在一项心脏肿瘤队列的前瞻性研究中，具有不确定潜能的克隆性造血与免疫检查点抑制剂相关性心肌炎风险增加有关。

Clonal hematopoiesis of indeterminate potential is associated with increased risk of immune checkpoint inhibitor myocarditis in a prospective study of a cardio-oncology cohort.

作者信息

Jaber Chehayeb Rachel, Singh Jaiveer, Matute-Martinez Carlos, Chen Nathan W, Guajardo Ana Ferrigno, Lin Derrick, Jayakrishnan Ritujith, Christofides Anthos, Leveille Etienne, Im Yunju, Biancon Giulia, VanOudenhove Jennifer, Ibrahim Eiman, Ardasheva Anastasias, Jha Alokkumar, Hwa John, Halene Stephanie, Kwan Jennifer M

机构信息

Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Yale School of Medicine, New Haven, CT, USA.

出版信息

Cardiooncology. 2024 Nov 26;10(1):84. doi: 10.1186/s40959-024-00289-z.

DOI:10.1186/s40959-024-00289-z

PMID:39587635

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11590368/

Abstract

BACKGROUND

Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to increase all-cause mortality and risk of cardiomyopathy in patients with solid malignancies. CHIP has also been shown to increase T cell activation in heart failure patients. It is unclear whether CHIP can affect the risk of immune checkpoint inhibitor (ICI) myocarditis in patients with cancer treated with immunotherapy.

METHODS

We enrolled patients with solid tumors in a prospective study, determined CHIP status at time of enrollment through blood whole exome sequencing, and assessed incidence of ICI myocarditis from time of enrollment through December 1st, 2023. We performed a competing risk cox regression to evaluate the role of CHIP in ICI myocarditis, accounting for patient demographics, cardiac comorbidities, cardiotoxic cancer therapy, and dual ICI use in our covariates. We also generated cumulative incidence curves using subdistribution hazards to evaluate development of ICI myocarditis stratified by CHIP vs no CHIP. Chart review was performed to evaluate patient co-morbidities, lab values, imaging findings and outcomes.

RESULTS

Among the 88 patients receiving ICI therapy, average age was 67 ± 14 years, of which 50% harbored CHIP variants. Among all comorbidities, including diabetes, heart failure and obstructive coronary artery disease, only coronary artery calcifications were significantly increased in patients with CHIP. There were no statistically significant differences in cancer therapy or cardiovascular drugs between patients with and without CHIP. Among examined outcomes, patients with CHIP had a statistically higher rate of ICI myocarditis (overall: 57%, CHIP: 73% (32/44), no CHIP: 41% (18/44), p = 0.003) and death (CHIP: 60%, no CHIP 31%, p = 0.011). In a multivariate competing risk analysis, CHIP status doubled the risk of developing ICI myocarditis, similar to the risk of dual ICI use (CHIP status HR 2.74, 95% CI: 1.44-5.22, p = 0.002 vs dual ICI use HR 2.39, 95% CI: 1.11-5.14, p = 0.026).

CONCLUSIONS

This study is the first to show that CHIP independently increases risk of ICI myocarditis, with implications for risk stratification of patients prior to ICI initiation and frequency of cardiac monitoring.

摘要

背景

不确定潜能的克隆性造血（CHIP）已被证明会增加实体恶性肿瘤患者的全因死亡率和心肌病风险。CHIP也被证明会增加心力衰竭患者的T细胞活化。尚不清楚CHIP是否会影响接受免疫治疗的癌症患者发生免疫检查点抑制剂（ICI）心肌炎的风险。

方法

我们纳入了实体瘤患者进行一项前瞻性研究，在入组时通过血液全外显子测序确定CHIP状态，并评估从入组到2023年12月1日期间ICI心肌炎的发生率。我们进行了竞争风险cox回归，以评估CHIP在ICI心肌炎中的作用，在协变量中考虑了患者人口统计学、心脏合并症、心脏毒性癌症治疗以及双联ICI使用情况。我们还使用亚分布风险生成累积发病率曲线，以评估按CHIP与无CHIP分层的ICI心肌炎的发生情况。进行病历审查以评估患者合并症、实验室检查值、影像学检查结果和结局。

结果

在88例接受ICI治疗的患者中，平均年龄为67±14岁，其中50%携带CHIP变异。在所有合并症中，包括糖尿病、心力衰竭和阻塞性冠状动脉疾病，只有CHIP患者的冠状动脉钙化显著增加。有CHIP和无CHIP患者在癌症治疗或心血管药物方面没有统计学显著差异。在检查的结局中，CHIP患者的ICI心肌炎发生率在统计学上更高（总体：57%，CHIP：73%（32/44），无CHIP：41%（18/44），p = 0.003），死亡率也更高（CHIP：60%，无CHIP：31%，p = 0.011）。在多变量竞争风险分析中，CHIP状态使发生ICI心肌炎的风险增加一倍，与双联ICI使用的风险相似（CHIP状态HR 2.74，95%CI：1.44 - 5.22，p = 0.002；双联ICI使用HR 2.39，95%CI：1.11 - 5.14，p = 0.026）。