Phase III study: For the patients with advanced stage B-cell NHL/B-AL (stage III and LDH > Nx2, any stage IV or B-AL) to test whether adding 6 injections of rituximab to standard LMB chemotherapy regimen, improves the EFS compared with LMB chemotherapy alone.
Phase II study:
To determine the efficacy of DA-EPOCH-R in children and adolescent PMLB in terms of EFS.
In Phase III and Phase II studies:
- To study the complete remission (CR) rate and the overall survival (OS).
- To evaluate safety on all study arms: including toxic deaths, adverse events recorded using the NCI-CTC V4 (non haematological toxicity grade3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and evolution of left ventricular ejection fraction and left ventricular shortening fraction), number of days with platelets transfusion, intensive care unit admission and number of days with red cells transfusion, rituximab infusion reactions.
- To study the rate of patients with Ig (G, A and M) level abnormally low and lymphocyte count abnormally low at 1 year and until 5-year follow-up, and to study the need for immunoglobuline infusions and levels of post (previous and re-)vaccination antibodies at 1 year.
In Phase III study:
- To study long term (at least 5 years) risks of the use of rituximab plus chemotherapy compared with LMB chemotherapy alone in children and adolescents with advanced stage B-NHL/B-AL (all events related (certain and probable) to therapy).
In Phase II study:
- To study the long term risk of DA-EPOCH-R regimen, especially the cardiac risk related to doxorubicin given at higher dose than usual in children, but infused over 96h (i.e. evaluation of CTC grade 2-5 and evolution of left ventricular ejection fraction and left ventricular shortening fraction).
EXPLORATORY SECONDARY OBJECTIVES (not done in all countries)
In Phase III and Phase II studies:
To obtain data on PET(-CT) in childhood pediatric B-cell NHL.
In phase III study:
- To evaluate the potential prognostic value of Minimal Dissiminated Disease (MDD) and Minimal Residual disease (MRD) in correlation with outcome.
- To perform an economic study comparing the cost-effectiveness ratio between 2 therapeutic strategies: LMB chemotherapy with versus LMB chemotherapy without Rituximab.
- To characterize the pharmacokinetics of rituximab in combination with LMB chemotherapy in a subset of patients.
Rituximab (antiCD20) in association with chemotherapy has extended the survival of adult patients with diffuse large B-cell lymphoma (DLBCL) and become the standard treatment of B-cell lymphoma in adults. However, there has never been a definitive clinical trial evaluating efficacy and safety of rituximab added to chemotherapy for childhood B-cell lymphoma. Results from adult B-lymphoma cannot be assumed to apply to children because of differences in the biology of childhood DLBCL and because >75% of childhood B lymphoma are Burkitt type, where efficacy of rituximab has never undergone definitive evaluation (either in adults or children). Because Event Free Survival (EFS) is already high in children with the current intensive chemotherapy regimen, and because rituximab is an expensive medication which could produce potential severe side effects (e.g. prolonged lymphoid B-cell depletion), a large randomized trial is necessary to evaluate whether rituximab can add benefit to the current chemotherapy regimen. Two pilot studies in children provide preliminary evidence of safety and activity of rituximab in this disease setting that support such a study. A Berlin-Frankfurt-Münster group (BFM) study, which tested a single dose of rituximab administered prior to chemotherapy, has shown tumor responses. A COG pilot study tested the safety and tolerability of the combination of rituximab with LMB chemotherapy and showed no increased short term toxicity. While EFS is 90% with either with the LMB or the BFM regimen, EFS of stages III with LDH level >Nx2 and of stages IV & B-AL is around 84%, indicating a need for therapeutic improvement and identifying a higher risk population in which to evaluate the potential benefit of rituximab.
Principal Investigator: Phillip Barnette
Department: Pediatric Administration
Co Investigator: Jennifer Wright
Co Investigator: Richard Lemons
Co Investigator: Anupam Verma
Co Investigator: Carol Bruggers
Co Investigator: Hassan Yaish
Co Investigator: Mark Fluchel