RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens and comparing how well they work in treating patients with newly diagnosed acute lymphoblastic leukemia.

Condition	Treatment or Intervention	Phase
untreated childhood acute lymphoblastic leukemia B-cell childhood acute lymphoblastic leukemia	Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: doxorubicin  Drug: mercaptopurine  Drug: methotrexate  Drug: pegaspargase  Drug: thioguanine  Drug: vincristine  Procedure: chemotherapy  Procedure: radiation therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare event-free survival of pediatric patients with newly diagnosed standard risk (SR)-average B-precursor acute lymphoblastic leukemia (ALL) treated with induction therapy followed by 1 of 3 intensified phases of post-induction therapy.
• Compare event-free survival of pediatric patients with SR-low ALL treated with consolidation and interim maintenance therapy with or without pegaspargase.

Secondary

• Correlate day 29 minimal residual disease (MRD) status with event-free survival and overall survival of patients treated with these regimens.
• Correlate early marrow response with day 29 MRD status in patients treated with these regimens.
• Determine whether outcome is improved for SR-high patients by identifying these patients by day 29 MRD status and subsequently treating these patients with a fully augmented Berlin Frankfurt Munster regimen.
• Correlate relative contributions of genetic factors and early treatment response with outcome in patients treated with these regimens.

OUTLINE: This is a 2-part, partially randomized, multicenter study. Patients are stratified according to early response to study induction therapy (rapid early response [standard risk (SR)-low or SR-average acute lymphoblastic leukemia (ALL)] vs slow early response [SR-high ALL]). After completion of induction therapy but before proceeding to part II therapy, patients are assigned to 1 of 3 groups based on stratification.

Part I

• All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally twice daily on days 1-28; pegaspargase intramuscularly (IM) on day 4, 5 or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD ≥ 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD ≥ 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.
• Patients receive dexamethasone IV or orally twice daily on days 1-14; vincristine IV on days 1 and 8; pegaspargase IM on day 4, 5, or 6; and daunorubicin IV over 15 minutes to 2 hours on day 1. Patients with M1 bone marrow and MRD < 1 % after extended induction therapy proceed to therapy in part II. Patients with M2 or M3 bone marrow after extended induction therapy are removed from the study.

Part II

• Patients are randomized to 1 of 2 treatment arms.
• Standard consolidation therapy: Patients receive vincristine IV on day 1; oral mercaptopurine on days 1-28; and methotrexate IT on days 1, 8, and 15.
• Standard interim maintenance therapy: Patients receive vincristine IV on days 1 and 29; dexamethasone IV or orally twice daily on days 1-5 and 29-33; oral mercaptopurine on days 1-50; oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50; and methotrexate IT on day 29.
• Standard delayed intensification (DI) therapy: Patients receive vincristine IV on days 1, 8, and 15; dexamethasone IV or orally twice daily on days 1-21; doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1 and 29.
• Experimental consolidation therapy: Patients receive vincristine, mercaptopurine, and methotrexate as in arm I and pegaspargase IM on days 1 and 22.
• Experimental interim maintenance therapy: Patients receive vincristine, dexamethasone, mercaptopurine, oral methotrexate, and methotrexate IT as in arm I and pegaspargase IM on days 15 and 36.
• Standard DI therapy: Patients receive standard DI therapy as in arm I.
• Patients are randomized to 1 of 4 treatment arms.
• Arm I: Patients receive standard consolidation therapy, standard interim maintenance therapy, and standard DI therapy as in group 1, arm I.
• Standard consolidation therapy: Patients receive standard consolidation therapy as in group 1, arm I.
• Augmented interim maintenance therapy: Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IM on days 2 and 22; and methotrexate IT on days 1 and 31.
• Augmented DI therapy: Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily on days 1-21; doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6 AND day 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36.
• Patients receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; pegaspargase IM on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. NOTE: *Patients with CNS3 disease at diagnosis do not receive methotrexate on days 15 and 22
• Standard interim maintenance therapy: Patients receive standard interim maintenance therapy as in group 1, arm I.
• Standard DI therapy: Patients receive standard DI therapy as in group 1, arm I.
• Intensified consolidation therapy: Patients receive intensified consolidation therapy as in group 2, arm III.
• Augmented interim maintenance therapy: Patients receive augmented interim maintenance therapy as in group 2, arm II.
• Augmented DI therapy: Patients receive augmented DI therapy as in group 2, arm II.
• Patients receive the following therapy:
• Intensified consolidation therapy: Patients receive intensified consolidation therapy as in group 2, arm III. Patients with testicular disease at diagnosis also undergo bilateral testicular radiotherapy once daily, 5 days a week, for approximately 2.5 weeks.
• Augmented interim maintenance therapy: Patients receive augmented interim maintenance therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses.
• Patients receive augmented DI therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses*. NOTE: *Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days 29-33 and 36-40 during course 2 only; these patients do not receive methotrexate on day 36 or thioguanine
• Maintenance therapy: Patients in groups 1, 2, and 3 receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and methotrexate IT on day 1. Courses repeat every 84 days for a total of 2 years from the start of interim maintenance therapy for female patients and 3 years from the start of interim maintenance therapy for male patients. After the completion of study treatment, patients are followed every 1-2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.

PROJECTED ACCRUAL: A total of 3,658 patients (1,206 for group 1, 2,070 for group 2, and 382 for group 3) will be accrued for this study within 4.25 years.

Ages Eligible for Study:  1 Year   -   9 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Newly diagnosed B-precursor acute lymphoblastic leukemia
• Standard-risk disease
• Concurrently enrolled on COG-AALL03B1

PATIENT CHARACTERISTICS: Age

• 1 to 9

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Initial WBC < 50,000/mm^3

Hepatic

• Not specified

Renal

• Not specified

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior cytotoxic chemotherapy except intrathecal cytarabine

Endocrine therapy

• Prior steroid therapy allowed

Radiotherapy

• No concurrent intensity modulated radiotherapy

Surgery

• Not specified

Study chairs or principal investigators

Kelly Maloney, MD,  Study Chair,  Children's Hospital Cancer Center   
Leonard August Mattano, MD, PhD,  Bronson Methodist Hospital   
Linda C. Stork, MD,  Doernbecher Children's Hospital at Oregon Health & Science University   

Study ID Numbers:  CDR0000409589; COG-AALL0331; NCT00103285
Record last reviewed:  January 2005
Last Updated:  February 15, 2005
Record first received:  February 7, 2005
ClinicalTrials.gov Identifier:  NCT00103285
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08