ITCC-104: HEM-iSMART International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Sub-Protocol E: Capivasertib + Venetoclax + Dexamethasone in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol E is a phase I/II trial evaluating the safety and efficacy of capivasertib + venetocolax in combination with dexamethasone in children and AYA with R/R ped ALL/LBL whose tumor present with alterations of the PAM pathway, or lacking any mutations.

开始日期2026-10-01

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

[+2]

NCT07153497

/ Not yet recruiting临床2期IIT

A Randomized Phase 2 Trial of Olutasidenib-Based Therapies in Patients With Newly Diagnosed IDH1-Mutant Myeloid Malignancies: A MyeloMATCH Substudy

This phase II MyeloMATCH treatment substudy tests the addition of olutasidenib to usual treatment in patients with higher-risk myelodysplastic syndrome (MDS) or patients with acute myeloid leukemia (AML) with a mutation in the IDH1 gene. Olutasidenib blocks the protein made by the mutated IDH1 gene. Blocking this protein may help keep cancer cells from growing. For patients with MDS, olutasidenib will be added to decitabine-cedazuridine (also called ASTX727). Decitabine is in a class of medications called hypomethylating agents and is the standard treatment for MDS. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. The cedazuridine makes it possible to take the decitabine by mouth. Adding olutasidenib to the usual treatment for MDS (ASTX727) may increase the likelihood of going into remission. For patients with AML, olutasidenib and ASTX727 will be combined with venetoclax, a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Adding olutasidenib to the usual treatment for AML (ASTX727 and venetoclax) may increase the likelihood of going into remission. For low risk MDS, the substudy tests whether giving olutasidenib alone helps improve blood counts.

开始日期2026-05-27

申办/合作机构

National Cancer Institute

NCT06802523

/ Suspended临床1期IIT

A Phase I Study of Lintuzumab-Ac-225 in Combination With Venetoclax and ASTX-727 in Adults With Newly Diagnosed AML

This phase I trial tests the safety, side effects, and best dose of lintuzumab-Ac225 in combination with venetoclax and ASTX-727, and how well they work in treating patients with newly diagnosed acute myeloid leukemia (AML). Lintuzumab-Ac225 is a monoclonal antibody, called lintuzumab, linked to a radioactive agent called actinium Ac 225. Lintuzumab attaches to CD33 positive cancer cells in a targeted way and delivers actinium Ac 225 to kill them. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. ASTX-727 is a combination of two drugs, cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Giving lintuzumab-Ac225 in combination with venetoclax and ASTX-727 may be safe and tolerable in treating patients with newly diagnosed AML and may improve the chance of going into remission and staying in remission for a longer period of time.

开始日期2026-04-21

申办/合作机构

National Cancer Institute

100 项与维奈克拉相关的临床结果

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100 项与维奈克拉相关的转化医学

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100 项与维奈克拉相关的专利（医药）

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4,861

项与维奈克拉相关的文献（医药）

2026-02-01·COMPUTATIONAL BIOLOGY AND CHEMISTRY

GC/MS analysis and computational evaluation of C. cinerea EO constituents for colorectal cancer: Molecular docking, dynamics, and quantum chemical insights into Cis-Verbenyl acetate

Article

作者: Bekkar, Yahia ; Bouraoui, Rania ; Neghmouche Nacer, Salah ; Lanez, Touhami ; Bourougaa, Lotfi ; Lanez, Elhafnaoui ; Garzoli, Stefania ; Larbi Benamor, Mohammed ; Samah, Bouchagra

The essential oil of Cotula cinerea was subjected to gas chromatography-mass spectrometry (GC-MS) analysis, leading to the identification of 31 chemical constituents. The major compounds were selected for comprehensive computational investigations to explore their potential anti-colorectal cancer activity. Among the identified constituents, cis-verbenyl acetate (CVA) exhibited the most favorable binding affinities across a panel of fifteen protein targets implicated in colorectal cancer. Notably, Tankyrase1 (PDB ID: 4OA7) and Tankyrase2 (PDB ID: 4UFU) emerged as the most promising targets, with docking scores of -9.49 and -8.46 kcal/mol, respectively. Molecular dynamics simulations conducted over 300 nanoseconds demonstrated the structural stability and sustained interactions of the CVA-protein complexes, characterized by low root mean square deviation (RMSD) values and limited conformational fluctuations. These findings were corroborated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations, which revealed highly favorable binding free energies, particularly in the CVA- TNKS2 complex (ΔGtotal = -45.64 kcal/mol). In silico ADMET profiling indicated high oral bioavailability and low predicted toxicity for CVA compared to native ligands. Furthermore, density functional theory (DFT) analysis provided insight into the electronic properties of CVA, revealing a stable electronic configuration, suitable frontier molecular orbital energies, and a well-distributed electrostatic potential surface. Thermodynamic evaluations supported its chemical stability, showing a consistent increase in entropy, enthalpy, and heat capacity with rising temperature. Collectively, these computational findings suggest that CVA is a thermodynamically stable, pharmacokinetically favorable, and potentially bioactive compound with dual-target affinity against colorectal cancer-related proteins, meriting further experimental validation.

