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NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression. NG2是MLL-AF4的一个靶基因,通过调节NR3C1的表达成为MLL-r B-ALL耐糖皮质激素的基础。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2023022050
Belén Lopez-Millan, Alba Rubio-Gayarre, Meritxell Vinyoles, Juan L Trincado, Mario F Fraga, Narcís Fernandez-Fuentes, Mercedes Guerrero-Murillo, Alba Martinez, Talia Velasco-Hernandez, Aïda Falgàs, Carla Panisello, Gemma Valcarcel, José Luis Sardina, Paula López-Martí, Biola M Javierre, Beatriz Del Valle-Pérez, Antonio García de Herreros, Franco Locatelli, Rob Pieters, Michela Bardini, Giovanni Cazzaniga, Juan Carlos Rodríguez-Manzaneque, Thomas Hanewald, Rolf Marschalek, Thomas A Milne, Ronald W Stam, Juan Ramón Tejedor, Pablo Menendez, Clara Bueno

Abstract: B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ∼85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival, relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL, and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here, we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.

B 细胞急性淋巴细胞白血病(B-ALL)是最常见的儿科癌症,长期总生存率约为 85%。然而,携带 MLL 基因(又称 KMT2A)重排的 B-ALL 被称为 MLLr B-ALL,常见于婴儿,且 5 年生存率较低 (
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引用次数: 0
Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study. 阿西米尼单药作为慢性期慢性髓性白血病的一线治疗:ASCEND研究结果
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024024657
David T Yeung, Naranie Shanmuganathan, John Reynolds, Susan Branford, Mannu Walia, Agnes S M Yong, Jake Shortt, Lynette Chee, Nicholas Viiala, Ilona Cunningham, David M Ross, Alwyn D'Souza, Matthew Wright, Rosemary Harrup, Cecily Forsyth, Robin Filshie, Steven Lane, Peter Browett, Carolyn Grove, Andrew P Grigg, Timothy P Hughes

Abstract: Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Asciminib是一种肉豆蔻酰基位点BCR::ABL1抑制剂,已被批准用于既往接受过≥2种疗法的慢性期慢性髓性白血病(CP-CML)患者。澳大拉西亚白血病与淋巴瘤组织(ALLG)开展了 ASCEND 研究,以评估 asciminib 对新诊断的 CP-CML 的疗效。患者开始服用阿昔米尼 40 毫克,每天两次(BID),之后根据分子指标进行管理。治疗失败的患者(定义为 3 或 6 个月时 BCR::ABL1 >10% (IS),或 12 或 18 个月时 >1%)除接受阿昔米尼治疗外,还接受伊马替尼、尼洛替尼或达沙替尼治疗。对于反应不理想的患者,即6个月时反应水平为1%-10%、12个月时反应水平>0.1%-1%或18个月时反应水平>0.01%-1%的患者,阿昔米尼的剂量增加到80毫克,每日两次。中位随访 21 个月(0-36 个月),82/101 例患者继续服用阿昔米尼。最常见的治疗中止原因是不良事件(6%)、反应消失(4%)和撤回同意(5%)。无死亡病例;1 名患者在 6 个月时出现淋巴细胞凋亡危象。共同主要终点是早期分子反应(3个月时BCR::ABL1≤10%),93%的患者(96% CI 86-97%)实现了这一目标,12个月时主要分子反应的实现率分别为79%;(95% CI 69.7-86.8%)。到24个月时,MR4.5的累积发生率为53%。一名患者发生了2次脑血管事件;未报告其他动脉闭塞事件。阿西米尼作为CP-CML的一线疗法,分子反应率高,耐受性好,因毒性停药率低。(澳新临床试验注册中心 ACTRN12620000851965)。
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引用次数: 0
Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia. 非典型梅宁靶点的表观遗传调控调节急性髓性白血病的梅宁抑制剂反应
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2023023644
Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin J Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu

Abstract: Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.

