Chronic myeloid leukemia (CML) is characterized by a reciprocal translocation between chromosome 9 and 22 in the hematopoietic stem cell that results in formation of the Philadelphia chromosome (Ph), encoding the BCR::ABL1 fusion gene [1]. The formation of the corresponding   BCR::ABL1 oncoprotein causes the depletion of the N-terminal cap of Abelson murine leukemia viral oncogene homolog 1 (ABL1), which under physiological conditions binds in the myristoyl pocket of the C-terminal lobe of the kinase domain and thereby negatively regulates its activity [2].

慢性粒细胞白血病（CML）的特征是造血干细胞中9号和22号染色体之间的相互易位，导致费城染色体（Ph）的形成，编码BCR：：ABL1融合基因。相应的BCR：：ABL1癌蛋白的形成导致Abelson鼠白血病病毒癌基因同源物1（ABL1）的N-末端帽的消耗，其在生理条件下结合在激酶结构域的C-末端叶的肉豆蔻酰基口袋中，从而负调节其活性。

Loss of ABL1 autoregulation contributes to the constitutive activation of BCR::ABL1, driven by homo-oligomerisation of BCR::ABL1 mediated by the coiled-coil domain of the breakpoint cluster region (BCR) protein [3], which in turn induces uncontrolled proliferation and survival of leukemia stem cells.

ABL1自动调节的丧失有助于BCR：：ABL1的组成型激活，这是由断点簇区（BCR）蛋白的卷曲螺旋结构域介导的BCR：：ABL1的同源寡聚化驱动的，进而诱导白血病干细胞的不受控制的增殖和存活。

Apart from the typical BCR::ABL1 transcripts e13a2 and e14a2, less than 2% of patients express atypical transcripts such as e1a2, e8a2, or e19a2. In these cases, however, reliable monitoring by routine real-time quantitative polymerase chain reaction (RT-qPCR) is not feasible, therefore an assessment of the individual molecular response with specific RT-qPCR primers is recommended [4, 5].The advent of tyrosine kinase inhibitors (TKIs), which competitively disrupt enzyme activity through binding on the adenosine triphosphate (ATP)-binding site of BCR::ABL1, has substantially improved outcome of CML patients and is now standard of care.

除了典型的BCR：：ABL1转录本e13a2和e14a2外，不到2%的患者表达非典型转录本，例如e1a2，e8a2或e19a2。然而，在这些情况下，通过常规实时定量聚合酶链反应（RT-qPCR）进行可靠监测是不可行的，因此建议使用特定的RT-qPCR引物评估个体分子反应[4，5]。酪氨酸激酶抑制剂（TKIs）的出现通过与BCR：：ABL1的三磷酸腺苷（ATP）结合位点结合而竞争性破坏酶活性，大大改善了CML患者的预后，现已成为标准治疗方法。

For first-line treatment of CML in chronic phase (CML-CP), imatinib as well as second-generation TKIs (2GTKIs) dasatinib, nilotinib, and bosutinib are recommended [6]. Compared to imatinib, 2GTKIs achieve earlier and deeper molecular response, permitting treatment-free remission (TFR) more .

对于慢性期CML（CML-CP）的一线治疗，建议使用伊马替尼以及第二代TKIs（2GTKIs）达沙替尼，尼罗替尼和博舒替尼（6）。与伊马替尼相比，2GTKIs可以实现更早和更深的分子反应，从而可以获得更多的无治疗缓解（TFR）。

ReferencesKurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988;319:990–8.Article

参考文献Kurzrock R，Gutterman JU，Talpaz M.费城染色体阳性白血病的分子遗传学。N Engl J Med。1988；319:990–8.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Pluk H, Dorey K, Superti-Furga G. Autoinhibition of c-Abl. Cell. 2002;108:247–59.Article

。细胞。2002年；108:247-59.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993;13:7587–95.CAS

McWhirter JR，Galasso DL，Wang JY。Bcr的卷曲螺旋寡聚结构域对于Bcr-Abl癌蛋白的转化功能至关重要。摩尔细胞生物学。1993年；13： 7587–95.CAS

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Schafer V, White HE, Gerrard G, Mobius S, Saussele S, Franke GN, et al. Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network. J Cancer Res Clin Oncol. 2021;147:3081–9.Article .