2026-02-01·JOURNAL OF BIOTECHNOLOGY

FRET two-hybrid assay-based target drug screening in living cells

Article

作者: Chang, Yuan ; Wang, Xiaoping ; Gan, Tian ; Qu, Rumeng ; Cao, Gengqiang ; Sun, Beini ; Chen, Tongsheng ; Wang, Yue ; Hu, Lin ; Hu, Min

Precise targeted drug screening is the key to improve the efficiency of tumour targeted therapy. This report presents a live cell FRET two-hybrid assay-based targeted drug screening method (FRET-HBTDS). In FRET-HBTDS, the cells co-expressing donor- and acceptor-labelled targets were cultured in 96-well plates, quantitative FRET imaging was then performed on a self-built automated FRET microscope (FRETscope) well-by-well, and FRET two-hybrid assay was used to obtain the maximum donor-centre FRET efficiency (E_Dmax), maximum acceptor-centre FRET efficiency (E_Amax) and stoichiometric ratios (N_A/N_D). The FRET-HBTDS method was performed on the FRETscope with a 20 × objective for the cells co-expressing CFP-Bcl-xL and YFP-Bak to assess the action of eight compounds (A1331852, S63845, AC, DSF/Cu, Met, REGO, SOFA, ABT199) on the interaction between Bcl-xL and Bak. After 7 h of treatment with these compounds respectively, only the A1331852 group showed significantly lower E_Dmax and E_Amax compared to the control group, and a significant increase in N_A/N_D, suggesting that A1331852 unlocks the direct interaction between Bcl-xL and Bak, thus releasing Bak to induce cell death. In addition, the N_A/N_D of the DSF/Cu group was significantly higher than of the control group, suggesting that DSF/Cu altered the stoichiometry of the Bcl-xL-Bak complex. Our data firmly demonstrate that A1331852 unlocks the binding state of Bcl-xL and Bak, while DSF/Cu modifies the structure of the Bcl-xL-Bak complex. These findings demonstrate that FRET-HBTDS can be used to assess the efficacy of a drug by revealing the binding state and complex molecular structure of the target proteins using FRET technology in living cells, which may be a potential targeted drug screening method.

2026-01-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia

Article

作者: de Franca Basto Silva, Marina ; Campregher, Paulo Vidal ; Lima, Keli ; Costa-Lotufo, Leticia Veras ; Cortez, Luiz Gustavo Ferreira ; Machado-Neto, João Agostinho ; de Queiroz, Gustavo Nery ; Guedes, Rafael Lucas Muniz ; Câmara, Niels Olsen Saraiva ; Tomaz, Victoria ; Cipelli, Marcella ; Rego, Eduardo Magalhães

Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM-13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased oxidative phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/AKT/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML.

