Non-Covalent Bruton's Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia.
Non-Covalent Bruton's Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia.
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DOI：
10.3390/cancers15143648
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发表时间：
2023-07-17
期刊：
影响因子：
5.2
通讯作者：
Thompson, Meghan C. C.
中科院分区：
文献类型：
--
作者：
Montoya, Skye;Thompson, Meghan C. C.
关键词：
正在研究非共价Bruton的酪氨酸激酶抑制剂（NCBTKI）用于治疗B细胞恶性肿瘤，包括慢性淋巴细胞性白血病（CLL）有望治疗CLL，尤其是在需要治疗的情况下，尤其IB用于疾病的肠道或进展。在CLL中使用NCBTKI的临床和临床数据显示，在先前使用BTKI治疗的CLL pirobrutinib对BTKI进行了持久的btki，我们还讨论了ncbtkis inceptive incy的突变，包括该位置，正在进行的临床试验将NCBTKI纳入CLL作为单一疗法或与其他药物的结合疗法。
Bruton的酪氨酸激酶抑制剂（CBTKI）导致了慢性淋巴细胞性白血病的治疗（CLL）的范式转移。毒性或疾病进展。非共价Bruton的酪氨酸激酶抑制剂（NCBTKI）通过与BTK靶标的结合，可以解决毒性的局限性，并获得了几个NCBTKI的抗药性。 AYS和/或难治性地幔细胞淋巴瘤（MCL）已显示出出色的安全性在第1阶段和2阶段试验中，CLL的初步有效性，该试验正在填充CBTKI后需要治疗的CLLL患者的医疗需求。 s （包括在C481位置以外的BTK中获得的新型突变）最近被描述了有关没有事先CBTKI暴露的患者的抵抗力的机制。 ncbtki之后的Cll终止策略正在研究中的新型治疗策略，以解决此类策略的疾病进展。恩斯。
Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) are being investigated for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). These agents hold promise for the treatment of CLL, especially CLL requiring treatment after prior discontinuation of covalent Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib for either intolerance or progression of disease. This review outlines current preclinical and clinical data for the use of ncBTKi in CLL. Recently reported data has shown durable responses for the ncBTKi pirtobrutinib in CLL patients previously treated with a covalent BTKi with a median PFS of 19.6 months. We also discuss recently discovered mechanisms of resistance to ncBTKis, including acquired mutations in the BTK protein not in the C481 position. In addition, we highlight ongoing clinical trials that are incorporating ncBTKis in CLL as monotherapy or in combination therapies with other agents. The results of these trials as well as ongoing research regarding mechanisms of resistance to ncBTKi and covalent Bruton’s Tyrosine Kinase inhibitors will be important to determine where ncBTKi may fit into the treatment of CLL. Covalent Bruton’s tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a “treat-to-progression” strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of “double exposed” CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.
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DOI：
10.1200/jco.21.01210
发表时间：
2021-11-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
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影响因子：
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作者：
Lu D;Jiang J;Liang Z;Sun M;Luo C;Shen B;Hu G
通讯作者：
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影响因子：
3.2
作者：
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影响因子：
10.1
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通讯作者：
Brown JR
影响因子：
7.5
作者：
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Tam, Constantine S.