去甲基化药物在骨髓增生异常综合征治疗中的进展

中国药物警戒 ›› 2018, Vol. 15 ›› Issue (9): 560-563.

去甲基化药物在骨髓增生异常综合征治疗中的进展

常炳庆¹, 孙婉玲^2*

¹北京航天总医院血液科,北京 100076;
²首都医科大学宣武医院血液科,北京 100053

收稿日期:2018-11-02 修回日期:2018-11-02 出版日期:2018-09-20 发布日期:2018-11-02
通讯作者: 孙婉玲,女,博士,主任医师·硕导,血液病学研究。E-mail：wanlingsun@xwhosp.org
作者简介:常炳庆,男,本科,副主任医师,血液病临床诊疗。
基金资助:
国家自然科学基金资助项目(81000200):骨髓增生异常综合征细胞亚群端粒长度与临床特征的关系;北京市卫生系统高层次卫生技术人才培养项目(2011-3-092)

Progress of Hypomethylating Agents in Treatment of Myelodysplastic Syndrome

CHANG Bingqing¹, SUN Wanling^2*

¹Department of Hematology, Beijing Aerospace General Hospital, Beijing 100075, China;
²Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

Received:2018-11-02 Revised:2018-11-02 Online:2018-09-20 Published:2018-11-02

摘要/Abstract

摘要： 骨髓增生异常综合征（myelodysplastic syndrome,MDS）是起源于造血干细胞的一组异质性髓系克隆性疾病,具有较高的急性髓系白血病转化风险。MDS患者自然病程及预后的异质性很大,必须根据患者的预后分层制定个体化治疗方案。目前去甲基化药物是高危MDS患者治疗的主要手段之一。本文总结归纳了目前具有代表性的去甲基化药物的研究进展,期望对该类药物的临床应用和研究提供参考信息。

关键词: 骨髓增生异常综合征, 高危, 去甲基化药物

Abstract: Myelodysplastic syndrome (MDS) is a group of heterogeneous myeloid clonal diseases originated from hematopoietic stem cells and has a high risk to transform into acute myeloid leukemia. The natural course and prognosis of MDS patients are highly heterogeneous, and individualized treatment plans must be developed according to the stratification of patients' prognosis. Currently, hypomethylating agents are one of the main treatments for high-risk MDS patients. This paper summarizes the research progress of representative hypomethylating agents in recent years, and hopes to provide references for the clinical application and research of these drugs.

Key words: myelodysplastic syndrome, high risk, hypomethylating agents

中图分类号:

R965

常炳庆, 孙婉玲. 去甲基化药物在骨髓增生异常综合征治疗中的进展[J]. 中国药物警戒, 2018, 15(9): 560-563.

CHANG Bingqing, SUN Wanling. Progress of Hypomethylating Agents in Treatment of Myelodysplastic Syndrome[J]. Chinese Journal of Pharmacovigilance, 2018, 15(9): 560-563.

