Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2022, Vol. 51 Issue (4): 507-514    DOI: 10.3724/zdxbyxb-2022-0090
综述     
FLT3抑制剂治疗急性髓系白血病患者研究进展
袁伟1,2,张世忠1,2,主鸿鹄3,*
1. 三峡大学医学院，湖北 宜昌 443000
2. 三峡大学中药药理三级实验室，湖北 宜昌 443000
3. 浙江大学医学院附属第一医院血液科，浙江 杭州 310003
Advances in clinical studies of FLT3 inhibitors in acute myeloid leukemia
YUAN Wei1,2,ZHANG Shizhong1,2,ZHU Honghu3,*
1. Medical College of China Three Gorges University, Yichang 443000, Hubei Province, China;
2. Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, China Three Gorges University, Yichang 443000, Hubei Province, China;
3. Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
 全文: PDF(533 KB)   HTML( 11 )
摘要：

急性髓系白血病（AML）是一种高度异质性的恶性血液肿瘤，其中伴 FLT3基因突变患者复发率较高、预后较差，因此 FLT3成为AML治疗的重要靶点。近年来，先后有第一代、第二代共8个FLT3抑制剂注册临床试验，其中可用于AML患者治疗的有米哚妥林、吉瑞替尼和奎扎替尼三种药物。FLT3抑制剂通过与标准化疗药物联用进一步提高疾病缓解率，在后续的维持治疗中，FLT3抑制剂同样可以降低患者的疾病复发率，改善患者整体预后。部分患者可出现因骨髓微环境导致的原发性耐药或用药后并发其他突变所致的继发性耐药。FLT3抑制剂与其他化疗药物联用可以减少耐药的发生。本文对常见FLT3抑制剂治疗AML患者的研究进展进行综述，以期为临床提供参考。
关键词： 急性髓系白血病;  酪氨酸激酶;  靶向治疗;  抑制剂;  耐药;  综述    
Abstract:

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. AML patients with FLT3 mutations tend to have a high relapse rate and poor outcome, so FLT3 gene has become an important target for AML treatment, and a series of FLT3 inhibitors have been developed. According to the characteristics of FLT3 inhibitors, they can be divided into first-generation FLT3 inhibitors and second-generation FLT3 inhibitors. So far, totally eight FLT3 inhibitors have been undergone clinical trials and only three were approved for the treatment of AML patients, including Midostourin, Quizartinib and Gilteritinib. FLT3 inhibitors can improve the response rate of patients by combining with standard chemotherapy; in the follow-up maintenance treatment, FLT3 inhibitors can also reduce the disease recurrence rate and improve the overall prognosis of patients. However, the primary drug resistance caused by the bone marrow microenvironment, as well as secondary resistance caused by other mutations may result in poor efficacy of FLT3 inhibitors. For such patients, the combination of FLT3 inhibitor with other drugs may reduce the occurrence of drug resistance and improve the subsequent efficacy of patients. This article reviews the current status of FLT3 inhibitors in clinical research of AML patients and the treatment of FLT3-resistant patients to provide reference for clinicians.
Key words: Acute myeloid leukemia    Tyrosine kinase    Targeted therapy    Inhibitor    Resistance    Review
收稿日期: 2022-03-07 出版日期: 2022-11-16
CLC:  R733  
基金资助: 浙江省领军型创新创业团队（2020R01006）; 浙江省“尖兵”研发攻关计划（2022C03005）
通讯作者: 主鸿鹄   
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
袁伟
张世忠
主鸿鹄

引用本文:

袁伟,张世忠,主鸿鹄. FLT3抑制剂治疗急性髓系白血病患者研究进展[J]. 浙江大学学报（医学版）, 2022, 51(4): 507-514.

YUAN Wei,ZHANG Shizhong,ZHU Honghu. Advances in clinical studies of FLT3 inhibitors in acute myeloid leukemia. J Zhejiang Univ (Med Sci), 2022, 51(4): 507-514.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0090    或    https://www.zjujournals.com/med/CN/Y2022/V51/I4/507

1 DÖHNER H , WEISDORF D J , BLOOMFIELD C D . Acute myeloid leukemia[J]N Engl J Med, 2015, 373( 12): 1136-1152.
doi: 10.1056/NEJMra1406184
2 NAIR R , SALINAS-ILLARENA A , BALDAUF H M . New strategies to treat AML: novel insights into AML survival pathways and combination therapies[J]Leukemia, 2021, 35( 2): 299-311.
doi: 10.1038/s41375-020-01069-1
3 STONE R M , MANDREKAR S J , SANFORD B L , et al.Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation[J]N Engl J Med, 2017, 377( 5): 454-464.
