Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents
- Conditions
- Mature B-cell Non-Hodgkin Lymphoma
- Interventions
- Registration Number
- NCT03206671
- Lead Sponsor
- University Hospital Muenster
- Brief Summary
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
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 650
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Newly diagnosed, histological or cytological and immunological proven aggressive mature B-cell Non-Hodgkin lymphoma including Burkitt lymphoma (BL), Burkitt leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), or mature B-cell NHL not further classified according to current WHO classification124. For rare subtypes (e.g. primary mediastinal large B-NHL, PMLBL, double hit lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements), consultation of the study center is recommended.
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availability of slides/blocks for reference pathology and international pathology panel (except in cases with immunological and cytomorphological assurance of diagnosis)
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age at diagnosis < 18 years
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diagnostics and treatment in one of the participating centers of the trial
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no previous chemotherapy, no previous lymphoma-directed treatment. No application of steroids for more than two days during the last month
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adequate hepatic, renal and cardiac function, except if alteration is due to lymphoma infiltration. Please contact the study center in case of unclear cases.
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signed informed consent of patient and/or parents/guardians for treatment according to the protocol, participation and transfer of data
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follow-up of at least two years after initial diagnosis is expected
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Certificate of vaccination against hepatitis B or negative serology, defined as
- evidence of immunization with HBs-antigen negative, anti-HBs positive and anti-HBc negative or
- negative hepatitis B serology with HBs-antigen negative, anti-HBs and anti- HBc negative
- patients with insufficient work up not allowing a correct stratification into the risk groups
- B-cell neoplasia as second malignancy
- any other medical, psychiatric or social condition prohibiting treatment according to the protocol (e.g. previous malignancy, prior organ transplant, HIV infection or AIDS or severe immunodeficiency, etc.)
- participation within a different trial for treatment of B-cell malignancies and/or concurrent treatment within any other clinical trial. Exceptions to this are the NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment which can run parallel to B-NHL 2013 without influencing the outcome of this trial e.g. trials on antiemetics, antibiotics, strategies for psychosocial support etc.
- overt hepatitis B or history of hepatitis B
- hypersensitivity to rituximab or to murine proteins or to any of the other excipients of the Investigational Medicinal Product rituximab (MabThera®) or to ingredients of other IMPs.
- lack of CD20 expression of the lymphoma cells
- pregnancy and lactation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description R3/R4 standard arm Rituximab window Rituximab window + standard chemotherapy R1/R2 stage I+II Rituximab window Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R3/R4 rituximab plus arm Vindesine Sulfate Rituximab window + standard chemotherapy plus six additional doses of rituximab R2 stage III experimental arm Rituximab window Rituximab window + Standard chemotherapy R2 stage III experimental arm Methotrexate Rituximab window + Standard chemotherapy R2 stage III standard arm Cyclophosphamide Standard chemotherapy R3/R4 rituximab plus arm Rituximab window Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Methotrexate Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Prednisolone Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 standard arm Dexamethasone Rituximab window + standard chemotherapy R3/R4 rituximab plus arm Additional doses of Rituximab Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 standard arm Vindesine Sulfate Rituximab window + standard chemotherapy R3/R4 standard arm Vincristine Rituximab window + standard chemotherapy R1/R2 stage I+II Cyclophosphamide Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Cytarabine Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Dexamethasone Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Etoposide Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Ifosfamide Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Vincristine Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Methotrexate Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R1/R2 stage I+II Prednisolone Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) R2 stage III experimental arm Cyclophosphamide Rituximab window + Standard