Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer. 2019 Feb 15;125(4):559-574. doi: 10.1002/cncr.31831. Epub 2018 Dec 3.
In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/phospholipase C gamma 2 (PLCG2) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited.
Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution.
The study group included 29 patients with BTKi-resistant CLL, 23 patients with disease progression, and 6 patients with Richter transformation (RT). The median times to disease progression and RT were 33.3 months and 13.3 months, respectively. In 11 patients, sequencing was possible at both baseline (prior to treatment with BTKi) and at time of disease progression/RT. Of these patients, 4 demonstrated BTK mutations at the time of disease progression/RT; patients without BTK mutations frequently acquired mutations associated with disease progression/RT in TP53, SF3B1, and CARD11, whereas additional mutations were rare in patients with BTK-mutated CLL. Sequencing of all 29 patients at the time of disease progression/RT identified BTK mutations at a frequency of 66%, including a novel V537I mutation. Among patients with disease progression, BTK mutations were observed in 16 patients (70%). The median time to disease progression was shorter in patients without BTK mutations compared with those with BTK-mutated CLL. Among patients with RT, SF3B1 mutations were more frequent than BTK mutations (67% vs 50%). Following BTKi discontinuation, we sequential mutation analysis was performed in 2 patients with RT and 3 patients with disease progression in the setting of persistent disease. Both patients with RT demonstrated disappearance of BTK and expansion of TP53 mutations. All 3 patients with disease progression received venetoclax and demonstrated suppression of BTK mutations.
Longitudinal, targeted, multigene deep sequencing is informative for the clinical monitoring of mutational evolution in patients with CLL who are receiving BTKi.
在一部分慢性淋巴细胞白血病（CLL）患者中，对布鲁顿酪氨酸激酶（BTK）抑制剂（BTKi）的耐药性归因于获得性 BTK/磷脂酶 Cγ2（PLCγ2）突变。然而，关于与 BTK/PLCγ2 突变相关的其他遗传病变以及缺乏 BTK/PLCγ2 突变的患者中的基因突变的知识是有限的。
在一家机构中，使用靶向深度测序评估了在接受伊布替尼/阿卡替尼治疗时出现 BTK 抑制耐药的 CLL 患者中与 CLL 和/或 BCR 信号通路相关的 29 个基因的突变。
研究组包括 29 例 BTKi 耐药性 CLL 患者，23 例疾病进展患者和 6 例 Richter 转化（RT）患者。疾病进展和 RT 的中位时间分别为 33.3 个月和 13.3 个月。在 11 例患者中，在基线（BTKi 治疗前）和疾病进展/RT 时均可以进行测序。其中 4 例在疾病进展/RT 时显示 BTK 突变；无 BTK 突变的患者在 TP53、SF3B1 和 CARD11 中经常获得与疾病进展/RT 相关的突变，而在 BTK 突变的 CLL 患者中，其他突变则很少见。在疾病进展/RT 时对所有 29 例患者进行测序，BTK 突变的频率为 66%，包括新的 V537I 突变。在疾病进展的患者中，有 16 例（70%）患者观察到 BTK 突变。与 BTK 突变的 CLL 患者相比，无 BTK 突变的患者疾病进展时间更短。在 RT 患者中，SF3B1 突变的频率高于 BTK 突变（67%比 50%）。在 RT 患者和疾病进展患者中，在持续疾病的情况下，我们在 BTKi 停药后进行了连续的突变分析。两名 RT 患者和 3 名疾病进展患者均显示 BTK 消失和 TP53 突变扩展。所有 3 名疾病进展患者均接受了 venetoclax 治疗，并显示 BTK 突变受到抑制。
纵向、靶向、多基因深度测序可为接受 BTKi 治疗的 CLL 患者的突变演变的临床监测提供信息。
