治疗FLT3突变的急性髓系白血病的新药米哚妥林

摘 要米哚妥林（midostaurin,Rydap）是瑞士诺华制药公司开发的一种口服多激酶受体抑制药。2017年5月被美国食品药品监督管理局批准上市,主要用于治疗携带FMS 样酪氨酸激酶 3( FMS like tyrosinekinase 3,FLT3)突变的急性髓系白血病（AML）。本文对米哚妥林的药效学、药动学特性、临床研究以及安全性等作一介绍,为其临床应用提供参考。     

急性髓系白血病靶向药物治疗新进展

急性髓系白血病(AML)是一种髓系细胞恶性克隆性疾病。近年来, 新型靶向药物的出现使癌症治疗发生了革命性变化, 有望在AML治疗上取得突破性进展。这些新药包括二代DNA甲基转移酶抑制剂、靶向B细胞淋巴瘤因子2(BCL-2)抑制剂、FMS样酪氨酸激酶3(FLT3)抑制剂、异柠檬酸脱氢酶抑制剂、抗CD33单克隆抗体、Smoothened Inhibitor(SMO)抑制剂、肿瘤蛋白p53靶向药物、抗CD47单抗、核输出蛋白1(XPO1)抑制剂等。本文就AML最新靶向治疗药物作一综述。     

FLT3抑制剂治疗急性髓系白血病及耐药机制研究进展

近年来,多药联合强烈化疗、支持治疗加强和造血干细胞移植术发展等,使急性髓系白血病(AML)预后得到较大改善,但耐药、化疗耐受性差和不良反应等因素使目前的治疗效果还不尽理想。FMS样酪氨酸激酶3(FLT3)的突变大约发生在30%的AML患者中,与白血病的发病密切相关,可作为治疗的靶点。目前研发的小分子的FLT3酪氨酸激酶抑制剂(TKI)已经用于治疗FLT3突变的AML,这些药物目前处于临床试验阶段。本综述总结关于目前FLT3抑制剂的临床试验及治疗的耐药机制。1 AML中的FLT3突变     

治疗急性髓系白血病新药:FLT3抑制剂 gilteritinib

FMS样酪氨酸激酶3 (FLT3)的基因在造血干细胞增殖、分化及存活方面发挥重要作用。FLT3内部串联重复突变(FLT3-ITD)在急性髓系白血病(AML)中常见,且与迅速复发及生存率低密切相关。gilteritinib (Gil)为新型FLT3抑制剂,由Astellas制药公司生产,于2018年11月经美国食品和药物管理局批准用于FLT3突变型复发难治性AML的治疗。临床试验表明对其他FLT3抑制剂耐药的AML患者,采用Gil治疗仍可取得较好疗效,其最常见的不良反应包括肌肉痛、关节痛、转氨酶升高、疲劳、发热等。     

FLT3 I836/M837位三碱基缺失的急性髓系白血病1例报告

FLT3属型受体酪氨酸酪激酶成员,对造血发育起重要调节作用。近年研究发现急性髓系白血病(AML)患者常带有FLT3突变,其中内部串联重复(FLTE-ITD)约占成人急性AML20%,酪氨酸激酶结构域(TKD)点突变约占7.7%,常位于D835及其附近。关于FLT3D835/I836缺失突变国外偶见报道[1],国内尚未     

Fms样酪氨酸激酶抑制剂治疗急性髓性白血病的新进展

Fms样酪氨酸激酶(FLT3)属于Ⅲ型受体酪氨酸蛋白激酶家族,其异常表达见于大部分急性髓性白血病(AML)病人,包括野生型受体与配体的协同表达,内部串连复制及活化环突变,表达持续性磷酸化活化的FLT3,对预后的判断具有重要意义。FLT3抑制剂主要有5类及热休克蛋白90抑制剂,实验室研究与初步的临床试验显示出其对AML的治疗价值。     

Gilteritinib (Xospata)

<正>Gilteritinib 由安斯泰来(Astellas)公司开发,分别于 2017 年在美国、2018 年在欧盟和日本被授予指定孤儿药地位。2018 年 11 月 28 日其富马酸盐片剂经美国 FDA 批准上市,用于治疗 FMS-样酪氨酸激酶 3(FLT3)突变阳性的复发性或难治性急性髓细胞白血病(AML)[1]。Gilteritinib 的中文化学名称:6-乙基-3-{3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯     

去甲基化药物联合非化疗药物治疗老年急性髓系白血病的研究进展

急性髓系白血病（AML）发病率随年龄增长而增加。约60%老年患者由于高龄、生理、认知功能损害及合并症增多等原因不能耐受常规化疗;未接受常规化疗的老年患者中位生存期仅为2个月。美国国立综合癌症网络（NCCN）发布的各种肿瘤临床实践指南优先推荐去甲基化药物联合B淋巴细胞瘤-2基因（BCL-2）抑制剂用于不适合强化治疗的老年AML患者。阿扎胞苷和地西他滨是临床上常用的2种去甲基化药物。本文主要对去甲基化药物联合BCL-2抑制剂、FMS样酪氨酸激酶3(FLT3)抑制剂、异柠檬酸脱氢酶（IDH）1/2抑制剂等小分子靶向药物,以及联合程序性死亡受体1(PD-1)单抗等免疫治疗及其他非化疗药物的研究进展进行综述。     

