Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
Blood Adv. 2022 Oct 25;6(20):5589-5592. doi: 10.1182/bloodadvances.2022008325.
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.
共价布鲁顿酪氨酸激酶抑制剂（BTKi）在治疗慢性淋巴细胞白血病（CLL）方面非常有效。伊布替尼的主要耐药机制是 BTK Cys481 密码子突变的发展。新一代、更具选择性的 BTKi 泽布替尼是否存在类似的耐药突变谱尚不清楚。在因 CLL 进展而接受诊断性下一代测序的样本中，与伊布替尼相比，我们在接受泽布替尼治疗的患者中观察到激酶失活 BTK Leu528Trp 突变的富集（54%，13 例中有 7 例；4%，24 例中有 1 例，P =.001）。我们描述了 2 例 BTK Leu528Trp 突变患者，他们在接受非共价 BTKi 派特鲁滨尼治疗时表现出临床交叉耐药性，并随着时间的推移 BTK Leu528Trp 突变逐渐富集。这 2 例患者随后均对维奈托克治疗有反应。总之，我们已经确定了在接受泽布替尼治疗的患者中 BTK Leu528Trp 突变的富集，这可能导致对非共价抑制剂派特鲁滨尼的交叉耐药性，因此可能对 CLL 中这些治疗的测序产生影响。
