A Randomised Multicentric Phase III Study for the Treatment of Young Patients With High Risk (IPI 2-3) Diffuse Large B-Cell Lymphoma. Dose Dense Chemotherapy + Rituximab +/- Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cells.
1. Age 18-60;
2. Histological confirmed diagnosis of Diffuse Large B-Cell Lymphoma CD20+ (newly
diagnosis or shifted from low grade NHL and not previously treated) or of Follicular
Lymphoma grade III according to REAL/WHO Classification.
3. Advanced stage II, stage III and stage IV with at least two aa-IPI risk factors.
4. Age-adjusted IPI 2-3.
5. ECOG performance status 0-2.
6. LVEF>45%, measured with echocardiography.
7. Normal hepatic, renal and pulmonary functions.
8. HIV, HCV and HBV negativity.
9. HCV+ admitted only in histologically confirmed absence of replication marks.
10. Positive serology for HBV (occult carriers: AntiHBcAg+, HbsAg-, AntiHBsAg+/-)
admitted only upon negativity of weakly positive HBV-DNA test.
11. Life expectancy > 3 months.
12. Negative pregnancy test.
13. Written Informed Consent.
1. Histological diagnosis of:
- Lymphoblastic NHL
- Burkitt's Lymphoma
- CD 20 negative B-cell Lymphoma
- grade I-IIIa Follicular Lymphoma
- Mantle Cell Lymphoma
- Primary mediastinal NHL with exclusively intrathoracic localization.
2. Age > 60
3. Stage I disease
4. Age-adjusted IPI 0-1
5. ECOG-PS>3, if not related to Lymphoma
6. Renal impairment (creatinine>1,2 mg/dl or creatinine clearance < 60ml/min)
7. Hepatic impairment (AST/ALT or bilirubin > 2,5 times normal limit, unless due to
8. HIV positive patients and/or with HBV or HCV active infection(documented by HBV-DNA
and HCV-RNA positive tests)
9. Clinically significant secondary cardiovascular disease e.g. uncontrolled
hypertension (resting diastolic blood pressure > 115 mmHG), uncontrolled multifocal
cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA
11. Severe diabetes mellitus difficult to control with adequate insulin therapy
12. Severe chronic obstructive pulmonary disease with hypoxemia
13. Active bacterial, viral of fungal infection requiring systemic therapy
14. Concurrent thrombohemolytic disease
15. HIV positivity
16. HBV positivity
17. Positive serology for HBV (occult carriers: AntiHBc+, HbsAg-, AntiHbs+/-) with
positive HBV-DNA test
18. HCV positivity in presence of replication marks (HCV+, CRP+, AST 1,5-2 times normal
19. CNS localization of disease
20. Prior (during last 3 years) or concurrent malignancy except adequately treated basal
cell carcinoma of the skin or carcinoma in situ of the cervix or early stage prostate
cancer not requiring systemic therapy, or early breast cancer treated with surgery
alone. Any other co.existing medical condition that would preclude study therapy
21. Pregnancy or breast-feeding women
22. Inability of the patient to give her/his informed consent
23. Known hypersensitivity or anaphylactic reaction to murine antibodies or proteins