慢性髓系白血病无治疗缓解的研究进展

随着酪氨酸激酶抑制剂（TKI）的引入,慢性髓系白血病（CML）的治疗取得了前所未有的突破性进展,大大提高了患者的生存及预后。国内外临床试验表明,部分获得深度分子学反应的慢性髓系白血病在数年后可以成功停药,并维持无治疗缓解。本文主要通过总结酪氨酸激酶抑制剂治疗慢性髓系白血病患者获得深度分子学缓解后停药的临床试验,对如何把握安全停药,达到无治疗缓解（TFR）作一综述。     

FDA批准罕用药Vandetanib用于治疗甲状腺髓样癌

<正>2011年4月6日,AstraZeneca宣布美国FDA已批准其罕用药Vandetanib用于治疗那些不能进行手术切除或者持续向身体其他部位扩散的甲状腺髓样癌患者。Vandetanib是一种合成的苯胺喹唑啉化合物,为小分子多靶点酪酸激酶抑制剂(TKI),可同时作用于肿瘤细胞EGFR、VEGFR和RET酪氨酸激酶,还可选择性的抑制其他酪氨酸激酶,以及丝氨酸/苏氨酸激酶。它是FDA批准的唯一的用于治疗甲状腺髓样癌的药物。     

索拉菲尼单药治疗FLT3-ITD突变阴性和CD117高表达的复发/难治型急性髓系白血病临床观察

目的 初步分析索拉菲尼单药治疗FLT3-ITD突变阴性和CD117高表达的复发/难治型急性髓系白血病（R/R AML） 患者临床疗效。方法 回顾性分析7例高表达CD117但FLT3-ITD突变阴性的R/R AML患者应用索拉菲尼单药治疗后的临床反应和生存情况。治疗不良反应依据常见不良反应事件评价标准 （CTCAE） v4.0进行评估, 缓解标准依据NCCN指南确定。结果 7例患者中4例治疗获得缓解, 诱导完全缓解所需中位时间为36 d。索拉菲尼维持治疗过程中1例因皮疹疼痛中断治疗。3例对索拉菲尼治疗无反应者中2例接受挽救性移植治疗, 1例接受挽救性化疗, 均再度缓解。治疗期间, 1例出现1级肝脏不良反应, 1例出现3级皮损不良反应, 所有患者均有粒细胞缺乏 （> 7 d）, 但未出现早期死亡。患者中位随访时间达到22个月, 3例缓解患者在索拉菲尼维持治疗后AML复发死亡, 其无病生存时间为2~20个月。无论索拉菲尼诱导治疗是否缓解, 接受了骨髓移植治疗的4例患者至今仍存活。7例患者的中位生存时间达650 d。结论 高表达CD117的R/R AML患者使用单药索拉菲尼治疗缓解表现较好, 有利于患者的长期生存。     

Gelatin‐coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

This study presents the design of a gold nanoparticle (AuNPs)—drug system with improved efficiency for the treatment of acute myeloid leukemia. The system is based on four different FLT3 inhibitors, namely midostaurin, sorafenib, lestaurtinib, and quizartinib, which were independently loaded onto gelatin‐coated gold nanoparticles. Detailed investigation of the physicochemical properties of the formed complexes lead to the selection of quizartinib—loaded AuNPs for the in vitro evaluation of the biological effects of the formed complex against OCI‐AML3 acute myeloid leukemia cells. Viability tests by MTT demonstrated that the proposed drug complex has improved efficacy when compared with the drug alone. The obtained results constitute a premise for further in vivo investigation of such drug vehicles based on AuNPs. To the best of our knowledge, this is the first study that investigates the delivery of the above‐mentioned FLT3 inhibitors via gelatin‐coated gold nanoparticles.     

The clinical development of FLT3 inhibitors in acute myeloid leukemia

INTRODUCTION: Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years. AREAS COVERED: The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms. EXPERT OPINION: Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.     

急性髓系白血病CD123表达及其与FLT3-ITD突变的临床意义

目的:探讨急性髓系白血病(AML)患者中CD123表达及其与FLT3-ITD突变同步检测的临床意义。方法:采用流式细胞仪检测32例AML患者CD123表达,聚合酶链反应(PCR)检测FLT3-ITD突变。结果:32例AML中24例CD123表达阳性,阳性率75.0%,对照组表达阴性。CD123+患者诱导化疗完全缓解(CR)率37.5%,低于CD123-患者(75.0%)(P<0.05)。CD123+患者18个月生存率20.8%,低于CD123-患者(62.5%)(P<0.05)。32例AML中有6例FLT3-ITD突变阳性,阳性率18.8%,其中4例伴有CD123表达阳性,均未获完全缓解,生存期6～8个月。结论:CD123可能作为诊断急性髓系白血病独立参考依据之一及评估预后指标。CD123表达阳性及FLT3-ITD突变同时存在的AML患者生存期更短,预后更差。FLT3-ITD突变阳性患者CD123表达阳性率增高,FLT3-ITD突变在CD123+白血病干细胞最终形成中的意义值得深入探讨。     

Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma.

