Phase II Study of Dose-Adjusted EPOCH-Rituximab in Adults With Untreated Burkitt Lymphoma and c-MYC+ Diffuse Large B-Cell Lymphoma

Background: * Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs dose intense multi-agent chemotherapy and though effective is associated with high morbidity. Therefore, novel approaches are needed that improve the therapeutic index of BL while maintaining or improving efficacy. In human immunodeficiency virus (HIV)+ BL, outcome has been poor, mainly due to the use of cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (CHOP) based regimens in this disease. * Two National Cancer Institute (NCI) phase II trials have used etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy with 1 or 2 doses of rituximab (R) per cycle in untreated BL. (Dose-adjusted) etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH)-Rituximab has been used in16 HIV negative BL, and 8 HIV positive patients have received 3 to 4 cycles of EPOCHRR to minimize toxicity and risk of opportunistic infections. All patients remain in continuous remission. Treatment was very well tolerated and represents a novel therapeutic strategy in BL. * This trial seeks to assess the effectiveness of a risk adaptive approach with DA-EPOCHR in untreated BL (HIV+/-). Because this treatment represents a major conceptual departure from standard treatment, it is important to obtain additional Phase II results in limited/advanced stage BL * c-MYC positive Diffuse large B cell (DLBCL) is a rare variant of Diffuse Large B-Cell Lymphoma (DLBCL). There is very little data on the biology of this disease and what the optimal therapeutic approach should be has not been defined. Therefore, based on our impression that this behaves aggressively and is likely characterized by a high tumor proliferation rate, we plan to accrue patients with this disease in addition to BL patients. * Plasmablastic lymphoma, another variant of DLBCL is frequently characterized by the activation of MYC and has had a poor outcome historically with standard treatment. We plan to include these patients in the study also. As they are cluster of differentiation 20 (CD20) negative, they will receive DA-EPOCH without Rituximab. Objectives: * Determine progression free survival (PFS), event free survival (EFS) and overall survival (OS) of risk adaptive DA-EPOCH-R in untreated BL and c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma. * Assess predictive value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans on PFS. * Obtain pilot comparative molecular profiling in HIV negative and positive BL and c- MYC + DLBCL, including c-MYC+ plasmablastic lymphoma. Eligibility: * Burkitt lymphoma, c-MYC + DLBCL and c-MYC + plasmablastic lymphoma age greater than or equal to 18 years. * No prior treatment except limited-field radiotherapy, short course of glucocorticoids and/or cyclophosphamide for an urgent problem at diagnosis. * Adequate major organ function unless impairment due to lymphoma. Study Design: * Phase II Study of risk adapted DA-EPOCH-R in BL, c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma * Low risk: DA-EPOCH-RR x 3 cycles. * High risk , c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma : DA-EPOCH (+/-) R x 6 cycles or 8 cycles in select patients. * Cerebrospinal fluid (CSF) cytology and flow cytometry for analysis of BL. * High Risk CSF negative - Prophylactic intrathecal treatment * CSF positive - Active intrathecal treatment * FDG-PET/CT pre- and post-cycle 2 in all patients. * A total of 194 patients will be enrolled in the protocol.