奥雷巴替尼治疗慢性髓系白血病的研究进展
Research Progress of Olverembatinib in the Treatment of Chronic Myeloid Leukemia
DOI: 10.12677/ACM.2023.1381727, PDF,   
作者: 余 甜:三峡大学基础医学院,湖北 宜昌;余 涛*:三峡大学附属仁和医院血液科,湖北 宜昌
关键词: 酪氨酸激酶抑制剂奥雷巴替尼慢性粒细胞白血病T315I突变Tyrosine Kinase Inhibitor Olverembatinib Chronic Myeloid Leukemia T315I Mutation
摘要: 在慢性粒细胞白血病患者中,野生型及发生继发性突变的BCR-ABL1融合基因,会激活下游信号通路,导致癌症的发生。然而BCR-ABL1的突变赋予了耐药的发生,潜在影响了酪氨酸激酶抑制剂治疗慢粒的有效性。其中,突变率最高的是T315I,它对所有的一代、二代TKI耐药,虽普纳替尼与阿西米尼对其有一定的疗效,但普纳替尼较高的副反应发生率,如心血管毒性及肝毒性,仍让一部分患者陷入困境,且两者均未在中国上市,购买不易。因此,由我国研制的第三代酪氨酸激酶抑制剂奥雷巴替尼,解决了我国伴T315I突变的慢粒患者的治疗空白。奥雷巴替尼在目前的临床试验中展现出了良好的有效性和安全性,未来是值得期待的。
Abstract: In patients with chronic myeloid leukemia, wild type and secondary mutation of BCR::ABL1 fusion gene can activate downstream signaling pathways, leading to the occurrence of cancer. However, mutations in BCR::ABL1 confer resistance, potentially affecting the effectiveness of tyrosine kinase inhibitors in the treatment of CML. T315I has the highest mutation rate, which is resistant to all first-generation and second-generation TKIs. Ponatinib and asciminib have a certain effect on it, but the high incidence of side effects of ponatinib, such as cardiovascular toxicity and liver toxicity, still makes some patients in trouble. Neither is listed in China, making it difficult to buy. Therefore, the third-generation tyrosine kinase inhibitor Olverembatinib developed by China has solved the treatment gap of patients with CML with T315I mutation in China. In the current clinical trials, Ol-verembatinib has shown good efficacy and safety, and the future is worth looking forward to.
文章引用:余甜, 余涛. 奥雷巴替尼治疗慢性髓系白血病的研究进展[J]. 临床医学进展, 2023, 13(8): 12321-12325. https://doi.org/10.12677/ACM.2023.1381727

参考文献

[1] Deininger, M.W., Shah, N.P., Altman, J.K., et al. (2020) Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 18, 1385-1415.
[2] Cortes, J.E., Saglio, G., Kantarjian, H.M., et al. (2016) Final 5-Year Study Results of DASISION: The Dasatinib versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. Journal of Clinical Oncology, 34, 2333-2340. [Google Scholar] [CrossRef
[3] Hochhaus, A., Saglio, G., Hughes, T.P., et al. (2016) Long-Term Benefits and Risks of Frontline Nilotinib vs Imatinib for Chronic Myeloid Leukemia in Chronic Phase: 5-Year Update of the Randomized ENESTnd Trial. Leukemia, 30, 1044-1054. [Google Scholar] [CrossRef] [PubMed]
[4] Cortes, J.E., Gambacorti-Passerini, C., Deininger, M.W., et al. (2018) Bo-sutinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results from the Randomized BFORE Trial. Journal of Clinical Oncology, 36, 231-237. [Google Scholar] [CrossRef
[5] Busque, L., Harnois, M., Szuber, N., et al. (2022) S159: Québec CML Research Group Analysis of Treatment Patterns in Chronic Myelogenous Leukemia: Switching Is Driven by Intol-erance and Similar across Tyrosine Kinase Inhibitors and Lines of Treatment. HemaSphere, 6, 60-61. [Google Scholar] [CrossRef
[6] Réa, D. and Hughes, T.P. (2022) Development of Asciminib, a Novel Allosteric Inhibitor of BCR-ABL1. Critical Reviews in Oncology/Hematology, 171, Article ID: 103580. [Google Scholar] [CrossRef] [PubMed]
[7] Scalzulli, E., Carmosino, I., Bisegna, M.L., et al. (2022) CML Resistant to 2nd-Generation TKIs: Mechanisms, Next Steps, and New Directions. Current Hematologic Malignancy Reports, 17, 198-205. [Google Scholar] [CrossRef] [PubMed]
[8] Ren, X., Pan, X., Zhang, Z., et al. (2013) Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region-Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib. Journal of Medicinal Chemistry, 56, 879-894. [Google Scholar] [CrossRef] [PubMed]
[9] 石大雨, 秦亚溱, 赖悦云, 等. BCR-ABL激酶区突变在酪氨酸激酶抑制剂耐药慢性髓性白血病患者中的分布及其影响因素[J]. 中华血液学杂志, 2020, 41(6): 469-476.