PURPOSE: The role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma (mRCC) is reviewed. SUMMARY: Sunitinib malate is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors, FMS-like tyrosine kinase 3 (FLT3), c-KIT, and platelet-derived growth factor (PDGF), which give the drug its direct antitumor and antiangiogenic properties. Sunitinib is currently approved as a second-line treatment of mRCC in patients who have either not responded to or who are not eligible to receive interleukin-2. Clinical trials of sunitinib have found similar rates of partial response, disease stabilization, and progression-free survival. Sorafenib inhibits VEGF receptors, PDGF receptors, FLT3, RAF-1, and BRAF in vitro and has been shown to prevent the growth of tumors but not to reduce tumor size. Sorafenib has been proven to improve survival in a novel randomized discontinuation trial and a Phase III randomized, placebo-controlled trial. No studies have directly compared the effectiveness of sunitinib to sorafenib in the treatment of advanced renal cell carcinoma. Sunitinib and sorafenib share a similar mechanism of action and primarily target tumor angiogenesis by inhibiting a variety of tyrosine kinases; the agents have similar toxicity, with the exception of an increased risk of hypertension associated with the use of sorafenib. Sorafenib does not result in tumor shrinkage, but sunitinib significantly reduces tumor size. CONCLUSION: The tyrosine kinase inhibitors sorafenib and sunitinib offer improved outcomes for patients with mRCC, but they are far short of a cure. Despite the introduction of sorafenib and sunitinib, palliative care is still an acceptable treatment option for mRCC because of the disease's extremely poor prognosis.     

The clinical development of FLT3 inhibitors in acute myeloid leukemia

Introduction: Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years.

Areas covered: The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms.

Expert opinion: Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.     

Fms样酪氨酸激酶3表达对评估急性髓系白血病预后的意义

目的 探讨Fms样酪氨酸激酶3(FLT3)表达对评估急性髓系白血病(AML)预后的意义.方法 选取AML患者50例,其中核型正常的AML患者20例,核型异常的AML患者30例.分别于化疗前抽取骨髓3 ml,用PCR方法检测白血病细胞FLT3的表达情况.结果 核型正常的AMLFLT3的表达率为5.0％,核型异常的AMLFLT3的表达率为26.7％.难治复发的AMLFLT3的表达率是33.3％,持续完全缓解的AMLFLT3的表达率是4.5％.FLT3的表达情况与骨髓中高白血病细胞所占比例和高外周血白细胞计数有关,与FAB亚型无关.有FLT3表达的AML患者无病生存(DFS)和总体生存(OS)时间短,无FLT3表达的AML患者DFS和OS时间长,二者差异有统计学意义(x2=4.17,P＜0.05).结论 FLT3是AML患者预后不好的因素,可以指导临床个体化治疗AML.     

急性髓细胞白血病FLT3-ITD基因的表达及临床意义

目的 通过对初诊急性髓细胞白血病(acute myeloid leukemia,AML)患者进行FLT3 -ITD基因突变检测,探讨FLT3-ITD基因突变与AML临床特征的相关性,为AML的临床分层治疗、分子靶向治疗及预后判断提供理论依据.方法 采用实时定量聚合酶链反应(RT-PCB)检测60例初治AML患者和10例对照组患者骨髓FLT3-ITD基因突变.结果 60例初治AML患者突变阳性率为25.0％( 15/60),10例对照组患者骨髓均未检测到该突变;依据法美英协作组(FAB)分型标准备亚型FLT3 -ITD突变率不同,其中以M3、M5型突变率较高;60例初治AML中,28例老年AML组与32例非老年AML组FLT3-ITD基因表达水平比较,差异有统计学意义(P＜0.05);FLT3-ITD阳性组患者具有外周血白细胞数、骨髓白血病细胞比例高的临床特点,并且FLT3-ITD阳性组化疗后完全缓解率(CR)低于FLT3-ITD阴性组(P＜0.05).结论 FLT3-ITD基因突变在AML患者中存在一定的突变率,且多见于M3、M5型患者,FLT3-ITD阳性患者具有外周血白细胞数、骨髓白血病细胞比例高,CR低的临床特点.     

Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.     

FLT3 Antibody‐based therapy for leukemia

Technological advances in antibody generation and production have facilitated recent clinical and commercial success with antibody‐based cancer therapeutics. The class III receptor tyrosine kinase FLT3 is highly expressed on the blast cells in most cases of acute myelogenous leukemia (AML) and B‐cell acute lymphoblastic leukemia (ALL). Activating mutations of FLT3 are detected in approximately 37% AML patients. FLT3 expression in normal tissue is limited to myeloid and B‐cell precursor cells. Therefore, over‐expressed or mutated FLT3 is an attractive target for therapeutic intervention using monoclonal antibodies. This review will discuss recent progress in the development of anti‐FLT3 antibodies as well as their therapeutic potentials in the treatment of AML and other hematological malignancies. Drug Dev. Res. 67:495–500, 2006. © 2006 Wiley‐Liss, Inc.