The purpose is to test whether early central nervous system (CNS) prophylaxis given at the beginning of therapy for young high risk diffuse large B-cell lymphoma (DLBCL) patients is feasible and could reduce the risk of CNS relapses. Early CNS prophylaxis with two courses high dose methotrexate (HD-MTX) in combination with rituximab-cyclophosphamide-doxorubicin-vincristine-prednison (R-CHOP) is followed by four courses of R-CHOP14 and etoposide (E) and one course of HD-Ara-C. In addition the patients will receive three courses of liposomal cytarabine intrathecally. The results will be compared to a recent Nordic CRY-04 study. Shifting of CNS prophylaxis to the beginning of the therapy offers a potential to overcome the subclinical disease and thus reduce the risk of early clinical CNS recurrence. As flow cytometry (FCM) can improve the sensitivity for detecting occult leptomeningeal disease over cytology , FCM from cerebrospinal fluid will be incorporated into the staging procedures.

Inclusion Criteria:

• Age ≥ 18 - < 65 years. Histologically confirmed CD20+ diffuse large B-cell lymphoma (DLBCL) based on WHO 2008 Lymphoma Classification
• Follicular lymphomas (FLs) grade 3b is allowed

Patients in at least stage II with age adjusted international prognostic score (IPI score) of 2 or 3:

• Stage III /IV and elevated LDH
• Stage III/IV and WHO performance status 2 - 3
• Stage II and elevated LDH and WHO performance status 2 - 3 And/or patients with
• More than one extranodal site
• Testicular lymphoma, stage IIE and higher
• Paranasal sinus and orbital lymphoma with destruction of bone
• Large cell infiltration of the bone marrow

Exclusion Criteria:

• Severe cardiac disease: cardiac function grade 3-4
• Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule
• Pregnancy/lactation
• Men and women of reproductive potential not agreeing to use an acceptable method of birth control during treatment and for six months after completion of treatment
• Patients with other severe medical problems and with an expected short survival for non-lymphoma reasons
• Known HIV positivity
• Uncontrolled infectious disease, including meningeal infection
• Active cancer except basal cell carcinoma and cervical carcinoma in situ during the last five years
• Earlier treatment containing anthracyclins
• Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol
• CNS disease as diagnosed by MRI or cerebrospinal fluid (CSF) cytology. Positive CSF flow cytometry below diagnostic threshold level by cytology is allowed
• Pleural or peritoneal fluid that cannot be drained safely
• Hypersensitivity to the active substance or any of the other ingredients
• Patients participating in other clinical studies, unless followed for survival