破坏 Menin-MLL 相互作用的 Menin 抑制剂有望治疗特定的急性髓性白血病亚型,包括 KMT2A 重排(KMT2A-r),但耐药性仍然是一个挑战。在这里,我们通过系统的染色质聚焦 CRISPR 筛选,以及在多种人类和小鼠 KMT2A-r AML 模型中进行的遗传学、表观遗传学和药理学研究,发现了一种独立于典型 Menin-MLL 靶点的潜在耐药机制。我们发现,一组非典型的 Menin 靶点(由活性 Menin 和抑制性 H2AK119ub 标记双价共占位)在 Menin 抑制后通常会下调。PCGF1 或 BCOR 等多聚核酸抑制复合体 1.1(PRC1.1)亚基的缺失会导致包括 MYC 在内的这些非经典靶点的表观遗传学再激活,从而导致 Menin 抑制剂耐药。遗传和药物抑制 MYC 可使 PRC1.1 缺失的白血病细胞对 Menin 抑制剂重新敏感。此外,我们还证明,缺失PRC1.1亚基的白血病细胞表现出单核细胞基因特征的减少,并易受BCL2抑制作用的影响,而venetoclax的联合治疗可克服PRC1.1缺陷白血病细胞对Menin抑制作用的耐药性。这些发现凸显了PRC1.1及其调控的非经典Menin靶点在调节Menin抑制剂反应中的重要作用,并为治疗PRC1.1功能受损的白血病提供了潜在的策略。
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引用次数: 0
Risk prediction for clonal cytopenia: multicenter real-world evidence. 克隆性细胞减少症的风险预测:多中心真实世界证据
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024024756
Zhuoer Xie, Rami Komrokji, Najla Al Ali, Alexandra Regelson, Susan Geyer, Anand Patel, Caner Saygin, Amer M Zeidan, Jan Philipp Bewersdorf, Lourdes Mendez, Ashwin Kishtagari, Joshua F Zeidner, Catherine C Coombs, Yazan F Madanat, Stephen Chung, Talha Badar, James Foran, Pinkal Desai, Charlton Tsai, Elizabeth A Griffiths, Monzr M Al Malki, Idoroenyi Amanam, Catherine Lai, H Joachim Deeg, Lionel Ades, Cecilia Arana Yi, Afaf E G Osman, Shira Dinner, Yasmin Abaza, Justin Taylor, Namrata Chandhok, Deborah Soong, Andrew M Brunner, Hetty E Carraway, Abhay Singh, Chiara Elena, Jacqueline Ferrari, Anna Gallì, Sara Pozzi, Eric Padron, Mrinal M Patnaik, Luca Malcovati, Michael R Savona, Aref Al-Kali

Abstract: Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

意义未定的克隆性细胞减少症(CCUS)是一种独特的疾病实体,其特点是在有不明原因的细胞减少症但没有髓系肿瘤(MN)的个体中,存在髓系相关的体细胞突变,其变异等位基因比例≥2%。值得注意的是,CCUS 有进展为 MN 的风险,特别是在具有高风险突变的病例中。了解CCUS需要进行专门研究,以阐明其风险因素和自然病史。我们对 357 例 CCUS 患者进行了分析,研究了克隆性、细胞减少和预后之间的相互作用。多变量分析确定了 3 个关键的不良预后因素:存在剪接突变(得分 = 2 分)、血小板计数(得分 = 1 分)、细胞减少(得分 = 1 分)。
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引用次数: 0
Genotyped RhD+ red cells for D-positive patients with sickle cell disease with conventional RHD and unexpected anti-D. 对常规 RHD 和意外抗 D 的 D 阳性镰状细胞病患者的 RHD+ 红细胞进行基因分型。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024025602
Stella T Chou, Julia Mewha, David F Friedman, Victoria Lazariu, Shaimaa Makrm, Gorka Ochoa, Sunitha Vege, Connie M Westhoff

Abstract: Anti-D can occur in D-positive patients who inherit RHD genetic variants encoding partial D antigen expression, but unexpected anti-D is also found in the plasma of patients with sickle cell disease who have conventional RHD gene(s) and are transfused with units from Black donors. These anti-D are likely stimulated by variant Rh expressed on donor cells; however, patients with anti-D, regardless of cause, are transfused for a lifetime with D-negative (Rh-negative) blood. This results in significant increased use of Rh-negative units, especially for those requiring chronic transfusion, which can strain Rh-negative blood inventories. We tested whether D-positive patients who made anti-D and had conventional RhD by RHD genotyping could safely be returned to D-positive transfusions without anti-D reappearance or compromised red blood cell survival using RHD genotype-matched units from Black donors. Five patients receiving chronic red cell exchange received an increasing number of D-positive units per procedure with a total of 72 D-positive RHD genotyped units transfused, with no anti-D restimulation. Unexpected anti-C and anti-E were identified during the study associated with donors with variant RHCE alleles. RH genotyping of D-positive units for transfusion may improve use and allocation of valuable Black donor units and reduce demand for Rh-negative blood. This trial was registered at www.clinicaltrials.gov as NCT04156906.

