Combination Chemotherapy in Treating Children With 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 may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective for acute lymphoblastic leukemia. PURPOSE: Phase III trial to determine the effectiveness of combination chemotherapy in treating children who have newly diagnosed acute lymphoblastic leukemia.

Detailed Description
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OBJECTIVES: Determine whether augmented BFM therapy is superior to ALinc 14/15 therapy in patients with newly diagnosed high-risk acute lymphoblastic leukemia. Determine whether minimal residual disease after induction therapy is predictive of an inferior prognosis in this patient population. Determine the correlation between event-free survival, minimal residual disease, and early response in this patient population treated with this multiple drug regimen. OUTLINE: Patients are stratified by CNS or testicular disease (yes vs no). Induction therapy (weeks 1-5): Patients receive oral prednisone 3 times daily on days 1-29; vincristine IV on days 1, 8, 15, and 22; daunorubicin IV on days 8, 15, 22; and asparaginase intramuscularly (IM) on days 2, 5, 8, 12, 15, and 19. Patients also receive methotrexate intrathecally (IT) on days 1 and 8. Patients with CNS 2 or 3 disease also receive methotrexate IT on days 15 and 22. Patients with M1 bone marrow proceed to consolidation therapy. Patients achieving M2 bone marrow on day 29 receive oral prednisone 3 times daily on days 29-42; vincristine IV and daunorubicin IV over 15 minutes on days 29 and 36; and asparaginase IM on days 29, 32, 36, and 39. If bone marrow is M3 on day 29 or M2 on day 43, then patient is off study. Consolidation therapy (weeks 6-14): Patients receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine subcutaneously (SC) or IV on days 2-5, 9-12, 30-33, and 37-40; oral mercaptopurine daily on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; asparaginase IM on days 15, 17, 19, 22, 24, 26, 43, 45, 47, 50, 52, and 54; and methotrexate IT on days 1, 15, 29, and 43. Patients then proceed to interim maintenance and delayed intensification on weeks 15-46. Courses repeat every 16 weeks. Maintenance I and II (weeks 15-22 and 31-38): Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; asparaginase IM on days 2, 12, 22, 32, and 42; and methotrexate IT on days 1 and 31. Delayed Intensification (weeks 23-36 and 39-42): Patients receive vincristine IV on days 57, 64, and 71; methotrexate IT on day 57; oral dexamethasone 2-3 times daily on days 57-63 and 71-77; doxorubicin IV over 15 minutes 3 times weekly on days 57, 64, and 71; and asparaginase IM on days 60, 62, 64, 67, 69, and 71. Delayed Intensification-Reconsolidation (weeks 27-30 and 43-46): Patients receive oral thioguanine on days 85-98; methotrexate IT on day 85; cyclophosphamide IV over 30 minutes on day 85; cytarabine IV or SC on days 86-89 and 93-96; asparaginase IM on days 99, 101, 103, 106, 108, and 110; and vincristine IV on days 99 and 106. Continuation therapy (weeks 47-130): Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily for 5 consecutive days on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Patients with CNS 3 disease or who are within 24 months of diagnosis with an initial WBC ≥ 100,000/mm^3 undergo whole brain radiotherapy (omit or discontinue mercaptopurine and IT methotrexate) on day 1. Testicular radiotherapy also begins on day 1. Patients may receive oral methotrexate on day 1 of each course (if IT methotrexate is not administered). Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 260 patients will be accrued for this study within 3.1 years.

Official Title
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ALinC 17: Protocol for Patients With Newly Diagnosed High Risk Acute Lymphoblastic Leukemia (ALL) - Evaluation of the Augmented BFM Regimen: A Phase III Study

Conditions
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Leukemia

Intervention / Treatment
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* Drug: asparaginase
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: dexamethasone
* Drug: doxorubicin hydrochloride
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: prednisone
* Drug: thioguanine
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of B-cell precursor acute lymphoblastic leukemia Registered on POG-9900 Classification Study Registered within 7 days of documenting complete response after induction on day 29 or, if 2 more weeks of induction are required, no later than day 49 Classified as high risk: No simultaneous trisomy 4 and 10 No TEL-AML1 gene Meets criteria for 1 of the following: Any age with WBC > 100,000/mm^3 CNS and bone marrow evaluations required for those patients with WBC > 100,000/mm^3 who are within 24 months of initial diagnosis Age over 12 (boys) or 16 (girls) If younger, WBC must be 1 of the following: Greater than 80,000/mm^3 (for boys age 8 or girls age 12) Greater than 60,000/mm^3 (for boys age 9 or girls age 13) Greater than 40,000/mm^3 (for boys age 10 or girls age 14) Greater than 20,000/mm^3 (for boys age 11 or girls age 15) At least one of the following: CNS 3 disease (CSF WBC at least 5/microliter with blasts present) Testicular leukemia MLL gene rearrangements PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified Other: Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: See Disease Characteristics Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified Other: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 1 Year
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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: asparaginase|nan|
|Drug: cyclophosphamide|nan|
|Drug: cytarabine|nan|
|Drug: daunorubicin hydrochloride|nan|
|Drug: dexamethasone|nan|
|Drug: doxorubicin hydrochloride|nan|
|Drug: mercaptopurine|nan|
|Drug: methotrexate|nan|
|Drug: prednisone|nan|
|Drug: thioguanine|nan|
|Drug: vincristine sulfate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Augmented Berlin Frankfurt Muenster (BFM) therapy is superior to ALinC 14/15 therapy | To determine for patients at high risk for treatment failure if the augmented Berlin Frankfurt Muenster (BFM) therapy is superior to ALinC 14/15 therapy, on the basis of historical controls. |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood acute lymphoblastic leukemia in remission, B-cell childhood acute lymphoblastic leukemia