Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Clin Cancer Res. 2021 Aug 15;27(16):4531-4538. doi: 10.1158/1078-0432.CCR-20-4890. Epub 2021 May 7.
aberration ( mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) aberrations remains unclear, particularly in the context of targeted agents.
We performed deep sequencing of using baseline samples collected from 51 aberrant patients treated with ibrutinib in a phase II study (NCT01500733).
We identified mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit , respectively. The multi-hit subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit compared with those with single-hit . Clinical outcomes were similar in patient subgroups stratified by 2 or >2 aberrations. In multivariable analyses, multi-hit CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib.
In this study, single-hit defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit 3 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit CLL..
在慢性淋巴细胞白血病（CLL）中，畸变（突变和/或 17p 缺失）是最重要的预测标志物。尽管每个畸变都被认为是同等的预后指标，但携带孤立（单打击）或多个（多打击）畸变的预后价值仍不清楚，尤其是在靶向药物治疗的背景下。
我们对 51 例接受伊布替尼治疗的 II 期研究（NCT01500733）中基线样本进行了深度测序。
我们在 43 例患者（84%）中发现了突变，在 47 例患者（92%）中发现了 del(17p)；9 例和 42 例患者分别携带单打击和多打击畸变。多打击畸变亚组患者更年轻，有既往治疗和未突变的免疫球蛋白重链可变区基因状态。与单打击畸变患者相比，多打击畸变患者的总生存期、无进展生存期（PFS）和进展时间（TTP）明显更短。在按 2 个或>2 个畸变分层的患者亚组中，临床结局相似。多变量分析显示，多打击 CLL 与较差的 PFS 和 TTP 独立相关。在敏感性分析中，排除 VAF 低于 1%的突变显示出相似的结果。这些结果在接受伊布替尼治疗的 112 例 CLL 患者的独立基于人群队列中得到了验证。
在这项研究中，单打击畸变定义了一个独特的亚组患者，他们对单药伊布替尼有极好的长期反应，而多打击畸变则与较短的 PFS 独立相关。这些结果需要进一步研究多打击 CLL 的预后和管理。