抗-D 可发生在遗传了编码部分 D 抗原表达的 RHD 基因变体的 D 阳性患者身上,但在具有传统 RHD 基因的镰状细胞病患者的血浆中也会发现意想不到的抗-D,这些患者输注的是来自黑人捐献者的血液。这些抗-D 很可能是由供体细胞上表达的变异型 Rh 刺激的,但抗-D 患者,无论病因如何,终生都要输注 D 阴性(Rh 阴性)血液。因此,Rh 阴性单位的使用量大大增加,尤其是需要长期输血的患者,这可能导致 Rh 阴性血液库存紧张。我们测试了抗 D 阳性且通过 RHD 基因分型检测为常规 RhD 的 D 阳性患者是否可以安全地恢复 D 阳性输血,而不会再次出现抗 D 阳性或使用来自黑人献血者的 RHD 基因型匹配单位影响红细胞存活率。五名接受慢性红细胞置换的患者每次接受的 D 阳性单位数量不断增加,总共输注了 72 个经 RHD 基因分型的 D 阳性单位,没有出现抗 D 再刺激现象。在研究过程中发现,意外的抗 C 和抗 E 与具有变异 RHCE 等位基因的供体有关。对用于输血的 D 阳性献血单位进行 RH 基因分型可改善宝贵的黑人献血单位的使用和分配,减少对 Rh 阴性血液的需求。
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引用次数: 0
Less-deformable erythrocyte subpopulations biomechanically induce endothelial inflammation in sickle cell disease. 不易变形的红细胞亚群在生物力学上诱发镰状细胞病的内皮炎症。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1182/blood.2024024608
Christina Caruso, Xiaopo Cheng, Marina E Michaud, Hannah M Szafraniec, Beena E Thomas, Meredith E Fay, Robert G Mannino, Xiao Zhang, Yumiko Sakurai, Wei Li, David R Myers, Clinton H Joiner, David K Wood, Manoj Bhasin, Michael D Graham, Wilbur A Lam

Abstract: Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

镰状细胞病(SCD)的典型特征是红细胞(RBC)变形能力降低,导致微血管阻塞和炎症。虽然已知镰状红细胞的生物物理特性会影响 SCD 的血管病变,但红细胞变形能力差对内皮功能障碍的影响还有待充分探讨。利用相互关联的体外和硅学方法,我们提出了一种 SCD 血管病变的新模式,即变形性差的镰状红细胞通过机械传导直接导致内皮功能障碍,内皮细胞能感知异常物理力并对其做出病理生理反应,而与微血管阻塞、粘附或溶血无关。我们证明,将镰状红细胞或药物脱水的健康红细胞灌注到小静脉大小的 "内皮化 "微流体中会导致与内皮细胞的病理性物理相互作用,从而直接诱发炎症通路。我们结合计算模拟和大静脉尺寸的内皮化微流体,观察到灌注不同变形能力的异质镰状红细胞亚群以及与正常红细胞混合的脱水正常红细胞悬浮液会导致变形能力较弱的红细胞亚群向血管壁异常边缘化,造成局部剪应力增加。血管壁应力的增加取决于亚群异质性和氧张力的程度,并通过机械传导途径导致炎症性内皮基因表达。我们的多层面方法证明,变形能力降低的镰状红细胞的存在直接导致病理物理(即直接碰撞和/或压缩力)和剪切力介导的与内皮细胞的相互作用,并诱发炎症反应,从而阐明了 SCD 中血管功能障碍的普遍性。
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引用次数: 0
Acute Promyelocytic Leukemia: Long-Term Outcomes from the HARMONY Project. 急性早幼粒细胞白血病:HARMONY 项目的长期结果。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-06 DOI: 10.1182/blood.2024026186
Maria Teresa Voso, Luca Guarnera, Sören Lehmann, Konstanze Döhner, Hartmut Döhner, Uwe Platzbecker, Nigel H Russell, Richard James Dillon, Ian Thomas, Gert J Ossenkoppele, Torsten Haferlach, Marco Vignetti, Edoardo La Sala, Alfonso Piciocchi, Paola Fazi, Ángela Villaverde Ramiro, Laura Tur Giménez, Carmelo Gurnari, Lars Bullinger, Jesus M Hernandez

Purpose: Treatment outcomes for acute promyelocytic leukemia (APL) have improved with the widespread use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Our study aimed to validate these data in a large patient cohort, and to redefine prognostic factors.

