A Phase 2/3 Randomized Trial Investigating Daratumumab on a Modified Augmented BFM (aBFM) Backbone in Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL)

This phase II/III trial tests the addition of daratumumab to chemotherapy for treating patients with newly-diagnosed T-ALL and T-LL. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with daratumumab may kill more cancer cells.

开始日期2026-03-30

申办/合作机构

The Children's Oncology Group Foundation, Inc.

NCT06390319

/ Recruiting临床2期IIT

SJALL23T: Adding Dasatinib Or Venetoclax To Improve Responses In Children With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (ALL) Or Lymphoma (T-LLY) Or Mixed Phenotype Acute Leukemia (MPAL)

This is a clinical trial testing whether the addition of one of two chemotherapy agents, dasatinib or venetoclax, can improve outcomes for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma or mixed phenotype acute leukemia.
Primary Objective
* To evaluate if the end of induction MRD-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231.
* To evaluate if the end of induction MRD-negative rate is higher in patients with ETP or near-ETP ALL treated with venetoclax compared to similar patients treated with 4-drug induction on AALL1231.
Secondary Objectives
* To assess the event free and overall survival of patients treated with this therapy.
* To compare grade 4 toxicities, event-free survival (EFS) and overall survival (OS) of patients treated with this therapy in induction and reinduction to toxicities of similar patients treated on TOT17.

开始日期2024-12-27

申办/合作机构

St. Jude Children's Research Hospital, Inc.

[+1]

NCT06210750

/ Withdrawn临床2期IIT

A Randomized Phase 2 Trial to Evaluate the Efficacy of BCL-2 Inhibitor Therapy With Chemotherapy Compared to Chemotherapy Alone in Adult Patients With Newly Diagnosed T-Cell ALL and T-Cell Lymphoblastic Lymphoma

This phase II trial tests the safety and effectiveness of giving chemotherapy with or without venetoclax and/or navitoclax for the treatment of patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax and navitoclax are in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. They may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving chemotherapy with or without venetoclax and/or navitoclax may be effective treatments for patients with newly diagnosed T-ALL or T-LBL.

开始日期2024-08-09

申办/合作机构

National Cancer Institute

100 项与奈拉滨相关的临床结果

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100 项与奈拉滨相关的转化医学

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100 项与奈拉滨相关的专利（医药）

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项与奈拉滨相关的文献（医药）

2025-07-29·LEUKEMIA & LYMPHOMA

Single-center experience with nelarabine, etoposide, and cyclophosphamide in adults with relapsed/refractory T-acute lymphoblastic leukemia/lymphoma

Article

作者: Olin, Rebecca L. ; Damon, Lloyd E. ; Sayre, Peter H. ; Lo, Mimi M. ; Andreadis, Charalambos B. ; Ferng, Timothy T. ; Martin, Thomas G. ; Lee, Jerry C. ; Othman, Tamer ; Gaensler, Karin M. L. ; Logan, Aaron C. ; Smith, Catherine C.

2025-07-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Connectivity-map unveils Gemcitabine's efficacy in overcoming nelarabine resistance in T-cell acute lymphoblastic leukemia

Article

作者: Zhou, Zitao ; Chen, Suchang ; Zhang, Luyong ; Wei, Min ; Liu, Bing ; Ximei Wu ; Gao, Jingjing ; Lin, Chunxu ; Wang, Hui

Resistance to Nelarabine, the primary FDA-approved therapy for relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL), is a major obstacle in this high-risk pediatric malignancy. To identify alternative therapies, we have developed two nelarabine-resistant T-ALL cell models and utilized the Connectivity Map (CMap) database to screen for compounds reversing resistance-associated expression profiles., Among the inhibitors screened, gemcitabine emerged as a lead candidate by inhibiting cell proliferation, inducing apoptosis, and suppressing DNA replication in resistant T-ALL cells. RNA sequencing revealed global transcriptomic changes in cells treated with gemcitabine, which were further validated by qRT-PCR. Critically, gemcitabine effectively controlled bone marrow tumor growth in an NSG mouse model with good tolerability. These findings highlight the potential of gemcitabine as a promising therapeutic strategy to overcome nelarabine-resistance in T-ALL.

2025-07-01·AMERICAN JOURNAL OF HEMATOLOGY

Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring

Review

作者: Kantarjian, Hagop ; Jabbour, Elias

ABSTRACT:

Disease Overview:

Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells arising in the bone marrow and extramedullary sites. While it is the most common pediatric cancer, ALL is a rare disease overall, with approximately 6500 new cases diagnosed in the United States, in 2024. Current treatment relies on multiagent chemotherapy administered over 2–3 years, resulting in long‐term survival in 80%–90% in pediatric patients compared to 40%–50% in adult patients, depending upon patient‐ and disease‐specific characteristics.

Philadelphia Chromosome‐Positive B‐Cell ALL:

Historically considered a poor risk ALL subtype, the treatment and outcome of Philadelphia chromosome (Ph)‐positive B‐cell ALL were drastically changed with the advent of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The combination of a TKI with a backbone of multiagent chemotherapy, or more recently blinatumomab, is the mainstay of therapy, resulting in 5‐year survival rates of 80+%. Achieving a complete molecular remission, particularly by next generation sequencing, is an important prognostic indicator, which may identify patients who may avoid allogeneic stem cell transplantation (SCT).

Philadelphia Chromosome‐Negative B‐Cell ALL:

The treatment approach for patients with Ph‐negative B‐cell ALL was historically composed of a chemotherapy backbone (either pediatric‐inspired, or Hyper‐CVAD based). Novel agents including inotuzumab ozogamicin and blinatumomab are being incorporated into these regimens to improve the rates of measurable residual disease negativity and long‐term outcomes. While differences in long‐term survival rates differ between age groups, such as adolescents and young adults compared to older adults (≥ 60 years), with these immunotherapy‐chemotherapy regimens, the 4‐year survival rates have improved to 80%–85% among patients who are able to receive these treatments. Elderly patients represent a difficult population to treat due to poor chemotherapy tolerance, high‐risk disease features, and increased risk of developing therapy‐related myeloid neoplasms. The use of inotuzumab ozogamicin and blinatumomab in lieu of intensive chemotherapy in this population has improved safety and efficacy in patients ≥ 60 years old. Clinical trials incorporating chimeric antigen receptor (CAR) T‐cell therapy into treatment for older patients are in progress.

T‐Cell ALL:

Combination chemotherapy regimens incorporating pegylated asparaginase and nelarabine are the standard for patients with T‐cell ALL. Early T‐cell precursor (ETP) ALL is a high‐risk subgroup for which allogeneic SCT should be considered. Inclusion of the BCL‐2 inhibitor venetoclax into treatment for patients with ETP‐ALL may be beneficial and is currently being investigated.

Salvage Therapy:

Several therapies are approved as single agents in the salvage setting. However, the best outcomes are obtained with combination therapy including chemo‐ and immuno‐ therapies followed by CAR T‐cell consolidation and allogeneic SCT. Clinical trials optimizing this approach are ongoing.