1,922

项与维奈克拉相关的新闻（医药）

2025-12-26

·康圣环球医学时间

Blood｜成人 B-ALL遗传亚型全景图

期刊：Blood发表时间：2025.04 B 细胞急性淋巴细胞白血病（B-ALL）是一种异质性极强的血液系统恶性肿瘤，成人患者预后长期落后于儿童群体。过去二十年间，基因组学技术的飞速发展揭开了 B-ALL 的遗传密码 —— 国际共识分类（ICC）已认可26种不同的分子亚型及其他暂定亚型（表1），这些亚型不仅决定了疾病的生物学特征，更直接影响治疗反应与长期生存。不同于儿童 B-ALL 的成熟诊疗体系，成人 B-ALL 的遗传谱分布、预后关联及治疗策略仍需深入探索。本文将系统解析成人 B-ALL 的核心遗传亚型、临床特征及精准医疗应用要点，为临床实践提供参考。表 1 B-ALL亚型的生物学和临床特征、成人患病率及诊断方法注：Chr：染色体；CGH：比较基因组杂交；CNAs：拷贝数异常；K：核型；FISH：荧光原位杂交；NA：不适用；ND：无数据；OGM：光学基因组图谱；RT-PCR：逆转录 - 聚合酶链反应；SNP：单核苷酸多态性；WBC：白细胞；WGS：全基因组测序；WTS：全转录组测序。经典细胞遗传学亚型的新见解经典亚型以特征性染色体易位或非整倍体为标志，是成人 B-ALL 最主要的遗传分类依据，其临床认知近年来不断更新。费城染色体（Ph）阳性（BCR::ABL1 融合型）这是成人 B-ALL 中最常见的遗传亚型，由 t (9;22)(q34;q11) 染色体易位产生 BCR::ABL1 融合基因（图 1）。其发病率随年龄显著升高，在 55 岁以上人群中占比可达 50%，是老年 B-ALL 的主要亚型。图 1 不同年龄组B-ALL遗传亚型的分布情况历史上，Ph+ ALL 对化疗反应极差，预后恶劣，但酪氨酸激酶抑制剂（TKIs）联合双特异性抗体（blinatumomab）的治疗方案彻底改变了这一局面，目前长期生存率已接近 80%。这一突破也促使学界重新评估化疗和异基因造血干细胞移植（allo-HSCT）的角色。近年研究发现，Ph+ ALL 存在显著生物学异质性：其一，特定共突变会影响预后。IKZF1plus 模式（IKZF1 缺失伴 PAX5 或 CDKN2A 缺失）是明确的高危因素；其二，32%-37% 的新发患者存在 “CML 样” 或 “多系受累” 特征 ——BCR::ABL1 融合基因不仅存在于淋巴母细胞，还可见于非淋巴系细胞，形成介于 Ph+ ALL 与慢性髓系白血病（CML）之间的独特实体（图2）。因此，采用免疫球蛋白 / T 细胞受体（IG/TR）基因重排监测微小残留病（MRD），比传统的 BCR::ABL1 定量检测更能准确反映残留肿瘤负荷。其三，转录组学研究揭示了Ph+ ALL的不同表达谱，这些谱式与B细胞分化阶段、谱系受累情况及共突变相关。图2 成人B-ALL的独特白血病发生模型低亚二倍体型该亚型的细胞遗传学特征为核型含 30-39 条染色体，长期以来被认为是一种少见且预后不佳的亚型。部分病例中，低亚二倍体细胞会发生全基因组重复，形成 “隐匿性低亚二倍体”，导致真实发病率被低估。最新数据显示，低亚二倍体患病率随年龄增长而升高，在老年成人的Ph阴性B-ALL中占比可达30%。TP53 双等位基因改变是其标志性特征（通常为一个突变 + 17 号染色体单体导致的拷贝缺失）。儿童病例中半数存在生殖细胞系 TP53 突变，而成人中则以体细胞多系受累为主，提示 TP53 突变型克隆性造血（CH）可能是重要易感因素。由于 TP53 突变型 CH 还可能进展为髓系恶性肿瘤，这类患者的缓解后治疗策略需综合考量多系肿瘤风险。 KMT2A 重排型由 t (v;11)(v;q23) 染色体易位驱动，融合伙伴基因具有谱系特异性，在 B-ALL 中 80% 以上为 KMT2A::AFF1 融合（t (4;11)(q21;q23)）。该亚型在婴儿白血病中高发，儿童中少见，但成人发病率回升，且常与既往恶性肿瘤的细胞毒性治疗相关。 KMT2A 重排型 ALL 在儿童和成人中均预后不良，成人患者虽常被推荐 allo-HSCT，但治疗结局仍不理想。最新研究发现，特定共突变（TP53 点突变、IKZF1 缺失）及诱导缓解后 MRD 状态可将其分为不同预后亚组：无不良因素者仅通过强化化疗即可获得优异结局，而高危患者则需探索替代治疗方案。由于白血病细胞具有固有谱系可塑性，B 细胞靶向治疗可能失效，Menin 抑制剂等新型药物研发已成为重点方向。其他经典亚型高超二倍体：儿童中最常见，但成人中不足 10%，特征为非随机性染色体增加，长期生存率可达 95% 以上（儿童数据），成人相关研究有限但提示预后较好。 ETV6::RUNX1 融合型：儿童中第二常见亚型，但成人中占比 < 2%，主要见于青少年和年轻成人（AYA），预后良好。