Status: Not yet recruiting
Keywords: B-Cell NHL , Burkitt leukaemia , Rituximab , Burkitt lymphoma
IRB Number: 00057876
Specialty: Pediatric Hematology and Oncology
Sub Specialties:

Brief Summary

Primary objectives:

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.


Detailed Description

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

Contact Information

Name:Jason Clawson
Phone: 801-213-3765

Inclusion Criteria



Phase III study:

- Histologically or cytologically proven B-cell malignancies, either Burkitt lymphoma or B-AL (=Burkitt leukaemia = L3-AL) or diffuse large B-cell NHL or aggressive mature B-cell NHL non other specified or specifiable.

- Stage III with elevated LDH level ("B-high"), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] or any stage IV or B-AL.

Phase II study:

- Histolo-cytologically proven PMLBL.

- PMLBL without CNS involvement.


- 6 months to less than 18 years of age at the time of consent.

- Males and females of reproductive potential must agree to use an effective contraceptive method during the treatment, and after the end of treatment: during twelve months for women, taking into account the characteristics of rituximab and during five months for men, taking into account the characteristics of methotrexate.


- Complete initial work-up within 8 days prior to treatment.


- Able to comply with scheduled follow-up and with management of toxicity.

- Signed informed consent from patients and/or their parents or legal guardians.


Exclusion Criteria



- Follicular lymphoma, MALT and nodular marginal zone are not included into this therapeutic study.

- In phase II study (PMLBL) patients with CNS involvement are not eligible.


- Patients with congenital immunodeficiency, chromosomal breakage syndrome, prior organ transplantation, previous malignancy of any type, or known positive HIV serology.

- Evidence of pregnancy or lactation period.

- There will be no exclusion criteria based on organ function.


- Past or current anti-cancer treatment except corticosteroids of less than 7 days duration in total 



- Tumor cell negative for CD20 (absence of result due to technical problems in the presence of other characteristics suggestive of BL/DLBCL, including genetic and phenotypic features, is not an exclusion criteria)

- Prior exposure to rituximab.

- Severe active viral infection, especially hepatitis B. Severe infection (such as sepsis, pneumonia, etc..) should be clinically controlled at the time of randomisation. EICNHL Only: Contact the national co-investigator for further advice if necessary.

- Hepatitis B carrier status history of HBV or positive serology.