Orelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series

Abstract

BackgroundRelapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL) is an intractable situation without sound treatment. Bruton’s tyrosine kinase (BTK) represents an attractive drug target in PCNSL. Orelabrutinib is a new-generation BTK inhibitor with high cerebrospinal fluid (CSF) concentration. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing combination therapy in patients with r/r PCNSL.MethodsWe retrospectively analyzed r/r PCNSL patients who received combination therapy with rituximab, high-dose methotrexate, temozolomide, orelabrutinib and lenalidomide, and further explored the relationship between the efficacy and genetic characteristics.ResultsA total of fifteen patients were included in this retrospective study. The overall response rate (ORR) was 86.7%, the complete remission (CR) rate was 73.3% and the disease control rate (DCR) was 93.3%. Among 13 responders, 9 patients are still receiving oral orelabrutinib and lenalidomide. The most common adverse event (AEs) was transaminase increase (66.7%). No grade 4 AE or drug-related death was reported. Genomic sequencing showed that patients who responded to orelabrutinib had abnormal NF-κB activation, while those who had no response were mainly enriched with transcriptional misregulation. Patients who had mutations in TLR, BCR, or NF-κB pathway achieved complete or partial response to the orelabrutinib-containing therapy. Moreover, the blood and cerebrospinal fluid circulating tumor DNA (ctDNA) were closely associated with tumor recurrence and treatment response and sustained tumor responses correlated with the clearance of ctDNA.ConclusionOrelabrutinib-containing regimen was effective and well-tolerated in patients with r/r PCNSL. Genome sequencing of tumor samples could help to screen patients who may respond to the orelabrutinib-containing regimen, and liquid biopsy may contribute to tracing tumor burden and monitoring treatment response.

Orelabrutinib versus ibrutinib for patients with refractory/relapsed primary central nervous system lymphoma: An efficacy and safety analysis

“…[7] Patients responded to the combination of rituximab and orelabrutinib therapy and had long-term immune-modulatory effects. [7] Therefore, progressive responses were fewer for the RO cohort. Orelabrutinib decreases the risk of progressive response.…”

“…Orelabrutinib has fewer unexpected adverse effects as compared to rituximab and ibrutinib. [7] Orelabrutinib has low off-target reactivity and high target selectivity. [14] Orelabrutinib is tolerated by patients as compared to rituximab and ibrutinib.…”

“…[16] A combination of orelabrutinib and rituximab does not show superiority to orelabrutinib alone and rituximab alone, yet. Based on the pre-clinical study, [16] our institute allows us to use 250 mg/m 2 intravenous rituximab [7] in combination with 150 mg oral orelabrutinib in clinical practice.…”

Bruton’s tyrosine kinase inhibitors in the treatment of primary central nervous system lymphoma: A mini-review

“…A retrospective analysis evaluated the efficacy and safety of orelabrutinib-based chemotherapy in 15 patients with R/R PCNSL. 86.7% patients achieved treatment response and the CR rate was 73.3% (95). Another retrospective analysis of orelabrutinib-based regimen for the treatment of PCNSL (newly diagnosed or R/R).…”

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

“…Among fifteen patients, the overall response rate (ORR), disease control rate (DCR) and complete remission (CR) rate were 86.7%, 73.3% and 93.3%, respectively. 105 …”