) that were significantly increased and clonally expanded in myeloma patients. CD4+ CTLs displayed transcriptional and phenotypic characteristics indicative of cytotoxicity, demonstrating their ability to directly kill myeloma cells. This cytotoxicity, however, was abrogated by NKG2D blockade. Notably, the abundance of NKG2D+CD4+ CTLs correlated with improved survival in myeloma patients. Our findings suggest that harnessing CD4+ CTLs could lead to novel strategies for enhancing immunotherapy outcomes in multiple myeloma.
276. Enhanced α2-3-linked sialylation determines the extended half-life of CHO-rVWF.
作者: Ciara Byrne.;Soracha Ward.;Jamie O'Sullivan.;Alain Chion.;Patricia Lopes.;Bogdan Baci.;Caoimhe Dowd.;Darragh Jordan.;Ross Baker.;Roger J S Preston.;Marco Monopoli.;Peter L Turecek.;Maximilianos Kotsias.;Jack Cheeseman.;Alan B Moran.;Richard A Gardner.;Daniel I R Spencer.;Ferdows Atiq.;James S O'Donnell.
来源: Blood. 2025年145卷23期2768-2773页
The half-life of recombinant human von Willebrand factor (rVWF) expressed in CHO cells (CHO-rVWF; Vonicog alfa; and Vonvendi/Veyvondi) is significantly longer than that of plasma-derived VWF (pdVWF). This finding is intriguing because CHO cells do not generate α2-6 sialylation, which constitutes the majority of human pdVWF sialylation. We hypothesized that glycan differences might regulate the longer half-life of CHO-rVWF. In lectin plate-binding assays and liquid chromatography-mass spectrometry analysis, we confirmed that CHO-rVWF lacked α2-6-linked sialylation. Conversely, however, α2-3-linked sialylation was significantly increased on CHO-rVWF, which also had reduced exposed β-galactose (β-Gal) compared to pdVWF. Consistent with human data, CHO-rVWF clearance was significantly (P < .001) reduced in VWF-/- mice compared to pdVWF. However, clearance of asialo-pdVWF and asialo-CHO-rVWF were identical. In keeping with the in vivo half-life prolongation, CHO-rVWF binding to murine macrophages (P = .012) and HepG2 cells (P = .001) was significantly decreased compared to pdVWF. Furthermore, CHO-rVWF binding to purified macrophage-galactose-type lectin (MGL) receptor and asialoglycoprotein receptor (ASGPR) was also significantly reduced. In contrast to pdVWF, in vivo studies in MGL1-/- mice and Asgr1-/- mice demonstrated that neither MGL nor ASGPR plays significant roles in regulating CHO-rVWF clearance. Together, our findings demonstrate that enhanced α2-3-linked sialylation on CHO-rVWF is responsible for its extended half-life.
277. STAT1-mediated interferon signatures are associated with preclinical JAK inhibitor sensitivity in T-ALL.
作者: Jason Xu.;Jonathan H Sussman.;Austin Yang.;Satoshi Yoshimura.;Jianzhong Hu.;Changya Chen.;Tiffaney Vincent.;Shovik Bandyopadhyay.;Elizabeth Y Li.;Tristan Lim.;Omar Elghawy.;Adam Barsouk.;Damjan Karanfilovski.;Shira L Wald.;Gregory M Chen.;David Wu.;Haley Newman.;Alexander Li.;Yusha Sun.;Chia-Hui Chen.;Kathrin Bernt.;Brent L Wood.;Stuart S Winter.;Kimberly P Dunsmore.;Elizabeth Raetz.;Meenakshi Devidas.;Stanley Pounds.;Mignon Loh.;Stephen P Hunger.;Mark Y Chiang.;Caroline Diorio.;Danika Di Giacomo.;Petri Pölönen.;Charles G Mullighan.;Jun J Yang.;Kai Tan.;David T Teachey.
