Rituximab, high-dose methotrexate plus orelabrutinib as induction therapy in newly diagnosed primary central nervous system lymphoma

For primary central nervous system lymphoma (PCNSL), high-dose methotrexate (HD-MTX)-based chemotherapy remains a widely accepted induction therapy of newly diagnosed PCNSL in fit patients [1].Despite significant advances in the treatment of PCNSL, such as cytarabine plus HD-MTX, and MATRix [2], these regimens had modest responses and a high risk of toxicities.No one regimen has been accepted as the optimal therapy.Bruton's tyrosine kinase inhibitor (BTKi)-based targeted immunochemotherapy has been recently investigated or under investigation [3,4]; however, definite benefits are pending full results.The life-threatening toxicities (e.g., aspergillosis) with ibrutinib also limited its clinical application [5], motivating steps toward less toxic options.Orelabrutinib is an approved, second-generation BTKi with improved selectivity and persistent occupancy for BTK target, less off-target inhibition and notable blood-brain barrier permeability [6].Previous studies have already reported encouraging signals of orelabrutinib combination in PCNSL [7].Here, we reported the results of a prospective, multicenter, investigator-initiated, phase II study (NCT05549284) investigating the rituximab, HD-MTX plus orelabrutinib (RMO) regimen for newly diagnosed PCNSL.We enrolled patients aged 18-75 years with newly diagnosed PCNSL, no previous treatment, and 1 measurable lesion.Eligible patients received induction therapy with rituximab (intravenously 375 mg/m 2 on day (1), methotrexate (intravenously 3.5 g/m 2 on day (2), plus orelabrutinib (orally 150 mg once daily) every 3 weeks.Responders after the four cycles of RMO induction proceeded to protocol-specified consolidation or maintenance therapy according to tolerability and personal choice.Details on study design of this study are in Supplementary Methods.The primary endpoint was the overall response rate (ORR; complete response [CR] plus partial response [PR]) at the end of