Inclusion Criteria:  Subjects aged 18-70 years Patients with diagnosis of diffuse large B-cell lymphoma Patients at high risk of CNS involvement (>2 extranodal sites plus an elevated LDH or /and involvement of high-risk extranodal sites including testes, paranasal sinuses, breast, liver, adrenal and renal) Patients who will receive HDMTX (three cycles) into R-CHOP regimen (6 cycles) prescribed according to normal clinical practice Absence of focal neurological signs Absence of CNS involvement determined by cerebrospinal fluid (CSF) cytometry flow test prior to start treatment Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Absolute neutrophil count 1800-7500/µL, platelet count 130.000- 450.000/ µL, hemoglobin 13,5-18 g/dL, Serum creatinine ≤1.5 x the upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥60ml/min/1.73m^2 Total serum bilirubin ≤2 x ULN. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 x ULN Ability to understand and the willingness to sign a written informed consent document In women of childbearing potential (from menarche and until becoming post-menopausal [i.e., no menses for 12 months with an alternative medical cause], unless permanently sterile) and men, use of highly effective measure of contraception (abstinence, hormonal contraception, intra-uterine device [IUD], intrauterine hormone-releasing system, [IUS], or anatomical sterility in self or partner) committed during 3 months after the last IMP administration.  Exclusion Criteria:  Malignant disease, other than those being treated in this study. Exceptions to this exclusion include malignancies that were treated curatively and have not recurred within 2 years after completion of treatment. Patients suffered from cardiovascular diseases (arrhythmias, previous heart failure, thromboembolic disease) Previous treatment with Glucarpidase Pregnant or breastfeeding women Concomitant treatment with agents which interact with methotrexate metabolism or excretion Known intolerance/hypersensitivity to Glucarpidase or any of its excipients.