Induction Intensification in Treating Infants With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one chemotherapy drug and giving them as induction intensification may kill more cancer cells. PURPOSE: This phase II trial is studying how well induction intensification works in treating infants with newly diagnosed acute lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Assess the feasibility of intensification with two courses of high-dose methotrexate followed by one course of cyclophosphamide/etoposide during induction and later as consolidation in infants with newly diagnosed acute lymphoblastic leukemia. Determine event-free survival after shortened, intensive therapy in these patients. Compare event-free survival rates of infants receiving this regimen whose leukemic blasts have or do not have translocations involving the 11q23 gene MLL. Secondary Correlate the presence of minimal residual disease at completion of induction, beginning of continuation, and at completion of therapy with patient outcome. Investigate the clinical prognostic features that may be associated with outcome in infants, such as bone marrow blast content at day 8, white blood cell count, and age. Correlate biologic characteristics of the leukemia cells at diagnosis (protocol POG-9900) with outcome in patients treated with this regimen. Characterize patterns of gene expression associated with host and disease characteristics and treatment response in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients are stratified according to participating center and presence of CNS disease (yes vs no). Patients receive induction chemotherapy comprising vincristine IV on days 1, 8, and 15; oral prednisone three times a day on days 1-21; daunorubicin IV over 30 minutes on days 1-2; cyclophosphamide IV over 30 minutes every 12 hours on days 3-4; and asparaginase intramuscularly (IM) on days 4, 6, 8, 10, 12, 15, 17, and 19. Patients also receive triple intrathecal therapy comprising methotrexate, hydrocortisone, and cytarabine on days 1, 8, and 15 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 5 and continuing until day 20, regardless of blood counts. Patients receive induction intensification chemotherapy comprising high-dose methotrexate IV over 24 hours; triple intrathecal therapy as per induction therapy on days 22 and 29; and leucovorin calcium IV every 6 hours for 2 doses beginning 42 hours after start of high-dose methotrexate and then orally every 6 hours for 3 doses. Patients also receive etoposide IV over 2 hours and cyclophosphamide IV over 30 minutes on days 36-40. Patients receive G-CSF SC or IV beginning on day 41 and continuing until blood counts recover. Patients achieving morphologic remission and recovery of blood counts while off G-CSF for 48 hours receive reinduction chemotherapy comprising the same regimen as in induction therapy with the exception of asparaginase IM beginning on day 1 (week 8) and continuing every Monday, Wednesday, and Friday for a total of 8 doses and triple intrathecal therapy on days 1 and 15 only (weeks 8 and 10). Patients receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. After blood count recovery, patients receive consolidation chemotherapy comprising triple intrathecal therapy as per induction therapy on day 1 (week 11); high-dose methotrexate IV over 24 hours on weeks 8 and 12; and leucovorin calcium IV every 6 hours for 2 doses beginning 42 hours after start of high-dose methotrexate and then orally every 6 hours for 3 doses. Patients also receive etoposide IV over 2 hours followed by cyclophosphamide IV over 30 minutes on days 15-19 (week 13). Patients receive G-CSF SC or IV beginning on day 20 and continuing until blood counts recover. On days 29-31 (week 15), patients receive high-dose cytarabine IV over 3 hours every 12 hours for 4 doses and asparaginase IM 6 hours after completion of high-dose cytarabine. Patients receive G-CSF beginning 24 hours after completion of asparaginase and continuing until blood counts recover. Patients achieving morphologic remission and blood count recovery while off G-CSF for 48 hours receive continuation therapy comprising vincristine IV on day 1; oral prednisone three times a day on days 1-5; and triple intrathecal therapy on day 1 (weeks 18 and 22). Patients also receive methotrexate IM once a week and oral mercaptopurine daily on weeks 19-21, 23, and 24. On week 25, patients receive etoposide IV over 2 hours daily followed by cyclophosphamide IV over 30 minutes daily on days 1-5 and G-CSF SC or IV beginning on day 6 and continuing until blood counts recover. Patients receive an additional course of continuation therapy on weeks 28-35. On weeks 38-48, patients receive another identical course of continuation therapy with the exclusion of the etoposide and cyclophosphamide combination regimen. Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: Approximately 58-104 patients will be accrued for this study within 2.1 years.

Official Title
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Induction Intensification in Infant ALL: A Children's Oncology Group Study

Conditions
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Leukemia

Intervention / Treatment
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* Biological: filgrastim
* Drug: asparaginase
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: etoposide
* Drug: leucovorin calcium
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: prednisone
* Drug: therapeutic hydrocortisone
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia No infants less than 36 weeks' gestation CNS or testicular disease permitted No B-cell ALL or acute myeloid leukemia Previously untreated except for the following: Steroid treatment within 48 hours of diagnosis allowed with physical examination and differential CBC immediately prior to beginning steroids Concurrent registration on protocol POG-9900 (ALL classification study) required Patients registered on POG-9407 are eligible for the pharmacokinetic part of the study PATIENT CHARACTERISTICS: Age: Under 1 at diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified Other: No uncontrolled infection Adequate major organ function PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Not specified Endocrine therapy: See Disease Characteristics No concurrent chronic steroid treatment Radiotherapy: Not specified Surgery: Not specified Other: No other concurrent anticancer therapy

Ages Eligible for Study
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Maximum Age: 1 Year

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: Chemo (Reduced Induction) No BMT (Open February 2004)<br> | Biological: filgrastim<br> <br> Drug: asparaginase<br> <br> Drug: cyclophosphamide<br> <br> Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> Drug: etoposide<br> <br> Drug: leucovorin calcium<br> <br> Drug: mercaptopurine<br> <br> Drug: methotrexate<br> <br> Drug: prednisone<br> <br> Drug: therapeutic hydrocortisone<br> <br> Drug: vincristine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of intensification |  |  | 
| Event-free survival |  |  | 
| Comparison of event-free survival rates in infants with and without leukemic blasts translocations |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of minimal residual disease at completion of induction, beginning of continuation, and at completion of therapy with patient outcome |  |  | 
| Clinical prognostic features associated with outcome |  |  | 
| Correlation of biologic characteristics of leukemia cells at diagnosis with outcome |  |  | 
| Patterns of gene expression |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated childhood acute lymphoblastic leukemia, acute undifferentiated leukemia