参考文献

[1] 中华医学会血液学分会. 骨髓增生异常综合征诊断与治疗中国专家共识[J]. 中华血液学杂志, 2014,11(35):1024-1048.
[2] Canaani J, Nagler A.Established and emerging targeted therapies in the myelodysplastic syndromes[J]. Expert Rev Hematol, 2016,9(10):997-1005.
[3] Ades L, Itzykson R, Fenaux P.Myelodysplastic syndromes[J]. Lancet, 2014,383(9936):2239-2252.
[4] Itzykson R, Fenaux P.Epigenetics of myelodysplastic syndromes[J]. Leukemia, 2014,28(3):497-506.
[5] Qin Y Z, Zhang Y H, Qin X Y, et al.Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes[J]. Oncol Lett, 2017,13(4):2823-2830.
[6] Zhang Q, Lin Z, Yin X, et al.In vitro and in vivo study of hydralazine, a potential anti-angiogenic agent[J]. Eur J Pharmacol, 2016,779:138-146.
[7] Halby L, Champion C, Senamaud-Beaufort C, et al.Rapid synthesis of new DNMT inhibitors derivatives of procainamide[J]. Chemb-iochem, 2012,13(1):157-165.
[8] Wang Y, Li Y, Liu X, et al.Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents[J]. Curr Cancer Drug Targets, 2013,13(5):506-518.
[9] Zwergel C, Valente S, Mai A.DNA Methyltransferases Inhibitors from Natural Sources[J]. Curr Top Med Chem, 2016,16(7):680-696.
[10] Fulkerson C M, Dhawan D, Jones D R, et al.Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs[J]. Vet Comp Oncol, 2017,15(1):226-236.
[11] Yun S, Vincelette N D, Abraham I, et al.Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systematic review of hypomethylating agents trials[J]. Clinical 7Epigenetics, 2016,8(1):1-9.
[12] Nakamura K, Nakabayashi K, Htet Aung K, et al.DNA Methyltransferase Inhibitor Zebularine Induces Human Cholangiocarcinoma Cell Death through Alteration of DNA Methylation Status[J]. PLOS ONE, 2015,10(3):e120545.
[13] Lee J, Kim Y, Sohn S K, et al.Benefits of hypomethylating therapy in IPSS lower-risk myelodysplastic syndrome patients: A retros-pective multicenter case series study[J]. Leukemia Research, 2017,60(60):135-144.
[14] Gore S D, Fenaux P, Santini V, et al.A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial[J]. Haematologica, 2013,98(7):1067-1072.
[15] Garcia-Manero G.Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management[J]. Am J Hematol, 2015,90(9):831-841.
[16] Mahfouz R Z, Jankowska A, Ebrahem Q, et al.Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy[J]. Clin Cancer Res, 2013,19(4):938-948.
[17] Chang C, Zhao Y, Xu F, et al.TP53 mutations predict decitabine-induced complete responses[J]. British Journal of Haematology, 2017,176(4):600-608.
[18] Momparler R L.Pharmacology of 5-Aza-2'-deoxycytidine (deci-tabine)[J]. Seminars in Hematology, 2005,42(3 suppl 2):9-16.
[19] Li X, Song Q, Chen Y, et al.Decitabine of reduced dosage in Chinese patients with myelodysplastic syndrome: a retrospective analysis[J]. PLoS One, 2014,9(4):e95473.
[20] Li H, Wang L, Wu Y, et al.Very-Low-Dose Decitabine Is Effective in Treating Intermediate- or High-Risk Myelodysplastic Syndrome[J]. Acta Haematologica, 2017,138(3):168-174.
[21] Ye L, Ren Y, Zhou X, et al.Decitabine priming prior to low-dose chemotherapy improves patient outcomes in myelodysplastic syndromes-RAEB: a retrospective analysis vs. chemotherapy alone[J]. Journal of Cancer Research and Clinical Oncology, 2017, 143(5):873-882.
[22] rskov A D, Treppendahl M B, Skovbo A, et al. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation[J]. Oncotarget, 2015,6(11):9612-9626.
[23] Prébet T, Gore S D, Esterni B, et al.Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure[J]. Journal of Clinical Oncology, 2011,29(24):3322-3327.
[24] Sekeres M A.Managing patients with higher-risk myelodysplastic syndrome with stable disease on hypomethylating agents[J]. Leuk Lymphoma, 2015,56(12):3267-3269.
[25] Komrokji R S.Treatment of Higher-Risk Myelodysplastic Syndromes After Failure of Hypomethylating Agents[J]. Clinical Lymphoma Myeloma and Leukemia, 2015,15:S56-S59.
[26] Loiseau C, Ali A, Itzykson R.New therapeutic approaches in myelodysplastic syndromes: Hypomethylating agents and lenalid-omide[J]. Exp Hematol, 2015,43(8):661-672.
[27] Garcia-Manero G, Gore S, Kambhampati S.Efficacy and safety of extended dosing schedules of CC-486[J]. Leukemia, 2016(30):889-896.
[28] Issa J J, Roboz G, Rizzieri D, et al.Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study[J]. oncology, 2015,16(9):1099-1110.
[29] Kantarjian H M, Roboz G J, Kropf P L, et al.Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial[J]. Lancet Oncol, 2017,18(10):1317-1326.
[30] Shahrabi S, Khosravi A, Shahjahani M, et al.Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights[J]. Oncology Reviews, 2016,10(2):311.
[31] Kuendgen A, Bug G, Ottmann O G, et al.Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid[J]. Clinical Epigenetics, 2011,2(2):389-399.
[32] Issa J, Garcia-Manero G, Huang X, et al.Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia[J]. Cancer, 2015,121(4):556-561.
[33] Candelaria M, Burgos S, Ponce M, et al.Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP) as epigenetic treatment for myelodysplastic syndrome (MDS)[J]. Ann Hematol, 2017,96(11):1825-1832.