The purpose of this study is to compare the standard CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to CPOP-R (same regimen, but substituting Doxorubicin with Pixantrone). The objective is to show that CPOP-R is not inferior to CHOP-R.

In preclinical studies, pixantrone has shown significantly less cardiotoxicity than other anthracyclines or anthracenediones. In addition, patients with relapsed disease, who have received prior maximum doses of anthracyclines, have tolerated high doses of pixantrone with minimal added cardiotoxicity. Pixantrone is currently being studied in a Phase III study in 3rd line aggressive NHL.

Inclusion Criteria:

1. Previously untreated and histologically confirmed diffuse large B-cell lymphoma according to REAL/WHO classification.

2. Stage II, III or IV disease

3. CD20+

4. Age ≥ 18 years

5. ECOG performance status ≤ 2

6. At least one objectively bidimensionally measurable lesion as demonstrated by CT, spiral CT, or MRI that can be followed for response as target lesion. Patients with the following sites of disease are NOT eligible:

   • Patients with only skin lesions or only palpable lymph nodes.
   • Patients with spleen or bone marrow as only site of disease.

7. Life expectancy ≥ 3 months

8. Serum bilirubin ≤ 1.5 x the institution's upper limit normal (ULN) and creatinine ≤ 2.0 ULN and AST or ALT ≤ 2.0 x the institution's ULN. If hepatic involvement by lymphoma is present, AST or ALT may be ≤ 5.0 x the institution's ULN.

9. LVEF ≥ 50% determined by MUGA scan.

10. Ability to comply with the visit schedule and assessments required by the protocol.

11. Signed approved informed consent, with understanding of study procedures.

Exclusion Criteria:

1. Any prior chemotherapy (except intrathecal chemotherapy at diagnosis and pretreatment corticosteroid therapy) or radiotherapy: Patients may receive corticosteroid pretreatment therapy for up to 7 days after randomization, pending Investigator's decision to reduce tumor burden.
2. Histological diagnosis of T-cell lymphoma or any B-cell lymphoma other than diffuse large B-cell.
3. History of indolent lymphoma
4. Active CNS involvement based on clinical evaluation .
5. HIV-related lymphoma.
6. Major thoracic and/or abdominal surgery within the 4 weeks before randomization from which the patient has not fully recovered except for diagnosis of NHL. Patients who have had minor surgery may be enrolled after a ≥ 1 week recovery period except for diagnosis of NHL.
7. Clinically significant cardiovascular abnormalities
8. Serious (NCI CTCAE grade 3-4) intercurrent infection at randomization or deep seated or systemic mycotic infections.
9. Clinical symptoms suggesting unresolved HIV, HBV or HCV infection. Patients with seropositivity presumed to be due to prior vaccination against Hepatitis B virus or resolved infection will not be excluded.
10. Active or history of another malignancy except cured basal cell carcinoma of skin or carcinoma in situ of uterine cervix. Patients who have been in remission from another previous malignancy for >5 years will be considered eligible.
11. Known hypersensitivity to the excipients or the study drugs that the patient will receive.
12. Any contraindications to the study drugs as described in the Summary of Product Characteristics or package inserts. 13. Neurological contraindication to vincristine (e.g. peripheral neuropathy).

14. Any condition which, in the judgment of the Investigator, would place the subject at undue risk, interfere with the results of the study, or make the subject otherwise unsuitable. 15. General status that, in the opinion of the Investigator does not permit the administration of eight courses of CHOP-R/CPOP-R. 16. Treatment with any other investigational study drug within 30 days before randomization. Patient must have recovered from all side effects of other investigational therapy. 17. Potentially fertile men and women and their sexual partners not willing to use adequate contraception as defined by the Investigator during the study and for 6 months after the last day of study drug administration.

18. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up.