This is an open, non comparative, multicentre phase II trial, to evaluate the efficacy and feasibility of a new sequential combination of HD-MTX-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by ASCT.

Treatment includes 6 courses of chemoimmunotherapy, the first three courses with an high dose methotrexate-based combination (MATRIX) followed by other three courses of R-ICE combination and finally a BCNU-thiotepa- containing conditioning and subsequent autologous stem cell transplantation.

MATRIX (courses 1, 2, 3):

Rituximab 375 mg/m2, Methotrexate 3.5 g/m2, Cytarabine 2 g/m2, Folinic rescue 15 mg/m2, Thiotepa 30 mg/m2, Intrathecal liposomial cytarabine 50 mg, rHuG-CSF 2,5 g/kg s.c.

R-ICE (courses 4, 5, 6):

Rituximab 375 mg/m2, Etoposide 100 mg/m2/d , Ifosfamide 5 g/m2, Intrathecal liposomial cytarabine 50 mg

Inclusion Criteria:

1. Histologically confirmed diagnosis of diffuse large B-cell lymphoma
2. CNS involvement (brain, meninges, cranial nerves, eyes and/or spinal cord) at diagnosis (concomitant to extra-CNS disease) or relapse after conventional chemo(-immuno)therapy
3. Diagnosis of CNS involvement either by brain biopsy or CSF cytology examination. Neuroimaging alone is acceptable when stereotactic biopsy is formally contraindicated or when the disease has been previously histologically documented in other areas and the CNS localization is concomitant with a diffuse progression of systemic disease.
4. No previous treatment with high-dose methotrexate-based chemotherapy and/or brain irradiation. One-two courses of R-CHOP combination as upfront therapy are admitted in patients with large amount and/or extensive extra-CNS disease that could condition prognosis in an early phase of treatment. Local investigator decides if initial R-CHOP is needed based on patient's conditions
5. Age 18-70 years
6. ECOG performance status 0-3
7. Adequate bone marrow (Platelets count ≥100.000/mm3, hemoglobin ≥9 g/dL, neutrophils count≥1.500/mm3), renal (creatinine clearance ≥60 mL/min), cardiac (LVEF ≥50%), and hepatic function (total serum bilirubine ≤3 mg/dL, AST/ALT and GGT ≤2.5 per upper normal limit value), unless the abnormality is due to lymphoma infiltration
8. Absence of HIV infection and of detectable HCV-RNA and/or HBsAg and/or HBV-DNA
9. No concurrent malignancies. Previous malignancies are accepted if surgically cured or if there was no evidence of disease in the last 3 years at a regular follow-up
10. Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
11. Female patients must be non-pregnant and non-lactating. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation
12. No treatment with other experimental drugs within the 6 weeks previous to enrolment
13. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice. Informed consent signed by a patient's guardian is acceptable if the patient is not able to decide inclusion in the study due to cognitive impairment

Exclusion Criteria:

1. Other lymphoma categories other than diffuse large B-cell lymphoma. In particular, patients with primary mediastinal lymphoma, intravascular large B-cell lymphoma or leg-type large B-cell lymphoma are excluded.
2. Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease.
3. Patients with exclusive CNS disease at presentation (primary CNS lymphoma) are excluded
4. Previous treatment with support of autologous or allogeneic stem cells/bone marrow transplantation.
5. Symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease)
6. Any other serious medical condition which could impair the ability of the patient to participate in the trial.