Objective Central nervous system(CNS)lymphoma is a rare type of non-Hodgkins lymphoma,most of which occur primarily in the brain,spinal cord or intraocularly.Elevated dose methotrexate(MTX)-based therapy has been documented as the first-line induction regimen,with or without combination of other chemotherapeutic drugs which can penetrate blood-brain-barrier(BBB).However,since few chemotherapeutic agents crossing BBB are available in China,the optimal dose of MTX and its therapeutic combination needs to be defined.Methods In this study,the outcome of newly-diagnosed(ND)or relapse/refractory(R/R)CNS lymphoma patients between March 2015 and June 2017 in Huashan Hospital of Fudan University were retrospectively analyzed.Among them,forty-one patients were treated with mega-dose(MD)MTX(8g/m2)-based regimen and 30 patients were treated with highdose(HD)MTX(3.5g/m2)-based regimen.The basic HD-MTX or MD-MTX regimen was 3.5g/m2 or 8g/m2 MTX intravenous infusion in 3 hours on day 1,with 15-20mg/d dexamethasone(DXM)intravenous infusion on day 1-3.In MD-MTX-based group,nearly 66%of the patients(27/41)received MD-MTX+DXM only,whereas in HD-MTX-based group,70%of the patients(21/30)received HD-MTX+DXM+X,which represents the addition of other chemotherapeutic agents or Rituximab to HD-MTX+DXM.To prevent the toxicity which is specifically related to MTX treatment,the patients were injected with calcium folinate until the serum MTX concentration reduced <0.15mmol/L.Results The serum concentration of MTX were evaluated at the end of MTX injection(0h),and 24h,48h,72h from the start of MTX administration.The median 0h concentration of MTX in MD-MTX-based group was more than twice of that in HD-MTX-based group,both of which declined quickly thereafter.Concentration of MTX higher than 5μ mol/L at 24h,which could predict the delayed clearance,were found in 11 cycles of 10 patients(24.4%)in MD-MTX-based group and 8 cycles of 6 patients(20%)in HD-MTX-based group(p =0.6619).The median time of MTX concentration <0.15μ mol/L,which was considered as the safe concentration for patients in either group was 3 days.There were 15 cycles of 13 patients(31.7%)in MD-MTX-based group and 10 cycles of 7 patients(23.3%)in HD-MTX-based group reaching MTX safe concentration >5 days(p= 0.4384).More patients in HD-MTX-based group showed hematological adverse events(AEs),especially significantly higher incidence of anemia than those in MD-MTX-based group,mainly because more patients in HD-MTX-based group were treated together with other chemotherapeutic agents.Almost all the patients in MD-MTX-based group and 93.3%patients in HD-MTX-based group were found hypoalbuminemia and proteinuria,which were severer in MD-MTX-based group.Fortunately,all the AEs were transient and rapid recovered in both groups.The patient experiencing AEs were well-tolerated to next cycle of MTX treatment at the same dose.Furthermore,the patients responses were evaluated at the end of the MTX-based chemotherapy.Fifty-five percent of patients in MD-MTX-based group and 33.3%in HDMTX-based group achieved complete remission(CR)or unconfirmed complete remission(uCR).The overall response rate(ORR)of MD-and HD-MTX-based groups were 60%and 43.3%,respectively(p=0.06).Compared with the patients in MD-MTX subgroup or HDMTX+X subgroup,the patients in MD-MTX+X subgroup had significantly longer progress free survival(PFS).Interestingly,especially newly-diagnosed(ND)patients in MDMTX-based group achieved higher response rate(RR)and improved PFS.During the median follow-up of 13 months(range 2-27 months)in MD-MTX-based group and 21 months(range 1-33 months)in HD-MTX-based group,no significant difference of overall survival(OS)between two groups was indicated.Conclusions In conclusion,elevation of MTX dose to 8g/m2 brought improved RR and PFS to lymphoma patients with CNS involvement.Mega-dose MTX-plus regimen,especially in combination with targeted therapy could be recommended to treat newly-diagnosed CNS lymphoma patients.The exploration of small molecular targeted agents capable of sufficiently penetrating into CNS is more urgent in primary CNS lymphoma(PCNSL)treatment as the fact that the outcomes of PCNSL patients lag further behind of other systemic diffuse large B cell lymphoma patients.