The Clinical Research Of Low-dose Lenalidomine Plus Rituximab For Naive Elderly Or Relapsed/refractory B-non-Hodgkin’s Lymphoma

ObjectiveTo evaluate the efficacy and safety of low-dose lenalidomide plus rituximab for naive elderly or relapsed/refractory B-cell non-Hodgkin’s lymphoma and their immunomodulatory effect in combination.MethodsFrom October 2015 to January 2019,34 naive elderly or relapsed/refractory B-cell non-Hodgkin’s lymphoma patients have recieved the low-dose lenalidomide plus rituximab treatment in the department of Hematology,Affiliated Cancer Hospital of Zhengzhou University.10 mg/d of lenalidomide was administered orally,375mg/m~2 of rituximab was intravenously given on day 1 every 3 weeks.6 cycles of rituximab for stage I-II patients and 8 cycles for stage III-IV patients.Then,followed by lenalidomide monotherapy for 2 years.During the treatment,blood routine,blood biochemical,electrolyte and urine routine were monitored,and the dose and time of the drug were adjusted according to platelet level and renal function.The proportion of immune cells in the peripheral blood and the expression of CXCR4 were examined by flow cytometry(FCM)at different time before and after the treatment.Bone marrow invasion patients would take bone marrow cell morphology and flow cytometry before each cycle,to detect their tumor cell load and minimal residual disease(MRD).Once the MRD was negative,the examination was prolonged to every 3 cycle.Imaging examinations of the lesion were performed every 2~3 cycles by using B-ultrasound,CT and/or MRI,and/or PET-CT to assess the efficacy.The efficacy and adverse reactions of the patients were observed also with a long-term follow-up.Results1.Overall response:34 naive elderly or relapsed/refractory B-NHL patients were treated with a low-dose of lenalidomide plus rituximab,the overall response rate(ORR)was 91.2%,of which 19(55.9%)patients achieved complete response(CR)compared 12(35.3%)patients achieved partial remission(PR),the median follow-up was 18 months(range 2~41 months),3-year progression free survival(PFS)was82.8%,3-year overall survival(OS)was 85.2%.2.Subgroup efficacy comparison:The CR rates of the naive elderly group and the relapsed/refractory group were 75.0%(15/20)and 28.6%(4/14),respectively;The CR rate was higher in the naive elderly group than in the relapse/refractory group(75.0%vs.28.6%),and the ORR was similar between the two groups(90.0%vs.92.9%),but there was no significant difference between the long-term efficacy of PFS(86.1%vs.80.8%)and OS(93.3%vs.79.5%)at 35 months in the two groups.Among the 14 relapsed/refractory patients,10 had received rituximab before,of which 4 achieved CR,5 achieved PR,the ORR was 90.0%(9/10).Compared the efficacy of different subtypes of NHL showed that the patients with follicular lymphoma and marginal zone lymphoma have better efficacy.There were no statistical significance in efficacy among age,gender,stage,IPI scores and bone marrow invasion.3.Changes in immune related indicators:The proportion of immune cell subsets and CXCR4 expression levels in peripheral blood of 14 patients were evaluated before,during and after treatment.Of the 14 patients tested,12 achieved CR and 2achieved PR.The proportion of CD3~+T(P<0.001,P=0.001,P=0.004),CD8~+T(P=0.020,P=0.001,P=0.001),the proportion of CD3~+CD16~+CD56~+NK/T(P=0.040,P=0.037,P=0.049)cells after 2 cycles,4 cycles and 6 cycles of treatment was significantly higher than before;The expression levels of CXCR4(P=0.017,P=0.004,P=0.011)after 2,4 and 6 cycles of treatment was significantly lower than before;while the proportion of CD4~+T,CD3~-CD16~+CD56~+NK cells did not change significantly after treatment.4.Safety:The low-dose lenalidomide plus rituximab for naive elderly or relapsed/refractory B-NHL patients with common adverse reactions such as myelosuppression,rash,infection,etc.,and can be tolerated when given symptomatic treatment in time,and no treatment-related deaths.Conclusion1.The low-dose lenalidomide plus rituximab in the treatment of naive elderly or relapsed/refractory B-NHL patients has significant efficacy and tolerable adverse event.The short-term efficacy for the naive elderly patients are better than relapsed/refractory patients,and it is still effective for relapsed/refractory patients after previous treatment with rituximab.Patients with follicular lymphoma and marginal lymphoma have the best efficacy.2.The low-dose lenalidomide plus rituximab may reduce the metastasis and drug resistance of tumor cells by down-regulating the expression of CXCR4,and enhanced anti-tumor by stimulating CD8~+T and NK/T cell expansion to activate cellular immunity effect.