Mature B-Cell Lymphoma And Leukemia Study III

• To perform transcriptional profiling and genome-wide analysis of DNA copy number abnormalities and loss-of-heterozygosity using DNA microarrays in children with newly diagnosed mature B cell lymphomas [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To describe the types and frequency of mutations in the ARF-HDM2-TP53 pathway, in B-cell lymphomas in the United States and those found in selected geographic regions of the world. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To describe the expression of ARF-HDM2-TP53 and PUMA-associated pathways in B-cell lymphomas in the United States and that found in B-cell lymphomas of other selected geographic regions of the world [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To describe the pattern and frequency of XLP gene mutations presenting with B-cell lymphomas in the United States and selected geographic regions. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To describe the pattern of EBV protein expression (e.g., EBNA 3) in EBV-positive lymphomas and to compare patterns of EBV protein expression with clinical, laboratory and outcome data. [ Time Frame: 5 years ] [ Designated as safety issue: No ]

This is a phase III clinical trial using risk-adapted therapy. Treatment outcomes for children with B-cell NHL are excellent. Further improvements in outcome will likely be achieved through more focused study of the biology of the tumors and prospective studies of the late effects of treatment. Toward this end, this study features a spectrum of prospective biologic and late effect studies performed in patients treated with a modified regimen derived from the very successful LMB-96 regimen.

1. This study will perform transcriptional profiling and genome-wide analysis of DNA copy number abnormalities and loss-of-heterozygosity using DNA microarrays in children with newly diagnosed diffuse large B-cell lymphomas (DLBCL) and small non-cleaved lymphomas from different parts of the world.
2. This study will describe the types and frequency of mutations in the ARF-HDM2-TP53 pathway, in "non-endemic" B-cell lymphomas (United States) and those found in selected geographic regions of the world.
3. This study will describe the expression of ARF-HDM2-TP53 and PUMA-associated pathways in B-cell lymphomas (United States) and that found in B-cell lymphomas of other selected geographic regions of the world.
4. This study will describe the pattern and frequency of XLP gene mutations presenting with B-cell lymphomas in the United States and selected geographic regions.
5. This study will describe the frequency of EBV-positive B-cell lymphomas in the United States and selected geographic regions of the world: and will describe the pattern of EBV protein and gene expression (e.g., EBNA 3) in EBV-positive lymphomas and the study will compare patterns of EBV protein and gene expression with clinical, laboratory and outcome data.

Secondary Objective:

To estimate the complete response rate, event-free survival, and overall survival rates in patients with Burkitt lymphoma (BL), Burkitt leukemia/B-cell acute leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) treated with a stage-adapted regimen based on the St. Jude B-cell II protocol.

• Drug: COPAD
  Vincristine Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF
  Other Names:

  • VCR
  • prednisone
  • Adriamycin
  • cytoxan
  • filgrastim
  • Neupogen
• Drug: COP, COPD M3, CYM
  GROUP B Treatment Details Intravenous fluids should be given at a rate of 3000 mL/m2/day. Use of rasburicase may preclude the need for HCO3 Pre-Phase: Cyclophosphamide, Vincristine, Prednis(ol)one, IT medications Induction (2 cycles): Vincristine, Prednis(ol)one, Methotrexate, Leucovorin, Cyclophosphamide, Doxorubicin, IT medications, G-CSF, Rituximab Consolidation (2 cycles): Methotrexate, Leucovorin, Cytarabine, IT medications, G-CSF, Rituximab
  Other Names:

  • Elitek
  • Cytoxan
  • VCR
  • prednisone
  • MTX
  • folinic acid
  • Adriamycin
  • filgrastim
  • Rituxan
  • Ara-C
• Drug: COP, COPADM8, CYVE

  Treatment: Intravenous fluids should be given at a rate of 3000 mL/m2/day. Use of rasburicase may preclude the need for HCO3.

  COP Pre-Phase: Cyclophosphamide, Vincristine, Prednis(ol)one, IT medications, Leucovorin.

