Mature B-Cell Lymphoma
Conditions
Keywords
Lymphoma, Leukemia, Non-Hodgkin's Lymphoma
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
1. 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. 2. 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. 3. 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. 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. Exploratory Aims: 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.
Interventions
DRUGCOPAD
Vincristine Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF In the event the patient cannot receive G-CSF, Pegfilgrastim can be substituted.
DRUGCOP, 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 In the event the patient cannot receive G-CSF, Pegfilgrastim can be substituted.
DRUGCOP, 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, 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.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
St. Jude participants and collaborating sites participating in therapeutic and biological objectives: 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, one intrathecal chemotherapy treatment, and/or emergency radiation). 3. Participant must be \< 22 years of age at the time of diagnosis 4. 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. 5. 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 6. 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. 7. 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. 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. 4. 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 known to be HIV positive (for therapeutic part of protocol, HIV participants are eligible for biology studies). 2. Participants who are pregnant or lactating. 3. Inability or unwillingness of research participant or legal guardian to consent. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gene Differential Expression Profiling of Burkitt Lymphoma (BL) vs. Non-BL in the US and Other Selected Geographic Regions of the World | 1 year after the participant is enrolled | 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. |
| Catalog and Estimate Frequencies of Copy Number Variations in Childhood Lymphomas | 1 year after the participant is enrolled | 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. The CNVs are derived from Affymetrix SNP arrays. |
| Integrated Analysis of CNVs and Gene Expressions in the US and Other Selected Geographic Regions of the World | 1 year after the participant is enrolled | 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. Gene expressions are measured by Affymetrix U133A arrays and CNVs are derived from Affymetrix SNP arrays. |
| Pattern and Frequency of XLP Gene Mutations Presenting With B-cell Lymphomas in the United States and Selected Geographic Regions | 1 year after the participant enrollment | 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. |
| Frequency of EBV Protein Expression (e.g., EBNA 3) in EBV-positive Lymphomas | 1 year after the participant is enrolled | Frequency of EBV-positive BL will be calculated for each geographical region. |
Countries
Egypt, Singapore, United States
Contacts
PRINCIPAL_INVESTIGATORRaul Ribeiro, MD
St. Jude Children's Research Hospital
Participant flow
Recruitment details
115 patients were recruited between 15APR1309Sept2010 and 31AUG2022. One patient died at the same day he was enrolled and did not start any treatment and risk was not determined and was excluded in the treatment outcome analysis. One was found to be ineligible after the start of treatment. Thirteen participants from diverse geographical regions were enrolled in the biology only part of the study and no outcome data is available.
Participants by arm
| Arm | Count |
|---|---|
| Group A Completely resected stage I or completely resected abdominal stage II lesions. | 5 |
| Group B All cases not eligible for Group A or Group C. (Murphy Stage III and non-CNS Stage IV) | 86 |
| 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 | 22 |
| Biology Only Participants enrolled on the biology only arm | 13 |
| Total | 126 |
Baseline characteristics
| Characteristic | Group A | Group B | Group C | Biology Only | Total |
|---|---|---|---|---|---|
| Age, Continuous | 13.7 years | 12.9 years | 14.4 years | 14.7 years | 13.4 years |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 0 Participants | 11 Participants | 16 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 12 Participants | 4 Participants | 0 Participants | 16 Participants |
| Race/Ethnicity, Customized Multiple Race (Not Otherwise Specified) | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 64 Participants | 18 Participants | 1 Participants | 87 Participants |
| Sex: Female, Male Female | 2 Participants | 21 Participants | 7 Participants | 2 Participants | 32 Participants |
| Sex: Female, Male Male | 3 Participants | 65 Participants | 15 Participants | 11 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 1 / 86 | 1 / 22 | 1 / 1 |
| other Total, other adverse events | 3 / 5 | 77 / 86 | 21 / 22 | 0 / 0 |
| serious Total, serious adverse events | 0 / 5 | 0 / 86 | 0 / 22 | 0 / 0 |
Outcome results
Primary
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. The CNVs are derived from Affymetrix SNP arrays.
Time frame: 1 year after the participant is enrolled
Population: We were unable to evaluate this measure due to challenges such as the PI leaving St. Jude, COVID-19 disruptions, stricter regulations on shipping tumor materials internationally, and unavailability of the required assay platform. One sample was received from Singapore, none from Egypt. No participant is analyzed, and no CNV data is generated because the Affymetrix SNPChip platform is no longer available. No participant will be analyzed, and no CNV data will be generated in the future.
Primary
Frequency of EBV Protein Expression (e.g., EBNA 3) in EBV-positive Lymphomas
Frequency of EBV-positive BL will be calculated for each geographical region.