Patients and methods: Leveraging the HARMONY Platform, we analyzed 1438 newly-diagnosed APL patients, diagnosed between 1999 to 2022. Patient data derived from the 2 international multicenter GIMEMA-APL0406 and NCRI-AML17 trials, and 4 European registries (HOVON, AMLSG, Swedish AML Registry and SAL).

Results: The study cohort included 721 males and 717 females, with a median age of 50.5 years (range 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO, and 747 AIDA-like chemotherapy. Early death (ED) occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz risk score (OR:1.06, 95% C.I: 1.04-1.08, and OR:4.65, 95% C.I.:2.55-8.51, respectively).The median follow-up was 5.5 years (IQR=3.2-7.5). ATRA-ATO regimen was associated with the best outcome, reaching 91% 7-year overall survival (vs 81% for AIDA-like, HR:2.14, 95%C.I.:1.51-3.05), 89% event-free survival (vs 71% for AIDA-like, HR:2.72 95%CI: 2.01-3.69) and 3% relapse (vs 13% for AIDA-like, HR:4.19, 95%CI:2.38-7.39, p<0.001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients' age, Sanz-risk score, and treatment scenario.

Conclusions: Our study confirms the superiority of ATRA-ATO over ATRA-chemotherapy in APL patients. ED represents an unmet medical need, in particular in older patients and in high-risk APL.

目的:随着全反式维甲酸(ATRA)和三氧化二砷(ATO)靶向疗法的广泛应用,急性早幼粒细胞白血病(APL)的治疗效果有所改善。我们的研究旨在在一个大型患者队列中验证这些数据,并重新定义预后因素:利用 HARMONY 平台,我们分析了 1999 年至 2022 年间确诊的 1438 例新诊断 APL 患者。患者数据来自两项国际多中心 GIMEMA-APL0406 和 NCRI-AML17 试验以及 4 个欧洲登记处(HOVON、AMLSG、瑞典 AML 登记处和 SAL):研究队列包括 721 名男性和 717 名女性,中位年龄为 50.5 岁(16-94 岁不等)。在开始接受治疗的 1309 名患者中,562 人接受了 ATRA-ATO 化疗,747 人接受了 AIDA-like 化疗。1438例患者中有85例(5.9%)在确诊APL后中位9天发生早期死亡(ED),且与年龄增加和Sanz风险评分高独立相关(OR:1.06,95% C.I.:1.04-1.08;OR:4.65,95% C.I.:2.55-8.51)。ATRA-ATO方案的疗效最好,7年总生存率达到91%(与AIDA样方案相比为81%,HR:2.14,95%C.I.:1.51-3.05),无事件生存率为89%(与AIDA样方案相比为71%,HR:2.72,95%CI:2.01-3.69),复发率为3%(与AIDA样方案相比为13%,HR:4.19,95%CI:2.38-7.39,P结论:我们的研究证实,在APL患者中,ATRA-ATO优于ATRA-化疗。ED 代表着一种尚未满足的医疗需求,尤其是在老年患者和高风险 APL 患者中。
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引用次数: 0
Long-term Outcomes of tyrosine kinase inhibitors in chronic myeloid leukemia. 酪氨酸激酶抑制剂对慢性髓性白血病的长期疗效。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-01 DOI: 10.1182/blood.2024026311
François Guilhot, Rüdiger Hehlmann

