Bcl-2抑制剂用于急性髓系白血病靶向治疗的研究进展

摘要： 急性髓系白血病 （AML） 是成人最常见的急性白血病, 诱导化疗仍是AML的一线治疗手段。但是, 由于 AML诱导化疗毒性较高, 且有高失败率及高复发率的特点, 在AML患者中应用受限。近年来, 去甲基化药物地西他滨和阿扎胞苷在AML表观遗传学治疗中得到深入研究, 已经动摇了诱导化疗在AML治疗中的地位。随着对AML生物学研究的深入, 发现越来越多的靶点可影响AML的生物学进程。针对这些靶点的靶向药物分为3类： 第一类是突变位点抑制剂, 如FLT3和IDH抑制剂; 第二类是调节代谢或信号通路的抑制剂, 如Bcl-2拮抗剂及表观遗传学药物;第三类是靶向细胞毒性药物。2017年美国血液学年会报道, AML靶向治疗最有前景的药物为调节代谢或信号通路的抑制剂, 其中BCL-2抑制剂Venetoclax在AML的临床试验报告被评为本届会议最佳。本文就BCL-2抑制剂在 AML的治疗进展做一综述。     

阿扎胞苷联合维奈克拉治疗老年急性髓系白血病效果观察

目的 观察阿扎胞苷联合维奈克拉治疗老年急性髓系白血病（AML）的效果及安全性。方法 回顾性分析该院2017年1月至2021年10月新诊断的老年AML患者80例临床资料，根据治疗方法不同分为观察组31例与对照组49例。观察组采用阿扎胞苷联合维奈克拉化疗方案治疗，对照组采用地西他滨联合高三尖杉酯碱/阿柔比星+阿糖胞苷+重组人粒细胞刺激因子方案治疗。两组治疗两个疗程后评估疗效及安全性。结果 观察组完全缓解率（61.3%,19/31）、1年无进展生存率（58.1%,18/31）高于对照组[38.8%(19/49)、12.2%(6/49)]，疾病进展者占比（41.9%,13/31）、血小板减少（77.4%,24/31）及谷丙转氨酶升高发生率（0）均低于对照组[87.8%(43/49)、93.9%(46/49)、12.2%(6/49)]。结论 对于不宜行标准化疗方案的老年AML患者可经阿扎胞苷联合维奈克拉化疗方案治疗，有助于减轻药物相关不良反应及改善无进展生存率。     

从B细胞淋巴瘤-2抑制剂开发看国内外药企专利布局的异同

B细胞淋巴瘤-2(B-cell lymphoma-2, Bcl-2)在多种血液系统恶性肿瘤中呈不同程度的高表达，其具有明显抑制细胞凋亡的作用。目前，许多公司都在开发Bcl-2抑制剂以用于血液系统恶性肿瘤治疗，其中艾伯维公司的维奈克拉（venetoclax）已在多个国家或地区获准上市，亚盛医药的APG-2575和百济神州的BGB-11417则分别处于临床Ⅱ期和Ⅰ/Ⅱ期研究阶段。本文从专利申请的内容及途径、核心化合物专利申请的保护范围、联合用药3个角度，分析上述3家药企在Bcl-2抑制剂专利布局上的异同，希望对其他药企的药物和技术研发活动有所启迪。     

Bcl-2抑制剂维奈克拉在B细胞淋巴瘤中的治疗进展

BCL-2是调节细胞凋亡的关键蛋白，在很多血液系统恶性肿瘤中高表达，发挥抗凋亡作用。维奈克拉是首个高度选择性的BCL-2抑制剂，在全球范围内其第一个适应证为慢性淋巴细胞白血病（CLL），目前临床研究更已拓展到多种B细胞淋巴瘤、骨髓增生异常综合征（MDS）等多个血液肿瘤。本文对维奈克拉在B细胞淋巴瘤中的治疗进展作一综述。     

