Clinical Study Of RMT Regimen In The Treatment Of PCNSL And Clinical And In Vitro Study Of MTOR Inhibitor RAD001 Combined With Gemcitabine In PTCL

Part I Retrospective analysis of RMT regimen in primary central nervous system lymphomaBackground:Primary central nervous system lymphoma(PCNSL)is a rare and aggressive non-Hodgkin’s lymphoma characterized by short course,rapid progression,short survival and poor prognosis.The preferred first-line treatment is high-dose methotrexate(HD-MTX)based chemotherapy combining with whole-brain radiotherapy.Blood-brain barrier affects the efficacy of methotrexate,and new combination therapy regimens are urgently needed.Temozolomide(TMZ),which has good blood-brain barrier penetration ability,is expected to improve the prognosis of patients by combining with HD-MTX.Objective:To investigate the clinical efficacy of RMT regimen(R,rituximab;M,HD-MTX;T,temozolomide)in the treatment of patients with primary central nervous system lymphoma(PCNSL).Methods:The clinical data of patients with PCNSL diagnosed and treated in Guangdong Provincial People’s Hospital from February 2010 to May 2017 was collected.The patient’s treatment options included the following steps.First,patients were given 6-8 cycles of MTX(3.5 g/m~2)for induction treatment,and then 12 cycles of TMZ(150 mg/m~2)for maintenance treatment.The day before induction treatment,patients were given rituximab 375 mg/m~2.A retrospective cohort study was performed on patients receiving HD-MTX+TMZ or HD-MTX+TMZ+R to analyze the survival of the patients.Results:There were 42 patients enrolled in the study,17 cases in HD-MTX+TMZ group and25 cases in HD-MTX+TMZ+R group.The median PFS and OS in HD-MTX+TMZ+R group was 56.7 months and N/A,respectively,while,7.3 months and 34.7 months in HD-MTX+TMZ group,respectively.In addition,there was no significant difference in median survival between patients who received TMZ maintenance therapy and those who were only actively monitored.During the induction period,all the patients had grade 1-2 nausea and vomiting,while in the consolidation treatment period,no grade 3/4 toxicity was observed.Conclusion:The combination of HD-MTX+TMZ+R in the treatment of PCNSL patients shows a definite short-term effect,which can increase the survival rate of the patients.The side effects are mild,and the patients can generally tolerate it.Part II Clinical and in vitro study of m TOR inhibitor RAD001 combined with gemcitabine in Peripheral T-cell lymphomas Background: Relapsed/refractory Peripheral T-cell lymphomas(R/R PTCL)is an aggressive and heterogeneous Non-Hodgkin’s T cell lymphoma,which is resistant to conventional chemotherapy with poor prognosis.Therefore,there is an urgent need to expore potential therapeutics and novel treatment for R/R PTCL patients.The PI3K/AKT/m TOR pathway plays an important role in the progression of PTCL,suggesting that targeting this pathway is an effective treatment to PTCL.However,recent research demonstrated that the m TOR inhibitor everolimus monotherapy has low response rate and short duration time in treating with R/R PTCL.Objective: To investigate the clinical efficacy of everolimus(RAD001)combined with gemcitabine in the treatment of patients with R/R PTCL,and to verify the synergistic effect of everolimus combined with gemcitabine in vitro.Methods: Clinical data of R/R PTCL patients who received everolimus(10mg/day)combined with gemcitabine(1000mg/m2,d1,d8)every 21 days in Guangdong Provincial People’s Hospital from 2018 to 2021 were collected for survival and prognosis analysis.In vitro validation and mechanism exploration were performed by luminescence assay of cell viability,flow cytometry,western blot and RNA-sequencing.Results: A total of 23 patients were enrolled in this cohort,with a complete response rate of 43.5%,a partial response rate of 26.1%,an objective response rate of 69.6%,a median survival of 18.4 months,and a median progression-free survival of 9.9 months.IHC analysis in patients’ samples indicated that the activity of p-AKT and p-S6 K has not correlation with prognosis.In vitro experiments showed that the combination treatment of everolimus and gemcitabine could inhibit cell proliferation effectively and promote apoptosis.Conclusion: Clinical efficacy of everolimus combining with gemcitabine in patients with R/R PTCL was better than everolimus monotherapy.In vitro we have verified that the combination treatment can inhibit cell proliferation effectively and promote apoptosis,and has synergistic effect on the inhibition of tumor.