利妥昔单抗诱导免疫耐受以消除血友病A高滴度抑制物的结果：通过指数衰减模型描述以及RNA测序分析不同结果的基因表达谱

Outcomes of immune tolerance induction with rituximab to eradicate high-titer inhibitor of hemophilia A: depicted by exponential decay model and the gene expression profile of different outcomes by RNA-sequencing.

作者信息

Li Zekun, Tang Yongqiang, Chen Zhenping, Liu Guoqing, Yao Wanru, Li Gang, Cheng Xiaoling, Peng Yaguang, Cai Siyu, Cui Chang, Ai Di, Zhang Jialu, Poon Man Chiu, Zhang Wensheng, Wu Runhui

机构信息

Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

State Key Laboratory of Multimodal Artificial Intelligence Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China.

出版信息

J Thromb Haemost. 2025 Aug;23(8):2436-2448. doi: 10.1016/j.jtha.2025.04.015. Epub 2025 Apr 24.

DOI:10.1016/j.jtha.2025.04.015

PMID:40286913

Abstract

BACKGROUND

Eradication of inhibitors is still a desirable goal for patients with hemophilia A inhibitors. Combining rituximab with immune tolerance induction (ITI) is the secondline regimen, but data and predictors are limited.

OBJECTIVES

To evaluate the efficacy of ITI-rituximab and to identify the predictors of prognosis.

METHODS

In total, 76 children with high-titer inhibitor prospectively using low-dose ITI together with 1-3 round(s) of rituximab were evaluated for outcomes: success or failure and rapidity (rapid or slow) of inhibitor negativity (ie, inhibitor titers turned negative, inhibitor negativity [IN]). The whole-transcriptome RNA-sequencing (RNA-seq) was used to analyze the gene expression profile of 4 failure patients (excluding F8 large deletion) and 4 rapid success-IN patients.

RESULTS

Success IN was achieved in 41 of 76 (53.9%) patients after first-round of rituximab, 50 of 76 (65.8%) after second-round of rituximab, and 51 of 76 (67.1%) after third-round of rituximab. Profile of inhibitor decay followed an exponential decay curve. Time to a given inhibitor titer during ITI-rituximab could be estimated by the model t=ln(Y0-PlateauY-Plateau)k. The newly observed poor prognostic factors included relapse after the first-round of rituximab and early occurence of poor-outcome events. RNA-seq analysis showed 186 upregulated differential expressed genes (DEGs) and 176 downregulated DEGs in failure subjects compared with those in patients with rapid success IN. The upregulated DEGs included CXCL8, NLRP6, CHI3L1, CLEC9A, THBD, and PROS1. The downregulated DEGs included STAT1, TLR7, C1Q, C2, IDO1, and CD38.

CONCLUSION

Success IN was achieved in 67% of children with hemophilia A with high-titer inhibitor treated by ITI-rituximab. A model based on the profile of inhibitor-titer decay can be used for predicting outcomes. Humoral immune response and complement and coagulation cascades may act as signals that influence ITI outcomes (ClinicalTrials.gov: NCT03598725).

摘要

背景

对于甲型血友病抑制物患者而言，消除抑制物仍是一个理想目标。将利妥昔单抗与免疫耐受诱导（ITI）联合使用是二线治疗方案，但相关数据和预测指标有限。

目的

评估ITI-利妥昔单抗的疗效，并确定预后的预测指标。

方法

总共对76名高滴度抑制物的儿童进行前瞻性评估，这些儿童前瞻性地使用低剂量ITI并联合1 - 3轮利妥昔单抗，评估结果包括：成功或失败以及抑制物转阴的速度（快速或缓慢）（即抑制物滴度转为阴性，抑制物转阴[IN]）。采用全转录组RNA测序（RNA-seq）分析4例失败患者（不包括F8大片段缺失）和4例快速成功转阴患者的基因表达谱。

结果

76例患者中，41例（53.9%）在第一轮利妥昔单抗治疗后实现抑制物转阴成功，第二轮利妥昔单抗治疗后76例中有50例（65.8%）成功，第三轮利妥昔单抗治疗后76例中有51例（67.1%）成功。抑制物衰减曲线呈指数衰减。在ITI-利妥昔单抗治疗期间达到给定抑制物滴度的时间可通过模型t = ln(Y0 - PlateauY - Plateau) / k估算。新观察到的不良预后因素包括第一轮利妥昔单抗治疗后复发以及不良结局事件的早期发生。RNA-seq分析显示，与快速成功转阴的患者相比，失败患者中有186个上调的差异表达基因（DEG）和176个下调的DEG。上调的DEG包括CXCL8、NLRP6、CHI3L1、CLEC9A、THBD和PROS1。下调的DEG包括STAT1、TLR7、C1Q、C2、IDO1和CD38。