Clinical Study On The Efficacy And Side Effects Of PD-1 Inhibitor Combined With P-Gemox-Dex Regimen In The Treatment Of Plasma Epstein-Barr Virus-positive ENKTCL

Background&Purpose:Extranodal natural killer/T cell lymphoma（ENKTCL）is a highly aggressive non-Hodgkin lymphoma（NHL）that occurs primarily in the nasal cavity and is closely associated with epstein-barr virus（EBV）infection.Plasma epstein-barr virus（EBV）is an independent poor prognosis factor in extranodal NK/T cell lymphoma.A Asparaginase Erwinia chrysanthemi chemotherapy regimen and（or）radiotherapy are effective for stage I and II ENKTCL,but not for advanced or relapsed ENKTCL.In recent years,many studies have found that targeted therapy with PD-1/PD-L1 inhibitors can benefit some relapsed and refractory ENKTCL patients.In our center’s previous retrospective study of PD-1 inhibitors combined with chemotherapy in newly diagnosed and advanced plasma EBV positive ENKTCL patients,PD-1 inhibitor combined with P-Gemox-Dex regimen was effective in the treatment of EBV became negative in advanced high-risk patients.The purpose of this study was to evaluate the efficacy and safety of PD-1 inhibitor combined with P-Gemox-Dex regimen in the treatment of EBV positive ENKTCL,to explore the factors influencing the efficacy of PD-1 inhibitor combined with chemotherapy.To provide basis for individual treatment of ENKTCL.Materials and methods:1.This single-arm prospective,single-center,open-label study included 15 newly diagnosed plasma EBV-positive ENKTCL patients.All patients were diagnosed by biopsy and histopathology in the our hospital.2.The clinical data were collected,including age,sex,B symptoms,primary lesion site,biochemical and immunological test results,and Ann Arbor staging,ECOG score,PINK score,etc.15 patients were divided into two groups according to whether or not the EBV turned negative after two courses of treatment:C₂-positive group and C₂-negative group.15 patients were divided into C4-CR group and C4-non-CR group based on whether they achieved complete remission（CR）after four courses of treatment.The clinical characteristics,prognosis and adverse reactions were analyzed and compared between groups with different treatment courses and curative effects.3.Immunohistochemical methods were used to detect the expression of DDX3,VISTA,BTLA,LAG3,PD1,and PDL1 in biopsy pathological specimens.4.The 80 genes that might be related to the prognosis and therapeutic effect of ENKTCL were selected for targeted sequencing,and the expression rate of hot genes in the samples was analyzed.Results:1.A total of 15 ENKTCL patients with plasma EBV-positive were enrolled.After 2 courses of PD-1inhibitor combined with P-Gemox-Dex regimen,the negative conversion rate of plasma EBV was 60%（9/15）,after 4 courses of treatment,the negative conversion rate of plasma EBV was 86.7%（13/15）.After 4courses of treatment,the CR rate,PR rate,and ORR rate of 15 patients were 80%,13.3%,and 93.3%,respectively.the 1-year and 2-year OS were 93.3%,the 1-year PFS was 93.3%,and the 2-year PFS was77.8%,respectively.Among them,9 patients were advanced stage patients.After 4 courses of treatment,the plasma EB virus negative rate was 88.9%（8/9）,the CR rate was 66.7%,the PR rate was 22.2%,the ORR rate was 88.9%,the 1-year and 2-year OS were 88.9%,the 1-year PFS was 88.9%,and the 2-year PFS was63.5%;2.The main adverse reactions in 15 patients were fibrinogen reduction（73.33%,11/15）,liver function injury（ALT/AST increase）（66.67%,10/15）,albumin reduction（66.67%,10/15）,most of the treatment-related adverse events were Grade I and II,and no grade IV adverse events were observed.All patients have good tolerance to these adverse reactions.3.The number of patients with primary lesion located in nose and PINK score<2 was significantly higher in C₂-negative group than in C₂-positive group（P=0.044,P=0.041）,the level of pre-treatment prealbumin in C₂-negative group was significantly higher than that in C₂-positive group（P=0.013）.4.There was a significant increase in Alkaline phosphatase levels after treatment in both the C₂-negative group and C₂-positive group（P=0.008,P=0.046）.The levels of percentage of CD8+T lymphocyte and Immunoglobulin G after treatment were significantly higher than before treatment in the C₂-negative group（P=0.038,P=0.011）,and the albumin levels in the C₂-positive group were significantly lower than before treatment（P=0.028）.5.The OS and PFS of patients in the C₄-CR group were significantly longer than those in the C₄-non-CR group（P=0.046,P=0.05）.From the survival curve,OS and PFS in the C₂-negative group were longer than those in the C₂-positive group,but there was no statistical significance（P>0.05）.6.The co-expression of DDX3 and BTLA was detected by immunohistochemistry in a patient with poor response to PD-1 inhibitor combined with chemotherapy.In gene analysis,in addition to TP53,JAK1and DDX3X mutations,CDKN2A,KRAS and PTEN mutations were also detected.7.KMT2D mutations were detected in 2 advanced patients who had good response to PD-1 inhibitor combined with chemotherapy.Conclusion1.For plasma EBV positive ENKTCL patients,PD-1 inhibitor combined with P-Gemox-Dex regimen can increase the negative conversion rate of plasma EBV and improve the prognosis;2.In ENKTCL patients with EBV positive plasma,the primary lesion was located in the nose,the PINK score was less than 2,and the high level of pre-treatment prealbumin was associated with the negative change of EBV in plasma;3.Patients who achieved CR after 4 courses of PD-1 inhibitor combined with P-Gemox-Dex regimen had significantly longer OS and PFS than those who did not achieve CR;4.PD-1 inhibitor combined with P-Gemox-Dex regimen in newly diagnosed plasma EBV positive ENKTCL patients caused mild and well-tolerated adverse events.