因此，成人与儿童中高危亚型（如Ph+、低亚二倍体、KMT2A重排型）和低危亚型（如高超二倍体、ETV6::RUNX1融合型）的患病率分布差异，在很大程度上解释了两者临床结局的显著不同（图1、表1）。 TCF3::PBX1 融合型：t (1;19)(q23;q13) 易位导致，成人与儿童中均占 4% 左右，常伴随中枢神经系统受累，预后因治疗方案而异，allo-HSCT 的价值仍存争议。 TCF3::HLF 融合型：t (17;19)(q22;p13) 易位驱动，极为罕见，预后极差，但近期 B 细胞靶向治疗及维奈克拉（venetoclax）和BET抑制剂显示出治疗潜力。 21 号染色体内部扩增（iAMP21）：罕见高危亚型，主要见于儿童和 AYA，强化化疗可改善预后。转录组和/或全基因组测序揭示的新兴遗传亚型全转录组测序（WTS）和全基因组测序（WGS）的应用，发现了一批由复杂分子异常定义的新型亚型，为成人 B-ALL 的精准治疗提供了新靶点。 Ph 样（BCR::ABL1 样）ALL Ph样ALL可见于所有年龄组，但在青少年和年轻成人（AYA）中略为常见，占B-ALL的比例高达30%，其基因表达谱类似 Ph+ ALL，但无 BCR::ABL1 融合。该亚型以 IKZF1 缺失频发、化疗反应差为特征，预后不良，但因存在细胞信号通路异常激活，对靶向药物敏感。全转录组测序（WTS）研究发现，其遗传改变主要分为两类：其一，ABL 类基因融合（ABL1、ABL2、PDGFRA 、PDGFRB、CSF1R），占 Ph样ALL的10%-15%，单独化疗诱导失败率高，添加 TKIs 可显著改善结局；其二，CRLF2 重排（包括IGH::CRLF2、P2RY8::CRLF2），占 50%，常伴随 JAK2 激活突变及 JAK-STAT 通路增强，同时伴随IKZF1、PAX5和CDKN2A缺失。JAK 抑制剂联合化疗的临床试验正在推进（NCT02723994 等）。由于遗传改变高度多样，WTS 是最有效的诊断方法。 ZNF384 重排型（ZNF384-r）由 ZNF384 基因与 EP300、TCF3、TAF15 等伙伴基因融合定义，所有融合均保留 ZNF384 完整编码区，形成特征性基因表达谱。该亚型具有独特免疫表型：CD10 弱表达、CD13和/或CD33 异常表达，甚至呈现 B / 髓系混合表型。 ZNF384-r ALL 预后为中等或良好，但其显著特征是多系分化潜能和谱系可塑性，可能在随访中发生免疫表型转换。有趣的是，ZNF384 融合蛋白可驱动 FLT3 基因表观遗传激活，使该亚型对 FLT3 抑制剂敏感，为靶向治疗提供了新方向。 DUX4 重排型（DUX4-r）最初通过与 ERG 基因内缺失的关联被识别，核心驱动事件为 IGH::DUX4 融合，可驱动 DUX4 异位表达。该亚型中，虽 IKZF1 缺失常见，但预后良好。诊断存在一定挑战：IGH::DUX4 融合呈细胞遗传学隐匿性，WTS 检测一致性不佳，仅三分之二病例存在 ERG 缺失，需通过全面基因表达谱或 WGS 确认。其独特生物学特征包括：诊断时可能出现单核样细胞、异常表达 CD371/CD2/CD56 等标志物，单细胞研究证实其具有向髓系和 T 细胞谱系分化的潜能，但目前尚未见逃避 B 细胞靶向治疗的病例报道。 PAX5 相关亚型 PAX5 是 B 细胞分化的关键调控因子，其异常分为两类亚型： PAX5 P80R 型：由 PAX5 p.P80R 点突变驱动，为原发性致癌事件，不与其他驱动因子共存该突变通常伴随PAX5另一个等位基因的突变或缺失（多由9号染色体短臂缺失导致），而9号染色体短臂缺失还会引发CDKN2A/B基因座丢失。成人预后中等至良好。 PAX5alt 型：ICC 暂定亚型，包含 PAX5 融合、基因内扩增及非 P80R 突变，需通过全面基因组分析识别，预后中等至不良，相关研究仍在推进。 CDX2/UBTF 型通过大型成人队列基因表达分析发现，核心改变为 13q12.2 微缺失（诱导 CDX2 异位过表达）和 17q21.3 微缺失（UBTF::ATXN7L3 融合），主要影响年轻女性。该亚型具有独特附加改变（1q 重复、CXCR4 突变），对治疗反应极差，复发率高，目前尚无有效治疗方案，亟需新型药物研发。其他罕见 / 暂定亚型 MYC/BCL2 型：即 “双打击” 亚型，由 MYC 和 BCL2（和/或BCL6）重排驱动，在 B-ALL 中罕见但预后恶劣，可尝试 B 细胞靶向治疗联合 BCL2 抑制剂。 MEF2D 重排型：MEF2D 与 BCL9 等基因融合，预后中等至不良，MEF2D过表达导致HDAC9 激活为潜在靶点，组蛋白去乙酰化酶抑制剂或可为该亚型的治疗带来获益。 CEBP/ZEB2 及 CEBPalt 型：涉及 C/EBP 家族基因重排，CEBPalt 型主要与唐氏综合征相关，成人中数据有限。 