项与奈拉滨相关的新闻（医药）

2025-10-27

·崔兴医生

儿童复发/难治性急性T淋巴细胞白血病的潜在生物学机制、治疗挑战及新观点

1 Abstract 摘要儿童复发/难治性急性T淋巴细胞白血病（R/R T-ALL）仍是临床治疗的重大难题。对于疾病复发或对初始治疗产生耐药的患儿，尽管已经采取了积极的治疗，其预后情况依然极差，生存率常低于25%。T-ALL具有遗传、表观遗传及转录后异质性，还存在器官和微环境特异性（如中枢神经系统特异性），这些因素共同驱动了疾病进展和治疗耐药。因此，为降低治疗毒性、改善预后，针对R/R T-ALL潜在生物学机制的个体化精准医疗策略尤为重要。本研究系统综述了当前对儿童T-ALL生物学复杂性的理解，探讨其临床转化价值，并强调需通过创新治疗手段提升R/R T-ALL的疗效。目前具有应用前景或已显示明确疗效的新兴治疗手段包括：蛋白酶体抑制剂、BCL-2拮抗剂，以及针对JAK（适用于JAK-IL-7R驱动的T-ALL病例）、ABL和SRC家族酪氨酸激酶（适用于LCK激活的T-ALL病例）、MEK或PI3K-mTOR通路的抑制剂。此外，MYC靶向药物、DNA去甲基化剂、组蛋白去乙酰化酶抑制剂、剪接调节剂，以及针对T-ALL代谢脆弱性的药物，也均是潜在的药物干预方向。免疫治疗尤其是靶向CD7及其他标志物的CAR-T细胞产品和生物制剂如靶向CD38的药物正处于研发阶段，且关注度持续提升。这些药物应当依据遗传学、表观遗传学及转录后水平，融入精准医疗的联合治疗方案中，这一点对于优化风险分层和降低耐药风险至关重要；同时，采用人工智能和机器学习的新方法或许能够加速科学研究发现，并优化治疗框架的设计与实施。复发/难治性疾病：儿童T-ALL重大临床挑战儿童复发/难治性急性T淋巴细胞白血病（R/R T-ALL）仍是儿童肿瘤领域的重要挑战。尽管一线治疗不断进展，患者整体生存率得到显著提高，但复发或初始治疗耐药患儿的预后仍然较差，生存率常低于25%。难治性疾病通常发生在一线治疗期间，具体表现为原发难治性疾病或诱导治疗失败，也可能在疾病复发时出现；在一线治疗方案下，T-ALL患儿发生原发难治性疾病的概率是B细胞急性淋巴细胞白血病（B-ALL）患儿的3倍，这类病例占所有T-ALL病例的10%；即使采用了包括造血干细胞移植（HSCT）在内的强化治疗方案，这种早期治疗失败仍然预示着不良预后。在目前的治疗策略下，ALL的总体复发率约为8%至20%，其中T-ALL的复发率持续高于B-ALL；此外，T-ALL的复发时间通常更早，并且常常累及中枢神经系统（CNS）。复发性B-ALL的治疗已取得显著进展，通过引入双特异性抗体如贝林妥欧单抗等免疫治疗药物，即使是侵袭性强或早期复发的病例，其总生存率（OS）也可提升至80%；相比之下，在1996年至2014年期间参与儿童肿瘤协作组（COG）一线ALL试验的复发性T-ALL患儿中，复发后的5年总生存率仅为35.5±3.3%，且许多患者未能达到缓解状态。长期以来，复发性T-ALL被视为预后不良的重要因素，无论复发时间或部位，均被列为需要包括HSCT在内的强化治疗的明确指征。尽管针对R/R T-ALL已开展多种新型药物的临床试验（见表1），但治疗进展仍然有限；奈拉滨作为脱氧鸟苷类似物阿糖鸟苷（ara-G）的前体药物，在体外实验中表现出对T-ALL的特异性活性，然而在R/R T-ALL的II期临床试验中，其单药疗效相对有限，即使与其他化疗药物联合使用，疗效也未见显著提升；近期霍顿等人的研究探讨了在复发性ALL治疗中添加蛋白酶体抑制剂硼替佐米的效果，结果显示复发性T-ALL患者的二次完全缓解率达到68%，这一结果令人鼓舞，但在随机一线COG AALL1231试验中，硼替佐米对新诊断T-ALL患儿的无事件生存率（EFS）和OS均无显著影响，这与在T淋巴母细胞淋巴瘤中的研究结果不一致；目前在高危复发的IntReALL-2010试验中，一项评估硼替佐米联合治疗效果的随机研究正在进行，初步结果预计即将公布。鉴于当前积极治疗下复发性T-ALL的预后仍然不佳，针对首次复发患者制定个体化精准医疗策略显得尤为重要。具体而言，对于存在IL-7R或JAK-STAT信号通路激活的患者，JAK抑制剂可能产生良好疗效；而对于存在LCK激活或ABL家族融合的患者，达沙替尼等酪氨酸激酶抑制剂可能带来临床获益。在靶向治疗方面，BCL-2/BCL-X蛋白家族抑制剂维奈克拉和Navitoclax在临床前研究中显示出显著活性，基于此开展的Ⅰ期临床试验采用两药联合方案治疗R/R ALL患者，取得了60%的完全缓解率，其中T-ALL患者的应答尤为突出。虽然Navitoclax近期因商业决策撤市，但新一代BCL-XL抑制剂及BCL-2/BCL-XL双靶点抑制剂有望填补这一治疗空白。例如，LP-118在慢性淋巴细胞白血病（CLL）的临床前研究中表现良好，目前正在开展涵盖ALL患者的Ⅰ期/Ⅱ期临床试验。此外，DT2216、利沙托克拉（APG-2575）、Pelcitoclax（APG-1252）、S65487和索托克拉（BGB-11417）等药物也在急性髓系白血病（AML）、CLL和其他恶性肿瘤中开展临床研究，但这些药物在R/R T-ALL中的应用潜力仍需进一步验证。值得注意的是，如下文所述，免疫治疗策略在T-ALL领域也展现出日益重要的应用前景。为制定最优的R/R T-ALL精准治疗策略，深入研究疾病的潜在生物学机制至关重要。后续章节将系统总结目前对儿童T-ALL的分子特征认知，并探讨这些发现对复发/难治性疾病治疗的临床转化价值。遗传学机制 T-ALL的核心特征在于主转录因子（TF）癌基因的失调，这种失调引发细胞分化阻滞，进而调控白血病细胞的整体基因表达谱和免疫表型特征。这类定义疾病亚型的分子病变能够驱动胸腺细胞异常表达原本不存在的转录因子如TLX1、TLX3，或导致发育关键转录因子如TAL1持续过表达。尽管T-ALL因高度遗传异质性导致分子机制解析困难，但仍可根据分化阻滞程度分为三个主要亚型：前皮质型（即早期T细胞前体急性淋巴细胞白血病，ETP-ALL）、皮质型（以CD1a阳性为特征）和皮质后型（常伴有TAL1/LMO病变）。 RAG蛋白的脱靶活性被证实与这些驱动性病变的致突变过程密切相关。RAG诱导的染色体断裂可使具有强发育活性的增强子如调控TCRA/B/D和BCL11B的增强子与癌性转录因子发生易位。此外，非编码驱动突变同样可激活这些转录因子——例如，非编码体细胞突变通过引入MYB结合位点形成超级增强子驱动TAL1异常表达，或通过构建新启动子激活LMO2。值得注意的是，这些突变很可能是疾病的早期启动事件，部分突变甚至在患者出生时即可检测到。近期一项针对1300余例儿童T-ALL样本的里程碑研究通过全基因组和转录组测序，将T-ALL划分为15个遗传学亚型。该研究不仅证实了全基因组测序的价值（约60%患者存在非编码驱动病变），还细化了过去已知的亚组并发现了新的预后相关亚型。具体而言： TAL/LMO亚型可进一步分为TAL1 DP样（CD4+CD8+，因RAG1/2高表达得名）和TAL1αβ样（TRAC过表达，因TCRαβ重排而分类）；携带KMT2A、TLX3和MLLT10突变的亚型具有前体T细胞特征；HOXA9-TCR、TLX1、NKX2-1和TAL1 DP样亚型则呈现增殖性双阳性T细胞特征；LMO2亚型与诱导治疗结束时微小残留病（MRD）阳性相关，可细分为LMO2γδ样（类似γδ/效应T细胞）和STAG2/LMO2（具有髓系特征）。该研究还对ETP-ALL分类做出重要修正：ETP-ALL富集两类突变，一是影响造血因子（RUNX1、ETV6）和表观遗传调控因子（EZH2、SUZ12）功能的突变，二是激活信号通路（如IL-7R-JAK-STAT、RAS-RAF-MEK-ERK）的突变。虽然成人与儿童ETP-ALL基因型相似，但儿童极少出现DNMT3A突变。这些遗传改变可能直接影响治疗应答，如STAT5突变、PRC2功能缺失、BCL2依赖和HOXA过表达均与疗效相关。单细胞分析显示ETP-ALL群体具有表型可塑性和异质性干细胞状态，这与复发风险及微环境免疫应答受损密切相关。解析复发机制需要深入理解基因组驱动因素与疾病结局的关联，但由于R/R T-ALL发病率低导致临床试验样本量不足，不同预后标志物的意义仍存争议。此外，风险适应性治疗的开展也显著影响了ETP-ALL免疫表型等生物标志物的预后价值。目前研究表明：预后较好的群体包括：TAL1 DP样（伴RPL10突变）、TLX1阳性及携带NOTCH1（除外内含子SNV和基因内缺失）、FBXW7或PHF6突变的患者。预后较差的群体包括：TAL1αβ样、STAG2/LMO2亚组及携带PTEN、RAS、EZH2、TP53突变的患者特别值得注意的是，诱导治疗失败且携带TAL1非编码驱动突变、MYC激活病变和/或RAS通路突变（TMR基因型）的患者预后极差，5年总生存率不足25%，这使得MYC靶向治疗在该群体中具有特殊意义。