治疗急性髓系白血病新药：Hedgehog信号通路抑制剂glasdegib

急性髓系白血病(AML)是成人常见的急性白血病。Hedgehog信号通路的异常与AML的发病密切相关。glasdegib (Gla)为一种Hedgehog信号通路抑制剂,由辉瑞制药公司生产,于2018年11月由美国食品和药物管理局批准上市,与低剂量阿糖胞苷联合用于治疗新确诊的75岁及以上或因其他合并症而无法接受高强度化疗的AML患者。临床试验表明,Gla联合低剂量阿糖胞苷可明显改善患者的生存期。最常见的不良反应包括贫血、疲劳、出血、发热、中性粒细胞下降、肌肉疼痛、血小板减少和呼吸困难等。     

异柠檬酸脱氢酶抑制剂对急性髓性白血病的精准医疗

急性髓性白血病(AML)的治疗在过去几十年中有了显著改善, 开发了针对与该疾病相关特定基因突变精准治疗的新药物。异柠檬酸脱氢酶(IDH)抑制剂作为其中之一, 对具有IDH1或IDH2突变的患者有显著的疗效。本文就IDH抑制剂在AML的精准医疗方面的研究进行综述。     

DNA去甲基化药物的研究进展

DNA甲基化是调节基因表达而不改变DNA碱基序列的表观遗传修饰,通过沉默肿瘤抑制基因在癌症发展中发挥关键作用。DNA去甲基化药物在临床上已经显示出疗效,然而,高效性和特异性的DNA去甲基化药物尚未出现。目前,在市场上已有2种药物阿扎胞苷和地西他滨用于治疗骨髓增生异常综合征。寻找直接结合靶点新的抑制剂是未来的方向。从抗肿瘤活性和临床研究方面介绍了DNA去甲基化药物的研究进展。     

急性髓系白血病blc—2与bax基因的比值和耐药

目的：了解凋亡抑制基因（Bcl-2)、凋亡诱导基因（Bax)在急性髓系白血病的表达及Bcl-2/Bax比值与耐药关系。方法：用免疫组织化学法检测Bcl-2、Bax抗原表达,细胞培养四氮唑蓝比色法（MTT）药敏试验检测急性髓系白血病（AML）耐药的情况。结果：AML患者Bcl-2高于正常对照组,Ｂax低于正常对照级,其Bcl-2/Bax比值显著高于正常对照组（P＜0．01）。产生耐药组的病例Bcl-2/Bax高于敏感组（P＜0．05）,Bcl-2/Bax高比值患者化疗反应差（P＜0．05）。结论：Bcl-2,Bax的异常表达在AML形成、发展和产生耐药起一定作用,检测Bcl-2,Bax比值对治疗药物选择、预后的判断有重要意义。     

靶向CD123嵌合抗原受体T细胞治疗急性髓系白血病最新进展

急性髓系白血病(acute myeloid leukemia,AML)是最常见的、死亡率最高的一类白血病。在过去的40年里,尽管人们对于AML的认识更加深入,但是与其他血液肿瘤相比,AML的治疗并没有明显的变化。CD123是AML相关抗原,高表达于白血病干细胞,低或不表达于正常造血干细胞。作为治疗AML的潜在治疗靶点,近期靶向CD123+细胞免疫治疗技术已经有了新的进展,尤其是嵌合抗原受体(chimeric antigen receptor,CAR)T细胞治疗技术发展迅速。早期研究也已经证实CD123 CAR-T细胞具有抗白血病效应,而且对正常造血系统有不同程度的影响,这也为临床治疗复发/难治AML提供了新的思路。     

骨髓增生异常综合征及急性髓系白血病表观遗传学治疗进展

表观遗传学改变在骨髓增生异常综合征(MDS)及急性髓系白血病(AML)的发病机制中起重要作用,也因此成为了重要的治疗靶点.虽然现阶段大部分表观遗传学药物作用机制尚不完全明确,临床治疗中面临着应答率低、联合治疗不良反应多和易复发等问题,无法给患者带来明确的生存效益;但是对于无法耐受强化治疗的患者,表观遗传学治疗是一种可以考虑的治疗方法.本研究旨在综述现阶段可能改善MDS及AML患者预后的几种表观遗传学药物,并指出现阶段治疗的不足及未来努力的方向.     

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

Introduction: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.

Areas covered: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.

Expert opinion: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.     

The role of azacitidine in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.     

The role of azacitidine in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.     

