Rituximab and Combination Chemotherapy 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