The purpose of this study is to find out what effects (good and/or bad) treatment with chemotherapy and stem cell transplant compared with chemotherapy alone will have on primary CNS B-cell lymphoma. Currently the best treatment for patients with primary CNS B-cell lymphoma is not known.

Primary Objective:

To compare the two-year progression-free survival (PFS) of patients treated with the myeloablative consolidation treatment strategy of HDT/ASCT versus those treated with non-myeloablative consolidation chemotherapy with cytarabine and etoposide

Secondary Objectives:

1. To compare the two-year event-free survival (EFS) of patients treated with consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine
2. To compare the overall survival (OS) of patients treated with the consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine
3. To assess the toxicities associated with consolidation HDT/ASCT versus consolidation consisting of etoposide and cytarabine
4. To determine diffusion MRI metrics (ADCmini, ADC25%, and ADCmean) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (CALGB 581101)
5. To determine brain FDG-PET metrics (tumor SUV and tumor versus background SUV) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (CALGB 581101)
6. To determine whether low baseline ADC measurements are associated with shorter PFS and OS (CALGB 581101)
7. To determine whether reduction in tumor SUV by > 25% on brain FDG-PET/CT after one cycle of induction therapy is associated with improved PFS and OS (CALGB 581101)
8. To determine which IHC-based biomarkers are predictive of an adverse prognosis (CALGB 151113)
9. To determine which IHC-based biomarkers are predictive of a favorable prognosis (CALGB 151113) for BCL6 (B-cell CLL/lymphoma 6), and STAT 6 (signal transducer and activator of transcription 6, interleukin-4 induced)
10. To analyze tumor tissue for gene expression profiles, and to correlate these profiles with treatment outcomes (CALGB 151113)
11. To determine whether CSF proteome is a predictor of outcomes (prognostic marker) irrespective of treatment arm (CALGB 151113) for (IL-10 (interleukin 10) and C3 (complement component 3)
12. To assess the neurocognitive function of patients treated with consolidation HDT/ASCT versus those treated with consolidation chemotherapy (etoposide and cytarabine) as measured by serial administration of the International PCNSL Collaborative Group (IPCG) neurocognitive battery and evaluate the long-term survivorship differences between the two arms (CALGB 71105)

1. Documentation of Disease: Diagnosis of primary CNS diffuse large B-cell lymphoma confirmed by one of the following: brain biopsy or resection, cerebrospinal fluid and vitreous fluid.
2. Other Lymphomas: Patients must have no evidence or history of non-Hodgkin lymphoma (NHL) outside of CNS.
3. Previous Treatment: Patients must have no prior chemotherapy or radiation therapy for lymphoma.
4. Age- Patients must be between the ages of 18 and 75 years.
5. Karnofsky Performance Scale - Patients must measure Karnofsky Performance Scale ≥ 30 (≥ 50 for patients ages 60-70).
6. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing; women of childbearing potential must have a negative serum or urine pregnancy test 10-14 days prior to registration; in addition, women and men of childbearing potential must commit to use an effective form of contraception throughout their participation in this study; appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom)
7. HIV - Patients must have negative HIV serology.
8. Hepatitis - Patients must have negative HCV serology (unless HBsAb positive patient has recently received HBV vaccine, in this case HBcAb should be negative). All patients must be screened for hepatitis B infection before starting treatment. Those patients who test positive for hepatitis B should be closely monitored for evidence of active HBV infection and hepatitis during and for several months after rituximab treatment. PCNSL patients with a history of hepatitis B infection should be treated with entecavir or lamivudine (physician discretion for choice of drug) as antiviral prophylaxis to prevent hepatitis B reactivation.
9. Organ Transplant or Immunosuppressant Therapy - Patient must have no history of organ transplantation or ongoing immunosuppressant therapy.
10. Required Initial Laboratory Values: ANC ≥ 1500/mcL, AST and ALT < 2 x upper limit of normal (ULN), total bilirubin ≤ 3 mg/dL, creatinine clearance ≥ 50 mL/min, platelet count ≥ 100,000/mcL