Midostaurin: A New Oral Agent Targeting FMS‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited. Induction chemotherapy with 7 + 3, the combination of continuous‐infusion cytarabine and intermittent dosing of an anthracycline administered over 7 and 3 days, respectively, has remained the standard of care since its introduction in 1973 in the United States. Midostaurin is a first‐generation FMS‐like tyrosine kinase 3 (FLT3) inhibitor (TKI) that was approved by the U.S. Food and Drug Administration in April 2017 for the treatment of FLT3‐mutant AML. We performed a search of the PubMed database (January 1990–January 2017) to review pertinent clinical trials of midostaurin. Phase I, II, and III trials reported in English evaluating the safety and efficacy of midostaurin in patients with AML or myelodysplastic syndrome were included. The ClinicalTrials.gov database was also searched for ongoing trials. In the only phase III trial that has been conducted to date, midostaurin demonstrated significant improvement compared with placebo in overall and event‐free survival in patients aged 18–59 years with newly diagnosed FLT3‐mutant AML treated with standard induction chemotherapy. The median overall survival for patients randomized to the midostaurin group was 74.7 months versus 25.6 months in the placebo group (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.63–0.96, p=0.009). Median event‐free survival was 8.2 months with midostaurin compared with 3.0 months with placebo (HR 0.78, 95% CI 0.66–0.93, p=0.002). In addition to being evaluated in combination with conventional chemotherapy, midostaurin has been studied as monotherapy, in combination with the hypomethylating agents azacitidine and decitabine, and as single‐agent maintenance. Studies evaluating midostaurin in the maintenance setting after allogeneic stem cell transplantation are underway. Midostaurin is the first oral multitargeted TKI to improve overall survival in patients with FLT3‐mutant AML and represents an important addition to the limited armamentarium against AML.     

组蛋白去乙酰化酶抑制剂联合FMS样酪氨酸激酶-3抑制剂对FLT3-ITD突变白血病细胞增殖、凋亡和周期的影响

目的 探讨组蛋白去乙酰化酶抑制剂(HDACi)联合FMS样酪氨酸激酶-3(FLT3)抑制剂对FLT3-ITD突变的急性髓系白血病(AML)细胞系增殖抑制作用及其相关机制。方法 将西达本胺(Chidamide)和奎扎替尼(Quizartinib, AC220)以不同浓度单药或联合作用于MV4-11、MOLM-13细胞系48 h后,CCK8检测细胞增殖能力;Compusyn 1.0软件分析两药联合作用的协同效应;流式细胞计数法测定各组细胞凋亡率、增殖周期;蛋白质印迹法测定P53、Bcl-2、Bax、FLT3、磷酸化FLT3(p-FLT3)及磷酸化AKT(p-AKT)蛋白表达水平。结果 随西达本胺及奎扎替尼单药或联合作用浓度升高,对MV4-11及MOLM-13细胞系的48h增殖抑制率均显著升高(P<0.05),并且两药具有协同抑制效应(均CI值<1)。在奎扎替尼1.0 nmol/L+西达本胺1.0μmol/L作用48 h后,细胞凋亡率MV4-11细胞株为31.697%±5.648%,MOLM-13细胞株为18.500%±1.751%,细胞周期阻滞于G0/G1期的比例MV4-11细...     

Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies.In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.     

Novel and emerging drugs for acute myeloid leukemia: pharmacology and therapeutic activity

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.     

Novel agents targeting leukemia cells and immune microenvironment for prevention and treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML), whose prognosis has been historically dismal. Given the rapid development of genomics and immunotherapies, the interference strategies for AML recurrence have been changing these years. More and more novel targeting agents that have received the U.S. Food and Drug Administration (FDA) approval for de novo AML treatment have been administrated in the salvage or maintenance therapy of post-HSCT relapse. Targeted strategies that regulate the immune microenvironment of and optimize the graft versus leukemia (GVL) effect of immune cells are gradually improved. Such agents not only have been proven to achieve clinical benefits from a single drug, but if combined with classic therapies, can significantly improve the poor prognosis of AML patients who relapse after allo-HSCT. This review will focus on currently available and promising upcoming agents and also discuss the challenges and limitations of targeted therapies in the allogeneic hematopoietic stem cell transplantation community.