IDH1/2 突变型：存在 IDH1 p.R132C、IDH2 p.R140Q 热点突变，为成人独特亚型，预后不良，IDH 抑制剂可能具有治疗价值。二次改变：影响预后的 “隐形推手” 除了亚型定义的原发性改变，二次改变在 B-ALL 发病和进展中发挥关键作用，主要包括拷贝数异常（CNAs）和点突变，涉及 B 淋巴系因子（如IKZF1、PAX5、EBF1）、细胞周期调控因子（CDKN2A、TP53）、信号通路基因（NRAS、KRAS、JAK2）及表观遗传因子（CREBBP、SETD2）等。部分二次改变与耐药直接相关（如 NT5C2、NR3C1 突变），且其分布和预后影响具有亚型特异性。例如，IKZF1 缺失在 Ph + 和 Ph 样 ALL 中高发，是高危因素，但在其他亚型中预后意义不明确。此外，二次改变的组合模式也至关重要，如 IKZF1plus 模式已成为 Ph+ ALL 的核心风险分层指标。由于不同年龄、遗传背景的队列及治疗方案会导致研究结论差异，二次改变的预后价值需在特定亚型中分析验证。临床诊断的现实挑战与技术选择成人 B-ALL 的精准分型依赖多元化检测技术，但临床应用需平衡检测通量、周转时间和成本：传统技术：核型分析是经典亚型的基础诊断方法，荧光原位杂交（FISH）、靶向分子检测（逆转录聚合酶链反应、多重连接依赖探针扩增、液滴数字聚合酶链反应等）等技术被用于补充检测反复出现的基因重排，但无法覆盖复杂变异。光学基因组图谱（OGM）：可检测大部分结构变异和拷贝数异常，实施简便，但不能检测点突变，是传统细胞遗传学的重要补充。全基因组测序（WGS）：可全面表征基因组变异，但成本高、耗时长，目前难以常规应用。全转录组测序（WTS）：兼具基因表达分析、融合基因和突变检测功能，无需内部数据集即可辅助亚型分类，性价比高，有望成为标准检测方法。临床实践中，建议采用 “分层检测策略”：先通过核型 + FISH/RT-PCR 筛查常见亚型，再对疑似病例或未明确亚型者进行 WTS/WGS 检测，确保精准性与实用性平衡。 MRD 监测：精准评估的关键环节微小残留病（MRD）是 B-ALL 预后评估和治疗调整的核心依据，但不同亚型的 MRD 监测需注意标志物选择： Ph + 和低亚二倍体 ALL：已分别观察到与BCR::ABL1融合基因和TP53突变相关的克隆性造血（CH）（图2），建议优先使用 IG/TR 基因重排或 IKZF1 缺失等二次改变作为 MRD 标志物。 KMT2A 重排型：IG/TR 重排可能在病程中丢失，建议以 KMT2A 融合作为核心监测标志物。具有谱系可塑性的亚型（KMT2A-r、ZNF384-r、DUX4-r）：流式细胞术可能因免疫表型转换漏检，需结合分子标志物联合监测。 B 细胞靶向治疗后：CD19/CD22 等抗原表位可能丢失，需动态调整监测策略。 B 细胞靶向治疗时代：亚型预后的重新定义 B 细胞靶向治疗（CD19/CD22 单抗、双特异性抗体等）的应用，使传统基于化疗敏感性的预后分层面临挑战：亚型特异性治疗反应：KMT2A-r 和 ZNF384-r 因谱系可塑性强，易通过向髓系转换丢失 CD19，导致靶向治疗逃逸；低亚二倍体因 16 号染色体缺失，CD19 基因易丢失，也增加逃逸风险。抗原表达差异影响疗效：PAX5 P80R 型 CD58 低表达，削弱 blinatumomab 的 T 细胞激活作用；KMT2A-r CD22 表达低下，对 inotuzumab ozogamicin 反应较差。这些发现提示，化疗时代的低危亚型在靶向治疗中可能仍需维持一定治疗强度，而高危亚型可通过靶向联合治疗改善结局，亚型特异性治疗策略亟待建立。展望与挑战成人 B-ALL 的精准医疗已取得显著进展，但仍面临多重挑战：其一，需开展大型国际合作研究，明确各亚型在靶向治疗时代的预后价值及遗传组合的影响；其二，深入解析亚型特异性致癌机制，研发 Menin 抑制剂、FLT3 抑制剂等新型靶向药物；其三，探索宿主因素（微环境、药物基因组学）对发病和治疗反应的影响，实现个体化治疗优化。随着基因组检测技术的普及和靶向药物的迭代，成人 B-ALL 的治疗正从 “一刀切” 转向 “量体裁衣”。精准分型是基础，动态 MRD 监测是保障，亚型特异性治疗是核心 —— 三者结合将持续提升成人 B-ALL 的治愈率，为患者带来新的生存希望。原文链接：https://doi.org/10.1182/blood.2023022919 获取原文：请回复"20251226" 大家都在看 RECOMMEND Clinical Chemistry｜多参数流式细胞术在急性髓系白血病中的应用：精准诊断、分类和监测的关键工具 Science｜流感治疗新范式 —— 挽救生命的关键在于 “促修复”，而非仅 “抗病毒” Clinical Cancer Research｜从分期到肿瘤本质：INPC-RG对神经母细胞瘤风险分层逻辑的重构撰写 | 龚伟伟审核 | 李金旺排版 | 田沁汶

