Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

PRIMARY OBJECTIVES:

I. For the patients with advanced stage B-cell non-Hodgkin lymphoma (NHL)/Burkitt acute
leukemia (B-AL) (stage III and lactate dehydrogenase (LDH) > twice the institutional upper
limit of the adult normal values (Nx2), any stage IV or B-AL), to test whether adding 6
injections of rituximab to standard Lymphome Malin B (LMB) chemotherapy regimen, improves
the event-free survival (EFS) compared with LMB chemotherapy alone. (Phase III) II. For
patients with primary mediastinal large B-cell lymphoma (PMLBL), to evaluate the EFS
following treatment with the regimen dose-adjusted etoposide, prednisone, vincristine
sulfate, cyclophosphamide, doxorubicin hydrochloride (DA-EPOCH)-rituximab. (Phase II)

SECONDARY OBJECTIVES:

I. To study the complete remission (CR) rate and the overall survival (OS). II. To evaluate
safety on all study arms including toxic deaths, adverse events recorded using the National
Cancer Institute (NCI)-Common Terminology Criteria (CTC) version (V)4 (non hematological
toxicity grade >= 3, 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.

III. To study the rate of patients with immunoglobulin (Ig) (G, A, and M) levels abnormally
low and lymphocyte count abnormally low at 1 year and until 5-year follow-up, and to study
the need for immunoglobulin infusions, and levels of post (previous and re-) vaccination
antibodies at 1 year.

IV. 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). (Phase III) V. 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 96 hours (i.e., evaluation of
CTC grade 2-5 and evolution of left ventricular ejection fraction and left ventricular
shortening fraction). (Phase II)

TERTIARY OBJECTIVES:

I. To obtain data on positron emission tomography (PET)-computed tomography (CT) scan in
childhood pediatric B-cell NHL. (Exploratory) II. To evaluate the potential prognostic value
of Minimal Disseminated Disease (MDD) and Minimal Residual disease (MRD) in correlation with
outcome. (Exploratory - Phase III) III. To perform an economic study comparing the
cost-effectiveness ratio between 2 therapeutic strategies: LMB chemotherapy with versus LMB
chemotherapy without rituximab. (Exploratory - Phase III) IV. To characterize the
pharmacokinetics of rituximab in combination with LMB chemotherapy in a subset of patients.
(Exploratory - Phase III)

OUTLINE:

Phase II (patients with PMLBL): Patients receive rituximab intravenously (IV) on day 1;
prednisone orally (PO) twice daily (BID) or IV on day on days 1-5; etoposide IV continuously
on days 1-4; doxorubicin hydrochloride IV continuously on days 1-4; vincristine sulfate IV
continuously on days 1-4; and cyclophosphamide IV on day 5. Patients also receive filgrastim
subcutaneously (SC) once daily (QD) beginning on day 6 until blood count recovers. Treatment
repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

Phase III:

Group I (pre-phase central nervous system [CNS]-negative, cerebral spinal fluid
[CSF]-negative): Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over
15 minutes on day 1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate
intrathecally (IT) and hydrocortisone IT on day 1. Patients are randomized to 1 of 2
treatment arms.

Arm I (R-COPADM induction therapy): Beginning 8 days later, patients receive rituximab IV on
day 1; vincristine sulfate IV on day 1; prednisone PO BID or methylprednisolone IV on days
1-5; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days 2-4;
cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride over 1 hour on
day 2; and methotrexate IT and hydrocortisone IT on days 2 and 6. Treatment repeats every
18-21 days for 2 courses. Consolidation therapy (R-COPADM): Patients receive rituximab IV on
day 1; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days
2-4; cytarabine IV continuously on days 2-6; methotrexate IT on day 2; hydrocortisone IT on
days 2 and 7; and cytarabine IT on day 7. Treatment repeats every 21 days for 2 courses.

Arm II (COPADM induction therapy): Beginning 8 days later, patients receive vincristine
sulfate, prednisone or methylprednisolone, methotrexate, leucovorin calcium,
cyclophosphamide, doxorubicin, methotrexate IT, and hydrocortisone IT as in arm I. Treatment
repeats every 18-21 days for 2 courses.

Consolidation therapy (COPADM): Patients receive methotrexate IV over 3 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cytarabine IV over 12 hours on days 2-6;
methotrexate IT on day 2; hydrocortisone IT on days 2 and 7; and cytarabine IT on day 7.
Treatment repeats every 21 days for 2 courses.