Schafer V，White HE，Gerrard G，Mobius S，Saussele S，Franke GN等。评估具有非典型BCR-ABL1融合转录本的慢性粒细胞白血病患者的个体分子反应：EUTOS合作网络的建议。癌症研究临床杂志。2021年；147:3081-9。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cross NCP, Ernst T, Branford S, Cayuela JM, Deininger M, Fabarius A, et al. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia. 2023;37:2150–67.Article

Cross NCP，Ernst T，Branford S，Cayuela JM，Deininger M，Fabarius A等。欧洲白血病网实验室关于慢性粒细胞白血病诊断和治疗的建议。白血病。2023年；37:2150–67.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.Article

Hochhaus A，Baccarani M，Silver RT，Schiffer C，Apperley JF，Cervantes F等。欧洲白血病网2020年治疗慢性粒细胞白血病的建议。白血病。2020年；34:966–84.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mahon FX, Pfirrmann M, Dulucq S, Hochhaus A, Panayiotidis P, Almeida A, et al. European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in chronic myeloid leukemia: final analysis and novel prognostic factors for treatment-free remission. J Clin Oncol. 2024;42:1875–80.Steegmann JL, Baccarani M, Breccia M, Casado LF, Garcia-Gutierrez V, Hochhaus A, et al.

Mahon FX，Pfirrmann M，Dulucq S，Hochhaus A，Panayiotidis P，Almeida A等。慢性粒细胞白血病的欧洲终止酪氨酸激酶抑制剂试验（EURO-SKI）：最终分析和无治疗缓解的新预后因素。J临床肿瘤学。2024年；42:1875–80.Steegmann JL，Baccarani M，Breccia M，Casado LF，Garcia Gutierrez V，Hochhaus A等。

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71.Article .

欧洲白血病网关于管理和避免慢性粒细胞白血病治疗不良事件的建议。白血病。2016年；30:1648-71。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Muller MC, Hochhaus A, et al. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis. Haematologica. 2013;98:1510–6.Article .

Nicolini FE，Ibrahim AR，Soverini S，Martinelli G，Muller MC，Hochhaus A等。在配对分析中，BCR-ABLT315I突变会影响对酪氨酸激酶抑制剂耐药的慢性期慢性粒细胞白血病患者的生存。血液学。2013年；98:1510-6。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mian AA, Schull M, Zhao Z, Oancea C, Hundertmark A, Beissert T, et al. The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL.

Mian AA，Schull M，Zhao Z，Oancea C，Hundertmark A，Beissert T等。看门人突变T315I通过增加或恢复ABL激酶活性以及内源性BCR的异常转磷酸化来赋予对小分子的抗性，即使在BCR/ABL的功能丧失突变体中也是如此。

Leukemia. 2009;23:1614–21.Article .

白血病。2009年；23:1614-21。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Haddad FG, Sasaki K, Bidikian A, Issa GC, Kadia T, Jain N, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation treated in the pre- and post-ponatinib era. Am J Hematol. 2023;98:1619–26.Article

Haddad FG，Sasaki K，Bidikian A，Issa GC，Kadia T，Jain N等。在ponatinib前后治疗的慢性粒细胞白血病和T315I突变患者的特征和结果。Am J Hematol。2023年；98:1619–26.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Hochhaus A, Rea D, Boquimpani C, Minami Y, Cortes JE, Hughes TP, et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. 2023;37:617–26.Article

Hochhaus A，Rea D，Boquimpani C，Minami Y，Cortes JE，Hughes TP等。先前用至少两种酪氨酸激酶抑制剂治疗的慢性粒细胞白血病中的Asciminib与bosutinib：ASCEMBL白血病的长期随访。2023年；37:617–26.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cortes JE, Sasaki K, Kim DW, Hughes TP, Etienne G, Mauro MJ, et al. Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after >/=1 prior tyrosine kinase inhibitor: 2-year follow-up results. Leukemia. 2024;38:1522–33.Cross NC, Melo JV, Feng L, Goldman JM.

Cortes JE，Sasaki K，Kim DW，Hughes TP，Etienne G，Mauro MJ等。先前酪氨酸激酶抑制剂>/=1后T315I突变的慢性期慢性粒细胞白血病患者的Asciminib单药治疗：2年随访结果。白血病。2024年；38:1522–33.Cross NC，Melo JV，Feng L，Goldman JM。

An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia. 1994;8:186–9.CAS .

用于检测血液疾病中BCR-ABL融合mRNA的优化多重聚合酶链反应（PCR）。白血病。1994年；8： 186-9年。

PubMed

PubMed

Google Scholar

谷歌学者

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393–404.Article

Cortes JE，Kim DW，Pinilla Ibarz J，le Coutre PD，Paquette R，Chuah C等。Ponatinib在费城染色体阳性白血病中的疗效和安全性：2期PACE试验的最终5年结果。血。2018年；

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsParticular thanks to Ms. Anja Waldau and Ms. Renate Zietz (Jena University Hospital) for support in sequencing and multiplex PCR of the primary samples, to Ms. Scarlett Schwabe (Leipzig University Hospital) for de-archiving nested PCR data from the first years of treatment and to Dr.