2025-12-26

·aptevotherapeutics.gcs-web.com

Aptevo Therapeutics Announces 1-for-18 Reverse Stock Split

SEATTLE, WA / ACCESS Newswire / December 26, 2025 / Aptevo Therapeutics Inc. (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immune-oncology therapeutics based on its proprietary ADAPTIR™ and ADAPTIR-FLEX™ platform technologies, today announced that it will conduct a reverse stock split of its outstanding shares of common stock, par value $0.001 per share ("Common Stock"), at a ratio of 1-for-18 (the "Reverse Stock Split"). The Reverse Stock Split is expected to become effective on December 29, at 5:01 p.m. Eastern Time (the "Effective Time"), with shares expected to begin trading on the Nasdaq Capital Market, on a split-adjusted basis, at market open on December 30, 2025. In connection with the Reverse Stock Split, every 18 shares of Common Stock issued and outstanding as of the Effective Time will be automatically converted into one share of Common Stock. No change will be made to the trading symbol for the Common Stock, "APVO," in connection with the Reverse Stock Split. The Reverse Stock Split was approved by the Company's stockholders at the Company's Annual Meeting of Stockholders held on July 24, 2025 (the "Annual Meeting") to be effected in the Board's discretion within approved parameters. Following the Annual Meeting, the final ratio was approved by the Company's Board on December 17, 2025. The Reverse Stock Split will reduce the number of shares of outstanding Common Stock from approximately 18 million shares (as of the date of this press release) to approximately 1 million shares, subject to adjustment for rounding, as discussed below and potential additional issuances through the effective date of the Reverse Stock Split. The Reverse Stock Split will affect all issued and outstanding shares of Common Stock. All outstanding options, restricted stock units, warrants, and other securities entitling their holders to purchase or otherwise receive shares of Common Stock will be adjusted as a result of the reverse split, as required by the terms of each security. The number of shares available to be awarded under the Company's equity incentive plans will also be appropriately adjusted. Following the reverse split, the par value of the Common Stock will remain unchanged at $0.001 par value per share. The Reverse Stock Split will not change the authorized number of shares of Common Stock or preferred stock. No fractional shares will be issued in connection with the Reverse Stock Split, and stockholders who would otherwise be entitled to receive a fractional share of Common Stock will be entitled to receive a cash payment (without interest). Additional information regarding the Reverse Stock Split is available in the Company's definitive proxy statement filed with the U.S. Securities and Exchange Commission ("SEC") on July 3, 2025, and a Current Report on Form 8-K which the Company plans to file following the Effective Time. About Aptevo Therapeutics Aptevo Therapeutics Inc. (NASDAQ:APVO) is a clinical-stage biotechnology company focused on developing novel bispecific and trispecific immunotherapies for the treatment of cancer. The Company has two clinical candidates. Mipletamig is currently being evaluated in RAINIER, a two-part Phase 1b/2 trial for the treatment of frontline acute myeloid leukemia in combination with standard-of-care venetoclax + azacitidine. Mipletamig has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act. ALG.APV-527, a bispecific conditional 4-1BB agonist, only active upon simultaneous binding to 4-1BB and 5T4, is being co-developed with Alligator Bioscience and was most recently evaluated in a Phase 1 clinical trial for the treatment of multiple solid tumor types likely to express 5T4. The Company has six preclinical candidates with different mechanisms of action designed to target a range of solid tumors. All pipeline candidates were created from two proprietary platforms, ADAPTIRand ADAPTIR-FLEX. The Aptevo mission is to improve treatment outcomes and transform the lives of cancer patients. For more information, please visit www.aptevotherapeutics.com. Forward-Looking Statements This press release includes "forward-looking statements", including information about management's view of the Company's future expectations, plans and prospects, within the safe harbor provisions provided under federal securities laws, including under The Private Securities Litigation Reform Act of 1995. Words such as "expect," "estimate," "project," "budget," "forecast," "anticipate," "intend," "plan," "may," "will," "could," "should," "believes," "predicts," "potential," "continue" and similar expressions are intended to identify such forward-looking statements. These forward-looking statements involve significant risks and uncertainties that could cause the actual results to differ materially from the expected results and, consequently, you should not rely on these forward-looking statements as predictions of future events. These forward-looking statements and factors that may cause such differences include, without limitation, our ability to continue as a going concern; a deterioration in Aptevo's business or prospects; further assessment of preliminary or interim data or different results from later clinical trials; adverse events and unanticipated problems and adverse developments in clinical development, including unexpected safety issues observed during a clinical trial; and changes in regulatory, social, macroeconomic and political conditions. These risks are not exhaustive, the Company faces known and unknown risks. Additional risks and factors that may affect results of the Company are set forth in the Company's filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2024, and its subsequent reports on Form 10-Q and current reports on Form 8-K. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from the Company's expectations in any forward-looking statement. Readers are cautioned not to place undue reliance upon any forward-looking statements, including but not limited to statements about the effectuation of the Reverse Stock Split. These reports and filings are available at www.sec.gov and are available for download, free of charge, soon after such reports are filed with or furnished to the SEC, on the "Investors" page of the Company's website at www.apvotherapeutics.com. Any forward-looking statement speaks only as of the date of this press release, and, except as required by law, the Company does not assume any obligation to update any forward-looking statement to reflect new information, events, or circumstances. Contact: Miriam Weber Miller Head, Investor Relations & Corporate Communications Aptevo Therapeutics Email: IR@apvo.com or Millerm@apvo.com Phone: 206-859-6628 SOURCE: Aptevo Therapeutics