目前MYC降解剂（如靶向CRL4泛素连接酶的A80.2HCl）和细胞穿透肽Omomyc已在临床前及Ⅰ期试验中显示出良好活性和安全性，针对MYC合成致死靶点（如BET家族蛋白BRD4或极光激酶家族）的新化合物也进入早期临床研究。值得关注的是，部分突变仅在复发时被检测到。例如约20%的T-ALL复发病例存在NT5C2突变，该突变导致对维持治疗药物巯基嘌呤耐药。有趣的是，NT5C2、PRPS1、NR3C1和TP53等基因的突变可由巯基嘌呤及其他硫代嘌呤类药物诱导产生，因此在治疗过程中识别此类病变有助于临床医生实时调整维持治疗方案。表观遗传学机制表观遗传学在T-ALL发病机制中的关键作用已得到充分证实。除了遗传异常，胸腺细胞的表观遗传失调同样是疾病发生的重要驱动因素。尽管PHF6、IDH1/2、DNMT3A等表观遗传调控因子的基因组改变与疾病复发密切相关，但本部分将重点探讨表观遗传异常本身在疾病分型和治疗指导中的潜在价值。在DNA甲基化研究领域，过去十年的进展揭示了T-ALL中存在的特征性甲基化模式。通过全基因组甲基化测序，研究人员发现了从低甲基化到高甲基化的连续谱系，这一梯度变化反映了疾病发展的不同阶段。值得注意的是，基于CpG岛甲基化表型（CIMP）的分类系统与临床预后显著相关，其中CIMP-low亚型 consistently 显示与不良预后相关。 DNA甲基化亚型与细胞增殖历史的关联为疾病发生机制提供了新见解。研究发现，CIMP-low/COSMe-I亚型与短期增殖史和特定基因异常（如STIL::TAL1融合、6q缺失）相关，而CIMP-high亚型则与长期增殖史及不同组基因表达特征相关。这种差异提示白血病可能存在多条发展路径（图1）。临床转化研究方面，北欧学者通过对348例T-ALL样本的分析证实，将CIMP分类与微小残留病（MRD）状态结合可显著改善风险分层效能。鉴于DNA甲基化分类在中枢神经系统肿瘤中已获WHO认可，其在T-ALL诊断体系中的整合应用前景广阔。治疗策略上，针对T-ALL普遍存在的高甲基化特征，去甲基化药物展现出潜在价值。虽然DNMT抑制剂在T-ALL中的临床证据尚有限，但临床前研究显示地西他滨可诱导全基因组低甲基化并改善生存结局。特别是其与BCL-2抑制剂维奈克拉的联合方案，在难治复发T-ALL中显示出协同作用，值得通过前瞻性临床试验验证。组蛋白修饰研究领域同样取得重要突破。组蛋白密码的异常调控在T-ALL发病机制中扮演关键角色，18株T-ALL细胞系的组蛋白翻译后修饰图谱揭示了显著的异质性。H3K27me3水平的差异与PRC2复合物突变密切相关，而组蛋白修饰调控因子在复发时的富集突变，进一步证实了表观遗传失调在治疗抵抗中的重要性。针对组蛋白修饰的治疗策略呈现多样化发展。HDAC抑制剂、组蛋白甲基转移酶抑制剂等表观遗传药物在临床前模型中显示出抗白血病活性，但其临床应用仍需克服耐药性问题。联合用药策略和新型选择性抑制剂（如组蛋白去甲基化酶抑制剂）的开发，为改善疗效提供了新方向。综上所述，表观遗传机制在T-ALL生物学中具有核心地位，其分类体系为精准医疗提供了重要依据。未来研究需着重探索表观遗传标志物在风险分层中的临床应用价值，并开发针对表观遗传靶点的新型治疗策略。通过整合多组学数据和先进计算模型，有望加速表观遗传指导的个体化治疗方案的实现。转录后调控异常 RNA稳态失调（包括多聚腺苷酸化、剪接和翻译）可促进疾病进展和药物耐药。2004年，De Keersmaecker等人首次在T-ALL中，发现了核糖体亚基（RPL5、RPL10）和多聚腺苷酸化因子CNOT3的突变。其中，RPL10 R98S突变可破坏核糖体生成，引发氧化应激和代谢改变，并通过BCL-2和JAK-STAT信号通路促进白血病细胞存活。CNOT3突变包括截短突变和位于第5外显子剪接供体位点的错义突变，这些突变可导致剪接缺陷和mRNA表达降低，提示CNOT3在T-ALL中发挥抑癌作用。剪接失调是白血病领域研究最多的转录后调控机制（图2），其可影响关键信号通路、细胞周期、DNA损伤应答及凋亡。在T-ALL中，对糖皮质激素敏感和耐药样本的分析显示出不同剪接模式，这提示剪接调控存在全局异常。研究发现，关键剪接因子（SF）（如U2AF1、HNRNPA1）的表达显著改变；能量代谢相关基因（包括糖酵解酶编码基因PFKL、PFKM，泛醌-细胞色素c还原酶成员编码基因UQCRC1、UQCRC2，以及NADH脱氢酶亚基编码基因）在糖皮质激素耐药T-ALL中表现出差异剪接，这些剪接改变涉及内含子滞留和选择性剪接位点选择。此外，具有致癌作用的转录本（如蛋白酶伴侣PSMG1和DNA损伤应答信号激酶CHK2的转录本）在T-ALL中也存在剪接异常。抑制U2剪接体复合物成分SF3B1，可破坏CHK2和PSMG1的剪接，并与CHK2抑制剂和蛋白酶体抑制剂协同作用，抑制T-ALL细胞生长。E7820和吲地司坦可通过DCAF15介导剪接调控因子RBM39降解，在R/R AML中无论是单药治疗还是联合化疗，均显示出临床应答，但毒性问题仍需解决。吲地司坦可导致T-ALL细胞广泛剪接缺陷，诱导细胞死亡并延缓体内T-ALL生长。目前，针对影响剪接的激酶（如CLK、SRPK1）的抑制剂，正在实体瘤和髓系恶性肿瘤中开展临床试验，但其与疾病相关通路抑制剂（如蛋白酶体抑制剂、凋亡抑制剂）联合治疗R/R T-ALL的潜力，仍需进一步研究。 T-ALL中其他转录后调控机制的研究相对有限。目前研究人员已发现超过170种RNA修饰，其中RNA甲基化（如N6-甲基腺苷，m6A）和RNA脱氨基（A-to-I转换）可能在T-ALL病理生理中发挥作用。NOTCH1和IRF8可发生m6A修饰，这种修饰会影响其表达；m6A阅读蛋白IGF2BP2可结合甲基化NOTCH1 mRNA，增强其稳定性和翻译效率，从而促进T-ALL进展和耐药。使用JX5抑制IGF2BP2可降低肿瘤负荷，这提示靶向m6A相关成分可能成为T-ALL的治疗方向。ADAR1是一种RNA结合蛋白和脱氨酶，可催化RNA的A-to-I编辑，其在T-ALL细胞中过表达，能支持白血病干细胞自我更新和化疗耐药。ADAR1通过增强RNA编辑，减少胞质双链RNA（dsRNA），从而抑制干扰素生成和干扰素刺激基因（ISG）表达，最终抑制细胞凋亡。基于FTO去甲基酶和ALKBH5等分子的广泛促癌作用，靶向RNA甲基化稳态（尤其是这些“擦除酶”的活性）在T-ALL中也值得关注。综上，靶向转录后调控以改善R/R T-ALL预后，是一个具有潜力的治疗方向，该方向仍需进一步研究探索。信号通路异常胸腺中T细胞发育由NOTCH、IL-7R、前T细胞受体（preTCR）和TCR等信号通路调控，这些通路的异常激活常导致T-ALL发生发展（图3）。大多数T-ALL病例存在NOTCH通路突变。尽管NOTCH1基因内缺失（第3~27外显子或第16~27外显子）和内含子SNV与总生存率和无事件生存率降低相关，但在无RAS、PI3K通路（PTEN、PIK3CA、PIK3R1）、TP53、DNMT3A、IDH1/2和IKZF1异常的情况下，NOTCH通路突变通常提示低风险。然而，NOTCH抑制剂的靶向毒性（如胃肠道毒性）和疗效限制，使其在R/R T-ALL中的应用面临挑战。目前，评估γ分泌酶抑制剂（NOTCH抑制剂）在T-ALL患者中最佳剂量和R/R T-ALL疗效的临床试验结果，尚未公布。有趣的是，近期临床前研究显示，联合抑制类泛素化（neddylation）通路，可预防γ分泌酶抑制剂导致的肠道毒性，并延长白血病小鼠的生存期。来源于皮质胸腺细胞的白血病原始细胞表达preTCR，该受体为发育中的CD4-CD8双阴性胸腺细胞提供存活和增殖信号，支持TCRA基因重排及TCRαβ CD4-CD8双阳性T细胞形成。preTCR信号在白血病原始细胞中仍具有功能活性。preTCR通路中的关键激酶LCK磷酸化，在对糖皮质激素诱导治疗应答不佳的T-ALL患者中富集。研究显示，酪氨酸激酶抑制剂（TKI）达沙替尼可使LCK去磷酸化并诱导细胞周期阻滞；达沙替尼与地塞米松具有协同作用，可逆转糖皮质激素耐药并在体内抑制T-ALL细胞增殖。两项独立体外研究表明，约30%~40%儿童T-ALL患者对纳摩尔浓度的达沙替尼敏感。基于这些临床前结果，早期临床试验HEM-iSmart-B和NCT06686108正在评估地塞米松、达沙替尼联合BH3模拟物维奈克拉的疗效。近期临床前研究还提示，以地塞米松和达沙替尼为基础，联合mTORC1抑制剂替西罗莫司具有协同作用。在一线治疗中，针对ETP-ALL或类ETP-ALL患者，研究人员将评估标准诱导治疗联合（或不联合）维奈克拉的效果；针对其他T-ALL患者，将评估联合（或不联合）达沙替尼的效果。未来针对LCK的临床治疗策略可能采用蛋白降解剂（PROTAC），该类药物在体内已显示出持续抑制LCK的效果。对于存在激酶激活病变（如ABL1/2、PDGFRA/B或TYK2基因重排）的T-ALL患者，酪氨酸激酶抑制剂也可能具有临床获益。新兴临床数据表明，在常规化疗基础上加入激酶抑制剂，可能提高部分患者的治疗应答。