The overall goal of this clinical research study was to find out which of two different chemotherapy drug combinations, R-CHOP and R-HCVAD, is more effective in treating B-cell lymphoma.

At this point, all participants will now be assigned to the R-HCVAD arm of the study. Researchers will study the safety and effectiveness of this drug combination.

This study originally involved 2 different study drug regimens, R-CHOP and R-HCVAD. R-CHOP is made up of rituximab, cyclophosphamide, vincristine, and prednisone, and is the most common treatment for patients with non-Hodgkin's lymphoma. This combination was compared with R-HCVAD, which is made up of rituximab, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.

Rituximab (Rituxan®) is a humanized monoclonal antibody against cluster of differentiation antigen 20 (CD20) (a receptor in the surface of malignant B-cell lymphocytes). The drug has activity against aggressive and nonaggressive NHL of B-cell origin, and has been used in combination with chemotherapy. Cyclophosphamide is a type of drug know as an alkylating agent. Vincristine is a type of drug called vinca alkaloids. It is typically used in lymphomas, leukemias, and other tumors. Prednisone is a type of steroid. Dexamethasone is a steroid that may have activity against lymphomas. Methotrexate is an anti-cancer drug and a folic acid antagonist. It is used to treat solid tumors, lymphomas, leukemias, and autoimmune diseases.

When this study began, participants were randomly assigned (as in the flip of a coin) to 1 of 2 arms: Arm A (R-HCVAD alternating with a combination of rituximab, methotrexate, and Ara-C) or Arm B (R-CHOP). From this point on, all new participants will be treated with the Arm A combination, which has shown to be better.

If you are found to be eligible to take part in this study, you will be given the study drugs in 21-day cycles. The cycles will alternate between R-HCVAD and a combination of rituximab, methotrexate, and Ara-C. During Cycle 1 (the R-HCVAD cycle), you will receive rituximab through a needle in your vein (intravenously, or "IV"), on Day 1. The infusion will take about 1 hour. Cyclophosphamide will be given by IV every 12 hours for 3 days. Each infusion of cyclophosphamide will take about 3 hours. Doxorubicin will be given as a 15-minute infusion on Day 5 with the supervision of a nurse. Your doctor may also choose to give you the doxorubicin over 24-48 hours using a small pump that you will carry around your waist in a "fanny pack." You will not have to stay in the hospital to receive this study drug. Vincristine will be given by IV, on Days 5 and 12. Each vincristine infusion will take about an hour. Dexamethasone will be given by mouth (as a pill, capsule, or tablet) on Days 2-5 and 12-15. You will also be given other standard medications to help prevent possible side effects of these medications (such as nausea, vomiting, or rash).

In Cycle 2 (the rituximab-methotrexate-Ara-C cycle), you will receive rituximab on Day 1. You will receive methotrexate by IV (after finishing the rituximab) on Days 2 and 3. The infusion will take about 24 hours. You will be given a small "fanny pack" with a pump inside that will slowly infuse the drug. You do not have to stay in the hospital while the drug is being given. You will be given Ara-C every 12 hours on Days 3-4 (a total of 4 doses). You will be given other standard medications to help prevent possible side effects of these medications (such as nausea, vomiting, or rash) during this cycle also.

Leucovorin is given 12 hours after each methotrexate infusion. It is used to stop the action of the methotrexate and to prevent/lessen any side effects that the methotrexate may cause.

During treatment, you will have blood draws (between 2-3 tablespoons) every week for routine tests. Every 4 weeks during treatment , you will be asked questions about your medical history and have a physical exam to check for any side effects. Every 2 cycles (about every 8 weeks), you will have bone marrow biopsies performed (if they were positive before starting on this study), until they come back negative. You will have a positron emission tomography (PET) scan to see if the tumor is responding. Once the PET scan comes back negative, it will be up to your physician to decide if you need additional PET scan tests, and when. You will have CT scans of the chest, abdomen, pelvis, and neck every 2 cycles, if they were positive at the beginning of the study also. You may have additional testing done while on this study, if your physician feels that it is needed (for example, if it is needed to check for side effects).

