Mature B-Cell Lymphoma And Leukemia Study III

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
This study will perform analysis of newly diagnosed mature B-cell lymphomas (e.g. Burkitt lymphoma/leukemia, DLBCL, and MLBCL) obtained from participants in different parts of the world. This study will describe the types and frequency of mutations in the ARF-HDM2-TP53 pathway, in B-cell lymphomas in the United States and that found in selected geographic regions of the world. This study will 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. 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. 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.

Official Title
-----------------
Mature B-Cell Lymphoma And Leukemia Study III

Conditions
-----------------
Mature B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: COPAD
* Drug: COP, COPD M3, CYM
* Drug: COP, COPADM8, CYVE


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: St. Jude participants and collaborating sites participating in therapeutic and biological objectives: 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. Participant must be previously untreated, (no more than 72 hours of steroids, one intrathecal chemotherapy treatment, and/or emergency radiation). Participant must be < 22 years of age at the time of diagnosis For selected higher-risk CD20+ Group B and all CD20+ Group C participants receiving rituximab only (e.g., those with MLBLC, Stage III with LDH ≥ 2 times upper limit of normal (ULN), and/or bone marrow/CNS involvement: All participants who will receive rituximab must have hepatitis screening prior to enrollment. Participants whose results indicate that they are carrier of hepatitis B can still be treated per Group B or C but will NOT receive rituximab. This screening must be done for eligibility for participants who will receive rituximab, 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 and C but will NOT receive rituximab 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. Informed consent must be obtained according to St. Jude guidelines before enrollment into study. Participants from Collaborating Sites Participating in Biological Objectives Only: 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. Participant must be < 22 years of age at the time of diagnosis. Participant must be previously untreated (no more than 72 hours of steroids, one intrathecal chemotherapy treatment, and/or emergency radiation) at the time of the diagnostic biopsy. 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: Participants known to be HIV positive (for therapeutic part of protocol, HIV participants are eligible for biology studies). Participants who are pregnant or lactating. Inability or unwillingness of research participant or legal guardian to consent. Participants from Collaborating Sites Participating in Biological Objectives Only: Inability or unwillingness of research participant or legal guardian to consent. Histologic diagnosis other than a mature B-cell lymphoma as defined in the WHO classification.

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A<br>Completely resected stage I or completely resected abdominal stage II lesions. Group A will include: COPAD x 2 cycles. | Drug: COPAD<br>* Vincristine Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF In the event the patient cannot receive G-CSF, Pegfilgrastim can be substituted.<br>* Other names: Neulasta®;|
| Other: Group B<br>All cases not eligible for Group A or Group C. (Murphy Stage III and non-CNS Stage IV) Group B will include the intervention COP, COPD M3, CYM as follows: Pre-Phase: COP Induction: COPAD M3 x 2 cycles Consolidation: CYM x 2 cycles. | Drug: COP, COPD M3, CYM<br>* 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 In the event the patient cannot receive G-CSF, Pegfilgrastim can be substituted.<br>* Other names: Neulasta®;|
| Other: Group C<br>Any CNS involvement and/or bone marrow involvement ≥ 25% blasts. For CNS involvement one or more of the following applies: Any L3 blasts in CSF Cranial nerve palsy (if not explained by extracranial tumor) Clinical spinal cord compression Isolated intracerebral mass Parameningeal extension: cranial and/or spinal Group C will include the intervention COP, COPADM8, CYVE as follows: Pre-Phase: COP Induction: COPADM8 cycle 1 Induction: COPADM8 Cycle 2 Consolidation: CYVE x 2 cycles and Maintenance | Drug: COP, COPADM8, CYVE<br>* 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, Rituximab, IT medications, G-CSF CYVE Consolidation (2 cycles): Cytarabine, High-Dose Ara-C, Etoposide, Rituximab, 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. In the event the patient cannot receive G-CSF, Pegfilgrastim can be substituted.<br>* Other names: Neulasta®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene differential profiling of Burkitt Lymphoma (BL) vs. non-BL | Gene expression levels in BL vs. non-BL will be analyzed through approximately 22,000 probesets on the Affymetrix U133A GeneChip by using two-factor analysis of variance model for each gene. | 1 year after the last participant is enrolled | 
| Catalog and estimate frequencies of copy number variations in childhood lymphomas | The prevalence of CNVs between different subtypes of childhood lymphomas and geographic regions will be reported and compared with exact chi-square or Fisher's test. | 1 year after the last participant is enrolled | 
| Integrated analysis of CNVs and gene expressions | The association between the identified CNVs and gene expressions in the study cohort will be examined by using general linear models, and multiple tests will be considered. | 1 year after the last participant is enrolled | 
| Pattern and frequency of XLP gene mutations presenting with B-cell lymphomas in the United States and selected geographic regions | Frequency of XLP mutation among boys will be calculated in each geographical region as well as in all regions pooled. The frequency is reported here as the number of boys with XLP gene mutations found in B-cell lymphomas boys. | 1 year after the last participant enrollment | 
| 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 | Point estimates and 95% CIs of the frequency of EBV-positive BL will be calculated for each geographical region. EBV protein expression will be described by summary statistics. Relationship of EBV protein expression with clinical, laboratory, and outcome features will be explored using appropriate statistical methods such as general linear models. | 1 year after the last participant is enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | Complete response rate will be estimated with exact 95% CI based on the binomial distribution, and it will be reported as the percentage of patients who reached complete remission among eligible patients treated at SJCRH | 5 years after completion of therapy | 
| Event-free survival | Event-free survival (EFS) will be estimated among eligible patients treated at SJCRH by the Kaplan-Meier estimator. The events will include: (1) death while in continuous CR, (2) relapse, (3) secondary malignancy, and (4) failure to achieve complete response (CR). | 5 years after completion of therapy | 
| Overall Survival | Overall survival (OS) will be estimated among eligible patients treated at SJCRH by the Kaplan-Meier estimator. | 5 years after completion of therapy | 
| Percentage of participants who complete therapy with the use of rituximab | Percentages of possible rituximab-related toxicities will be described in terms of the estimates of the number of episodes and the cumulative incidence throughout the treatment period for each type of toxicity. | at the end of therapy (maximum of 9 months after enrollment) | 
| Number of possible rituximab-related toxicities | The number of episodes and the cumulative incidence throughout the treatment period for each type of possible rituximab-related toxicity will be estimated and reported. | at the end of therapy (up to 9 months after enrollment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lymphoma, Leukemia, Non-Hodgkin's Lymphoma