为前瞻性评估这一策略在T-ALL中的效果，ALLTogether 1试验中，新诊断且存在上述病变的T-ALL患者将接受伊马替尼治疗；Ⅲ期临床试验NCT03007147也将评估伊马替尼联合常规治疗，在新诊断费城染色体阳性急性淋巴细胞白血病中的疗效。 RAS通路病变（NRAS和KRAS功能获得性突变，或NF1和cCBL功能失活性突变/缺失）是新诊断和复发性ALL的常见驱动因素，发生率为12%~30%。在部分治疗方案中，RAS通路突变可用于识别治疗失败风险较高的T-ALL患者。多种RAS通路抑制剂已进入临床阶段，但由于突变常为亚克隆性，其获益仍需验证。临床前模型显示，MEK抑制剂司美替尼与地塞米松在ALL中具有协同作用；另一MEK抑制剂曲美替尼联合地塞米松的疗效，将在Hem-iSmart试验中评估。 IL-7R功能获得性突变及信号效应分子（尤其是JAK-STAT，还包括PI3K-AKT-mTOR和MEK-ERK通路成员，均为IL-7R下游激活通路）病变，可影响超过40%的T-ALL病例。野生型IL-7R高表达也可驱动T-ALL发生，且IL-7可促进表达IL-7R的T-ALL病例疾病进展。对R/R T-ALL而言，IL-7R信号可促进糖皮质激素耐药（该耐药可通过抑制下游信号通路逆转），且IL-7R突变与复发病例的极高风险相关。 JAK1/2抑制剂鲁索替尼可抑制T-ALL细胞增殖和存活，即使在无IL-7R或JAK-STAT通路突变但表达IL-7R的病例中，也显示出显著疗效。HEM-iSMART-C试验将评估鲁索替尼联合维奈克拉、地塞米松、环磷酰胺和阿糖胞苷的疗效；另一项正在招募患者的Ⅰ/Ⅱ期临床试验，将评估鲁索替尼联合西达本胺治疗T-ALL的效果。其他JAK/STAT抑制剂（如托法替尼）在临床前模型中显示出有效性，尤其对存在IL7R、JAK1和JAK3突变的病例。 PI3K-Akt-mTOR通路持续激活在T-ALL中较为常见，可驱动化疗耐药（尤其是糖皮质激素耐药）和复发。尽管PI3K和/或mTOR抑制剂（如达可替尼、艾代拉利司、度维利塞）已获批用于其他癌症，但在T-ALL中的应用仍处于实验阶段。值得注意的是，目前尚无评估PI3K抑制剂在T-ALL中疗效的临床试验，其安全性和有效性仍需进一步研究。相比之下，近期已有多项Ⅰ期或Ⅰ/Ⅱ期临床试验，评估mTOR抑制剂依维莫司和替西罗莫司在R/R白血病/淋巴瘤（包括T-ALL）中的疗效。仅替西罗莫司剂量递增试验NCT01614197公布了结果：无患者出现剂量限制性毒性，但不同剂量组的微小残留病水平仍较高；其余研究结果将为mTOR抑制剂的治疗潜力提供更全面的参考。除超过70%的T-ALL病例存在CDKN2A/B基因失活外，上述多数信号通路均可上调CDK4/6，推动细胞从G1期进入S期。临床前研究证实，CDK4/6抑制剂帕博西尼和瑞博西尼（尤其与糖皮质激素联合时）具有疗效，这推动了多项Ⅰ期儿童临床试验的开展，以评估瑞博西尼或帕博西尼联合化疗的效果。代谢异常代谢谱失调是T-ALL发病机制和治疗耐药的重要基础。T-ALL原始细胞同时上调三羧酸循环（TCA）和氧化磷酸化（OxPhos），还会增加糖酵解水平，这些通路为疾病进展所需的生物合成和能量代谢过程提供支持。 T-ALL的致癌驱动因子（如NOTCH1、RUNX2、AKT）或抑癌基因缺失（如PTEN），均与T-ALL发病或治疗耐药过程中的代谢重编程相关。例如，NOTCH1信号与谷氨酰胺代谢增强相关，可促进白血病发生，而抗NOTCH1治疗可导致代谢停滞；PTEN缺失可通过增强糖酵解水平缓解这种代谢危机，从而规避抗NOTCH1治疗的抑制作用。T-ALL原始细胞通过动态重编程核心代谢过程以维持生物合成需求，这是其产生疾病耐药和逃避治疗的关键机制。尽管致癌驱动因子在T-ALL代谢中的作用近期才被认识，但甲氨蝶呤和L-门冬酰胺酶作为靶向代谢的T-ALL经典治疗药物，已应用多年。甲氨蝶呤（抗叶酸药物）通过抑制一碳代谢阻碍核苷酸合成；L-门冬酰胺酶通过降解核苷酸合成所需的天冬酰胺发挥作用。尽管这些药物疗效明确，但代谢重编程介导的耐药机制，已导致侵袭性R/R T-ALL的发生。具体而言，甲氨蝶呤耐药与叶酸多谷氨酸合成酶基因突变（该酶负责甲氨蝶呤的多谷氨酸化）、甲氨蝶呤靶点二氢叶酸还原酶扩增及甲氨蝶呤转运障碍等因素相关；而L-门冬酰胺酶耐药机制则包括天冬酰胺合成酶表达增加、HAP1缺失及后续钙蛋白酶-1-Bid-半胱天冬酶-3/12通路下调、Wnt信号异常（通过GSK3依赖的泛素化/降解活性规避天冬酰胺耗竭），以及胱氨酸/谷氨酸转运体SLC7A11/xCT表达上调。近期，大量临床前研究正在探索靶向代谢的药物，以克服R/R T-ALL。例如，体外实验中对甲氨蝶呤耐药的细胞，对新型丝氨酸羟甲基转移酶（SHMT）抑制剂SHIN2敏感性增强；另一SHMT1/2抑制剂RZ-2994在甲氨蝶呤耐药T-ALL中显示出疗效，可诱导细胞周期停滞于S/G2期，且抑制SHMT1/2可在体内延缓白血病进展。此外，T-ALL代谢谱可影响L-门冬酰胺酶敏感性。PTEN缺陷细胞糖酵解反应增强，且伴随AKT过度激活，这两者共同导致L-门冬酰胺酶耐药。有趣的是，抑制自噬可通过ROS-p53正反馈环，增强L-门冬酰胺酶的细胞毒性。综上，适应性代谢重编程通过规避现有化疗药物作用，促进R/R T-ALL发生。尽管这些传统治疗药物的疗效逐渐减弱，但近期临床前研究已发现多个可干预的代谢靶点，有望恢复耐药T-ALL对治疗的敏感性。尽管这些机制仍需进一步细化，但新型肿瘤代谢治疗药物在R/R T-ALL中展现出良好应用前景。微环境调控癌症进展不仅由细胞内在改变驱动，还依赖于肿瘤细胞与其周围微环境的动态相互作用。在微环境中，细胞可受多种因素影响，包括可溶性因子、细胞间相互作用、细胞外基质、缺氧及代谢刺激。目前多数研究聚焦于骨髓（BM）微环境（造血干细胞起源地）。通过先进的三维成像研究，研究人员得知骨髓中存在多个微解剖位点和细胞类型，其分布与造血干细胞的功能异质性相关。与造血干细胞不同，近期研究发现T-ALL细胞具有高度动态行为，在骨髓空间内无偏好性亚定位。此外，对T-ALL患者骨髓细胞的单细胞测序显示，在部分病例中，多能祖细胞可能是疾病起源细胞。从骨髓出发，白血病前克隆迁移至胸腺，在那里积累更多突变，最终导致细胞失控生长增殖，引发白血病（图4）。霍金斯等人研究发现，化疗后骨髓中白血病原始细胞的活动性增强，这提示T-ALL细胞甚至可能不需要骨髓微环境的保护作用。胸腺、骨髓、血液、淋巴结和中枢神经系统是影响T-ALL发生发展及治疗耐药的主要器官。例如，异种移植实验显示，ETP-ALL细胞对维奈克拉的敏感性具有组织微环境依赖性：在脾脏中，维奈克拉单药治疗耐药与分化因子上调及BCL2下调相关，这与ETP-ALL比分化程度更高的T-ALL更依赖BCL2的特征一致。 “胸腺自主性”即无需骨髓前体细胞输入即可实现胸腺细胞自我更新，在T细胞分化调控中发挥关键作用，也可能促进T-ALL的发生和增殖。趋化因子受体CXCR4在T-ALL中广泛过表达，其配体CXCL12是T-ALL体内定植和进展的必要条件。胸腺内白血病进展导致CXCL12消耗增加，浓度降低，使T-ALL细胞离开胸腺，定植于其他产生CXCL12的微环境如骨髓。靶向CXCL12-CXCR4轴可能是T-ALL治疗的重要策略。T-ALL细胞还高度依赖IL-7（正常T细胞发育的关键细胞因子）。小鼠模型中IL-7缺失可减少T-ALL对髓外器官的浸润，这提示靶向IL-7信号可能对T-ALL具有治疗作用。靶向IGF1/IGF1R轴是另一潜在治疗方向：胸腺树突状细胞可激活T-ALL细胞中的IGF1R信号，促进白血病细胞存活；此外，IGFBP7与IGF1R持续激活相关，且已知可诱导T-ALL对长春新碱耐药。因此，靶向微环境介导的IGF1R激活，可能成为T-ALL包括R/R病例的治疗靶点。研究显示，CCL19通过CCR7、CXCL12通过CXCR4介导的信号，在T-ALL中枢神经系统浸润中发挥关键作用。下文将详细探讨中枢神经系统在R/R T-ALL中的重要性，无论如何，靶向这两个信号轴的药物均具有治疗意义。过去数十年中，研究人员对T-ALL骨髓微环境的理解不断深入，已识别出多个可药物靶向的靶点。另一方面，T-ALL细胞具有高度活动性与正常T细胞相似，这提示需明确是否可通过靶向治疗特异性抑制白血病细胞与微环境的相互作用。未来还需研究T-ALL细胞如何通过不同髓外微环境迁移，为靶向治疗提供新方向。中枢神经系统受累 T-ALL的中枢神经系统复发率高于B-ALL，但其潜在机制差异尚不明确。目前中枢神经系统导向治疗虽总体有效，但可导致严重的急性和慢性神经毒性，包括癫痫、卒中样综合征，以及长期学习记忆障碍——20%~40%幸存者存在不良神经认知结局。中枢神经系统受累的诊断和治疗面临独特挑战，这源于中枢神经系统微环境的特殊性（图5）。目前基于脑脊液（CSF）样本细胞形态学的诊断方法，严重低估了初诊时中枢神经系统受累的发生率，且传统CNS-1/2/3分期无法准确分层T-ALL的复发风险。近期采用的脑脊液流式细胞术检测显示，亚临床中枢神经系统浸润的发生率远高于此前认知。