来源: Blood. 2025年145卷23期2793-2798页
We used single-cell genomics to characterize a patient with T-cell acute lymphoblastic leukemia treated in the Children's Oncology Group AALL0434 trial with poor clinical outcome despite favorable genomic features, identifying a STAT1-mediated interferon-related transcriptional signature and inflammatory microenvironment associated with sensitivity to small-molecule JAK inhibition.
278. Prognostic biomarkers in MCL: insights from the SHINE trial on the impact of MCL35 score and TP53 mutation status.
作者: Ciara L Freeman.;Srimathi Srinivasan.;Brendan Hodkinson.;Sanjay Deshpande.;Todd Henninger.;Merrill Boyle.;Michael L Wang.;Martin Dreyling.;David W Scott.
来源: Blood. 2025年145卷25期3052-3056页
The MCL35 gene expression assay encompasses key risk features and stratified older patients with mantle cell lymphoma (MCL) using routine biopsies. In the SHINE trial, high-risk patients had poor outcomes despite adding ibrutinib to bendamustine-rituximab, highlighting an urgent need for novel strategies in high-risk MCL.
279. Considerations on the dose and schedule of tyrosine kinase inhibitors for chronic myeloid leukemia: does dose matter?
Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for patients with chronic myeloid leukemia. The standard dose has been established for each drug according to the indication for the various stages of the disease and whether as initial therapy or after failure of previous therapies. The recommended doses are fixed for all patients and dose adjustments are mostly recommended for management of adverse events. The standard doses have been derived largely from phase 1 studies, but as we discuss in this review, the current model may not be optimal for this purpose for drugs such as TKIs that are meant to be used for extended periods of time. Subsequent studies have led to changes in the initial recommendations for some drugs. In others, experience and real-world data have led to the use of TKIs using doses and adjustments that may be different than what clinical trials have recommended. In other scenarios, available data suggest that the current standard dose may need to be revisited. It may also be time to reconsider the standard approach of starting therapy with the standard dose and adjusting merely based on adverse events. We propose a flexible model that perhaps reflects more accurately what is being done frequently in the clinic.
280. Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma.
作者: Sha Ma.;Jieyun Xia.;Miao Zhang.;Wenyu Li.;Meng Xiao.;Yuqian Sha.;Wenya Wang.;Jianteng Zhou.;Ying Wang.;Kunming Qi.;Chunling Fu.;Zengtian Sun.;Dian Zhou.;Qian Sun.;Tingting Qiu.;Zhiling Yan.;Feng Zhu.;Wei Chen.;Hai Cheng.;Wei Sang.;Jiang Cao.;Depeng Li.;Zhenyu Li.;Mariateresa Fulciniti.;Yao Yao.;Kailin Xu.;Mingshan Niu.
来源: Blood. 2025年146卷2期178-190页
G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a novel target for chimeric antigen receptor (CAR) T-cell therapy, demonstrating promising efficacy in multiple myeloma (MM). However, disease relapse is still common, and the mechanism of resistance remains poorly understood. In this study, we conducted whole-genome sequencing and whole-genome bisulfite sequencing on MM samples from 10 patients who relapsed after GPRC5D CAR T-cell therapy. Among these patients, 8 had GPRC5D loss, whereas 2 presented mixed expression (GPRC5D+/-). Genetic alterations were identified in 3 cases: one had a homozygous deletion in the GPRC5D gene, another had a biallelic loss in the regulatory regions of GPRC5D, and the third had homozygous deletions in both TNFRSF17 and GPRC5D after sequential anti-B-cell maturation antigen and anti-GPRC5D CAR T-cell therapies. No genetic changes were detected at GPRC5D locus in the remaining 7 cases. However, multiple hypermethylation sites were present in the transcriptional regulatory elements of the GPRC5D gene in 5 post-treatment MM samples. In MM cell lines, GPRC5D expression was inversely correlated with methylation levels in its regulatory regions. Furthermore, azacitidine treatment induced GPRC5D messenger RNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance.
|