下载参考文献致谢特别感谢Anja Waldau女士和Renate Zietz女士（耶拿大学医院）对主要样品的测序和多重PCR的支持，感谢Scarlett Schwabe女士（莱比锡大学医院）对治疗第一年的巢式PCR数据进行去存档，并感谢Dr。

Kerstin Schäfer-Eckart and Ms. Anja Windisch (Nürnberg Hospital) for de-archiving and providing bone marrow smears of the primary diagnosis. Many thanks to Ms. Melinda Kolb for the native-language proofreading.FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthors and AffiliationsKlinik für Innere Medizin II, Universitätsklinikum Jena, Comprehensive Cancer Center Central Germany, Campus Jena, Jena, GermanyPhilipp Ernst, Jenny Rinke, Thomas Ernst & Andreas HochhausKlinik und Poliklinik für Hämatologie, Zelltherapie, Hämostaseologie und Infektiologie, Universitätsklinikum Leipzig, Comprehensive Cancer Center Central Germany, Campus Leipzig, Leipzig, GermanyGeorg-Nikolaus FrankeMLL Münchner Leukämielabor, München, GermanyFrank Dicker & Torsten HaferlachAuthorsPhilipp ErnstView author publicationsYou can also search for this author in.

Kerstin Schäfer Eckart和Anja Windisch女士（纽伦堡医院）进行了去归档并提供了初步诊断的骨髓涂片。非常感谢梅琳达·科尔布女士的母语校对。。作者信息作者和附属机构Linik für Innere Medizin II，耶拿大学，中央综合癌症中心，耶拿大学，耶拿大学，德国菲利普·恩斯特，詹妮·林克，托马斯·恩斯特和安德烈亚斯·霍豪斯克利克和波利克利克·für Hämatologie，泽尔特赫拉比，Hämostaseologie和Infektiologie，莱比锡大学，中央综合癌症中心，莱比锡大学München，GermanyFrankDicker＆TorstenHaferlachAuthorsPhilippErnstview作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarJenny RinkeView author publicationsYou can also search for this author in

PubMed谷歌学者Jenny RinkeView作者出版物您也可以在

PubMed Google ScholarGeorg-Nikolaus FrankeView author publicationsYou can also search for this author in

PubMed谷歌学术杂志Nikolaus FrankeView作者出版物您也可以在

PubMed Google ScholarFrank DickerView author publicationsYou can also search for this author in

PubMed Google ScholarFrank DickerView作者出版物您也可以在

PubMed Google ScholarTorsten HaferlachView author publicationsYou can also search for this author in

PubMed Google ScholarTorsten HaferlachView作者出版物您也可以在

PubMed Google ScholarThomas ErnstView author publicationsYou can also search for this author in

PubMed Google ScholarAndreas HochhausView author publicationsYou can also search for this author in

PubMed Google ScholarAndreas HochhausView作者出版物您也可以在

PubMed Google ScholarContributionsPE and AH collected and analyzed the data and wrote the manuscript. JR, GNF, FD, TH, and TE provided clinical and molecular data. All authors reviewed the manuscript.Corresponding authorCorrespondence to

PubMed谷歌学术贡献SPE和AH收集并分析了数据并撰写了手稿。JR，GNF，FD，TH和TE提供了临床和分子数据。所有作者都审阅了手稿。对应作者对应

Andreas Hochhaus.Ethics declarations

安德烈亚斯·霍克豪斯。道德宣言

Competing interests

相互竞争的利益

PE, JR, GNF, TE, and AH received support from Novartis through the European Treatment and Outcome Study (EUTOS) for CML. AH received research support from Novartis, BMS, Pfizer, Incyte, Enliven, and TERNS and is Editor-in-Chief of the journal LEUKEMIA. TH declares equity ownership. FD is employed by the MLL.

PE，JR，GNF，TE和AH通过欧洲CML治疗和结果研究（EUTOS）获得了诺华的支持。AH获得了诺华，BMS，辉瑞，Incyte，Enliven和TERNS的研究支持，并且是《白血病》杂志的主编。TH宣布拥有股权。FD由MLL使用。

GNF received fees and travel support from Novartis and served on scientific boards for Incyte. PE received fees for consulting services from Pfizer..

GNF获得了诺华的费用和旅行支持，并在Incyte的科学委员会任职。PE从辉瑞公司获得咨询服务费。。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。权限和权限

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleErnst, P., Rinke, J., Franke, GN. et al. Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation.

转载和许可本文引用了这篇文章Ernst，P.，Rinke，J.，Franke，GN。等人在非典型e19a2 BCR：：ABL1转录本和T315I突变的慢性粒细胞白血病中用asciminib进行三线治疗后的无治疗缓解。

Leukemia (2024). https://doi.org/10.1038/s41375-024-02327-2Download citationReceived: 11 June 2024Revised: 20 June 2024Accepted: 26 June 2024Published: 04 July 2024DOI: https://doi.org/10.1038/s41375-024-02327-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

白血病（2024）。https://doi.org/10.1038/s41375-024-02327-2Download引文收到日期：2024年6月11日修订日期：2024年6月20日接受日期：2024年6月26日发布日期：2024年7月4日OI：https://doi.org/10.1038/s41375-024-02327-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供