Long-term outcomes with tyrosine kinase inhibitors (TKI) show that their impact on CML is sustained as shown by 13 studies with 5- to 14-year-follow-up and numerous shorter-term studies of newly diagnosed chronic-phase CML. Twenty-five years of imatinib (IM)-treatment confirm its beneficial effect on survival and possibly cure of CML. Large randomized academic treatment optimization studies have confirmed and extended the pivotal International Randomized Study on Interferon and STI571 (IRIS). The 3 academic trials in Germany, France and the UK did not show benefit of the IM-interferon (IFN) combination, despite the immunomodulatory properties of IFN. Second generation (2G)-TKI induce responses faster than IM and recognize IM-resistance-mutations, but do not prolong survival compared to IM. Serious drug related reactions (ADR) limit the general use of 2GTKI despite frequent, but mostly mild IM-ADR. Molecular monitoring of treatment efficacy has been established serving as an example for other neoplasms. Comorbidities, transcript type and the negative impact of high-risk additional chromosomal abnormalities (ACA) were addressed. A new prognostic score (EUTOS-long-term-survival or ELTS-score) accounts for the fact that the majority of CML-patients die of other causes. Non-CML determinants of survival have been identified. Large and long-term observational studies demonstrate that progress with CML-management has also reached routine care in most, but not all instances. Despite merits of 2GTKI IM remains the preferred treatment option for CML due to its efficacy and superior safety.

酪氨酸激酶抑制剂(TKI)的长期疗效表明,它们对慢性骨髓性白血病的影响是持续性的,13 项为期 5 至 14 年的随访研究和许多针对新诊断的慢性期慢性骨髓性白血病的短期研究都证明了这一点。长达 25 年的伊马替尼(IM)治疗证实了其对 CML 生存的有利影响,并有可能治愈 CML。大型随机学术治疗优化研究证实并扩展了关键的干扰素和 STI571 国际随机研究(IRIS)。尽管 IFN 具有免疫调节特性,但德国、法国和英国的 3 项学术试验并未显示 IM-干扰素(IFN)联合治疗的益处。第二代(2G)-TKI诱导反应的速度比IM快,并能识别IM耐药突变,但与IM相比并不能延长生存期。严重的药物相关反应(ADR)限制了第二代(2G)TKI 的普遍使用,尽管第二代(2G)TKI 经常出现轻微的 IM-ADR。对治疗效果的分子监测已经建立起来,为其他肿瘤的治疗提供了范例。研究还探讨了合并症、转录本类型和高风险额外染色体异常(ACA)的负面影响。新的预后评分(EUTOS-长期生存评分或 ELTS-评分)考虑到了大多数 CML 患者死于其他原因这一事实。非 CML 存活率的决定因素已经确定。大型长期观察研究表明,在大多数情况下,但并非所有情况下,CML 的管理也取得了进展。尽管 2GTKI 有其优点,但由于其疗效和卓越的安全性,IM 仍然是 CML 的首选治疗方案。
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引用次数: 0
Childhood Langerhans cell histiocytosis hematological involvement: severity associated with BRAFV600E loads. 儿童朗格汉斯细胞组织细胞增生症血液学受累:严重程度与 BRAFV600E 负载有关。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-01 DOI: 10.1182/blood.2024025625
Julian Thalhammer, Eric Jeziorski, Perrrine Marec-Berard, Mohamed-Aziz Barkaoui, Anne Pagnier, Pierre-Simon Rohrlich, Aurore Chevallier, Liana Carausu, Nathalie Aladjidi, Charlotte Rigaud, Amaury Leruste, Saba Azarnoush, Thomas Lauvray, Solenne Le Louet, Virginie Gandemer, Pauline Treguier, Ludovic Mansuy, Marlène Pasquet, Laura Olivier, Angélique Rome, Paul Saultier, Florentina Isfan, Cecile Renard, Valérie Li Thiao Te, Alexandra Salmon, Laurence Blanc, Wadih Abou Chahla, Anne Lambilliotte, Jean-Louis Louis Stephan, Frederic Geissmann, Julien Lejeune, Coralie Mallebranche, Yves Reguerre, Audrey Grain, Caroline Thomas, Zofia Hélias-Rodzewicz, Despina Moshous, Odile Fenneteau, Aurore Coulomb-L'hermine, Hélène Lapillonne, Geneviève de Saint Basile, Jean-Francois Emile, Sébastien Héritier, Jean Donadieu

Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL and/or platelets <100 G/L and/or leukopenia (white blood cell count <4 G/L) and/or neutrophils <1.5 G/. Among the 2313 patients <18 years old enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis: 1 year); median follow-up lasted 8.1 years. Bone-marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis or myelofibrosis but never confirm the diagnosis. Fifty-eight (17%) patients developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 G/L, respectively) and severe HI (SHI; ≤7 g/dL and ≤20 G/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities and outcomes (respective MHI and SHI 10-year survival rates: 98% and 73%). Since 1998, mortality first declined with combination Cladribine-cytarabine therapy, and then with mitogen-activated protein-kinase inhibitors since 2014. Forty-one (12%) patients developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, as it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted-therapy approaches would be better adapted for these patients, while MHI can be managed with classic therapies.

