Rituximab and Combination Chemotherapy in Treating Patients With Newly Diagnosed, HIV-Associated Burkitt's Lymphoma
Condition: Lymphoma
MeSH terms: Burkitt Lymphoma; Lymphoma
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): filgrastim; pegfilgrastim; rituximab; cyclophosphamide; cytarabine; doxorubicin hydrochloride; etoposide; ifosfamide; leucovorin calcium; liposomal cytarabine; methotrexate; therapeutic hydrocortisone; vincristine sulfate
Intervention type(s): Biological; Biological; Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): given subcutaneously; given subcutaneously; given IV; given IV; given intrathecally; given IV; given IV; given IV; given IV; given intrathecally; given intrathecally; given intrathecally; given IV
Intervention MeSH terms: Leucovorin; Cytarabine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Ifosfamide; Rituximab; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Levoleucovorin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage I adult Burkitt lymphoma; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; contiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult Burkitt lymphoma; AIDS-related peripheral/systemic lymphoma