NHL16: Study For Newly Diagnosed Patients With Acute Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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This is a phase II clinical trial using risk-adapted therapy. The treatment is acute lymphoblastic leukemia (ALL)-based therapy, using multi-agent regimens comprising of induction, consolidation, and continuation (maintenance) phases delivered over 24-30 months. Participants will be classified into 3 treatment stratums, based on bone marrow/peripheral blood lymphoma cells involvement at diagnosis and day 8 for T-lymphoblastic lymphoma and bone marrow/peripheral blood lymphoma cells involvement at diagnosis for B-lymphoblastic lymphoma. The Primary Objective of this study is: To improve the outcome of children with lymphoblastic lymphoma (LL) who have minimal disseminated disease (MDD) equal to or more than 1% at diagnosis by using MDD- and minimal residual disease (MRD)- based risk-adapted therapy. The Secondary Objectives of this study are: To estimate the event-free survival and overall survival of children with lymphoblastic lymphoma who are treated with MDD- or MRD-based risk- directed therapy. To evaluate the prognostic value of levels of MDD at diagnosis and MRD on day 8 of remission induction.

Detailed Description
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TREATMENT PLAN Treatment will consist of 3 main phases: remission induction, consolidation [only for patients with any central nervous system (CNS) disease and/or testicular involvement], and continuation. Induction (6-7 weeks). Consolidation for participants with CNS involvement or those with testicular disease only (10 weeks). Reintensification - Participants with residual disease any time after induction therapy may receive 1-2 cycles of re-intensification therapy and may proceed to allogeneic stem cell transplant if suitable donor is available. Continuation Therapy (98-120 weeks). Intrathecal Chemotherapy (days 1 and 15; if needed also on days 8 and 22) TREATMENT SCHEME T lymphoblastic lymphoma: bone marrow/peripheral blood (BM/PB) involvement (MDD/MRD): Diagnosis: less than 1%; Day 8: +/- (Stratum 1) Induction Single dose of Cyclophosphamide Steroid: prednisone Continuation: 98 weeks T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: - (Stratum 2) Induction Fractionated Cyclophosphamide Steroid: prednisone Continuation : 98 weeks T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: + (Stratum 3) Induction Fractionated Cyclophosphamide Steroid: prednisone and dexamethasone Continuation: 120 weeks B lymphoblastic lymphoma: Stage I-III (Stratum 1) Induction Single dose of Cyclophosphamide Steroid: prednisone Continuation: 98 weeks B lymphoblastic lymphoma: Stage IV or testicular (Stratum 2) Induction Fractionated Cyclophosphamide Steroid: prednisone Continuation: 98 weeks Patients with CNS or testicular involvement will receive Consolidation therapy prior to continuation therapy and receive extended maintenance therapy (120 weeks). Any patient with detectable disease (MRD, bone marrow or biopsy of residual mass) at the end of induction may be considered for reintensification and/or hematopoietic stem cell transplantation (HSCT).

Official Title
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NHL16: Study For Newly Diagnosed Patients With Acute Lymphoblastic Lymphoma

Conditions
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Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: Prednisone
* Drug: Vincristine
* Drug: Daunorubicin
* Drug: PEG-asparaginase
* Drug: Erwinia asparaginase
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Thioguanine
* Drug: Clofarabine
* Drug: Methotrexate
* Drug: Mercaptopurine
* Drug: Dexamethasone
* Drug: Hydrocortisone
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of newly diagnosed lymphoblastic lymphoma (patients must have <25% tumor cells in bone marrow by morphology) Age ≤ 21 years Limited prior therapy, including systemic glucocorticoids for 1 week or less, 1 dose of vincristine, emergency radiation therapy to the mediastinum, and 1 dose of IT chemotherapy. Other circumstances must be cleared by PI or co-PI. Written, informed consent and assent following guidelines of the Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP). Exclusion Criteria: Participants with prior therapy, other than therapy specified in 3 above. Participants who are pregnant or lactating. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Patients will undergo treatment as described in the intervention section. Interventions include: Remission induction: prednisone, vincristine, daunorubicin, PEG-asparaginase (or Erwinia asparaginase), IT-MHA (Methotrexate, hydrocortisone, and cytarabine), cyclophosphamide, cytarabine, thioguanine Consolidation: PEG-asparaginase, High-dose methotrexate (HD-MTX), mercaptopurine Postremission continuation: Dexamethasone, doxorubicin, vincristine, mercaptopurine, PEG-asparaginase, cyclophosphamide, cytarabine, methotrexate Reintensification: dexamethasone, cytarabine, etoposide, PEG-asparaginase, clofarabine, cyclophosphamide All patients receive IT-MHA on days 1 and 15. Some patients also receive additional IT-MHA on days 8 and 22. | Drug: Prednisone<br>* Given orally (PO).<br>* Other names: Prednisolone;Drug: Vincristine<br>* Given intravenously (IV).<br>* Other names: Vincristine sulfate;Drug: Daunorubicin<br>* Given IV.<br>* Other names: Cerubidine®;Drug: PEG-asparaginase<br>* Given intramuscularly (IM) or IV.<br>* Other names: Oncaspar®;Drug: Erwinia asparaginase<br>* Given IM or IV if allergy occurs with the first or second PEG-asparaginase dose.<br>* Other names: Erwinase®;Drug: Doxorubicin<br>* Given IV.<br>* Other names: Adriamycin®;Drug: Cyclophosphamide<br>* Given IV.<br>* Other names: Cytoxan®;Drug: Cytarabine<br>* Given IV or IT.<br>* Other names: Cytosar-U®;Drug: Thioguanine<br>* Given PO.<br>* Other names: Purine antimetabolite;Drug: Clofarabine<br>* Given IV.<br>* Other names: Clolar^TM;Drug: Methotrexate<br>* Given IV, IM or IT.<br>* Other names: High-dose methotrexate (HD-MTX);Drug: Mercaptopurine<br>* Given PO.<br>* Other names: Purinethol®;Drug: Dexamethasone<br>* Given PO or IV.<br>* Other names: Decadron®;Drug: Hydrocortisone<br>* Given IT.<br>* Other names: Cortef®;Drug: Etoposide<br>* Given IV.<br>* Other names: Vepesid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Event-free Survival (EFS) | For EFS, relapse and second malignancies are considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS curves are computed, along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages. | Two years post therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Overall Survival (OS) | For OS, only deaths are considered failures for OS. Kaplan-Meier estimates of the OS curves are computed along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages. | Two years post therapy. | 
| Minimal Disseminated Disease (MDD) | Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable) | At Diagnosis | 
| Minimal Residual Disease (MRD) | Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable) | Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoblastic lymphoma