Group II (pre-phase B-AL, CNS-negative OR CNS-positive, CSF-negative OR CSF-positive):
Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over 15 minutes on day
1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate IT, hydrocortisone
IT, and cytarabine IT on days 1, 3, and 5; and leucovorin calcium PO BID on days 2 and 4.
Patients are randomized to 1 of 2 treatment arms.

Arm III (R-COPADM induction therapy): Patients receive rituximab IV on days -2 (course 1)
and 1; vincristine sulfate IV on day 1; prednisone PO or methylprednisolone IV on days 1-5;
high-dose methotrexate IV over 4 hours* on day 1; leucovorin calcium PO every 6 hours on
days 2-4; cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride IV on
day 2; and methotrexate IT, hydrocortisone IT, and cytarabine IT on days 2, 4, and 6.
Treatment repeats every 21 days for 2 courses.

NOTE: *During the second course, patients with CSF-positive disease receive high-dose
methotrexate IV over 24 hours (instead of 4 hours).

Consolidation therapy (R-COPADM): Patients receive rituximab IV on day 1; hydrocortisone IT
and methotrexate IT on day 1; cytarabine IV over 12 hours on days 1-5; high-dose cytarabine
IV over 3 hours on day 2-5; and etoposide IV over 2 hours on days 2-5. If CSF-positive,
patients receive high-dose methotrexate IV over 24 hours on day 18, methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 19, and leucovorin calcium PO every 6 hours on
days 19-21. Treatment repeats every 21 days for 2 courses.

Maintenance therapy (R-COPADM): Patients receive vincristine sulfate IV on day 1; prednisone
PO or methylprednisolone IV on days 1-5; high-dose methotrexate IV over 4 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cyclophosphamide IV over 15 minutes on days
2-3; doxorubicin hydrochloride over 1 hour on day 2; and methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 2. Beginning 28 days later, patients receive cytarabine
subcutaneously (SC) every 12 hours on days 1-5 and etoposide IV over 90 minutes on days 1-3.

Arm IV (COPADM induction therapy): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, and methotrexate, hydrocortisone, and cytarabine IT as in arm
III. NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24
hours (instead of 4 hours).

Consolidation therapy (COPADM): Patients receive hydrocortisone and methotrexate IT,
cytarabine, high-dose cytarabine, and etoposide as in arm III consolidation therapy.

Maintenance therapy (COPADM): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, methotrexate IT, hydrocortisone IT, cytarabine IT, cytarabine SC,
and etoposide as in arm III maintenance therapy.

NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24 hours.

After completion of study treatment, patients are followed up for 5 years.

Inclusion Criteria:

- Histologically or cytologically proven B-cell malignancies; either Burkitt leukemia
or B-AL (= Burkitt leukemia = L3-AL), or diffuse large B-cell NHL, or aggressive
mature B-cell NHL non otherwise specified or specifiable (phase III)

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

- Histolo-cytologically proven PMLBL (phase II)

- PMLBL without central nervous system (CNS) involvement

- Slides will be reviewed by the national pathology panel, but review is not
mandatory before registration

- 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 that allows definite
staging

- 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, Mucosa-Associated Lymphoid Tissue (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 human
immunodeficiency virus (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 cluster of differentiation (CD)20 (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
randomization; contact the national co-investigator for further advice if necessary

- Hepatitis B carrier status history of hepatitis B virus (HBV) or positive serology; a
patient is considered as HBV carrier or to have (had) HBV infection in case of:

- Unimmunized and hepatitis B surface antigen (HBsAg) and/or anti-HBs antibody
and/or anti- HBc antibody positive,

- Immunized and HBsAG and/or anti-HBc antibody positive

- Important note: for the phase III trial, a patient without a known history
of hepatitis B could be randomized in the study if the serology results are
not available at the time of the randomization; however, if the serology
results are positive or not available at day 6 (the first day would be due
to receive rituximab, if so randomized), the patient must be withdrawn from
the study whatever the allocated treatment arm; the data center must be
informed immediately; for the phase II trial, the hepatitis B serology
results must be available before registration; in each case indicating a
carrier status or history for hepatitis B infection, the patients must not
receive rituximab, and therefore must not be included in the rituximab
trials on any treatment arm; in case of high-risk patients, the
recommendation is to treat these patients with the standard LMB regimen
corresponding to the patient prognostic group; in the case of PMLBL the
physician is left to choose the most appropriate therapy

- Participation in another investigational drug clinical trial

- Patients who, for any reason, are not able to comply with the national legislation