这些发现支持对所有T-ALL患者进行中枢神经系统导向治疗，但要实现治疗的风险适应性调整，仍需开发更优的中枢神经系统复发风险预测生物标志物。治疗方案需在有效清除中枢神经系统白血病细胞与降低神经毒性风险之间取得平衡，尤其对于大脑仍在发育的儿童患者。颅脑放疗（CRT）是最具争议的治疗手段之一，由于其可导致继发性肿瘤、内分泌疾病和神经毒性发生率显著升高，目前临床应用已大幅减少。对COG T-ALL试验（AALL0434和AALL1231）的近期分析显示，CNS-2状态患者接受颅脑放疗无额外获益；对UKALL2003和UKALL2011试验中T-ALL患者的进一步分析，则支持CNS-3状态患者也可省略颅脑放疗。为替代颅脑放疗，已证实可降低中枢神经系统复发率的全身药物包括地塞米松、卡皮齐方案甲氨蝶呤和奈拉滨。目前最受关注的是奈拉滨——在AALL0434试验中，奈拉滨联合治疗方案似乎显著降低了中枢神经系统复发率，但两组间全身治疗的其他差异也可能对预后改善有贡献。该试验中所有CNS-3状态患者均接受了颅脑放疗，尽管中枢神经系统复发率降低，但总生存率未受影响。因此，仍需独立验证上述结果，开发无需颅脑放疗的最佳联合方案，并明确奈拉滨应答的生物标志物。值得注意的是，奈拉滨可能导致严重神经毒性，但在一线治疗中发生率低于复发治疗，且通过间歇给药和严格剂量限制或可降低风险。尽管优化现有治疗方案具有重要意义，但要实现疾病治疗的突破性进展，仍需开发替代传统药物的新型治疗手段。中枢神经系统微环境与骨髓微环境存在显著差异，这可能意味着独特的治疗脆弱性。另一个重要考量是药物能否穿透中枢神经系统并达到有效治疗浓度。尽管面临这些挑战，已有多种药物在中枢神经系统T-ALL临床前模型中显示出靶向浸润和存活机制的潜力，包括达沙替尼和MEK/PI3K抑制剂。T-ALL的双特异性抗体和细胞治疗仍处于早期阶段，其对中枢神经系统疾病的疗效尚未明确。令人欣慰的是，现有证据表明，在成人血液系统疾病中，CAR-T细胞相关神经毒性的严重程度与中枢神经系统受累无显著关联。免疫系统与免疫治疗尽管研究人员对ALL免疫微环境及免疫细胞如何调控白血病发生和治疗耐药的理解仍不充分，但B-ALL治疗已因高效免疫治疗（单克隆抗体、双特异性T细胞衔接器、CAR-T细胞治疗）的出现而发生革命性变化。相比之下，T-ALL免疫治疗进展缓慢，核心挑战在于T-ALL与正常T细胞共享表面蛋白：例如，CD19靶向治疗后的B细胞缺乏可通过免疫球蛋白替代治疗缓解，而T细胞缺乏则会导致严重免疫缺陷，增加致命性感染风险。此外，CAR-T细胞制备还面临“自相残杀”（CAR-T细胞被自身表达的CAR靶向杀伤）和白血病细胞转导风险升高的问题。尽管存在这些障碍，针对多种抗原的免疫治疗仍在积极研发中，以下将重点介绍最具前景的策略（图6）。 CD7是一种几乎在所有T细胞和T-ALL细胞上均表达的跨膜蛋白，因此成为研究最广泛的靶点，目前已开发多种策略规避自相残杀。多个研究团队采用CD7蛋白阻断策略，在患者或供体来源的自体CAR-T细胞中抑制CD7表面表达，相关产品已在较大样本量患者队列中进行测试，多数患者实现分子缓解。重要的是，为避免长期免疫抑制，多数患者在缓解后需接受造血干细胞移植。为降低白血病细胞转导风险，研究人员还在T-ALL患者中测试了多种异基因CAR-T细胞产品。这些产品通过CRISPR或碱基编辑敲除CD7和TCR，以避免自相残杀和移植物抗宿主病（GvHD）。在小样本量患者队列中，这些产品显示出良好疗效，但缓解后仍需接受巩固性造血干细胞移植。约40%的T-ALL表达CD1a，而多数成熟T细胞不表达CD1a，因此CD1a成为潜在靶点。但需注意的是，许多复发/难治性T-ALL病例为CD1a阴性，这限制了抗CD1a CAR-T细胞在R/R疾病中的应用。尽管如此，临床前研究已证实可制备无自相残杀、疗效良好的抗CD1a CAR-T细胞，目前相关临床试验正在开展。 CCR9是一种局限于胸腺细胞和肠道T细胞的趋化因子受体，但在多数T-ALL病例中表达。临床前研究显示，抗CCR9 CAR-T细胞在小鼠模型中疗效良好，Ⅰ期临床试验即将启动。有趣的是，临床前证据表明，双靶向CCR9/CD1a的CAR-T细胞比单靶向CAR-T细胞更有效，尤其对表型异质性白血病群体。 CD5是一种在大多数T-ALL病例中表达的糖蛋白，在正常T细胞上也有表达但水平较低，这使得CAR-T细胞制备可避免自相残杀。抗CD5 CAR-T细胞在临床前研究中显示出疗效，近期一项纳入19例患者的试验也取得了可喜结果，目前新的临床试验正在招募患者。 CD38在活化T细胞上诱导表达，在T-ALL包括复发/难治性病例中高表达。靶向CD38的单克隆抗体（如达雷妥尤单抗、艾沙妥昔单抗）已获批用于多发性骨髓瘤治疗，临床前测试显示其对T-ALL小鼠模型具有优异疗效。Ⅱ期DELPHINUS试验评估了达雷妥尤单抗在复发性ALL中的疗效，结果显示其与化疗联合治疗儿童复发性T-ALL的总应答率达83.3%，目前计划推进至Ⅲ期研究；另一项Ⅱ期临床试验正在招募化疗难治性T-ALL患者。而艾沙妥昔单抗的两项临床试验，因获益-风险比不佳和未达到Ⅱ期疗效标准，已被赛诺菲公司终止。如前文所述，IL-7R信号在T-ALL中具有重要作用。靶向IL-7Rα的单克隆抗体在临床前模型（包括复发性T-ALL）中显示出诱导抗体依赖性细胞介导的细胞毒性和/或吞噬作用、改善预后的潜力。芦维奇单抗（OSE-127）是一种非细胞毒性抗IL-7R单克隆抗体，在健康人群中显示出良好安全性，在B-ALL和T-ALL（包括R/R病例）临床前异种移植模型中显示出疗效，尤其与联合化疗联用时效果更佳。对T-ALL免疫细胞亚群的更深入表征可能进一步推动免疫治疗发展。近期研究通过单细胞测序发现，初诊时对化疗应答与最终复发的患者相比，γδ T细胞和CD8效应T细胞的频率存在差异，这提示免疫系统可能在T-ALL化疗应答中发挥关键作用，且这一机制或可用于治疗开发。未来展望在前文系统阐述的基础上，本节将重点讨论如何将儿童T-ALL的多维度生物学认知转化为临床实践。当前研究已充分揭示，改善R/R T-ALL患儿预后需要建立基于多组学特征的精准医疗体系，这要求我们开发智能化的联合治疗方案——这些方案需综合考虑恶性细胞的遗传特征、表观遗传调控、转录后修饰、翻译后修饰及代谢特性等分子特征，同时兼顾中枢神经系统浸润等微环境异质性。为深入理解治疗耐药机制（包括治疗相关耐药和器官特异性耐药），亟需构建能够模拟人类不同微环境特征的实验模型，从而准确评估疾病演进规律和治疗反应特别是对免疫治疗的反应模式。尽管我们对T-ALL的分子图谱认知日益完善，但将复杂生物学知识转化为临床获益仍面临重大挑战。为突破这一瓶颈，研究者开始采用计算生物学方法深度挖掘基因组数据，不仅成功识别出新的致癌驱动因子，还通过生物网络分析发现了潜在的治疗靶点。值得关注的是，机器学习与人工智能技术的最新进展为T-ALL研究带来了革命性机遇——特别是采用注意力机制的Transformer深度学习架构该技术已彻底改变自然语言处理领域，这些方法能够从海量多维数据中自动提取背景信息和潜在规律，已在多个生物医学领域展现出强大潜力。我们有理由预测，这类先进计算工具将在以下方面发挥关键作用：解析T-ALL分子网络的动态调控机制；优化新型生物标志物的发现与验证流程（包括表观遗传标志物、蛋白表达谱和药物反应标志物等）；为个体化治疗方案的设计提供数据驱动的决策依据。通过整合多模态生物数据与临床信息，这些智能算法有望构建预测性更强的治疗响应模型，最终推动T-ALL治疗范式从传统化疗向精准靶向治疗的转型。然而，要实现这一目标，仍需解决数据标准化、模型可解释性以及临床转化路径等关键问题。未来研究应着重建立跨学科合作框架，将计算生物学、临床医学和基础研究紧密结合，加速人工智能驱动的新发现向临床实践的转化。附录图1.T-ALL中研究最深入的组蛋白与DNA表观遗传修饰图2.T-ALL中RNA失调及相关机制概述图3.R/R T-ALL治疗具有潜力的信号通路和靶向治疗图4.运动性驱动的T-ALL发生：全机体参与的白血病病程图5.中枢神经系统微环境在诊断和治疗中枢神经系统受累T-ALL中带来的挑战图6.T-ALL的主要免疫治疗靶点表1.用于治疗R/R T-ALL的在研治疗策略崔兴医生山东中医药大学第二附属医院肿瘤中心主任，主任医师、教授、医学博士后、博士生导师、泰山学者青年专家、美国艾奥瓦大学访问学者。中华中医药学会血液病创新研究与转化平台副主任，中华中医药学会血液病分会常务委员，中华中医药学会肿瘤分会常务委员，山东中西医结合学会儿童血液与肿瘤专业委员会主任委员，山东中医药学会肿瘤精准医学专委会主任委员，中国抗癌协会中西整合多发性骨髓瘤专委会常务委员。研究方向与专长：中西医结合治疗血液和肿瘤疾病临床及实验研究。擅长多发性骨髓瘤、肺癌、结直肠癌、白血病、淋巴瘤、乳腺癌及胃癌等多种血液病及实体肿瘤的诊断与化疗、消融及中西医结合治疗，精于造血干细胞移植技术。门诊时间：周二上午，周三下午咨询电话：0531-58261302

