Risk-Adapted Therapy in Treating Young Patients with Mature B-Cell Lymphoma or Leukemia

BIOLOGIC PRIMARY OBJECTIVES:

I. To perform genomic analysis of childhood newly diagnosed mature B cell lymphomas (e.g. Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma [DLBCL], and mediastinal large B-cell lymphoma [MLBCL]) obtained from different parts of the world.

II. To describe the types and frequency of mutations in the alternative reading frame (ARF)-HDM2-TP53 pathway, in B-cell lymphomas in the United States and those found in selected geographic regions of the world.

III. To describe the expression of ARF-HDM2-TP53 and p53-upregulated modulator of apoptosis (PUMA)-associated pathways in B-cell lymphomas in the United States and that found in B-cell lymphomas of other selected geographic regions of the world.

IV. To describe the pattern and frequency of X-linked lymphoproliferative disease (XLP) gene mutations presenting with B-cell lymphomas in the United States and selected geographic regions.

V. To describe the frequency of Epstein-Barr virus (EBV)-positive B-cell lymphomas in the United States and selected geographical regions of the world.

Va. To describe the pattern of EBV protein and gene expression (e.g., Epstein-Barr nuclear antigen [EBNA] 3) in EBV-positive lymphomas.

Vb. To compare patterns of EBV protein and gene expression with clinical, laboratory and outcome data.

EXPLORATORY OBJECTIVES:

I. In participants who develop acute, clinically symptomatic neurotoxicity during treatment:

Ia. To obtain data, especially during the early acute phase of events in order to improve our understanding of the likely sequential pathophysiological processes in acute methotrexate-induced leukoencephalopathy using diffusion-based magnetic resonance imaging (MRI) surrogate biomarkers (apparent diffusion coefficient [ADC], fractional anisotropy [FA]) and other advanced magnetic resonance (MR) techniques (magnetic resonance spectroscopy [MRS], dynamic susceptibility contrast [DSC]-perfusion MRI). (Neuroimaging)

II. In participants who do not develop overt, clinically symptomatic neurotoxicity during treatment:

IIa. To determine the incidence of measurable ADC and FA changes in white matter (in particular, in normal appearing white matter) in various brain regions during the course of treatment. (Neuroimaging)

IIb. To describe the topographical and temporal predilections of subclinical white matter lesions in order to propose a clinically feasible screening strategy for future patients receiving such treatment with the ultimate goal to develop preventive measures to reduce the long-term burden of neurotoxicity. (Neuroimaging)

III. To describe cerebral artery perfusion rates at baseline and at various time points during therapy. (Neuroimaging)

IV. To establish the prevalence and type of neuropsychological sequelae associated with a regimen derived from the malignant B-cell lymphoma (LMB)-96 regimen, and to compare them with neuro-imaging findings. (Neuropsychology Late Effects)

V. To prospectively estimate bone marrow disease (BMD) at diagnosis and correlate with risk factors for potential BMD deficits in pediatric patients with non-Hodgkin lymphoma (NHL). (Bone Mineral Density)

VI. To prospectively estimate BMD at end of therapy and correlate with risk factors for potential BMD deficits in pediatric patients with NHL. (Bone Mineral Density)

VII. To establish the prevalence of gonadal and germ cell dysfunction in children treated with this regimen. (Fertility Late Effects)

VIII. To establish the prevalence and degree of cardiac toxicity associated with this regimen. (Cardiac Late Effects)

IX. To establish a tumor bank of mature B-cell lymphoma samples for future molecular studies aimed to clarify the role of myelocytomatosis (c-MYC) oncogene and its associated pathways, and other pathways found to harbor genetic alterations from the genomic profiling studies. (Tumor Bank)

X. To determine the feasibility of administration and toxicity profile of the St. Jude B-cell III (SJBC3) protocol, which features the use of rituximab for selected higher-risk group B and all group C participants. (Tumor Bank)

XI. To describe the relationship between treatment outcome and clinical, biological, and radiological features (including day 7 positron emission tomography [PET]). (Tumor Bank)

XII. To estimate the complete response rate, event-free survival, and overall survival rates in patients with Burkitt lymphoma (BL), Burkitt leukemia/B-cell acute leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) treated with a stage-adapted regimen based on the St. Jude B-cell II (SJBCII) protocol. (Tumor Bank)

OUTLINE: Patients are assigned to 1 of 3 treatment groups based on extent of disease.

GROUP A (resected stage I and resected abdominal stage II):

CYCLES I and II (induction): Patients receive COPAD chemotherapy comprising vincristine intravenously (IV) on days 1 and 6, prednisone orally (PO) twice daily (BID) or prednisolone IV BID on days 1-7, cyclophosphamide IV over 15 minutes every 12 hours on days 1-3, doxorubicin hydrochloride IV over 6 hours on day 1, and filgrastim subcutaneously (SC) on days 7-21. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

GROUP B (patients not meeting criteria for Group A or C):

CYCLE I (pre-phase, days 1-7): Patients receive COP chemotherapy comprising vincristine IV on day 1, prednisone PO BID or prednisolone IV BID on days 1-7, cyclophosphamide IV over 15 minutes on day 1, methotrexate intrathecally (IT) on day 1, therapeutic hydrocortisone IT on day 1, and cytarabine IT on day 1.

