Rituximab and Combination Chemotherapy in Treating Patients With Newly Diagnosed, HIV-Associated Burkitt's Lymphoma
Rituximab and Combination Chemotherapy in Treating Patients With Newly Diagnosed, HIV-Associated Burkitt's Lymphoma
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different
 ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and
 help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in
 different ways to stop the growth of cancer cells, either by killing the cells or by stopping
 them from dividing. Giving rituximab together with combination chemotherapy may kill more
 cancer cells.

 PURPOSE: This phase II trial is studying how well giving rituximab together with combination
 chemotherapy works in treating patients with newly diagnosed, HIV-associated Burkitt's
 lymphoma.
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.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed Burkitt's lymphoma (BL) or new WHO 2009 criteria B-cell
 lymphoma unclassified (with features intermediated between difuse large B-cell
 lymphoma and BL)

 -  Any stage disease

 -  Newly diagnosed disease

 -  Meets 1 of the following criteria for disease risk:

 -  Low-risk disease, defined by 1 of the following:

 -  Stage I with a single focus of disease < 10 cm AND normal lactate
 dehydrogenase (LDH) level

 -  Totally resected intra-abdominal disease only AND normal LDH post surgery

 -  High-risk disease, defined as not meeting criteria for low-risk disease

 -  Measurable or nonmeasurable disease

 -  HIV-positive confirmed by enzyme-linked immunosorbent assay and Western blot OR by
 measurable HIV viral load

 -  No visceral Kaposi's sarcoma

 PATIENT CHARACTERISTICS:

 -  Karnofsky performance status 40-100%

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  LVEF ≥ 50% by MUGA or echocardiogram

 -  Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

 -  Absolute neutrophil count ≥ 1,000/mm³

 -  Platelet count ≥ 50,000/mm³ (unless related to lymphoma)*

 -  Direct bilirubin ≤ 2.0 mg/dL OR total bilirubin ≤ 3.5 mg/dL AND direct bilirubin
 normal (if elevated bilirubin secondary to antiretroviral therapy)

 -  AST and ALT ≤ 3 times upper limit of normal

 -  No other malignancy within the past 5 years except curatively treated cutaneous basal
 cell or squamous cell carcinoma, carcinoma in situ of the cervix, or cutaneous
 Kaposi's sarcoma

 -  No other medical illness unrelated to non-Hodgkin's lymphoma, including any of the
 following:

 -  Uncontrolled infection (including opportunistic infection)

 -  Chronic renal insufficiency

 -  Myocardial infarction within the past 6 months

 -  Unstable angina

 -  Cardiac arrhythmias other than chronic atrial fibrillation

 -  Patients with active hepatitis B infection are eligible provided they receive
 concurrent dual antiviral therapy NOTE: *Patients with bone marrow involvement are
 eligible irrespective of blood count

 PRIOR CONCURRENT THERAPY:

 -  See Disease Characteristics

 -  No prior therapy for this disease except for 1 of the following :

 -  Seven consecutive days of steroids alone or in combination with a non-CHOP
 regimen necessary for patient stabilization (e.g., cyclophosphamide and steroids
 steroids for normalization of disease-related hyperbilirubinemia)

 -  One course of CHOP or fractionated CHOP (e.g. CODOX) with or without rituximab

 -  No epoetin alfa or filgrastim (G-CSF) within 24 hours of study chemotherapy

 -  No concurrent zidovudine