免疫疗法细胞疗法

2025-07-15

·Business Wire

Shorla Oncology Announces FDA Orphan Drug Designation for SH-110 to Treat Rare Brain Cancer Using Oral Liquid

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Shorla Oncology (‘Shorla’), a U.S.-Ireland specialty pharmaceutical company, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for SH-110, a palatable oral suspension to treat Glioma - a rare brain cancer - by providing a liquid form of treatment for patients who have difficulty swallowing. While SH-110 will increase coverage and compliance by allowing more flexibility in dose preparation and site of care, its biggest impact will be for patients with Glioma who develop dysphagia, or have difficulty swallowing. These patients often rely on obtaining compounded treatments from a specialized pharmacy or self-compound capsules to fight their disease. “For too long, many patients with Glioma and their pharmacists and caregivers had no other choice but to break open capsules and expose themselves to unnecessary hazards,” said Sharon Cunningham, chief executive officer of Shorla. “SH-110 is a proprietary product that offers them a safer and more convenient formulation to treat this rare brain cancer.” SH-110 will join a growing portfolio of patient-friendly cancer medications developed by Shorla that have recently been approved by regulators. “This is a difference maker in the lives of those who suffer from Glioma,” said Orlaith Ryan, chief technical officer and co-founder of Shorla. “SH-110 complements our other Shorla treatments that are designed to be easier for patients to use, and for caregivers and providers to administer.” According to the National Brain Tumor Society, about 13,000 adults and 2,000 children are diagnosed each year in the U.S. with Glioma, an orphan disease. About SH-110 SH-110 is a palatable oral suspension to treat Glioma addressing the unmet medical need for patients with difficulty swallowing. This proprietary product will benefit patients by reducing treatment burden and providing a palatable age-appropriate treatment. SH-110 represents the third oral liquid in Shorla’s growing portfolio of products. About Shorla Oncology Shorla Oncology is a privately- held, U.S. and Ireland- based commercial stage specialty pharmaceutical company established by Sharon Cunningham and Orlaith Ryan. The company has an advanced pipeline of innovative oncology drugs for orphan and pediatric cancers. Shorla is focused on indications where existing treatments are limited, in shortage or the drug applications are inadequate for the target population. The company’s growing portfolio brings accessible, affordable and life-saving treatments to patients, delivering a major contribution to patient care. Shorla currently markets four products, a reliable supply of Nelarabine for the treatment of T-cell leukemia, JYLAMVO™ an oral liquid methotrexate for the treatment of acute lymphoblastic leukemia and other indications, IMKELDI an oral liquid imatinib for acute lymphoblastic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumors and other indications, and TEPYLUTE® the first and only ready-to-dilute multi-dose vial of thiotepa to treat breast and ovarian cancer. For further information, please visit https://shorlaoncology.com/pipeline/ All trademarks are the property of Shorla Oncology. ©SHORLA ONCOLOGY® 2025

