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Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)

Rituximab window + standard chemotherapy plus six additional doses of rituximab

Rituximab window

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, 1 dose of rituximab before the start of the third chemotherapy cycle, 1 dose of Rituximab before the start of the forth chemotherapy cycle

Additional doses of Rituximab

Doxorubicin hydrochloride

Vindesine Sulfate

Birgit Burkhardt, Prof. Dr. Dr.

The trial B-NHL 2013 is a collaborative prospective, multi-national, multi-center, randomized trial with participating centers of the NHL-BFM group (Austria, Switzerland, Czech Republic, Germany) and the Scandinavian NOPHO group (Denmark, Finland, Norway, Sweden). The aim of the trial is to evaluate the role of rituximab in the treatment of mature aggressive B-cell Non-Hodgkin lymphoma and leukemia (B-NHL and B-AL) in children and adolescents.

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 and R2 stage I and II) of substituting anthracyclines by the rituximab window without compromising survival rates.
* the effectiveness (event-free survival) in pediatric patients with limited mature B-NHL (R2 stage III) randomly assigned to receive the rituximab window plus standard chemotherapy or standard chemotherapy without the rituximab window.
* the effectiveness (event-free survival) and the immune reconstitution (recovery of CD19+ B-cells, IR) in pediatric patients with advanced mature B-NHL/B-AL (R3 and R4 incl. R4 CNS+) treated with BFM-type chemotherapy and randomly assigned schedules of one versus seven doses rituximab.

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
* adverse event and severe adverse event profile
* inter-individual variability of rituximab response
* role of different mechanisms of action of rituximab in advanced B-NHL/B-AL

Risk group stratification:

R1/R2 stage I+II:

* R1: resection status: complete
* R2: resection status: incomplete, stage I and II

R2 III:

- R 2: resection status: incomplete, stage III and LDH \< 2 x ULN (according to local reference value for adults)

R3/R4:

* R3: resection status: incomplete, stage III and LDH ≥ 2 x ULN but \< 4 x ULN or stage IV/B-AL and LDH \< 4 x ULN and CNS negative
* R4: resection status: incomplete, Stage III and LDH ≥ 4 x ULN or stage IV/B-AL and LDH ≥ 4 x ULN and CNS negative
* R4 CNS +: stage IV/B-AL and CNS positive

For patients with very limited disease (R1/R2 stage I/II), the addition of rituximab might allow the omission of anthracyclines 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 when all patients receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy as a substitute for anthracyclines.

For patients with limited disease (R2 stage III) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different treatment regimens will be evaluated in a randomized design: Patients in the standard arm will receive the standard chemotherapy. Patients of the rituximab plus arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy.

For patients with advanced disease (R3/R4) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different rituximab regimens will be evaluated in a randomized design: Patients in the standard arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy. Patients of the rituximab plus arm will receive the rituximab window and additional six doses of rituximab added to the first four courses of chemotherapy. In addition the immune reconstitution will be analyzed comparing the effect of the two regimens of rituximab added to standard chemotherapy.

Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents

B-NHL 2013 - Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents

EFS is defined as time from start of treatment/randomization 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, treatment related death, death of any other cause or diagnosis of secondary malignancies.

Immune reconstitution rate is defined as percentage of patients achieving age adjusted normal B-cell counts (CD19 positive subpopulations) 12 months after start of treatment.

OS is defined as time from start of treatment/randomization up to death of any cause or to date of last contact for patients alive.

RFS is defined as time from start of treatment/randomization 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.

Complete response, partial remission, objective effect, stable disease or progressive disease

Rate of patients with acute toxicity defined as grade III/IV/V AE

Deutsche Krebshilfe e.V., Bonn (Germany)

University Hospital Muenster

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents	NCT03206671	Mature B-cell N...	Rituximab windo... Additional dose... Cyclophosphamid... Cytarabine Dexamethasone Doxorubicin hyd... Vindesine Sulfa... Etoposide Ifosfamide Methotrexate Prednisolone Vincristine	- 18 Years	University Hospital Muenster
Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents	NCT03206671	Mature B-cell N...	Rituximab windo... Additional dose... Cyclophosphamid... Cytarabine Dexamethasone Doxorubicin hyd... Vindesine Sulfa... Etoposide Ifosfamide Methotrexate Prednisolone Vincristine	- 18 Years	University Hospital Muenster

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