CYCLES II and III (induction, days 8-50): Patients receive COPADM3 chemotherapy comprising vincristine IV on day 1, prednisone PO BID or prednisolone IV BID on days 1-7, methotrexate IV over 3 hours on day 1, leucovorin calcium PO or IV every 6 hours for a total of 12 doses beginning on day 2, cyclophosphamide IV over 15 minutes every 12 hours on days 2-4, doxorubicin hydrochloride IV over 6 hours on day 2, methotrexate IT on days 2 and 6, therapeutic hydrocortisone IT on days 2 and 6, and filgrastim SC on days 7-21. Patients with higher risk (MLBCL, stage III with lactate dehydrogenase [LDH] >= 2 x upper limit of normal [ULN], and/or bone marrow positive at diagnosis only) receive rituximab IV on days 1 and 3. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES III and IV (consolidation): Patients receive CYM consolidation chemotherapy comprising methotrexate IV over 3 hours on day 1, leucovorin calcium PO or IV every 6 hours for a total of 12 doses beginning on day 2, cytarabine IV continuously on days 2-6, methotrexate IT on day 2, therapeutic hydrocortisone IT on days 2 and 7, cytarabine IT on day 7, and filgrastim SC on days 7-21. Patients with higher risk (MLBCL, stage III with LDH >= 2 x ULN, and/or bone marrow positive at diagnosis only) also receive rituximab IV on day 1. Patients then undergo excision (or biopsy if excision is not possible) of any residual mass. Patients with negative histology undergo a second cycle of CYM. Patients with positive histology continue on to Group C, starting with CYVE.

GROUP C (B-ALL with > 25% blasts; central nervous system [CNS] involvement, Group B COP failures i.e., < 20% reduction):

CYCLE I (pre-phase): Patients receive COP chemotherapy comprising cyclophosphamide IV over 15 minutes on day 1; vincristine IV on day 1; prednisone PO BID or prednisolone IV BID on days 1-7; methotrexate IT on days 1, 3, and 5; cytarabine IT on days 1, 3, and 5; therapeutic hydrocortisone on days 1, 3, and 5; and leucovorin calcium PO on days 2 and 4.

CYCLES II and III (induction): Patients receive COPADM8 chemotherapy comprising vincristine IV on day 1; prednisone PO BID or prednisolone IV BID on days 1-7; methotrexate IV over 4 hours on day 1; leucovorin calcium PO or IV every 6 hours for a total of 12 doses beginning on day 2; cyclophosphamide IV over 15 minutes every 12 hours on days 2-4; doxorubicin hydrochloride IV over 6 hours on day 2; rituximab IV on days 1 and 3; methotrexate IT on days 2, 4, and 6; cytarabine IT on days 2, 4, and 6; therapeutic hydrocortisone IT on days 2, 4, and 6; and filgrastim SC on days 7-21. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES IV and V (consolidation): Patients receive CYVE chemotherapy comprising cytarabine IV continuously over 12 hours on days 1-5, high-dose cytarabine IV over 3 hours on days 2-5, etoposide IV over 2 hours four times daily (QID) on days 2-5, rituximab IV on day 1, and filgrastim SC on days 7-21. Treatment repeats every 21 days for up 2 to cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE SEQUENCE I (continuation): Patients receive vincristine IV on day 1, prednisone PO BID or prednisolone IV BID on days 1-7, cyclophosphamide IV over 30 minutes on days 2 and 3, methotrexate IV over 4 hours on day 1, leucovorin calcium PO or IV every 6 hours for a total of 12 doses beginning on day 2, doxorubicin hydrochloride IV over 6 hours on day 2, methotrexate IT on day 2, cytarabine IT on day 2, therapeutic hydrocortisone IT on day 2, and filgrastim SC on day 7.

MAINTENANCE SEQUENCE II (continuation): Patients receive cytarabine SC every 12 hours on days 1-5, etoposide IV over 90 minutes on days 1-3, and filgrastim SC on day 6. CNS positive patients also receive methotrexate IT on day 1, therapeutic hydrocortisone IT on day 1, and cytarabine IT on day 1.

MAINTENANCE SEQUENCE III (continuation): Patients receive vincristine IV on day 1, prednisone PO BID or prednisolone IV BID on days 1-7, cyclophosphamide IV over 30 minutes on days 1 and 2, doxorubicin hydrochloride IV over 6 hours on day 1, and filgrastim SC on day 6. CNS positive patients also receive methotrexate IT on day 1, therapeutic hydrocortisone IT on day 1, and cytarabine IT on day 1.

MAINTENANCE SEQUENCE IV (continuation): Patients receive cytarabine SC every 12 hours on days 1-5, etoposide IV over 90 minutes on days 1-3, and filgrastim SC on day 6. CNS positive patients also receive methotrexate IT on day 1, therapeutic hydrocortisone IT on day 1, and cytarabine IT on day 1.

After completion of study treatment, patients are followed up monthly for 1 year, every 3 months for 1 year, and annually thereafter.