[10] O’Hare, T., Shakespeare, W.C., Zhu, X., et al. (2009) AP24534, a pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance. Cancer Cell, 16, 401-412. [Google Scholar] [CrossRef] [PubMed]
[11] Deininger, M.W., Hodgson, J.G., Shah, N.P., et al. (2016) Com-pound Mutations in BCR-ABL1 Are Not Major Drivers of Primary or Secondary Resistance to Ponatinib in CP-CML Patients. Blood, 127, 703-712. [Google Scholar] [CrossRef] [PubMed]
[12] Qiang, W., Antelope, O., Zabriskie, M.S., et al. (2017) Mech-anisms of Resistance to the BCR-ABL1 Allosteric Inhibitor Asciminib. Leukemia, 31, 2844-2847. [Google Scholar] [CrossRef] [PubMed]
[13] Jiang, Q., Li, Z., Qin, Y., et al. (2022) Olverembatinib (HQP1351), a Well-Tolerated and Effective Tyrosine Kinase Inhibitor for Patients with T315I-Mutated Chronic Myeloid Leukemia: Results of an Open-Label, Multicenter Phase 1/2 Trial. Journal of Hematology & Oncology, 15, 113. [Google Scholar] [CrossRef] [PubMed]
[14] 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)恶性血液病诊疗指南(2022) [Z]. 2022.
[15] Jiang, Q., Li, Z.R., Qin, Y.-Z., et al. (2022) A Five-Year Fol-low-up on Safety and Efficacy of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase In-hibitor (TKI), in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML) in China. Blood, 140, 198-199. [Google Scholar] [CrossRef
[16] Zabriskie, M.S., Eide, C.A., Tantravahi, S.K., et al. (2014) BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. Cancer Cell, 26, 428-442. [Google Scholar] [CrossRef] [PubMed]
[17] Gibbons, D.L., Pricl, S., Posocco, P., et al. (2014) Molecular Dy-namics Reveal BCR-ABL1 Polymutants as a Unique Mechanism of Resistance to PAN-BCR-ABL1 Kinase Inhibitor Therapy. Proceedings of the National Academy of Sciences of the United States of America, 111, 3550-3555. [Google Scholar] [CrossRef] [PubMed]
[18] Jiang, Q., Li, Z.R., Hou, Y., et al. (2022) Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation. Blood, 140, 203-204. [Google Scholar] [CrossRef
[19] Jabbour, E., Koller, P.B., Oehler, V.G., et al. (2022) Olverembat-inib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leu-kemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL). Blood, 140, 200-202. [Google Scholar] [CrossRef
[20] Cortes, J.E., Kim, D.W., Pinilla-Ibarz, J., et al. (2018) Ponatinib Efficacy and Safety in Philadelphia Chromosome-Positive Leukemia: Final 5-Year Results of the Phase 2 PACE Trial. Blood, 132, 393-404. [Google Scholar] [CrossRef] [PubMed]
[21] Jain, P., Kantarjian, H., Boddu, P.C., et al. (2019) Analysis of Cardiovascular and Arteriothrombotic Adverse Events in Chronic-Phase CML Patients after Frontline TKIs. Blood Ad-vances, 3, 851-861. [Google Scholar] [CrossRef] [PubMed]
[22] Byrgazov, K., Lucini, C.B., Valent, P., et al. (2018) BCR-ABL1 Compound Mutants Display Differential and Dose Dependent Responses to Ponatinib. Haematologica, 103, e10-e12. [Google Scholar] [CrossRef] [PubMed]