慢性粒细胞白血病靶向治疗研究进展

酪氨酸激酶抑制剂（TKI）的应用革命性地改善了慢性粒细胞白血病（CML）患者的治疗结果和生存。当前治疗CML的新目标是如何获得持续的深度分子生物学反应，以减少耐药复发，甚至实现无治疗的缓解维持和治愈。国际上已有4种TKI获批用于一线治疗初诊的慢性期CML，并且不断有新的药物和治疗方案在研发和临床研究中。文章结合第62届美国血液学会年会相关报道介绍CML靶向治疗研究进展。     

酪氨酸激酶抑制剂治疗中停药问题及根除慢性髓系白血病干细胞的治疗选择：第55届美国血液学会年会报道

酪氨酸激酶抑制剂（TKI）的问世极大程度地改善了慢性粒细胞白血病（CML）的临床疗效,使众多CML患者从中获益,TKI治疗后达到长期完全分子生物学缓解（CMR）的患者停药是否安全,目前仍有争议.TKI治疗后清除残留白血病细胞、防止CML复发的解决方案,特别是针对CML干细胞的靶向治疗应用研究可能有望使CML患者达到长期无病生存,甚至治愈,因此成为人们近年来关注的重点.文章就第55届美国血液学会（ASH）年会上关于TKI停药选择以及清除CML干细胞的研究相关进展进行报道.     

慢性粒细胞白血病治疗中关于停药及治愈问题的研究进展:第54届美国血液学会年会报道

 【摘要】　伊马替尼（IM）及其他酪氨酸激酶抑制剂（TKI）在临床应用中的巨大成功,使慢性粒细胞白血病（CML）的治疗走在肿瘤靶向治疗的前沿。尽管TKI的出现极大地改善了CML患者的预后,然而长期TKI治疗可能给患者带来耐药、严重不良反应、依从性差、沉重的经济负担等问题。近年来,关于CML患者在达到长期完全分子生物学缓解（CMR）后能否安全停药及停药后能否达到治愈是CML研究中的关注点。就2012年第54届美国血液学会（ASH）年会关于CML患者停药及治愈问题的研究进展进行报道。     

慢性粒细胞白血病患者血液肿瘤相关基因突变研究进展

慢性粒细胞白血病（CML）是以Ph染色体异位为特征的骨髓增殖性疾病,酪氨酸激酶抑制剂（TKI）的应用显著改善了CML患者的预后。细胞遗传学和分子学监测用于评估TKI疗效并指导疾病管理已成为CML治疗的重要组成部分。然而,在疾病诊断、转化和耐药性方面扩大基因组分析是CML研究中尚未完全探索的领域。文章旨在探讨CML最初诊断和治疗失败转化时的基因突变频率和类别,分析诊治中基因突变与CML患者预后的关系。     

慢性髓性白血病的现代治疗

 伊马替尼（IM）以及二代酪氨酸激酶抑制剂（TKI）的问世不仅彻底改革了慢性髓性白血病（CML）的治疗模式, 也成为其他肿瘤发病机制和治疗研究的范例。 IM可使90 %以上慢性期患者获得血液学缓解,80 %以上的患者获得遗传学完全缓解（CCyR）及主要分子学缓解（MMoR）。明显延长无病生存期,使CML自然病程大为改观。然而,也存在目前难以克服的缺点：TKI并非疾病基因清除剂,对CML干细胞不敏感,获得CCyR／MMoR者仍需长期持续服用,小部分患者发生抗药或不耐受。现阶段的TKI 仍是根治CML的起始。     

尼洛替尼联合异基因造血干细胞移植治疗慢性粒细胞白血病急变期二例并文献复习

目的观察第2代酪氨酸激酶抑制剂（TKI）尼洛替尼联合异基因造血干细胞移植（allo-HSCT）治疗慢性粒细胞白血病（CML）急变期的安全性及疗效。方法2例CML急变期患者,移植前给予尼洛替尼治疗后桥接allo-HSCT。结果2例患者全部获得造血重建,并达到长期完全分子生物学缓解。结论CML急变后应早期采用第2代TKI治疗,尽早行allo-HSCT术,使疾病回到慢性期,达到疾病的长期缓解。     

异基因造血干细胞移植在慢性粒细胞白血病治疗中仍有一定地位

慢性粒细胞白血病（CML）是成年人常见的白血病,我国CML的年发病率稍低于西方国家。对CML的治疗而言,酪氨酸激酶抑制剂（TKI）——伊马替尼（imatinib mesylate,IM）的问世是继白消安（myleran,busulfan）、     

慢性粒细胞白血病的治疗：停用酪氨酸激酶抑制剂能否带来治愈

 【摘要】 慢性粒细胞白血病患者应用伊马替尼（IM）等酪氨酸激酶抑制剂（TKI）治疗后可达到完全分子生物学缓解（CMR）,此时是否还要继续治疗,成为临床医生和患者都关注的问题。长期服用TKI伴随着沉重的经济负担与发生慢性不良反应的风险。约40 %的CML患者达CMR至少2年后可以停用IM,并且其CMR能维持至少2年。因而,CML患者达到稳定CMR后能否停用TKI以及停药后的复发风险,成为研究CML是否能被治愈的新焦点。就2011年第53届美国血液学会（ASH）年会在这方面的研究进展作一报道。     

