Combination Chemotherapy With or Without Donor Bone Marrow Transplantation in Treating Infants With Previously Untreated Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Giving the drugs in different combinations may kill more cancer cells. Bone marrow transplantation allows the doctor to give higher doses of chemotherapy and kill more cancer cells. PURPOSE: Phase II trial to compare the effectiveness of combination chemotherapy with or without donor bone marrow transplantation in treating infants who have previously untreated acute lymphoblastic leukemia.

Detailed Description
-----------------
OBJECTIVES: Determine the feasibility of dexamethasone-based induction chemotherapy followed by augmented Berlin-Frankfurt-Munster (BFM) consolidation chemotherapy with or without allogeneic bone marrow transplantation in infants with previously untreated acute lymphoblastic leukemia. Determine the event-free survival of patients treated with this regimen. Determine the clinical prognostic features associated with outcome in these patients. Compare the biologic characteristics of the leukemia cells with outcome in these patients. OUTLINE: This is a multicenter study. Patients receive induction therapy comprising oral dexamethasone 3 times daily on days 1-14; daunorubicin IV on days 1, 8, and 15; vincristine IV on days 1, 8, 15, and 22; and asparaginase intramuscularly (IM) on days 4, 6, 8, 11, 13, 15, 18, 20, and 22. Patients also receive methotrexate intrathecally (IT) on days 1, 8, and 15 (and days 4 and 22 for overt CNS disease). Patients with M1 or M2 marrow after induction therapy receive augmented consolidation therapy when blood counts recover. Patients receive cyclophosphamide IV on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 2-5, 9-12, 30-33, and 37-40; 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, and 15. Patients who do not receive bone marrow transplantation (BMT) proceed to interim maintenance #1 when blood counts recover. Patients receive methotrexate IT on days 1, 11, 22, and 32; methotrexate IV and vincristine IV on days 1, 11, 22, 32, and 43; and pegaspargase IM on days 2 and 23. When blood counts recover, patients receive delayed intensification #1 comprising vincristine IV on days 1, 8, 15, 43, and 50; doxorubicin IV on days 1, 8, and 15; oral dexamethasone 3 times daily on days 1-7 and 15-21; pegaspargase IM on days 4 and 43; cyclophosphamide IV on day 29; methotrexate IT on days 29 and 36; oral thioguanine on days 29-42; and cytarabine IV or SC on days 30-33 and 37-40. When blood counts recover, patients receive interim maintenance #2 comprising vincristine as in interim maintenance #1; methotrexate IT on day 1 and IV on days 1, 11, 22, 32, and 41; and pegaspargase IM on days 2 and 23. When blood counts recover, patients receive delayed intensification #2 comprising vincristine, doxorubicin, dexamethasone, pegaspargase, cyclophosphamide, cytarabine, and thioguanine as in intensification #1. Patients also receive methotrexate IT on days 1 and 29. When blood counts recover, patients receive maintenance therapy comprising methotrexate IT on day 1 and orally on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; vincristine IV on days 1, 29, and 57; oral dexamethasone 3 times daily on days 1-5, 29-33, and 57-61; and oral mercaptopurine daily. Treatment repeats every 84 days for 6 courses. Patients with an allergy to pegaspargase replace it with asparaginase IM on the days after receiving methotrexate IV during interim maintenance #1 and #2 and daily over 6 days in place of each dose of pegaspargase during delayed intensification #1 and #2. After augmented consolidation therapy, patients meeting the following criteria may receive BMT in place of chemotherapy: In remission Exhibiting chromosome translocation involving 11q23 or Ph+{(9;22)} Available HLA-A, B, DR genotypic identical relative donor No uncontrolled infection Adequate organ function Within 3-4 weeks of consolidation therapy, patients undergoing allogeneic BMT receive cytarabine IV over 1 hour on days -8 to -5; cyclophosphamide IV over 30 minutes on days -7 and -6; and methylprednisolone IV twice daily on days -2 to 0. Patients also undergo total body irradiation twice daily on days -3 to 0. Patients receive allogeneic BMT on day 0. Patients also receive cyclosporine IV every 12 hours beginning on day -1, switching to oral when possible, and continuing until day 60. Patients then taper cyclosporine over the next 60-120 days. Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1-2 years, and then annually thereafter. PROJECTED ACCRUAL: A maximum of 20-40 patients will be accrued for this study within 2 years.

Official Title
-----------------
A Study of Modified Augmented BFM Therapy for Infants With Acute Lymphoblastic Leukemia

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Drug: asparaginase
* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: dexamethasone
* Drug: doxorubicin hydrochloride
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: methylprednisolone
* Drug: pegaspargase
* Drug: thioguanine
* Drug: vincristine sulfate
* Procedure: allogeneic bone marrow transplantation
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of previously untreated acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia CNS or testicular disease allowed No L3 sIg+ ALL or acute myelogenous leukemia At least 36 weeks gestation for congenital ALL PATIENT CHARACTERISTICS: Age: Under 366 days at diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Not specified Endocrine therapy: Steroid therapy within 48 hours of study allowed if complete blood counts and lumbar puncture results known No chronic steroid treatment for other disease Radiotherapy: Not specified Surgery: Not specified Other: No other concurrent cytotoxic therapy

Ages Eligible for Study
-----------------
Maximum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Modified Augmented BFM Therapy<br> | Drug: asparaginase<br> <br> Drug: cyclophosphamide<br> <br> Drug: cyclosporine<br> <br> Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> Drug: dexamethasone<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: mercaptopurine<br> <br> Drug: methotrexate<br> <br> Drug: methylprednisolone<br> <br> Drug: pegaspargase<br> <br> Drug: thioguanine<br> <br> Drug: vincristine sulfate<br> <br> Procedure: allogeneic bone marrow transplantation<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish whether the CCG Augmented Regimen (AR) can be successfully administered in the infant age group |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or 4 non-hematologic toxicity rates |  |  | 
| Event-free survival |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
untreated childhood acute lymphoblastic leukemia, L1 childhood acute lymphoblastic leukemia, L2 childhood acute lymphoblastic leukemia, acute undifferentiated leukemia