Scholarlink

<p>Primary central nervous system large B-cell lymphoma (PCNS-LBCL) exhibits the worst prognosis among all extranodal LBCLs, with the enriched genetic mutations in <i>MyD88</i><sup><i>L265P</i></sup>, <i>CD79B</i> and <i>PIM1</i>. However, the upfront incorporation of targeted therapies remains an unmet need in newly diagnosed (ND) patients. In this study, we found that in the presence of <i>MyD88</i><sup><i>L265P</i></sup> context, B-cell receptor downstream bruton’s tyrosine kinase (BTK) was significantly overexpressed, which subsequently enhanced the stability of PIM1 oncoprotein. To evaluate the intracranial delivery of BTK inhibitor(BTKi), patient-derived PCNS-LBCL xenografted mice models were treated with highly-selective BTKi orelabrutinib, either monotherapeutically or in combining with methotrexate. Interestingly, orelabrutinib showed excellent efficiency crossing BBB with the functional BTK blockade and promoted PIM1 degradation, providing the molecular basis of incorporating BTKi into PCNS-LBCL therapy. Thus, we determined the efficacy and toxicity of orelabrutinib in combination with high-dose methotrexate in a prospective dose-escalating cohort and real-world practice. The patients being treated with orelabrutinib-included ORMD regimen showed better response and more prolonged survival compared to those with RMD regimen. We further investigated the genetic mutations of PCNS-LBCL across tumor tissue, cerebrospinal fluid (CSF) and plasma. The mutations in CSF circulating tumor DNA (ctDNA) rather than plasma-ctDNA were more consistent to those in tumor tissue, indicating that CSF-ctDNA is a useful tool for monitoring PCNS-LBCL. In summary, our data provided the molecular rationale as well as clinical evidences that incorporation of BTKi into frontline induction therapy is a promising strategy for ND PCNS-LBCL.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

BTKi orelabrutinib improved the outcome of newly-diagnosed PCNS-LBCL by alleviating MyD88L265P-induced PIM1 stability

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月17日

查看全文
  • Yan Yuan,
  • Bo Dai,
  • Haoshu Zhong,
  • Jiajun Zheng,
  • Zhen Fan,
  • Di Chen,
  • Qian Wang,
  • Hao Wu,
  • Yuan Li,
  • Ping Zhu,
  • Tianling Ding,
  • Shu Wang,
  • Kunpeng Wu,
  • Yu Zhang,
  • Zhenhua Wang,
  • Rui Feng,
  • Fengping Zhu,
  • Kang Zheng,
  • Zhiyong Qin,
  • Bojie Yang,
  • Hong Chen,
  • Xiaolei Lin,
  • Yu Yao,
  • Dongxiao Zhuang,
  • Zhifeng Shi,
  • Ying Mao,
  • Tong Chen

摘要

Primary central nervous system large B-cell lymphoma (PCNS-LBCL) exhibits the worst prognosis among all extranodal LBCLs, with the enriched genetic mutations in MyD88L265P, CD79B and PIM1. However, the upfront incorporation of targeted therapies remains an unmet need in newly diagnosed (ND) patients. In this study, we found that in the presence of MyD88L265P context, B-cell receptor downstream bruton’s tyrosine kinase (BTK) was significantly overexpressed, which subsequently enhanced the stability of PIM1 oncoprotein. To evaluate the intracranial delivery of BTK inhibitor(BTKi), patient-derived PCNS-LBCL xenografted mice models were treated with highly-selective BTKi orelabrutinib, either monotherapeutically or in combining with methotrexate. Interestingly, orelabrutinib showed excellent efficiency crossing BBB with the functional BTK blockade and promoted PIM1 degradation, providing the molecular basis of incorporating BTKi into PCNS-LBCL therapy. Thus, we determined the efficacy and toxicity of orelabrutinib in combination with high-dose methotrexate in a prospective dose-escalating cohort and real-world practice. The patients being treated with orelabrutinib-included ORMD regimen showed better response and more prolonged survival compared to those with RMD regimen. We further investigated the genetic mutations of PCNS-LBCL across tumor tissue, cerebrospinal fluid (CSF) and plasma. The mutations in CSF circulating tumor DNA (ctDNA) rather than plasma-ctDNA were more consistent to those in tumor tissue, indicating that CSF-ctDNA is a useful tool for monitoring PCNS-LBCL. In summary, our data provided the molecular rationale as well as clinical evidences that incorporation of BTKi into frontline induction therapy is a promising strategy for ND PCNS-LBCL.