doi: 10.1056/NEJMoa1614359
4 KENNEDY V E , SMITH C C . FLT3 mutations in acute myeloid leukemia: key concepts and emerging controversies[J]Front Oncol, 2020, 612880.
doi: 10.3389/fonc.2020.612880
5 DAVER N , SCHLENK R F , RUSSELL N H , et al.Targeting FLT3 mutations in AML: review of current knowledge and evidence[J]Leukemia, 2019, 33( 2): 299-312.
doi: 10.1038/s41375-018-0357-9
6 DÖHNER H , ESTEY E , GRIMWADE D , et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel[J]Blood, 2017, 129( 4): 424-447.
doi: 10.1182/blood-2016-08-733196
7 SHORT N J , KANTARJIAN H , RAVANDI F , et al.Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia[J]Ther Adv Hematol, 2019, 2040620719827310.
doi: 10.1177/2040620719827310
8 WANG Z , CAI J , CHENG J , et al.FLT3 inhibitors in acute myeloid leukemia: challenges and recent developments in overcoming resistance[J]J Med Chem, 2021, 64( 6): 2878-2900.
doi: 10.1021/acs.jmedchem.0c01851
9 SERVE H , KRUG U , WAGNER R , et al.Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial[J]J Clin Oncol, 2013, 31( 25): 3110-3118.
doi: 10.1200/JCO.2012.46.4990
10 UY G L , MANDREKAR S J , LAUMANN K , et al.A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001[J]Blood Adv, 2017, 1( 5): 331-340.
doi: 10.1182/bloodadvances.2016003053
11 RÖLLIG C , SERVE H , HÜTTMANN A , et al.Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial[J]Lancet Oncol, 2015, 16( 16): 1691-1699.
doi: 10.1016/S1470-2045(15)00362-9
12 RÖLLIG C , SERVE H , NOPPENEY R , et al.Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial[J]Leukemia, 2021, 35( 9): 2517-2525.
doi: 10.1038/s41375-021-01148-x
13 RAVANDI F , ALATTAR M L , GRUNWALD M R , et al.Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation[J]Blood, 2013, 121( 23): 4655-4662.
doi: 10.1182/blood-2013-01-480228
14 OHANIAN M , GARCIA-MANERO G , LEVIS M , et al.Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia[J]Am J Hematol, 2018, 93( 9): 1136-1141.
doi: 10.1002/ajh.25198
15 XUAN L , WANG Y , HUANG F , et al.Effect of sorafenib on the outcomes of patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation[J]Cancer, 2018, 124( 9): 1954-1963.
doi: 10.1002/cncr.31295
16 XUAN L , WANG Y , HUANG F , et al.Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial[J]Lancet Oncol, 2020, 21( 9): 1201-1212.
doi: 10.1016/S1470-2045(20)30455-1
17 BURCHERT A , BUG G , FRITZ L V , et al.Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (sormain)[J]J Clin Oncol, 2020, 38( 26): 2993-3002.
doi: 10.1200/JCO.19.03345
18 PROPPER D J , MCDONALD A C , MAN A , et al.Phase Ⅰ and pharmacokinetic study of PKC412, an inhibitor of protein kinase C[J]J Clin Oncol, 2001, 19( 5): 1485-1492.
doi: 10.1200/JCO.2001.19.5.1485
19 STONE R M , FISCHER T , PAQUETTE R , et al.Phase ⅠB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia[J]Leukemia, 2012, 26( 9): 2061-2068.
doi: 10.1038/leu.2012.115
20 LEVIS M . Midostaurin approved for FLT3-mutated AML[J]Blood, 2017, 129( 26): 3403-3406.
doi: 10.1182/blood-2017-05-782292
21 TALLMAN M S , WANG E S , ALTMAN J K , et al.Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology[J]J Natl Compr Canc Netw, 2019, 17( 6): 721-749.
doi: 10.6004/jnccn.2019.0028
22 SIERRA J , MONTESINOS P , THOMAS X , et al.Phase 3b study assessing the safety and efficacy of midostaurin in younger and older patients with newly diagnosed, FLT3-mutated acute myeloid leukemia who are eligible for 7+3 or 5+2 chemotherapy[J]Blood, 2020, 136( Supplement 1): 23-24.
doi: 10.1182/blood-2020-136083
23 LARSON R A , MANDREKAR S J , HUEBNER L J , et al.Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial[J]Leukemia, 2021, 35( 9): 2539-2551.
doi: 10.1038/s41375-021-01179-4
24 MAZIARZ R T , LEVIS M , PATNAIK M M , et al.Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication- positive acute myeloid leukemia[J]Bone Marrow Transplant, 2021, 56( 5): 1180-1189.