You may receive additional medication called "CNS prophylaxis" before receiving the study treatments. Your doctor will discuss these medications with you. The "CNS prophylaxis" consists of an alternating dose of either doxorubicin or methotrexate. The methotrexate will be given either by IV pump or by a "lumbar puncture" (a needle inserted into the space between the vertebrae in your back to infuse the drug directly into the spinal area). The doxorubicin will be given by IV. Changes in the dose level of CNS prophylaxis will be approved if you are at risk for or are experiencing serious side effects.

You will receive the study drugs for up to 6-8 cycles on an outpatient basis. This means you will not have to be admitted to the hospital to receive the study drugs. You may be taken off study if the disease gets worse. If you experience intolerable side effects while taking any of the study drugs, your study doctor may decide to delay your treatment for up to 3 weeks (one study cycle) or to continue your therapy on the drugs at a lower dose. If the side effects become very severe, your doctor may decide to take you off of the study and stop the medication.

At the end of your scheduled treatments, you will be asked to return to the clinic for follow-up visits every 6 months for the first, second, third, and fourth year after treatment on this study. You will then be followed every year after that. If your doctor feels it is necessary, you may have blood tests (about 3-5 teaspoons) performed at these visits. You will have bone marrow biopsies every other year for the first 2 years, if they were positive before you started on this study, and then every year after that. At these visits, you will be asked about any side effects you may have experienced and whether or not your cancer has come back. If your doctor feels there is a chance that the cancer has come back, he or she may schedule x-rays or scans in order to check. You will also be asked about any other therapies you may be having to treat your cancer, if it has come back.

If you are taken off study for any reason, you will be asked to come back to the clinic for an end-of-treatment visit within 4 weeks from the last treatment. This visit will include a physical exam, routine blood tests (about 5-8 teaspoons), a blood-pregnancy test for women who are able to get pregnant, an ECG, and a chest x-ray.

This is an investigational study. All of the study drugs are approved by the FDA for the treatment of lymphoma. Up to 66 patients will take part in this study. All of the patients will be enrolled at MD Anderson.

Inclusion Criteria:

1. Confirmed diagnosis of previously untreated large B-cell Non Hodgkin's, Large Cell Lymphoma and B-Cell with high grade features. Other aggressive lymphomas such as Primary Mediastinal large B-cell Lymphomas will be also allowed to be included.
2. Patients with performance status of 0-2 (Zubrod Scale).
3. Serum bilirubin <1.5 mg/dl and serum creatinine < 2.0 mg/dl unless due to lymphoma; absolute neutrophil count (ANC) >1000/mm^3 and platelets >100,000/mm^3 unless due to lymphoma.
4. Cardiac ejection fraction 50% or greater.
5. Ages 16 - 60 years (due to the fact that CHOP-R is not studied enough in younger patients and is not considered standard of care).
6. Patients must be willing to receive transfusions of blood products.
7. Age adjusted International Prognostic Index Score of 2 or more
8. Previous steroids are allowed (if used to relieve some symptoms such as SVC, etc).

Exclusion Criteria:

1. Pregnancy (excluded due to the teratogenicity of the involved chemotherapy agents
2. Positive HIV serology because of poor tolerance to this intense chemotherapy regimen
3. Burkitt's lymphomas, and Mantle cell lymphoma, transformed follicular center cell lymphoma, follicular grade III.
4. Any clinical or cytological diagnosis of central nervous system (CNS) involvement
5. Any co-morbid medical, such as Child's Class C liver cirrhosis, end-stage renal disease, and symptomatic congestive heart failure, or psychiatric illnesses that preclude treatment with intense dose chemotherapy as determined by the primary investigator.
6. Concurrent or previous malignancy whose prognosis is poor (< 90% probability of survival at 5 years)
7. Active Hepatitis B or C. Chronic carriers for Hepatitis B will be excluded.