RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which combination chemotherapy regimen is most effective for treating infants with acute lymphoblastic leukemia.

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens in treating infants who have newly diagnosed acute lymphoblastic leukemia.

Condition	Treatment or Intervention	Phase
untreated childhood acute lymphoblastic leukemia	Drug: asparaginase  Drug: busulfan  Drug: cyclophosphamide  Drug: cyclosporine  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: etoposide  Drug: leucovorin calcium  Drug: mercaptopurine  Drug: methotrexate  Drug: prednisolone  Drug: prednisone  Drug: thioguanine  Drug: vincristine  Procedure: allogeneic bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: supportive care/therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Determine the outcome of induction chemotherapy followed by consolidation and reinduction chemotherapy with or without late intensification chemotherapy followed by a maintenance regimen or allogeneic bone marrow transplantation in infants with newly diagnosed acute lymphoblastic leukemia.
• Determine the value of a late intensification course between reinduction and maintenance therapy in these patients.
• Determine the prognostic value of age, immunophenotype, WBC, day 15 bone marrow status, and MLL gene rearrangement in patients treated with these regimens.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified according to risk (high vs standard).

Patients receive induction therapy comprising prednisone orally or IV three times a day on days 1-7; dexamethasone orally or IV three times a day on days 8-35; vincristine IV on days 8, 15, 22, and 29; cytarabine IV over 30 minutes on days 8-21; daunorubicin IV over 60 minutes on days 8 and 9; asparaginase IV over 1 hour or intramuscularly (IM) on days 15, 18, 22, 25, 29, and 33; methotrexate intrathecally (IT) on days 1 and 29; and cytarabine IT on day 15. Patients receive prednisolone IT in combination with any dose of intrathecal chemotherapy. Patients with CNS involvement receive additional doses of methotrexate IT on days 8 and 22 and then weekly after day 29 until there is no evidence of CNS leukemia.

After achieving complete remission, patients receive MARAM chemotherapy comprising oral mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV 36, 42, and 48 hours after beginning each dose of oral methotrexate; methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice daily on days 15, 16, 22, and 23; and asparaginase IV over 1 hour or IM on days 16 and 23. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate.

At least 2 weeks after the completion of MARAM chemotherapy, patients receive OCTADD chemotherapy comprising oral dexamethasone three times a day on days 1-21; oral thioguanine daily on days 1-28 and 36-49; vincristine IV on days 1, 8, 15, and 22; daunorubicin IV over 60 minutes on days 1, 8, 15, and 22; cytarabine IV on days 2-5, 9-12, 16-19, 23-26, 37-40, and 45-48; cytarabine IT on days 1 and 15; and cyclophosphamide IV over 1 hour on days 36 and 49. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate.

Patients are randomized to one of two treatment arms for late intensification therapy.

• Arm I: Beginning at least 1 week after the completion of OCTADD chemotherapy, patients receive VIMARAM chemotherapy comprising vincristine IV on days 1, 8, 15, and 22; oral mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV 36, 42, and 48 hours after the beginning of each dose of oral methotrexate; methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice daily on days 15, 16, 22, and 23; and asparaginase IV over 1 hour or IM on days 16 and 23. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate. Patients then receive the appropriate maintenance therapy.
• Arm II: Patients do not receive VIMARAM chemotherapy but receive appropriate maintenance therapy. At least 2 weeks after the completion of the last course of chemotherapy, patients receive maintenance therapy. Patients with a good response to initial therapy with prednisone receive maintenance therapy comprising oral dexamethasone three times daily on weeks 1 and 2; vincristine IV on day 2 of weeks 1 and 2; oral mercaptopurine daily on weeks 1-14; and oral methotrexate once weekly on weeks 1-14.

Patients with a poor response to initial therapy with prednisone receive maintenance therapy comprising oral mercaptopurine daily for weeks 1-14; oral methotrexate once weekly for weeks 1-14; oral dexamethasone three times daily for weeks 1 and 2; vincristine IV on day 1 of weeks 1 and 2; etoposide IV over 2 hours once weekly on weeks 8 and 9; and cytarabine IV over 1 hour once weekly on weeks 8 and 9.

Treatment repeats in both maintenance therapy regimens every 14 weeks for a total of 3 courses. Patients also receive methotrexate IT on day 1 of the first and third course of therapy and cytarabine IT on day 1 of the second course of therapy. Patients receive prednisolone IT in combination with any dose of intrathecal chemotherapy.

Beginning after the completion of maintenance therapy, all patients receive continuing maintenance therapy comprising oral mercaptopurine daily and oral methotrexate once a week. Treatment continues until 104 weeks after initial diagnosis.

Patients with a poor response to initial therapy with prednisone may receive allogeneic bone marrow transplantation if a donor is available. The patient undergoes transplantation immediately after OCTADD chemotherapy rather than being randomized and receiving maintenance therapy. These patients receive conditioning regimen comprising oral busulfan four times a day on days -8 to -5, etoposide IV over 4 hours on day -4, methotrexate IT on day -3, and cyclophosphamide IV over 1 hour on days -3 and -2. Allogenic bone marrow is transplanted on day 0. Patients then receive cyclosporine orally or IV on days 1-180 as graft-versus-host disease prophylaxis.

Patients are followed annually.

PROJECTED ACCRUAL: A total of 350 patients will be accrued for this study within 5 years.

Ages Eligible for Study:  up to  1 Year,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)
• Newly diagnosed
• Morphological verification by cytochemistry and immunophenotyping
• CNS or testicular leukemia at diagnosis allowed
• Trisomy 21 allowed

PATIENT CHARACTERISTICS: Age:

• 365 days or less

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:

• No prior chemotherapy for leukemia

Endocrine therapy:

• At least 4 weeks since prior systemic corticosteroids
• Prior inhaled steroids allowed

Radiotherapy:

• No prior radiotherapy for leukemia

Surgery:

• Not specified

Massachusetts
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
Tennessee
      St. Jude Children's Research Hospital, Memphis,  Tennessee,  38105-2794,  United States; Recruiting
Austria
      St. Anna Children's Hospital, Vienna,  A-1090,  Austria; Recruiting
Belgium
      Hopital Universitaire Des Enfants Reine Fabiola, Brussels,  1020,  Belgium; Recruiting
Czech Republic
      University Hospital Motol, Prague,  150 06,  Czech Republic; Recruiting
France
      Hopital Saint-Louis, Paris,  75475,  France; Recruiting
Germany
      Medizinische Hochschule Hannover, Hannover,  D-30625,  Germany; Recruiting
      Universitaets-Krankenhaus Eppendorf, Hamburg,  D-20246,  Germany; Recruiting
Italy
      Nuovo Ospedale San Gerardo at University of Milano-Bicocca, Monza,  20052,  Italy; Recruiting
      Ospedale San Gerardo, Monza,  20052,  Italy; Recruiting
Netherlands
      Erasmus MC - Sophia Children's Hospital, Rotterdam,  3015 GJ,  Netherlands; Recruiting
Sweden
      Ostra Sjukhuset, GOTHENBURG,  41685,  Sweden; Recruiting

Study chairs or principal investigators

Rob Pieters, MD, MSC, PhD,  Study Chair,  Erasmus MC - Sophia Children's Hospital   

Study ID Numbers:  CDR0000068529; ICU-INTERFANT99; EU-20063; NCT00015873
Record last reviewed:  December 2002
Last Updated:  April 4, 2005
Record first received:  May 6, 2001
ClinicalTrials.gov Identifier:  NCT00015873
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08