血液受累(HI)是朗格汉斯细胞组织细胞增生症(LCH)中威胁生命的危险器官(RO)之一。自 1975 年以来,Lahey 标准将 HI 分别定义为血红蛋白 7 g/dL 和 >20 G/L)和严重 HI(SHI;≤7 g/dL 和≤20 G/L)。每种类型都有不同的器官参与、实验室参数、突变状态、血液中的 BRAFV600E 负载、药物敏感性和结果(MHI 和 SHI 的 10 年生存率分别为 98% 和 73%)。自1998年以来,克拉利宾-卡他滨联合疗法的死亡率首次下降,自2014年以来,丝裂原活化蛋白激酶抑制剂的死亡率也有所下降。41名患者(12%)出现了神经退行性并发症,这已成为长期幸存者的一个风险。这些结果表明,HI-RO的定义应仅限于SHI,因为它几乎涵盖了LCH的所有内科并发症。未来的临床试验可能会证明,靶向治疗方法更适合这些患者,而MHI则可以通过传统疗法来控制。
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引用次数: 0
Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia. 培加氯普兰治疗冷凝集素病和温抗体自身免疫性溶血性贫血的安全性和有效性。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-01 DOI: 10.1182/blood.2023022549
Eloy Roman, Bruno Fattizzo, Merrill Kingman Shum, Wahid T Hanna, Steven R Lentz, Sergio Schusterschitz S Araujo, Mohammed Al-Adhami, Federico V Grossi, Morie A Gertz

Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in two cohorts, one for patients with CAD and the other wAIHA. In each cohort, patients were randomly assigned to receive 270 or 360 mg/day pegcetacoplan for up to 48 weeks. Safety endpoints included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy endpoints included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue scale. Thirteen (100%) and 10 out of 11 (91%) patients with CAD and wAIHA respectively experienced at least 1 TEAE. Ten patients had at least 1 serious adverse event; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90 to 3.00) and 1.7 g/dL (‑1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective in patients with CAD and wAIHA. Registered at www.clinicaltrials.gov (NCT03226678).

冷凝集素病(CAD)和暖抗体自身免疫性溶血性贫血(wAIHA)是一种罕见的自身免疫性溶血性贫血,其特点是红细胞破坏,主要是补体激活导致血管内和血管外溶血。Pegcetacoplan是一种皮下注射的C3靶向疗法,可能适用于治疗CAD和wAIHA。在这项开放标签的 2 期研究中,对两个队列进行了分析,一个队列针对 CAD 患者,另一个队列针对 wAIHA 患者。在每个队列中,患者被随机分配接受 270 或 360 毫克/天的培高氯普兰治疗,疗程长达 48 周。安全性终点包括治疗突发不良事件(TEAE)和特别关注不良事件(AESI)的发生率和严重程度。疗效终点包括血红蛋白(Hb)、乳酸脱氢酶、绝对网织红细胞计数、血红蛋白、间接胆红素和慢性病治疗功能评估(FACIT)-疲劳量表与基线相比的变化。13名(100%)和11名(91%)CAD和wAIHA患者中分别有10名和10名(91%)出现了至少1次TEAE。10 名患者至少出现了 1 次严重不良事件,但无一被认为与培高氯普兰有关。唯一与治疗相关的 AESI 是注射部位反应。在最初几周,培加氯普兰可提高血红蛋白水平、减少溶血并增加 FACIT 疲劳量表评分;第 48 周时,CAD 组和 wAIHA 总分组的血红蛋白与基线相比的中位数(四分位间范围)变化分别为 2.4(0.90 至 3.00)和 1.7 g/dL(-1.40 至 2.90),溶血和 FACIT 疲劳量表评分的改善得以保持。这项研究表明,培加氯普兰的耐受性普遍良好,对患有 CAD 和 wAIHA 的患者有一定疗效。注册于 www.clinicaltrials.gov (NCT03226678)。
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