doi: 10.1038/s41409-020-01153-1
25 WANG E S, TALLMAN M S, STONE R M, et al. Low relapse rate in younger patients ≤60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy[J]. , 2017, 130(Supplement 1): 566
26 GOLDBERG A D , COLLINS R H , STONE R M , et al.Addition of crenolanib to induction chemotherapy overcomes the poor prognostic impact of co- occurring driver mutations in patients with newly diagnosed FLT3-mutated AML[J]Blood, 2018, 132( Supplement 1): 1436.
doi: 10.1182/blood-2018-99-117016
27 LOSCHI M , SAMMUT R , CHICHE E , et al.FLT3 tyrosine kinase inhibitors for the treatment of fit and unfit patients with FLT3-mutated AML: a systematic review[J]Int J Mol Sci, 2021, 22( 11): 5873.
doi: 10.3390/ijms22115873
28 ALTMAN J K , FORAN J M , PRATZ K W , et al.Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia[J]Am J Hematol, 2018, 93( 2): 213-221.
doi: 10.1002/ajh.24974
29 CORTES J E , KHALED S , MARTINELLI G , et al.Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial[J]Lancet Oncol, 2019, 20( 7): 984-997.
doi: 10.1016/S1470-2045(19)30150-0
30 YILMAZ M , KANTARJIAN H M , MUFTUOGLU M , et al.Quizartinib with decitabine +/- venetoclax is highly active in patients (pts) with FLT3-ITD mutated (mut) acute myeloid leukemia (AML): clinical report and signaling cytof profiling from a phase Ⅰb/Ⅱ trial[J]Blood, 2020, 136( Supplement 1): 19-20.
doi: 10.1182/blood-2020-142687
31 LEE L Y , HERNANDEZ D , RAJKHOWA T , et al.Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor[J]Blood, 2017, 129( 2): 257-260.
doi: 10.1182/blood-2016-10-745133
32 PERL A E , ALTMAN J K , CORTES J , et al.Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study[J]Lancet Oncol, 2017, 18( 8): 1061-1075.
doi: 10.1016/S1470-2045(17)30416-3
33 PERL A E , MARTINELLI G , CORTES J E , et al.Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML[J]N Engl J Med, 2019, 381( 18): 1728-1740.
doi: 10.1056/NEJMoa1902688
34 WANG J , JIANG B , LI J , et al.Gilteritinib versus salvage chemotherapy for relapsed/refractory FLT3-mutated acute myeloid leukemia: a phase 3, randomized, multicenter, open-label trial in asia[J]Blood, 2021, 138( Supplement 1): 695.
doi: 10.1182/blood-2021-145436
35 WANG E S , MONTESINOS P , MINDEN M D , et al.Phase 3, open-label, randomized study of gilteritinib and azacitidine vs azacitidine for newly diagnosed FLT3-mutated acute myeloid leukemia in patients ineligible for intensive induction chemotherapy[J]Blood, 2021, 138( Supplement 1): 700.
doi: 10.1182/blood-2021-145379
36 DAVER N , ALTMAN J K , MALY J , et al.Efficacy and safety of venetoclax in combination with gilteritinib for relapsed/refractory FLT3-mutated acute myeloid leukemia in the expansion cohort of a phase Ⅰb study[J]Blood, 2020, 136( Supplement 1): 20-22.
doi: 10.1182/blood-2020-139705
37 SHORT N J , DINARDO C D , DAVER N , et al.A triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia: results from a phase Ⅰ/Ⅱ study[J]Blood, 2021, 138( Supplement 1): 696.
doi: 10.1182/blood-2021-153571
38 ZHAO J C , AGARWAL S , AHMAD H , et al.A review of FLT3 inhibitors in acute myeloid leukemia[J]Blood Rev, 2022, 100905.
doi: 10.1016/j.blre.2021.100905
39 EGUCHI M , MINAMI Y , KUZUME A , et al.Mechanisms underlying resistance to FLT3 inhibitors in acute myeloid leukemia[J]Biomedicines, 2020, 8( 8): 245.
doi: 10.3390/biomedicines8080245
40 TRAER E , MARTINEZ J , JAVIDI-SHARIFI N , et al.FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia[J]Cancer Res, 2016, 76( 22): 6471-6482.
doi: 10.1158/0008-5472.CAN-15-3569
41 CHEN F , ISHIKAWA Y , AKASHI A , et al.Co-expression of wild-type FLT3 attenuates the inhibitory effect of FLT3 inhibitor on FLT3 mutated leukemia cells[J]Oncotarget, 2016, 7( 30): 47018-47032.
doi: 10.18632/oncotarget.10147
42 SMITH C C , WANG Q , CHIN C S , et al.Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia[J]Nature, 2012, 485( 7397): 260-263.
