This randomized phase II trial is studying two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell lymphoma.

objectives:

1. To compare the response rates and toxicity of R-CHOP versus DA-EPOCH-R in untreated CD20+ diffuse large B-cell lymphomas.
2. To compare the event-free survival of R-CHOP versus DA-EPOCH-R chemotherapy in untreated CD20+ diffuse large B-cell lymphomas.
3. To develop predictors of outcome of R-CHOP and DA-EPOCH-R chemotherapy.

Inclusion Criteria:

• 1. Histologically documented de novo CD20+ DLBCL with stage II, III or IV disease.

Stage I primary mediastinal (thymic) DLBCL is also eligible. Diagnosis should be based on an adequate tissue sample, including open biopsy or core needle biopsy.

Needle aspiration for primary diagnosis is unacceptable.

Patients must have one of the following WHO classification subtypes:

Diffuse large B-cell lymphoma (includes morphological variants: centroblastic, immunoblastic, T-cell/histiocyte rich, and anaplastic) Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Patients without adequate frozen material should have a biopsy performed to obtain material.

2. Patients may be entered if they have received prior limited field radiation therapy or a short course of glucocorticoids (< 10 days) for an urgent local disease complication at diagnosis (e.g., cord compression, SVC syndrome).

3. Age >16 years old. 4. ECOG Performance Status 0-2 5. If there is suspicion of cardiac disease, a cardiac ejection fraction must show LVEF > 45%.

6. Required Initial Laboratory Values (unless non-Hodgkin lymphoma):

• ANC ≥ 1000/μL
• Platelets ≥ 100,000/μL
• Creatinine≤ 1.5 mg/dL or creatinine clearance ≥ 50 cc/min
• Total Bilirubin ≤ 2 mg/dL (unless a history of Gilbert's Disease)

Exclusion Criteria:

• 1- Patients with an underlying low-grade lymphoma, such as a transformed lymphoma or low-grade lymphoma in the bone marrow, are not eligible.

  2- Patients with low international prognostic index are not eligible. 3- Prior cytotoxic chemotherapy or rituximab. Patients who have received chemotherapy for prior malignancies are not eligible.

  4- Active ischemic heart disease or congestive heart failure. 5- Known lymphomatous involvement of the CNS. A lumbar puncture prior to study is not required in the absence of neurological symptoms.

  6- Known HIV disease. Patients with a history of intravenous drug abuse or any other behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible.

  7- Pregnant and non-nursing. Treatment would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective form of contraception.

  8- Patients with active medical processes (e.g., uncontrolled bacterial or viral infection, bleeding) not related to their lymphoma should be excluded.