Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.
Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.
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DOI：
10.1182/bloodadvances.2022008325
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发表时间：
2022-10-25
期刊：
影响因子：
7.5
通讯作者：
Tam, Constantine S.
中科院分区：
文献类型：
--
作者：
Blombery, Piers;Thompson, Ella R.;Lew, Thomas E.;Tiong, Ing Soo;Bennett, Rory;Cheah, Chan Y.;Lewis, Katharine Louise;Handunnetti, Sasanka M.;Tang, Chloe Pek Sang;Roberts, Andrew;Seymour, John F.;Tam, Constantine S.
共价的布鲁顿酪氨酸激酶抑制剂（BTK）对慢性淋巴细胞白血病（CLL）的治疗非常有效。用BTKi伊曲替尼观察到的主要耐药机制是BTK Cys 481密码子突变的发展。对于新一代，更有选择性的BTKi zanurotinib是否存在类似的耐药突变谱尚不清楚。在进行性CLL患者的诊断性下一代测序样本中，我们观察到zanuinib治疗患者的激酶死亡BTK Leu 528 Trp突变富集，与伊曲替尼相比（54%; 7/13 vs 4%; 1/24，P = 0.001）。我们描述了2例BTK Leu 528 Trp突变患者，当用非共价BTKi pirtoclutinib治疗时，这些患者显示出临床交叉耐药和BTK Leu 528 Trp突变随时间的进行性富集。两名患者随后对基于维奈托克的治疗有反应。总之，我们已经确定了在接受扎努替尼治疗的患者中出现的BTK Leu 528 Trp突变的富集，这可能会对非共价抑制剂吡托替尼产生交叉耐药性，因此可能对CLL中这些治疗的测序产生影响。与那些在依那替尼上进展的CLL患者相比，在扎努替尼上进展的CLL患者具有BTK Leu 528 Trp的富集。交叉耐药可能在接受BTK Leu 528 Trp突变的扎努替尼和后续吡托替尼治疗期间进展的患者中观察到。
The covalent Bruton’s tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL. Patients with CLL progressing on zanubrutinib have an enrichment of the BTK Leu528Trp compared with those who progress on ibrutinib. Cross-resistance may be observed in patients who progress while on zanubrutinib with BTK Leu528Trp mutations and subsequent pirtobrutinib.
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DOI：
10.1056/nejmoa2114110
发表时间：
2022-02-24
期刊：
The New England journal of medicine
影响因子：
--
作者：
通讯作者：
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在先前治疗的慢性淋巴细胞性白血病中，阿卡劳替尼与伊布鲁替尼：第一次随机III期试验的结果。
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：
--
作者：
Byrd JC;Hillmen P;Ghia P;Kater AP;Chanan-Khan A;Furman RR;O'Brien S;Yenerel MN;Illés A;Kay N;Garcia-Marco JA;Mato A;Pinilla-Ibarz J;Seymour JF;Lepretre S;Stilgenbauer S;Robak T;Rothbaum W;Izumi R;Hamdy A;Patel P;Higgins K;Sohoni S;Jurczak W
通讯作者：
Jurczak W
影响因子：
3.4
作者：
Pan, Zhengying;Scheerens, Heleen;Palmer, James T.
通讯作者：
Palmer, James T.
影响因子：
45.3
作者：
Woyach, Jennifer A.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
6.4
作者：
Gango, Ambrus;Alpar, Donat;Bodor, Csaba
通讯作者：
Bodor, Csaba