Clinical Efficacy And Safety Of BTK Inhibitor In The Treatment Of Primary Central Nervous System Lymphoma

Objective: Primary central nervous system lymphoma(PCNSL),as a rare malignant brain tumor,is characterized by easy recurrence and poor prognosis.Currently,a number of studies have shown that BTK inhibitors are highly effective in the treatment of primary central nervous system lymphoma.However,this drug has been on the market for a short time in China,and corresponding clinical research results are lacking.By analyzing the clinical efficacy and safety of BTK inhibitors in the treatment of primary central nervous system lymphoma,this paper provides reference for clinical treatment and prognosis,and improves the overall survival rate of this disease.Methods: A retrospective analysis was performed on the clinical data of 22 HIV-negative patients with primary central nervous system lymphoma treated with BTK inhibitors who were confirmed pathologically in the first affiliated hospital of China Medical University from January 2018 to December 2022.SPSS26.0 software was used for statistical analysis.Kaplan-Meier test and Log rank test were used for univariate prognostic analysis.Cox proportional risk model was used for multivariate analysis of significant univariate factors,and independent factors affecting the survival time of OS and PFS were obtained.P<0.05 was considered statistically significant.Results:1.Clinical characteristics:(1)According to the inclusion and exclusion criteria,a total of22 patients with PCNSL were hospitalized in the first affiliated hospital of China Medical University from January 2018 to December 2022,including 14 males and 8 females,with a male-to-female ratio of 1.75:1.The median age at diagnosis was 61 years.There were 12 newly treated PCNSL patients,and their characteristics were as follows: male patients were8(66.7%),female patients were 4(33.3%),male patients: female patients =2:1;The mean age at diagnosis was 60 years old,and the median age was 62 years old,with 6 cases < 60 years old(50%)and 6 cases ≥60 years old(50%).KPS score ≥70 in 12 cases(100%);ECOG score < 2 points in 1 case(8.3%),≥2 points in 11 cases(91.7%);Serum LDH level was normal in 4 cases(33.3%)and elevated in 8 cases(66.7%).Ki-67 expression ≤80% in3 cases(25%),and > 80% in 9 cases(75%);Serum β2 microglobulin was normal in 5patients(41.7%)and elevated in 7 patients(58.3%).There are three kinds of BTKi:ibrutinib,Zebutinib and aubutinib.There were 4 patients in ibrutinib combined with HD-MTX,R and TMZ group,2 patients in Zebrutinib combined with HD-MTX and R combined with TMZ group,3 patients in Zebrutinib combined with HD-MTX and R group,3 patients in obrutinib combined with HD-MTX and R group,and 12 patients initially treated with PCNSL,2 cases(16.7%)were confirmed by craniotomy,and 10cases(83.3%)were confirmed by stereotaxic puncture biopsy.All pathological specimens were confirmed by pathology department as non-Hodgkin’s lymphoma(DLBCL),of which 1 case(8.3%)and 11 cases(91.4%)were of non-germinal center origin.(2)There were 10 patients with R/R-PCNSL,and their characteristics were as follows: 6 patients were male(60%),4 patients were female(40%),male patients: female patients =1.5:1;The mean age at diagnosis was 61 years old,and the median age was 60 years old,including 4patients < 60 years old(40%)and 6 patients ≥60 years old(60%).There were 3 patients(30%)with KPS score < 70,and 7 patients(70%)with KPS score ≥70.One patient(10%)had an ECOG score < 2,and 9 patients(90%)had an ECOG score ≥2.Serum LDH level was normal in 4 cases(40%)and elevated in 6 cases(60%).Ki-67 expression > 80% in 5cases(50%),expression ≤80% in 5 cases(50%);Serum β2 microglobulin was normal in 4cases(40%)and elevated in 6 cases(60%).Among the 10 patients with R/R-PCNSL,4(40%)without monotherapy BTKi were confirmed by craniotomy,and 6(60%)were confirmed by stereotaxic puncture biopsy.All pathological specimens were confirmed by pathology department as non-Hodgkin’s lymphoma with pathological type of DLBCL,and1(10%)of them was from germinal center.Nine cases(90%)were of non-germinal origin.2.Efficacy analysis:(1)Among the 12 patients initially treated with PCNSL,9 patients obtained CR,3 patients obtained PR,CR rate was 75%,ORR rate was 100%,no PD,SD patients,among the 12 patients,6 patients received BTKi monotherapy maintenance therapy after receiving CR,1 patient stopped the drug due to severe rash intolerance.The patients were still CR at the follow-up date,and the PFS rate at 6 months was100%.(2)Among the 10 R/R-PCNSL patients,8 patients had previously received first-line chemotherapy,2 patients had previously received second-line chemotherapy,and all patients were treated with BTKi combined with other chemotherapy regiments.Among them,1 patient obtained CR,6 patients obtained PR,1 patient obtained SD,and 2 patients developed PD,with CR rate of 10%,ORR rate of 70%,and DCR rate of 80%.By the end of follow-up,a total of 3 patients died and 7 patients survived.3.Survival analysis:During the follow-up time,12 patients with PCNSL initially treated with a median follow-up time of 15 months survived,10 patients with R/R-PCNSL with a median follow-up time of 16 months,7 patients survived(70%),3 patients died(30%),the cause of death was relapse or progression of the disease.The average OS was 30.875months(95%CI: 25.093-36.6571),the mean OS2 was 6.557 months(95%CI: 5.147-7.967),and the mean PFS2 was 6.000 months(95%CI: 4.060-7.940).4.Prognosis analysis:Univariate analysis was performed on 10 patients with followup R/R-PCNSL for the factors that might be related to the prognosis of the disease,and P<0.05 was considered to be statistically significant.Kaplan-Meier method was used to evaluate the survival curve,and unreasonable factors were eliminated due to the small sample size.It is concluded that Bcl-2 expression may be an independent risk factor for poor prognosis of R/R-PCNSL.5.Safety:In this study,a total of 22 patients took BTKi,and a total of 33 adverse events(36.4%)were observed,mainly grade 1-2 adverse events,but grade 3-4 adverse events were rare.All patients were followed up and could tolerate related adverse reactions.All adverse reactions were recovered after symptomatic treatment.Only 1 case was discontinued due to severe rash,and no treatment-related death was reported.Conclusion:1.The application of BTKi in the initial treatment of PCNSL showed a high remission rate,a long remission duration and a good effect.2.For R/R-PCNSL patients,the use of BTKi still has a certain effect,can benefit some patients,and the tolerance is good,for patients to win the survival opportunity.3.Bcl-2 expression may be an independent risk factor for poor prognosis in patients with R/R-PCNSL.4.BTKi was well tolerated in the treatment of PCNSL,with mild adverse reactions and no treaty-related death,and the safety was acceptable.