doi: 10.1038/nature11016
43 MCMAHON C M , FERNG T , CANAANI J , et al.Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia[J]Cancer Discovery, 2019, 9( 8): 1050-1063.
doi: 10.1158/2159-8290.CD-18-1453
44 ZHANG H , SAVAGE S , SCHULTZ A R , et al.Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms[J]Nat Commun, 2019, 10( 1): 244.
doi: 10.1038/s41467-018-08263-x
45 YAMAURA T , NAKATANI T , UDA K , et al.A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations[J]Blood, 2018, 131( 4): 426-438.
doi: 10.1182/blood-2017-05-786657
46 YU Z , DU J , HUI H , et al.LT-171-861, a novel FLT3 inhibitor, shows excellent preclinical efficacy for the treatment of FLT3 mutant acute myeloid leukemia[J]Theranostics, 2021, 11( 1): 93-106.
doi: 10.7150/thno.46593
47 WANG R , LI Y , GONG P , et al.Arsenic trioxide and sorafenib induce synthetic lethality of FLT3-ITD acute myeloid leukemia cells[J]Mol Cancer Ther, 2018, 17( 9): 1871-1880.
doi: 10.1158/1535-7163.MCT-17-0298
48 BRINTON L T , ZHANG P , WILLIAMS K , et al.Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia[J]J Hematol Oncol, 2020, 13( 1): 139.
doi: 10.1186/s13045-020-00973-4
49 DINARDO C D , JONAS B A , PULLARKAT V , et al.Azacitidine and venetoclax in previously untreated acute myeloid leukemia[J]N Engl J Med, 2020, 383( 7): 617-629.
doi: 10.1056/NEJMoa2012971
[1] 陈洁,陆婧媛,洪秀理,鹿全意. 托珠单抗联合芦可替尼治疗造血干细胞移植后激素耐药的移植物抗宿主病患儿六例[J]. 浙江大学学报（医学版）, 2022, 51(4): 470-473.
[2] 李芸,陈新. T淋巴细胞体外发育方法的研究进展[J]. 浙江大学学报（医学版）, 2022, 51(4): 491-499.
[3] 周璐佳,梁景岩,熊天庆. 间充质干细胞来源的外泌体调节缺血性脑卒中后炎症反应的研究进展[J]. 浙江大学学报（医学版）, 2022, 51(4): 500-506.
[4] 邹杰林,毛靖,石鑫. 牙髓-牙本质复合体再生的影响因素及其生物学策略[J]. 浙江大学学报（医学版）, 2022, 51(3): 350-361.
[5] 孙萍萍,邹炜. 活细胞RNA成像技术及其在生物医学中应用研究进展[J]. 浙江大学学报（医学版）, 2022, 51(3): 362-372.
[6] 邵玥明,荀静娜,陈军,卢洪洲. 人类免疫缺陷病毒感染早期启动抗逆转录病毒治疗的意义[J]. 浙江大学学报（医学版）, 2022, 51(3): 373-379.
[7] 杨朝森,张晓明. 囊泡转运在肌萎缩侧索硬化中的作用研究进展[J]. 浙江大学学报（医学版）, 2022, 51(3): 380-387.
[8] 刘志超,钱周旸,王英男,王慧明. 程序性坏死在骨关节炎病理机制和治疗中的作用[J]. 浙江大学学报（医学版）, 2022, 51(2): 261-265.
[9] 李健宜,佟丹丹,林俊生. 恶性肿瘤饥饿疗法研究现状[J]. 浙江大学学报（医学版）, 2022, 51(2): 241-250.
[10] 叶柏新,胡永仙,张明明,黄河. 脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用[J]. 浙江大学学报（医学版）, 2022, 51(2): 185-191.
[11] 刘娇,涂晓璇,刘璐璐,方维佳. 嵌合抗原受体T细胞治疗恶性实体瘤新进展[J]. 浙江大学学报（医学版）, 2022, 51(2): 175-184.
[12] 胡珂嘉,黄玥,胡永仙,黄河. 嵌合抗原受体T细胞治疗血液系统恶性肿瘤研究进展[J]. 浙江大学学报（医学版）, 2022, 51(2): 192-203.
[13] 张少琪,孙洁. 纳米药物递送系统在急性髓细胞性白血病治疗中的应用[J]. 浙江大学学报（医学版）, 2022, 51(2): 233-240.
[14] 邢敬慈,揭伟. 甲基转移酶SET结构域家族及其在心血管发育和疾病中的作用[J]. 浙江大学学报（医学版）, 2022, 51(2): 251-260.
[15] 刘德坤,刘佳丽,张丹,杨雯晴. 细胞衰老与动脉粥样硬化的相关研究进展[J]. 浙江大学学报（医学版）, 2022, 51(1): 95-101.