Time frame: 1 year after the participant is enrolled
Population: We were unable to fully evaluate this measure due to PI leaving St. Jude, COVID-19 disruptions, and stricter regulations on sending tumor material from other countries. We received 5 participants at our institution and none showed EBV positivity. No sample was received from international sites. No EBV positivity test will be performed, and no further data will be generated in the future.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Biology Samples-United States (US) | Frequency of EBV Protein Expression (e.g., EBNA 3) in EBV-positive Lymphomas | 0 Participants |
| Biology Samples-Singapore | Frequency of EBV Protein Expression (e.g., EBNA 3) in EBV-positive Lymphomas | 0 Participants |
| Biology Samples-Egypt | Frequency of EBV Protein Expression (e.g., EBNA 3) in EBV-positive Lymphomas | 0 Participants |
Primary
Gene Differential Expression Profiling of Burkitt Lymphoma (BL) vs. Non-BL in the US and Other Selected Geographic Regions of the World
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.
Time frame: 1 year after the participant is enrolled
Population: No data was generated for this measure due to the PI leaving St. Jude, COVID-19 disruptions, stricter regulations on international tumor material shipping, and unavailability of the required assay platform. One sample was received from Singapore, none from Egypt. No participant is analyzed, and no gene expression data is generated because the Affymetrix U133A GeneChip is no longer available. No participant will be analyzed, and no gene expression data will be generated in the future.
Primary
Integrated Analysis of CNVs and Gene Expressions in the US and Other Selected Geographic Regions of the World
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. Gene expressions are measured by Affymetrix U133A arrays and CNVs are derived from Affymetrix SNP arrays.
Time frame: 1 year after the participant is enrolled
Population: No data was generated for this measure due to PI leaving St. Jude, COVID-19 disruptions, stricter regulations on international tumor material shipping , unavailability of the required assay platform. 1 sample was received from Singapore, 0 from Egypt. No participant is analyzed, and no gene expression and CNV data is generated because the Affymetrix U133A GeneChip and SNPChip are unavailable. No participant will be analyzed, and no gene expression and CNV data will be generated in the future.
Primary
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.
Time frame: 1 year after the participant enrollment
Population: We cannot obtain samples from other countries; thus cannot evaluate this objective, due to the PI leaving, difficulties caused by COVID-19, and, most importantly, changes in regulations on sending tumor material from institutions in other countries. We received 1 sample from Singapore and none from Egypt. For international sites, no clinical, laboratory or outcome features are available. Among US samples, 1 was tested XLP positive. No data was generated from the Singapore sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Biology Samples-United States (US) | Pattern and Frequency of XLP Gene Mutations Presenting With B-cell Lymphomas in the United States and Selected Geographic Regions | 1 Participants |
| Biology Samples-Singapore | Pattern and Frequency of XLP Gene Mutations Presenting With B-cell Lymphomas in the United States and Selected Geographic Regions | 0 Participants |
| Biology Samples-Egypt | Pattern and Frequency of XLP Gene Mutations Presenting With B-cell Lymphomas in the United States and Selected Geographic Regions | 0 Participants |
Other Pre-specified
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
Time frame: Up to 5 years after completion of therapy
Population: Only the 89 patients treated at St. Jude Children's Hospital are included in this analysis.The study objective requires to obtain and analyze long-term outcome (OS and EFS) and toxicities in Groups A, B, C only. Patients in the Biology Only group only provide samples and are not treated on this protocol. Therefore EFS, OS and toxicities are only analysed and reported for Groups A, B and C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biology Samples-United States (US) | Complete Response Rate | 100 percentage of participants |
| Biology Samples-Singapore | Complete Response Rate | 90.14 percentage of participants |
| Biology Samples-Egypt | Complete Response Rate | 82.35 percentage of participants |
p-value: 0.6181Chi-squared
Other Pre-specified
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).
Time frame: Up to 5 years after completion of therapy
Population: The study objective requires to obtain and analyze long-term outcome (OS and EFS) and toxicities in Groups A, B, C only. Patients in the Biology Only group only provide samples and are not treated on this protocol. Therefore EFS, OS and toxicities are only analysed and reported for Groups A, B and C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biology Samples-United States (US) | Event-free Survival | 100 percentage of participants |
| Biology Samples-Singapore | Event-free Survival | 90.6 percentage of participants |
| Biology Samples-Egypt | Event-free Survival | 81.8 percentage of participants |
p-value: 0.3605Log Rank
Other Pre-specified
Overall Survival
Overall survival (OS) will be estimated among eligible patients treated at SJCRH by the Kaplan-Meier estimator.
Time frame: Up to 5 years after completion of therapy
Population: The study objective requires to obtain and analyze long-term outcome (OS and EFS) and toxicities in Groups A, B, C only. Patients in the Biology Only group only provide samples and are not treated on this protocol. Therefore EFS, OS and toxicities are only analysed and reported for Groups A, B and C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biology Samples-United States (US) | Overall Survival | 100 percentage of participants |
| Biology Samples-Singapore | Overall Survival | 98.0 percentage of participants |
| Biology Samples-Egypt | Overall Survival | 94.7 percentage of participants |
p-value: 0.555Log Rank