Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Comparison of Different Combination Chemotherapy Regimens in Treating Infants With Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	365 days and under	Other	ICU-INTERFANT99 UKCCSG-LK-1999-05, EU-20063, EU-20588, NCT00015873

Objectives

1. 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.
2. Determine the value of a late intensification course between reinduction and maintenance therapy in these patients.
3. Determine the prognostic value of age, immunophenotype, WBC, day 15 bone marrow status, and MLL gene rearrangement in patients treated with these regimens.

Entry 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

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

Patient Characteristics:

Age:

• 365 days or less

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Expected Enrollment

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

Outcomes

Event-free survival at 3-4 years after diagnosis

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, 16, 22, and 30; 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 2, 8, 16, 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 2 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.

Lönnerholm G, Valsecchi MG, De Lorenzo P, et al.: Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 52 (5): 596-601, 2009.[PUBMED Abstract]

van der Linden MH, Valsecchi MG, De Lorenzo P, et al.: Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 114 (18): 3764-8, 2009.[PUBMED Abstract]

Van der Velden VH, Corral L, Valsecchi MG, et al.: Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 23 (6): 1073-9, 2009.[PUBMED Abstract]

Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007.[PUBMED Abstract]

Pieters R, Schrappe M, de Lorenzo P, et al.: Outcome of infants less than one year of age with acute lymphoblastic leukemia treated with the Interfant-99 protocol. [Abstract] Blood 108 (11): A-145, 2006.

Trial Contact Information

Trial Lead Organizations

Dutch Childhood Oncology Group

Rob Pieters, MD, MSC, PhD, Protocol chair		Ph: 31-10-463-6691 Email: rob.pieters@erasmusmc.nl

Registry Information
Official Title		International Collaborative Treatment Protocol for Infants Under One Year with Acute Lymphoblastic Leukemia
Trial Start Date		1999-05-01
Registered in ClinicalTrials.gov		NCT00015873
Date Submitted to PDQ		2001-02-06
Information Last Verified		2006-10-05

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