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

Trial Status: Active

Many children and young adults with mature B-cell lymphoma can be cured with current standard treatments, but these standard treatments do not stop every child’s cancer from coming back. Furthermore, many children have significant side effects from treatment, both at the time of treatment and for many years after treatment is completed (late effects). That is why there is still much to be learned about this disease and its treatment. This study is being done to help researchers learn more about the biology and genetics of this disease in children in the United States (U.S.) and at several international sites and to study the effects (good and bad) of this treatment in St. Jude participants in order to help researchers guide treatment for children and young adults with this disease in the future.

Inclusion Criteria

  • PARTICIPANTS FROM ST. JUDE AND COLLABORATING SITES PARTICIPATING IN THERAPEUTIC AND BIOLOGICAL OBJECTIVES:
  • Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma not-otherwise specified [NOS]) as defined in the World Health Organization (WHO) classification
  • Participant must be previously untreated, (no more than 72 hours of steroids, one intrathecal chemotherapy treatment, and/or emergency radiation)
  • For selected higher-risk CD20+ group B and all CD20+ group C participants receiving rituximab only (e.g., those with MLBCL, stage III with LDH >= 2 x ULN, and/or bone marrow/central nervous system [CNS] involvement): all participants who will receive rituximab must have hepatitis screening prior to enrollment; participants whose results indicate that they are carrier of hepatitis B can still be treated as per group B or C but will NOT receive rituximab; this screening must be done for eligibility for participants who will receive rituximab, BUT the results are not needed prior to enrollment: * Hepatitis B immunization status (vaccination yes or no) * Hepatitis B surface antigen (HBsAg) * Anti-hepatitis B surface (HBs) antibody * Anti-hepatitis B core (HBc) antibody
  • All participants must have screening prior to enrollment; participants whose results indicate that they are carrier of hepatitis B can still be treated per group B and C but will NOT receive rituximab
  • Human immunodeficiency virus (HIV) test has been obtained within 42 days; participants who test positive for HIV cannot be enrolled on therapeutic part of study but are still eligible for biology studies
  • Informed consent must be obtained according to St. Jude guidelines before enrollment into study
  • PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN BIOLOGICAL OBJECTIVES ONLY: Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification
  • PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN BIOLOGICAL OBJECTIVES ONLY: Participant must be previously untreated, (no more than 72 hours of steroids, one intrathecal chemotherapy treatment, and/or emergency radiation) at the time of the diagnostic biopsy
  • PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN BIOLOGICAL OBJECTIVES ONLY: Informed consent must be obtained by local principal investigator (PI) or his/her designee according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH/Good Clinical Practice and local guidelines before enrollment into study

Exclusion Criteria

  • PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN THERAPEUTIC AND BIOLOGICAL OBJECTIVES:
  • Participants known to be HIV positive (for therapeutic part of protocol, HIV participants are eligible for biology studies)
  • Participants who are pregnant or lactating
  • Inability or unwillingness of research participant or legal guardian to consent
  • PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN BIOLOGICAL OBJECTIVES ONLY:
  • Inability or unwillingness of research participant or legal guardian to consent
  • Histologic diagnosis other than a mature B-cell lymphoma as defined in the WHO classification

California

San Diego
Rady Children's Hospital - San Diego
Status: ACTIVE
Contact: Deborah E. Schiff
Phone: 858-966-5811

Tennessee

Memphis
Saint Jude Children's Research Hospital
Status: ACTIVE
Contact: Raul Correa Ribeiro
Phone: 901-595-3300

Egypt

El Saida Zenab
Children's Cancer Hospital
Status: COMPLETED
Contact: Hany Abdel Rahman

Singapore

Singapore
National University Hospital Singapore
Status: ACTIVE
Contact: Allen Eng Juh Yeoh

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.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Saint Jude Children's Research Hospital

Principal Investigator
Raul Correa Ribeiro

  • Primary ID SJBC3
  • Secondary IDs NCI-2011-01251, NCI-2010-00129
  • Clinicaltrials.gov ID NCT01046825