临床1期免疫疗法孤儿药

2025-12-25

·ioncology

Neoplasia丨王建祥/邱少伟教授团队揭示FLT3-ITD突变AML预后异质性：克隆起源与13q UPD是关键驱动因素

点击蓝字关注我们急性髓系白血病（AML）是一种高度异质性的恶性血液肿瘤。其中，携带 FLT3-ITD 突变的患者占比约 20%-30%。FLT3-ITD是AML的重要驱动突变，在AML发病过程中常作为晚期突变事件，常与NPM1、DNMT3A、WT1等突变共存。尽管该突变通常预示预后不良，但临床观察发现，不同 FLT3-ITD+ 患者的生存结局存在巨大差异。以往研究多关注FLT3-ITD本身的分子特征，但其克隆起源对预后的影响常被忽视。此外，从初治到难治/复发（R/R）过程中，驱动耐药的关键遗传学演化规律仍待挖掘。前言近日，中国医学科学院血液病医院（中国医学科学院血液学研究所）王建祥/邱少伟教授团队于2025年12月在《Neoplasia》(IF=7.7分)在线发表论著“Clonal architecture of FLT3-ITD and acquired 13q uniparental disomy define prognostic heterogeneity and therapeutic vulnerabilities in acute myeloid leukemia”。该研究揭示了 FLT3-ITD 的克隆起源及 13q UPD 在 AML 精准分层与治疗中的关键作用。研究团队回顾性分析了自2020年4月至2023年7月期间该院收治的149例FLT3-ITD突变阳性的AML患者临床数据，并整合基因组、转录组数据，首次根据克隆起源将患者分为四种亚型：DNMT3A/NPM1突变、IDH/NPM1突变、转录因子（TF）基因突变或融合基因、其他（Other）变异克隆起源。研究发现，不同起源亚型的预后截然不同，这为精准分层提供了全新的视角。在四种亚型中，DNMT3A/NPM1 起源的患者预后最差，这与既往的研究报道一致。但该克隆起源的患者仍具有一定的异质性，其内部根据细胞分化状态进一步分为“造血干细胞（HSC）样”和“单核细胞(Mono)样”两个亚群。其中，呈现 HSC 表达特征的患者初诊时肿瘤负荷更高，无病生存（EFS）显著缩短。通过纵向全外显子测序，研究发现 13q UPD（单亲二倍体）是疾病进展的核心驱动力。特别是在 DNMT3A/NPM1 起源的 R/R 患者中，13q UPD 的检出率高达 100%（8/8）。研究进一步阐明了 13q UPD 导致化疗耐药与复发的两种模式：1）治疗诱导型：治疗过程中获得的13q UPD赋予初诊时的FLT3-ITD杂合克隆存活及增殖优势，在疾病进展时扩增（50%，4/8）（左）；2）预存逃逸型：初诊时即已存在微小13q UPD克隆，在治疗压力下成功逃逸并持续存在，最终导致复发（50%，4/8）（右）。单细胞分析显示，DNMT3A/NPM1 起源的肿瘤细胞内 DNA 同源重组修复（HRR）通路显著活跃，这可能成为潜在的治疗突破口。基于此发现，研究团队提出：针对该类高危人群，未来可尝试使用 PARP 抑制剂，或将其与现有的维奈克拉（Venetoclax）及 FLT3 抑制剂联合使用。这种精准打击 DNA 修复途径的方案，有望为难治性 FLT3-ITD 突变 AML 患者提供更有效的治疗策略。中国医学科学院血液病医院（中国医学科学院血液学研究所）王建祥教授、邱少伟教授为共同通讯作者，赖安丽博士（现中国医学科学院血液病医院住院医师）、博士后刘文兵(现天津医学健康研究院助理研究员)为共同第一作者。上述研究得到国家自然科学基金、中国医学科学院医学与健康科技创新工程、天津市自然科学基金等多个项目支持。撰稿人：赖安丽审核：邱少伟王建祥教授中国医学科学院血液病医院（中国医学科学院血液学研究所）临床首席专家国家血液系统疾病临床医学研究中心主任；教授，主任医师，博士生导师；中国医学科学院北京协和医学院首批长聘教授；国家百千万人才工程国家级人选；中华医学会血液学分会第十届主任委员；中国医师协会内科医师分会副会长、血液科医师分会副会长等职务；天津授衔专家、海河医学学者、首届天津名医、获天津市“十佳”医务工作者、“中国好医生”月度人物；从事血液病临床与基础工作多年，对各种血液病的诊治具有丰富的临床经验，现主要从事白血病及血液肿瘤的临床与基础研究。邱少伟教授中国医学科学院血液病医院（中国医学科学院血液学研究所）白血病诊疗中心病区主任北京协和医学院硕士生导师北京协和医学院医学博士美国阿拉巴马大学伯明翰分校访问学者天津市青年科技优秀人才研究领域为急性白血病发病耐药机制和免疫靶向治疗以第一作者或通讯作者在Blood, Cancer research, Leukemia, J Clin Invest, Blood Cancer journal, Haematologica, Br J Haematol等杂志发表SCI论文20余篇，主持国自然基金和天津市自然基金等，科技部重点研发计划项目骨干。（来源：《肿瘤瞭望–血液时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床结果临床1期

100 项与维奈克拉相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10679	维奈克拉	L01XX52	DB11581

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
复发性套细胞淋巴瘤	日本	AbbVie LLC	2025-03-27
难治性套细胞淋巴瘤	日本	AbbVie LLC	2025-03-27
难治性慢性淋巴细胞白血病	日本	AbbVie LLC	2019-09-20
复发性慢性淋巴细胞白血病	日本	AbbVie LLC	2019-09-20
小淋巴细胞淋巴瘤	美国	AbbVie, Inc.	2018-06-08
成人急性髓性白血病	欧盟	AbbVie Deutschland GmbH & Co. KG	2016-12-04
成人急性髓性白血病	冰岛	AbbVie Deutschland GmbH & Co. KG	2016-12-04
成人急性髓性白血病	列支敦士登	AbbVie Deutschland GmbH & Co. KG	2016-12-04
成人急性髓性白血病	挪威	AbbVie Deutschland GmbH & Co. KG	2016-12-04
急性髓性白血病	加拿大	AbbVie AS	2016-10-31
慢性淋巴细胞白血病	美国	AbbVie, Inc.	2016-04-11

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤溶解综合征	临床3期	美国	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	澳大利亚	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	法国	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	希腊	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	塞尔维亚	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	西班牙	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	中国台湾	AbbVie, Inc.	2024-08-05
肿瘤溶解综合征	临床3期	英国	AbbVie, Inc.	2024-08-05
复发性急性髓细胞白血病	临床3期	美国	Genentech, Inc.	2022-10-01
复发性急性髓细胞白血病	临床3期	美国	AbbVie, Inc.	2022-10-01