孤儿药上市批准

2025-04-29

·Business Wire

Shorla Oncology Announces FDA Approval of TEPYLUTE® 100mg, First and Only Ready-to-Dilute Multi-Dose Vial of Thiotepa to Treat Breast and Ovarian Cancer and Commercial Launch of TEPYLUTE 15mg and 100mg Vials in the U.S.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Shorla Oncology (‘Shorla’), a U.S.-Ireland specialty pharmaceutical company, announced today that the U.S. Food and Drug Administration has granted approval for 100 mg/10mL multi-dose vial of TEPYLUTE, a ready-to-dilute formulation of thiotepa to treat breast and ovarian cancer, that eliminates the need for reconstitution and may reduce preparation time and errors offering more scheduling flexibility for their patients. Shorla Oncology Announces FDA Approval of TEPYLUTE® 100mg, First and Only Ready-to-Dilute Multi-Dose Vial of Thiotepa to Treat Breast and Ovarian Cancer and Commercial Launch of TEPYLUTE 15mg and 100mg Vials in the U.S. “We are pleased to offer another viable treatment option for patients with breast and ovarian cancer,” said Sharon Cunningham, Chief Executive Officer and Co-Founder of Shorla Oncology. “Once opened, our 100mg vial of TEPYLUTE is stable for 14 days when properly stored, giving providers the flexibility they need when preparing and administering this very important treatment. TEPYLUTE is a ready to dilute formulation of a well-established, standard of care oncology drug thiotepa that has been manufactured as freeze-dried powder since the 1950s. “This is a huge win for providers because TEPYLUTE avoids the need for complicated and time-consuming reconstitution,” said Orlaith Ryan, Chief Technical Officer and Co-Founder of Shorla Oncology. We are excited to bring TEPYLUTE to the US Market. It provides consistent dosing accuracy and allows for “just in time” preparation, which benefits everyone, especially patients.” said Rayna Herman, Chief Commercial Officer, Shorla Oncology. The American Cancer Society estimates that more than 300,000 women will be diagnosed with breast cancer in the U.S in 2025.2 About 20,890 women will be diagnosed with ovarian cancer in the U.S. in 2025.3 About Shorla Oncology Shorla Oncology is a privately- held, U.S. and Ireland- based commercial stage specialty pharmaceutical company established by Sharon Cunningham and Orlaith Ryan. The company has an advanced pipeline of innovative oncology drugs for orphan and pediatric cancers. Shorla is focused on indications where existing treatments are limited, in shortage or the drug applications are inadequate for the target population. The company’s growing portfolio brings accessible, affordable and life-saving treatments to patients, delivering a major contribution to patient care. Shorla currently markets three products, Nelarabine for the treatment of T-cell leukemia, JYLAMVO™ for the treatment of acute lymphoblastic leukemia and other indications and IMKELDI for the treatment of Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumors (GISTs) and other indications. For further information, please visit www.shorlaoncology.com. TEPYLUTE® (thiotepa) Injection for Intravenous Use INDICATION TEPYLUTE is an alkylating drug indicated for the treatment of adenocarcinoma of the breast or ovary. IMPORTANT SAFETY INFORMATION WARNING: SEVERE MYELOSUPPRESSION and CARCINOGENICITY • TEPYLUTE may cause severe marrow suppression, and high doses may cause marrow ablation with resulting infection or bleeding. Monitor hematologic laboratory parameters. • TEPYLUTE should be considered potentially carcinogenic in humans. CONTRAINDICATIONS TEPYLUTE is contraindicated in patients with severe hypersensitivity to thiotepa and in concomitant use with live or attenuated vaccines. WARNINGS AND PRECAUTIONS Myelosuppression : For patients receiving TEPYLUTE for treatment of adenocarcinoma of the breast or adenocarcinoma of the ovary, if the bone marrow has been compromised by prior irradiation or chemotherapy, or is recovering from chemotherapy, the risk of severe myelosuppression with TEPYLUTE may be increased. Perform periodic complete blood counts during the course of treatment with TEPYLUTE. Provide supportive care for infections, bleeding, and symptomatic anemia. Inform patients of the possibility of developing low blood cell counts and the need for hematopoietic progenitor cell infusion. Instruct patients to immediately report to their healthcare provider if bleeding or fever occurs. Hypersensitivity: Clinically significant hypersensitivity reactions, including anaphylaxis, have occurred following administration of thiotepa. If anaphylactic or other clinically significant allergic reaction occurs, discontinue treatment with TEPYLUTE, initiate appropriate therapy, and monitor until signs and symptoms resolve. Counsel patients on the signs and symptoms of hypersensitivity and to seek immediate emergency assistance if they develop any of these signs and symptoms. Cutaneous Toxicity: TEPYLUTE and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. Treatment with TEPYLUTE may cause skin discoloration, pruritus, blistering, desquamation, and peeling that may be more severe in the groin, axillae, skin folds, in the neck area, and under dressings. Instruct patients to shower or bathe with water at least twice daily through 48 hours after administration of TEPYLUTE. Change the occlusive dressing and clean the covered skin at least twice daily through 48 hours after administration of TEPYLUTE. Change bed sheets daily during treatment. Skin reactions associated with accidental exposure to TEPYLUTE may occur. Wash the skin thoroughly with soap and water in case the TEPYLUTE solution contacts the skin. Flush mucous membranes in case of TEPYLUTE contact with mucous membranes. Concomitant Use of Live and Attenuated Vaccines: Do not administer live or attenuated viral or bacterial vaccines to a patient treated with TEPYLUTE until the immunosuppressive effects have resolved. Hepatic Veno-Occlusive Disease: Monitor by physical examination, serum transaminases, and bilirubin, and provide supportive care to patients who develop hepatic veno-occlusive disease. Central Nervous System Toxicity: Fatal encephalopathy has occurred in patients treated with high doses of thiotepa. Other central nervous system toxicities, such as headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behavior, and forgetfulness have been reported to occur in a dose-dependent manner during or shortly after administration of high-dose thiotepa. Do not exceed the recommended dose of TEPYLUTE. If severe or life-threatening central nervous system toxicity occurs, discontinue administration of TEPYLUTE and provide supportive care. Carcinogenicity: Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals. Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. There is an increased risk of secondary malignancy with the use of TEPYLUTE. Inform patients that TEPYLUTE can increase the risk of secondary malignancy. Polyethylene glycol (PEG) 400 toxicity : TEPYLUTE contains a high concentration of PEG 400. Based on findings in animals, administration of high amounts of PEG 400 may cause damage to the kidneys and liver at dosages higher than recommended. When prescribing TEPYLUTE, take into consideration the PEG 400 load from concomitant medications. Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, TEPYLUTE can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of TEPYLUTE in pregnant women. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥1 mg/kg (3.2 mg/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2 ), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥3 mg/kg (21 mg/m 2 ), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m 2 ), approximately two times the maximum recommended human therapeutic dose based on body-surface area. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use highly effective contraception during TEPYLUTE treatment and for 6 months after therapy/the last dose. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise males with female partners of reproductive potential to use effective contraception during TEPYLUTE treatment and for 1 year after therapy/the last dose. ADVERSE REACTIONS The most common adverse reactions (incidence greater than 10%) are neutropenia, anemia, thrombocytopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase (AST), elevated bilirubin, mucositis, cytomegalovirus infection, hemorrhage, diarrhea, hematuria, and rash. The clinically significant adverse reactions include myelosuppression, infection, hypersensitivity, cutaneous toxicity, hepatic veno-occlusive disease, central nervous system toxicity, and carcinogenicity. DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors and Inducers: In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite triethylene phosphoramide (TEPA). Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity. Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions. Effect of TEPYLUTE on Cytochrome CYP2B6 Substrates: In vitro studies suggest that thiotepa inhibits CYP2B6. Thiotepa may increase the exposure of drugs that are substrates of CYP2B6 in patients; however, the clinical relevance of this in vitro interaction is unknown. The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4‑hydroxycyclophosphamide; the effect appears sequence-dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours before the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide. The reduction in 4-hydroxycyclophosphamide levels may potentially reduce the efficacy of cyclophosphamide treatment. USE IN SPECIFIC POPULATIONS Pregnancy: TEPYLUTE can cause fetal harm when administered to a pregnant woman based on findings from animals and the drug’s mechanism of action. Limited available data on thiotepa use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of thiotepa to pregnant mice and rats during organogenesis produced teratogenic effects (neural tube defects and malformations of the skeletal system of the fetus) at doses approximately 0.125 and 1 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. Thiotepa was lethal to rabbit fetuses at approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. Consider the benefits and risks of TEPYLUTE for the mother and possible risks to the fetus when prescribing TEPYLUTE to a pregnant woman. Lactation: There is no information regarding the presence of thiotepa in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including the potential for tumorigenicity shown for thiotepa in animal studies, advise patients not to breastfeed during TEPYLUTE treatment and for 1 week after therapy/the last dose. Females and Males of Reproductive Potential: TEPYLUTE can cause fetal harm when administered to a pregnant woman. Pregnancy Testing - Verify the pregnancy status of females of reproductive potential before initiating TEPYLUTE therapy. Contraception for Females - Advise females of reproductive potential to avoid pregnancy during TEPYLUTE treatment and for 6 months after therapy/the last dose. Advise females to immediately report pregnancy. Contraception for Males - TEPYLUTE may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during TEPYLUTE treatment and for 1 year after therapy/the last dose. Infertility - Based on nonclinical findings, male and female fertility may be compromised by treatment with TEPYLUTE. Advise patients that TEPYLUTE can produce infertility. Inform male patients about the possibility of sperm conservation before the start of therapy. Pediatric Use: Safety and effectiveness of TEPYLUTE in neonates have not been established. Safety and effectiveness of TEPYLUTE for the treatment of adenocarcinoma of the breast and adenocarcinoma of the ovary in pediatric patients have not been established. Geriatric Use: Clinical studies of thiotepa for treatment of adenocarcinoma of the breast and adenocarcinoma of the ovary did not include sufficient numbers of subjects aged 65 years and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasing hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: In patients with moderate (creatinine clearance [CLcr] of 30 mL/min to 59 mL/min) renal impairment, decreased renal excretion may result in increased plasma levels of thiotepa and TEPA. This may result in increased toxicity. Monitor patients with moderate to severe (CLcr <30 mL/min) renal impairment for signs and symptoms of toxicity following treatment with TEPYLUTE for an extended period of time. Hepatic Impairment: Thiotepa is extensively metabolized in the liver. Patients with moderate (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal and any AST) hepatic impairment may have increased plasma levels of thiotepa. This may result in toxicity. Monitor patients with moderate to severe (bilirubin levels greater than 3 times the upper limit of normal and any AST) hepatic impairment for signs and symptoms of toxicity following treatment with TEPYLUTE for an extended period of time. To report suspected adverse reactions, contact Shorla Oncology at 1-844-668-3940 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Print: Please see the accompanying full Prescribing Information, including Boxed Warning. For Digital: Please click here for full Prescribing Information, including Boxed Warning. All trademarks are the property of Shorla Oncology. ©SHORLA ONCOLOGY® 2025. PRO-TEP-1377-v1 04/2025

