OBJECTIVES:
Primary
* Determine the efficacy of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and high-dose methotrexate (R-CODOX-M ) alone or alternating with rituximab and ifosfamide, etoposide phosphate, and high-dose cytarabine (IVAC) and intrathecal CNS prophylaxis in patients with newly diagnosed, previously untreated, HIV-associated Burkitt's lymphoma or atypical Burkitt's lymphoma.
* Determine the safety of this regimen in these patients.
Secondary
* Evaluate downstream effectors of apoptosis as mechanisms of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.
* Evaluate multi-drug resistance gene expression as a mechanism of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.
* Confirm the use of flow cytometry in the identification of occult leptomeningeal disease and determine whether abnormal flow cytometry is predictive when CNS cytology is negative for malignant cells.
* Determine the biologic and prognostic significance of Epstein-Barr virus (EBV)-positive Burkitt's lymphoma in the highly active antiretroviral therapy era and perform exploratory analysis of their relationship to treatment effect.
* Compare genotyping in patients with HIV-associated Burkitt's lymphoma with that of patients who are HIV-negative and determine whether they are uniform in their genetic profile or whether some cases are more like diffuse large B-cell lymphoma.
* Determine if EBV detection in cerebrospinal fluid at diagnosis is predictive of leptomeningeal disease.
OUTLINE: This is a prospective, multicenter study. Patients are stratified according to risk category (low-risk vs high-risk). Patients with low-risk disease receive 3 courses of R-CODOX-M chemotherapy as described below. Patients with high-risk disease receive 4 alternating courses of R-CODOX-M/IVAC chemotherapy as described below in an A/B/A/B sequence.\* Courses repeat every 21-28 days in the absence of disease progression or unacceptable toxicity.
NOTE: \*In patients presenting with anasarca, pleural effusion, or ascites, methotrexate can pool causing difficulties with clearance; in this case, treatment may be given in a reverse sequence: B/A/B/A.
* Regimen A (R-CODOX-M chemotherapy): Patients receive rituximab\*\* IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim subcutaneously (SC) on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until the methotrexate level is less than 50 nmol/L. Patients receive CNS prophylaxis comprising methotrexate intrathecally (IT), cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive filgrastim (G-CSF) SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
* Regimen B (rituximab and IVAC chemotherapy): Patients receive rituximab\*\* IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover.
Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
NOTE: \*\*Rituximab may be given up to 3 days before a chemotherapy course and anytime during the course for 3 (low-risk disease) or 4 (high-risk disease) total doses.
Patients undergo blood and cerebrospinal fluid collection and tumor biopsies periodically during study treatment for correlative studies of prognostic biomarkers predictive of survival (e.g., c-flip protein expression; p53 mutations \[by immunohistochemistry (IHC)\]; multidrug resistance gene expression \[by IHC\]; and Epstein-Barr virus in tumor DNA or cerebrospinal fluid \[by polymerase chain reaction\]); genotyping of Burkitt's lymphoma; and flow cytometry as a tool (by staining) for detecting occult positivity of leptomeningeal disease in Burkitt's lymphoma.
After completion of study treatment, patients are followed every 4 months for at least 2 years.
PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.