  COPADM8 Induction (2 cycles): Vincristine, Prednis(ol)one, Methotrexate, Leucovorin, Cyclophosphamide, Doxorubicin, IT medications, G-CSF CYVE Consolidation (2 cycles): Cytarabine, High-Dose Ara-C, Etoposide, G-CSF. Maintenance No.1: Vincristine, Prednis(ol)one, Cyclophosphamide, Methotrexate, Leucovorin, Doxorubicin, IT medications, G-CSF.

  Maintenance No.2: Cytarabine, Etoposide, G-CSF, IT Medications. Maintenance No.3: Vincristine, Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF, IT Medications.

  Maintenance No. 4: Cytarabine, Etoposide, G-CSF, IT Medications.

  Other Names:

  • Elitek
  • cytoxan
  • VCR
  • prednisone
  • folinic acid
  • Adriamycin
  • filgrastim
  • Ara-C
  • VP16
  • MTX

• Group A

  Completely resected stage I or completely resected abdominal stage II lesions.

  Group A will include: COPAD x 2 cycles.

  Intervention: Drug: COPAD
• Group B

  All cases not eligible for Group A or Group C. (Murphy Stage III and non-CNS Stage IV)

  Group B will include:

  Pre-Phase: COP; Induction: COPAD M3 x 2 cycles; Consolidation: CYM x 2 cycles.

  Intervention: Drug: COP, COPD M3, CYM
• Group C

  Any CNS involvement and/or bone marrow involvement ≥ 25% blasts. For CNS involvement one or more of the following applies:

  1. Any L3 blasts in CSF
  2. Cranial nerve palsy (if not explained by extracranial tumor)
  3. Clinical spinal cord compression
  4. Isolated intracerebral mass
  5. Parameningeal extension: cranial and/or spinal

  Group C will include:

  Pre-Phase: COP; Induction: COPADM8 cycle 1; Induction: COPADM8 Cycle 2; Consolidation: CYVE x 2 cycles and Maintenance

  Intervention: Drug: COP, COPADM8, CYVE

Inclusion Criteria:

St. Jude Participants:

1. Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification.
2. Participant must be previously untreated, (no more than 72 hours of steroids and/or emergency radiation)
3. Participant must be < 22 years of age at the time of diagnosis

4. For Group B participants with mediastinal large B cell lymphoma (MLBCL) disease only (receiving rituximab) - Hepatitis screening has been obtained. This screening must be done for eligibility BUT the results are not needed prior to enrollment:

   • Hepatitis B immunization status (vaccination Yes or No)
   • HBsAg
   • Anti-HBs antibody
   • Anti-HBc antibody. All participants must have screening prior to enrollment. Participants whose results indicate that they are carrier of hepatitis B can still be treated per Group B but will NOT receive rituximab.
5. HIV test has been obtained within 42 days. Participants who test positive for HIV cannot be enrolled on therapeutic part of study, but are still eligible for biology studies.
6. Informed consent must be obtained according to St. Jude guidelines before enrollment into study

Participants from Collaborating Sites Participating in Biological Objectives Only:

1. Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification
2. Participant must be < 22 years of age at the time of diagnosis
3. Informed consent must be obtained by local PI or his/her designee according to ICH/Good Clinical Practice and local guidelines before enrollment into study

Exclusion Criteria:

Participants from Collaborating Sites Participating in Therapeutic and Biological Objectives:

1. Participants with prior therapy (except steroids or RT)
2. Participants known to be HIV positive (for therapeutic part of protocol, HIV participants are eligible for biology studies).
3. Participants who are pregnant or lactating
4. Inability or unwillingness of research participant or legal guardian to consent
5. Participants who received emergent steroids and/or radiation prior to biopsy may be included in therapeutic part of study, but will be excluded from biology studies.

Participants from Collaborating Sites Participating in Biological Objectives Only:

1. Inability or unwillingness of research participant or legal guardian to consent
2. Histologic diagnosis other than a mature B-cell lymphoma as defined in the WHO classification
3. Participants who received emergent steroids and/or radiation prior to biopsy