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASH2025	N/A	-	215	Venetoclax	製蓋鏇築願衊獵鬱繭窪(網獵憲艱窪選鏇鏇糧獵) = 淵鹹築齋願憲窪簾網糧蓋遞顧觸膚鏇選觸選艱 (鹹齋艱鬱築襯膚鏇鑰襯, 0.32 ~ 0.58) 更多	积极	2025-12-06
				Venetoclax (≤2 prior lines)	製蓋鏇築願衊獵鬱繭窪(網獵憲艱窪選鏇鏇糧獵) = 網壓鏇壓願選願鏇夢糧蓋遞顧觸膚鏇選觸選艱 (鹹齋艱鬱築襯膚鏇鑰襯 ) 更多
ASH2025	N/A	急性髓性白血病	85	HMA+venetoclax	觸鹹膚齋窪遞觸夢艱鏇(鑰淵窪鹽築餘製願鹹艱) = 醖鹽餘淵選鑰憲範鬱鹽齋夢築夢膚廠繭蓋構壓 (窪壓簾獵壓衊夢顧觸窪 ) 更多	积极	2025-12-06
				HMA monotherapy	-
ASH2025	N/A	急性髓单核细胞白血病一线	56	Hypomethylating agent + venetoclax (Newly diagnosed (1L))	膚顧鬱醖鑰製壓鹽繭艱(鑰簾願夢鬱鑰壓顧構鑰) = 製襯糧膚膚顧糧淵鏇蓋窪壓顧鹽網鹽糧餘繭餘 (鏇鏇鹽鹹壓鹹鏇艱艱願 ) 更多	不佳	2025-12-06
				Hypomethylating agent + venetoclax (Relapsed/refractory (RR))	膚顧鬱醖鑰製壓鹽繭艱(鑰簾願夢鬱鑰壓顧構鑰) = 顧網選餘襯鏇製顧遞廠窪壓顧鹽網鹽糧餘繭餘 (鏇鏇鹽鹹壓鹹鏇艱艱願 ) 更多
ASH2025	临床1/2期	t(11;14)	12	Venetoclax ± Dexamethasone	鏇顧顧獵簾製淵廠簾淵(鏇糧顧簾鏇構顧醖膚醖) = only one patient that developed grade 3 infection (lung infection; COVID-19) 鏇壓夢憲廠膚襯鹹築襯 (醖襯鑰願夢鏇鏇獵夢鏇 ) 更多	积极	2025-12-06
ASH2025	N/A	急性髓性白血病	37	XAB regimen	遞顧鏇獵夢鬱製鹹選醖(餘齋齋簾廠齋鏇簾鹹築) = 襯網憲選構選醖壓艱願窪醖窪繭廠憲廠蓋廠觸 (獵願餘餘蓋鬱淵鹽膚範 ) 更多	积极	2025-12-06
				XAB regimen	遞顧鏇獵夢鬱製鹹選醖(餘齋齋簾廠齋鏇簾鹹築) = 構醖鏇簾憲鑰鑰憲鏇製窪醖窪繭廠憲廠蓋廠觸 (獵願餘餘蓋鬱淵鹽膚範 )
ASH2025	N/A	急性髓性白血病	218	Hydroxyurea + Hypomethylating agents (azacitidine or decitabine) + Venetoclax	構襯糧衊網醖鬱簾選糧(襯襯淵餘膚觸夢憲鏇鏇) = 糧衊醖鬱壓淵鑰齋鑰鹹廠窪糧窪夢壓蓋築鏇壓 (窪願獵觸窪構獵淵艱夢 ) 更多	积极	2025-12-06
				Hypomethylating agents + Venetoclax	構襯糧衊網醖鬱簾選糧(襯襯淵餘膚觸夢憲鏇鏇) = 壓齋鑰鬱築膚夢夢願鑰廠窪糧窪夢壓蓋築鏇壓 (窪願獵觸窪構獵淵艱夢 ) 更多
ASH2025	N/A	急性髓性白血病一线	254	7-day venetoclax exposure + azacitidine	鏇獵齋蓋憲願膚顧糧願(糧構夢糧衊願淵顧淵齋) = 蓋齋遞鏇壓餘齋襯艱鏇憲襯選襯製積夢齋網簾 (範鹹壓願蓋襯繭獵構鬱 ) 更多	不佳	2025-12-06
				standard venetoclax exposure + azacitidine	鏇獵齋蓋憲願膚顧糧願(糧構夢糧衊願淵顧淵齋) = 繭憲積簾艱願壓觸齋遞憲襯選襯製積夢齋網簾 (範鹹壓願蓋襯繭獵構鬱 ) 更多
NCT06644183 (ASH2025)	临床1/2期	复发性慢性淋巴细胞白血病	28	Roginolisib + Venetoclax + Rituximab	膚鏇衊膚簾積願鏇鹹衊(醖鏇繭築齋顧鬱膚積製) = 膚壓構觸選憲願齋餘淵獵醖簾餘糧鑰鹹鑰淵觸 (獵鬱襯壓積繭鹹鹽繭襯 )	积极	2025-12-06
NCT03613532 (ASH2025)	临床1期	急性髓性白血病 \| 高危骨髓增生异常综合征	23	Ven+FluBu2 with PTCy/Tac/MMF	遞衊淵憲衊蓋鹽衊艱選(鹽積網艱壓遞艱廠觸願) = 繭襯壓鑰鏇艱蓋鬱餘襯鏇鏇淵鏇齋網鹽蓋選繭 (顧選獵選遞膚繭窪糧夢 ) 更多	积极	2025-12-06
				Ven+FluBu2+Tac/MTX	憲餘淵選願構襯蓋窪窪(蓋醖願顧觸憲窪鹹積構) = 選鹹糧範構夢遞願網願顧鬱襯製蓋艱構夢憲衊 (鬱構壓廠憲壓觸齋壓餘 ) 更多
NCT05379166 (ASH2025)	临床2期	骨髓增生异常综合征	23	Venetoclax + Azacitidine	夢繭鏇鹹製壓網壓鏇衊(鑰範鬱鏇糧糧鹽衊構範) = 齋鬱構簾廠遞糧艱製襯選鹹構壓鏇艱繭糧網鏇 (衊艱觸鹽衊鹽膚壓築構 ) 更多	积极	2025-12-06