B-cell Mature Non-Hodgkin's Lymphoma Treatment Protocol in Children and Adolescents 2021

Study Overview
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Brief Summary
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The aim of the trial is to evaluate the molecular characteristics and MDD/MRD of B-NHL in pediatric patients in order to identify on the one hand the very high risk group and to prescribe them more intensive treatment on the other hand to identify those patients who don't need very aggressive therapy. One more study question is to evaluate the role of PET/CT in assessment of the completeness of remission. The following primary study questions are going to be analyzed: the effectiveness (event-free survival) in pediatric patients with very limited mature B-NHL (R1 - stage I and II R) of substituting anthracyclines and vincristine by the rituximab without compromising survival rates. the effectiveness (event-free survival) in pediatric patients with limited mature B-NHL (R2 - stage I and II NR) of substituting anthracyclines by the rituximab without compromising survival rates. the effectiveness (event-free survival) in pediatric patients with advanced VHR mature B-NHL (R4 - stages with unfavourable genetics of substituting standard chemotherapy by second-line block VICI in order to improve results Secondary study questions will address additional parameters for immune reconstitution, lymphocyte subpopulations, immunoglobulin levels, vaccination titers and infection rates kinetics of immune reconstitution after treatment

Detailed Description
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Detailed Description: Risk group stratification: R1: resection status: complete, stage I and II R2: resection status: incomplete, stage I and II R3: resection status: incomplete, stage III and LDH < 2 x ULN R4: resection status: incomplete, stage III and LDH ≥ 2 x ULN, stage IV/B-AL and CNS negative; CNS + For patients with very limited disease (R1- stage I/II СR), the addition of rituximab might allow the omission of anthracyclines and vincristine without jeopardizing survival rates but reducing acute and long term toxicities. In this treatment arm, it is tested whether the event-free survival is similar to that of the historical control For patients with limited disease (R2- stage I/II NR), the addition of rituximab might allow the omission of anthracyclines without jeopardizing survival rates but reducing acute and long term toxicities. For patients with limited disease (R3 - stage III and LDH < 2 x ULN ), the addition of rituximab might allow reduce the number of blocks to four without jeopardizing survival rates but reducing toxicities For patients with obligate factors of poor prognosis (additional adverse cytogenetic findings (TP-53, 11qLOH) it is tested whether the event-free survival can be improved by adding rituximab and adding blocks R-VICI

Official Title
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B-cell Mature Non-Hodgkin's Lymphoma Treatment Protocol in Children and Adolescents 2021 (B-NHL-M-2021)

Conditions
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Non-hodgkin Lymphoma,B Cell, Burkitt Lymphoma, Primary Mediastinal Lymphoma, Primary CNS Lymphoma, Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Etoposide, Ifosfamide, Methotrexate
* Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Etoposide, Ifosfamide, Methotrexate, Vincristine
* Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Doxorubicin hydrochloride, Etoposide, Ifosfamide, Methotrexate, vincristine
* Drug: Cyclophosphamide , Cytarabine, Dexamethasone, Doxorubicin hydrochloride, Etoposide, Ifosfamide, Methotrexate, Vincristine, Сarboplatine, CCNU/ BCNU, Melphalan, Idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at diagnosis 0 to 18 years. The diagnosis of Burkitt's lymphoma, Diffuse large B-cell lymphom, primary mediastinal lymphoma, primary CNS lymphoma, B-cell (Burkitt) AL Informed consent of the patient parents (guardians) to be treated Exclusion Criteria: previous malignancy, prior organ transplant, HIV infection or AIDS or severe immunodeficiency hypersensitivity to rituximab or to ingredients of other IMPs. no informed consent of the patient parents (guardians) to be treated

