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

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.