上市批准临床结果

100 项与奈拉滨相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D05134	奈拉滨	L01BB07	DB01280

研发状态

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10 条最早获批的记录,

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适应症	国家/地区	公司	日期
T细胞急性淋巴细胞白血病/淋巴瘤	日本	Sandoz Pharmaceuticals AG	2007-10-19
前体T淋巴细胞白血病淋巴瘤	美国	Sandoz, Inc.	2005-10-28

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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
前体 T 细胞淋巴母细胞淋巴瘤	临床3期	中国	正大天晴药业集团股份有限公司	2024-05-01
难治性 T 急性淋巴细胞白血病	临床3期	中国	正大天晴药业集团股份有限公司	2024-05-01
复发性T淋巴母细胞淋巴瘤	临床2期	美国	GSK Plc	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	美国	Novartis AG	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	澳大利亚	Novartis AG	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	澳大利亚	GSK Plc	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	奥地利	GSK Plc	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	奥地利	Novartis AG	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	加拿大	Novartis AG	2010-06-01
复发性T淋巴母细胞淋巴瘤	临床2期	加拿大	GSK Plc	2010-06-01

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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


ASH2023	N/A	前体T淋巴细胞白血病淋巴瘤	133	Nelarabine (NEL)	憲蓋遞簾網憲蓋築衊鑰(壓齋鑰顧廠製淵餘廠窪) = 襯淵膚襯糧繭艱選築窪艱顧選鏇鏇遞範淵艱鬱 (餘獵獵鑰願構餘繭膚醖 )	-	2023-12-11
				Pegylated Asparginase (PEG)	憲蓋遞簾網憲蓋築衊鑰(壓齋鑰顧廠製淵餘廠窪) = 獵膚衊鬱獵艱製膚願觸艱顧選鏇鏇遞範淵艱鬱 (餘獵獵鑰願構餘繭膚醖 )
NCT02619630 (GRAALL-2014/T, ASH2023)	临床2期	前体T淋巴细胞白血病淋巴瘤巩固	325	Nelarabine	淵獵壓網願簾鹹獵顧窪(夢鹹膚築窪範顧鹹醖構) = 獵範積糧糧顧膚壓壓齋膚鏇觸觸夢築醖簾齋憲 (選鬱遞鏇範簾淵糧窪遞, 20 ~ 37) 更多	-	2023-12-11
NCT01094860 (Pubmed)	临床1期	肿瘤	-	Nelarabine	壓醖鹽網淵糧網艱膚鏇(顧憲鹹簾艱膚鬱夢繭構) = 製鏇襯蓋網遞鑰製築範遞簾選淵鑰選範獵壓願 (鹹觸遞鏇齋鏇夢醖網觸 ) 更多	-	2022-11-29
EHA2022	N/A	T细胞急性淋巴细胞白血病/淋巴瘤	120	HyperCVAD + Nelarabine	淵鹹餘鏇繭鏇鬱鹹醖壓(襯鏇糧繭獵廠鹽窪網築) = elevated liver enzymes in 25 pts (21%) 廠窪艱顧積製壓築構醖 (構鑰齋鹹襯醖艱壓壓鹹 ) 更多	-	2022-05-12
				HyperCVAD + Nelarabine + PEGylated Asparaginase
NCT00501826 (ASH 12020 \| ASH 22020) 人工标引	临床2期	前体T淋巴细胞白血病淋巴瘤 \| 复发性T淋巴母细胞淋巴瘤一线	96	Peg-Asparaginase+Nelarabine	襯積鏇艱窪衊夢構簾鹹(鬱構夢淵鑰窪簾夢壓範) = 鹽膚膚鑰襯簾壓廠積觸艱憲網遞鬱壓壓餘淵艱 (簾淵簾蓋獵餘鬱積鑰膚 ) 更多	积极	2020-11-05
				Peg-Asparaginase+Nelarabine (T-ALL)	襯鑰憲餘鏇遞醖餘夢廠(餘餘簾廠鑰簾獵選顧壓) = 醖鏇觸選獵鬱齋遞膚蓋廠窪築簾築鏇鑰製簾網 (簾積衊鏇鹹窪鹹網淵艱 )
NCT00408005 (AALL0434, Pubmed \| J Urol \| J Clin Oncol) 人工标引	临床3期	前体T淋巴细胞白血病淋巴瘤	659	Berlin-Frankfurt-Muenster +Nelarabine	襯築淵獵顧構鹽築網衊(醖範鏇鏇繭壓齋蓋淵齋) = 範顧夢膚鏇繭壓醖憲顧範夢簾顧餘積齋觸築遞 (壓蓋簾醖醖膚艱壓鹹鬱, 2.4)	优效	2020-10-01
				Berlin-Frankfurt-Muenster	襯築淵獵顧構鹽築網衊(醖範鏇鏇繭壓齋蓋淵齋) = 鏇膚選構膚窪鬱鬱鬱膚範夢簾顧餘積齋觸築遞 (壓蓋簾醖醖膚艱壓鹹鬱, 2.7)
NCT00981799 (CTgov)	临床1/2期	复发性T淋巴母细胞淋巴瘤 \| T细胞急性淋巴细胞白血病复发 \| T淋巴细胞减少症	23	Etoposide+Cyclophosphamide+Filgrastim+Nelarabine+Methotrexate (Nelarabine Dose Level 1)	網製簾選遞壓觸鏇醖齋 = 壓築醖鹽糧選衊鏇鑰夢遞窪夢獵遞餘築壓構簾 (簾鏇觸積醖簾窪憲糧廠, 餘蓋觸範鏇憲網積鏇繭 ~ 夢築鹽顧簾蓋艱觸網製) 更多	-	2020-10-01
				Etoposide+Cyclophosphamide+Filgrastim+Nelarabine+Methotrexate (Nelarabine Dose Level 2)	網製簾選遞壓觸鏇醖齋 = 積網獵觸遞獵衊繭壓簾遞窪夢獵遞餘築壓構簾 (簾鏇觸積醖簾窪憲糧廠, 廠夢繭壓遞選繭糧簾獵 ~ 憲觸獵範構艱襯構衊鑰) 更多
EHA2019	临床4期	T细胞急性淋巴细胞白血病/淋巴瘤	118	Nelarabine	鹹鬱夢糧齋鹹襯選餘範(廠衊鏇鹹廠遞願餘鹹鏇) = 壓廠構壓鏇齋製繭齋遞餘簾衊鏇選積鬱膚製獵 (襯鏇築觸獵鑰鏇願築醖 ) 更多	-	2019-06-16
EHA2019	N/A	前体T淋巴细胞白血病淋巴瘤	9	Nelarabine	淵衊鹽積獵鏇廠齋襯膚(範憲簾觸鹽醖糧憲鹽構) = 憲鬱觸鹹廠簾衊簾製鑰淵憲餘淵願網淵鹽醖衊 (壓蓋構獵鑰繭網觸夢觸 ) 更多	-	2019-05-16
NCT00408005 (COG AALL0434, ASCO2018)	临床3期	肿瘤	1,895	Nelarabine	構壓衊淵淵顧獵窪壓鏇(鹹夢憲獵鏇淵積鬱鬱餘) = 鏇餘積獵齋鏇膚艱淵餘鬱觸構淵繭繭壓繭遞膚 (淵膚憲醖餘鹽壓網願齋, 2.2) 更多	积极	2018-06-01
				No Nelarabine	構壓衊淵淵顧獵窪壓鏇(鹹夢憲獵鏇淵積鬱鬱餘) = 築壓製膚糧積鹹製壓淵鬱觸構淵繭繭壓繭遞膚 (淵膚憲醖餘鹽壓網願齋, 2.5)