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R1: stage I and II<br>R1: resection status: complete, stage I and II | Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Etoposide, Ifosfamide, Methotrexate<br>* For patients with very limited disease (R1- stage I/II СR), the addition of rituximab might allow the omission of anthracyclines and vincristine without jeopardizing survival rates but reducing acute and long term toxicities. In this treatment arm, it is tested whether the event-free survival is similar to that of the historical control<br>|
| Experimental: R2: incomplete, stage I and II<br>R2: resection status: incomplete, stage I and II | Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Etoposide, Ifosfamide, Methotrexate, Vincristine<br>* R2: Drug: Rituximab 2 doses of Rituximab (375 mg/m²) before the start of the first chemotherapy cycle, 2 doses of Rituximab before the start of the second chemotherapy cycle<br>|
| Experimental: R3: incomplete, stage III and LDH < 2 x ULN<br>R3: resection status: incomplete, stage III and LDH < 2 x ULN | Drug: Cyclophosphamide, Cytarabine, Dexamethasone, Doxorubicin hydrochloride, Etoposide, Ifosfamide, Methotrexate, vincristine<br>* 2 doses of Rituximab (375 mg/m²) before the start of the first chemotherapy cycle, 2 doses of Rituximab before the start of the second<br>|
| Experimental: R4: stage III and LDH ≥ 2 x ULN, stage IV/B-AL and CNS negative; CNS +<br>R4: resection status: incomplete, stage III and LDH ≥ 2 x ULN, stage IV/B-AL and CNS negative; CNS + | Drug: Cyclophosphamide , Cytarabine, Dexamethasone, Doxorubicin hydrochloride, Etoposide, Ifosfamide, Methotrexate, Vincristine, Сarboplatine, CCNU/ BCNU, Melphalan, Idarubicin<br>* Rituximab 4 doses of Rituximab (375 mg/m²) before the start of the first chemotherapy cycle, Further<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Event-free survival The following occurrences are defined as an event: non-response, progressive disease or relapse, treatment related death, death of any other cause or diagnosis of secondary malignancies. | 3 years after the start of therapy | 
| Event-free survival | Event-free survival The following occurrences are defined as an event: non-response, progressive disease or relapse, treatment related death, death of any other cause or diagnosis of secondary malignancies. | 7 years after the start of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| assessment of MDD and MRD indicators, p53 and 11qLOH status in patients on the B-NHL-M-2021 protocol |  | 3 years after the start of therapy | 
| assessment of MDD and MRD indicators, p53 and 11qLOH status in patients on the B-NHL-M-2021 protocol |  | 7 years after the start of therapy | 
| assessment of PET-CT results - initial and control points (early PET response).after the 2nd block | measurement of tumor volume at diagnosis and measurement of tumor volume reduction after therapy in percent after the 2nd block - CT with CL of the involved areas, PET-CT examination on the 14th day (maximum on the 17th day) after the last injection of CT, IPT, MRD in the bone marrow | after the 2nd block - CT with CL of the involved areas, PET-CT examination on the 14th day (maximum on the 17th day) after the last injection of CT, IPT, MRD in the bone marrow - after 4th block - CT with the CL of the involved areas | 
| assessment of PET-CT results - initial and control points (early PET response) after 4th block | measurement of tumor volume at diagnosis and measurement of tumor volume reduction after therapy in percent after 4th block - CT with the CL of the involved areas , PET-CT examination on the 14th day (maximum on the 17th day) after the last administration of CT, MRD in the bone marrow if present after the 2nd block After the 6th block - CT with CL of the involved areas | PET-CT examination on the 14th day (maximum on the 17th day) after the last administration of CT, MRD in the bone marrow if present after the 2nd block | 
| Relapse-free survival (RFS) | RFS is defined as time from start of treatment up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease, or relapse. | 3 years after the start of therapy | 
| Relapse-free survival (RFS) | RFS is defined as time from start of treatment up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease, or relapse. | 7 years after the start of therapy | 
| Response rate (RR) [ and after second course and after two injections of rituximab]. Complete response, partial remission, stable disease or progressive disease |  | 3 years after the start of therapy | 
| Response rate (RR) [ and after second course and after two injections of rituximab]. Complete response, partial remission, stable disease or progressive disease |  | 7 years after the start of therapy | 
| Rate of patients achieving normal immunoglobulin level |  | 12 months after start of treatment | 
| Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment |  | 12 months after start of treatment | 
| Interval to normal lymphocyte subpopulations in the peripheral blood. |  | 7 years after the start of therapy | 
| Rate of patients with sufficient titers after vaccination one year after start of treatment |  | 1 year after start of treatment | 
| Immune reconstitution rate (only in R1/R2 patients) |  | 1 year after start of treatment | 
| Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood. |  | 1 year after start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell mature non-Hodgkin's lymphoma, Burkitt's lymphoma, Diffuse large B-cell lymphoma, primary mediastinal lymphoma, primary CNS lymphoma, rituximab, children, adolescents, treatment