慢性髓系白血病治疗新进展：第55届美国血液学会年会报道

慢性期慢性髓系白血病（CML-CP）患者在伊马替尼（IM）治疗得到稳定的完全分子生物学缓解（CMR）后,能否及何时安全停药成为第55届美国血液学会（ASH）年会的讨论热点.来自法国及澳大利亚著名的“停药试验”表明长期单用酪氨酸激酶抑制剂（TKI）不能治愈大部分CML患者.如何清除CML患者体内的残留病灶达到治愈以及长期的“无治疗缓解”和“无白血病生存”成为一线临床医师的关注点.文章就第55届ASH年会相关报道,阐述TKI靶向治疗时代CML潜在的联合治疗方法.     

bcr-abll激酶抑制剂耐药突变研究及治疗进展:第52届美国血液学年会的热点问题

伊马替尼（Imatinib）是人工设计的一种酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）,由于其出色的临床疗效,很快成为慢性粒细胞白血病（CML）的一线治疗药物。但伊马替尼仍不能很快根治CML,需要长期持续用药。不幸的是,许多患者应用不久后就出现了耐药现象。TKI耐药问题越来越被重视。在2010年12月在奥兰多召开的第52届美国血液学年会（Annual Meeting of American Society of Hematology,ASH）上,TKI耐药的研究是非常热门的话题。     

Monitoring patients with chronic myeloid leukemia receiving Abl tyrosine kinase inhibitor therapy

The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). Complete cytogenetic remissions are standard for patients treated in chronic phase; however, treatment outcomes in advanced-phase disease are far less promising. Because hematopoietic cell transplantation is potentially curative in CML and newer TKIs are now available, the use of imatinib necessitates careful monitoring in order to identify cases in which transplantation or alternative TKI therapy might be indicated. Monitoring CML with cytogenetics and molecular methods such as the polymerase chain reaction can define subsets of patients at low or high risk of relapse and progression. In this review, we define the types of tests used to monitor the disease, provide clinically relevant endpoints, and outline guidelines for monitoring patients with CML receiving imatinib therapy.     

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.     

酪氨酸激酶抑制剂耐药的分子机制及耐药后治疗策略

酪氨酸激酶抑制剂(TKI)治疗慢性粒细胞性白血病(CML)的效果虽然显著,但治疗过程中产生的耐药问题仍无法避免.因此,TKI耐药是CML治疗失败的主要原因之一.据报道,约5%的患者对TKI存在原发性耐药,20%~30%的患者对TKI产生继发性耐药.目前已知的TKI耐药分子机制有bcr-abl过表达、基因突变、DNA修复机制缺陷、ATP-binding cassette(ABC)转运蛋白介导的药物外排、异常信号通路及骨髓微环境等.同时,针对各种耐药机制开发的药物多处于临床前或临床研究阶段,这些药物的研究为克服TKI耐药提供了可能.本文拟对TKI耐药的分子机制及耐药后治疗策略的进展进行综述.     

Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells

Although discovery of the tyrosine kinase inhibitor (TKI) imatinib mesylate has significantly improved the prognosis of chronic myeloid leukemia (CML) patients, a rare population of CML stem cells is known to be resistant to TKI therapy, causing recurrence of CML. However, recent progress in CML stem cell biology may present a novel therapeutic avenue for CML patients. In this review, we focus on mechanisms used by CML stem cells to maintain TKI‐resistance. Comprehensive approaches including mouse genetics, prospective identification of CML stem cells, and syngenic transplantation techniques have identified several key molecules or signaling pathways, including hedgehog (Hh)/Smo, promyelocytic leukemia (PML), 5‐lipoxygenase (5‐LO), and forkhead box class O (FOXO), that function in CML stem cell maintenance. Inhibiting some of these factors in combination with TKI administration successfully antagonized resistance of CML stem cells to TKI therapy, resulting in efficient eradication of leukemia cells in vivo. Thus, development of methods that sensitize CML stem cells to TKI therapy may lead to novel therapies to treat CML patients. (Cancer Sci 2010)     

Tailoring tyrosine kinase inhibitor therapy to tackle specific BCR-ABL1 mutant clones

Several tyrosine kinase inhibitors (TKIs) are currently under development for the treatment of patients with chronic myelogenous leukemia (CML) resistant or intolerant of imatinib therapy, including nilotinib, dasatinib, and bosutinib. The current paradigm of TKI therapy involves a sequential use of these compounds, with imatinib invariably used as frontline therapy followed by either dasatinib or nilotinib on an empiric basis. A more sensible approach to this sequence is the selection of the TKI best suited to overcome the resistance conferred by BCR-ABL1 mutations detected at each time-point. As more TKIs are becoming available, the management of patients with CML will require degree of “finesse” to better match each patient with the best TKI available. This match is best made based on available in vitro data regarding the activity of each agent against each specific mutation. The case herein reported supports such strategy.