Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; thirty-seven patients carried mutations. Ten of these carried mutations originating from clonal hematopoiesis. Using unsupervised hierarchical clustering, we identified five distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persists despite successful TKI response (Pattern 1), while patients exhibiting mutation clearance (Pattern 3) show mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (Pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.

多种髓系肿瘤中常见的体细胞突变，尚未在慢性髓系白血病（chronic myeloid leukemia, CML）中得到系统性研究。本研究对100例慢性髓系白血病患者的共计300份系列样本开展靶向深度测序，其中37例患者携带体细胞突变。该37例患者中，10例的突变源于克隆性造血（clonal hematopoiesis）。通过无监督分层聚类分析，本研究鉴定出酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）治疗后突变动态变化的五种截然不同的模式。本研究表明，突变的获得、持续存在与清除模式存在差异，但与临床结局存在多项值得关注的关联。尽管酪氨酸激酶抑制剂治疗应答良好，但突变负荷仍常持续存在（模式1）；而表现出突变清除的患者（模式3）则呈现混杂的临床结局。不出所料，治疗期间获得新突变的患者酪氨酸激酶抑制剂治疗失败（模式2）。上述模式表明，慢性髓系白血病患者在酪氨酸激酶抑制剂治疗后的突变动态特征，与其他髓系肿瘤存在显著差异。综上，对于慢性髓系白血病患者突变谱及其动态特征的临床意义，应谨慎解读。