chemotherapy R2 stage III experimental arm Etoposide Rituximab window + Standard chemotherapy R2 stage III experimental arm Dexamethasone Rituximab window + Standard chemotherapy R2 stage III experimental arm Doxorubicin hydrochloride Rituximab window + Standard chemotherapy R2 stage III experimental arm Cytarabine Rituximab window + Standard chemotherapy R2 stage III experimental arm Ifosfamide Rituximab window + Standard chemotherapy R2 stage III standard arm Cytarabine Standard chemotherapy R2 stage III experimental arm Prednisolone Rituximab window + Standard chemotherapy R2 stage III experimental arm Vincristine Rituximab window + Standard chemotherapy R2 stage III standard arm Dexamethasone Standard chemotherapy R2 stage III standard arm Doxorubicin hydrochloride Standard chemotherapy R2 stage III standard arm Etoposide Standard chemotherapy R2 stage III standard arm Ifosfamide Standard chemotherapy R2 stage III standard arm Prednisolone Standard chemotherapy R2 stage III standard arm Methotrexate Standard chemotherapy R2 stage III standard arm Vincristine Standard chemotherapy R3/R4 rituximab plus arm Cyclophosphamide Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Cytarabine Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Dexamethasone Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Doxorubicin hydrochloride Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Etoposide Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Ifosfamide Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 rituximab plus arm Vincristine Rituximab window + standard chemotherapy plus six additional doses of rituximab R3/R4 standard arm Cytarabine Rituximab window + standard chemotherapy R3/R4 standard arm Cyclophosphamide Rituximab window + standard chemotherapy R3/R4 standard arm Doxorubicin hydrochloride Rituximab window + standard chemotherapy R3/R4 standard arm Etoposide Rituximab window + standard chemotherapy R3/R4 standard arm Ifosfamide Rituximab window + standard chemotherapy R3/R4 standard arm Methotrexate Rituximab window + standard chemotherapy R3/R4 standard arm Prednisolone Rituximab window + standard chemotherapy
- Primary Outcome Measures
Name Time Method Event-free survival (EFS) through study completion, maximal seven years 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 (only in R3/R4 patients) 12 months after start of treatment 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.
- Secondary Outcome Measures
Name Time Method Relapse-free survival (RFS) through study completion, maximal seven years 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.
Adverse event rate from the first day of protocol defined treatment until two years after start of protocol defined treatment Rate of patients with acute toxicity defined as grade III/IV/V AE
Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood. through study completion, maximal seven years Overall survival (OS) through study completion, maximal seven years 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.
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. through study completion, maximal seven years Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until 24 months after start of treatment 24 months after start of treatment Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until immune reconstitution (achievement of age adjusted normal B-cell counts) through study completion, maximal seven years Rate of patients with sufficient titers after vaccination one year after start of treatment 1 year after start of treatment Response rate (RR) after rituximab window on day 5, after prephase (patients with rituximab window on day 10, patients without rituximab window on day 6) and after second course (on an average 5 to 6 weeks after start of treatment) Complete response, partial remission, objective effect, stable disease or progressive disease
Rate of patients achieving normal immunoglobulin level 12 months after start of treatment 12 months after start of treatment Time interval to normal immunoglobulin level through study completion, maximal seven years Immune reconstitution rate (only in R1/R2 patients) 12 months after start of treatment 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.
Trial Locations
- Locations (88)
Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-Onkologie
🇦🇹Graz, Austria
Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I
🇦🇹Innsbruck, Austria
Klinikum Klagenfurt am Wörthersee, Abteilung für Kinder- und Jugendheilkunde
🇦🇹Klagenfurt, Austria
Kepler Universitätsklinikum, Med Campus IV / Onkologie
🇦🇹Linz, Austria
LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie
🇦🇹Salzburg, Austria
St. Anna Kinderspital
🇦🇹Wien, Austria
Department of Pediatric Hematology and Oncology, University Hospital Motol
🇨🇿Prague, Czechia
Børneonkologisk afsnit 303B, Børneafdelingen, Aalborg Universitetshospital Nord
🇩🇰Aalborg, Denmark
Børn og Unge afsnit 4, Børneafdelingen, Aarhus Universitetshospital Skejby
🇩🇰Aarhus, Denmark
Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet
🇩🇰Kobenhavn, Denmark
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