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

Alternate Title

Combination Chemotherapy and Imatinib Mesylate in Treating Children With Relapsed Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	1 to 21 at time of relapse	NCI	COG-AALL01P2 AALL01P2, NCT00049569

Objectives

1. Determine the feasibility and safety of an intensified sequential induction regimen in children with an initial bone marrow relapse of acute lymphoblastic leukemia.
2. Determine the remission reinduction rates and 4-month event-free survival of patients treated with this regimen.
3. Determine the feasibility of combining this regimen with imatinib mesylate in these patients.
4. Correlate post-remission events with disease burden during induction in these patients.

Entry Criteria

Disease Characteristics:

• Diagnosis of acute lymphoblastic leukemia (ALL) in first relapse involving the bone marrow (M3 marrow)
  • Philadelphia chromosome-positive patients eligible with or without extramedullary disease
  • No prior isolated extramedullary relapse



• No B-cell ALL (L3 morphology or evidence of myc translocation by molecular or cytogenetic technique)



• No Down syndrome

Prior/Concurrent Therapy:

Biologic therapy

• At least 12 months since prior stem cell transplantation
• No other concurrent immunomodulating agents

Chemotherapy

• Prior cumulative anthracycline exposure no greater than 350 mg/m²
• No other concurrent anticancer chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No other concurrent cytotoxic therapy
• No concurrent immunosuppressive therapy for graft-vs-host disease

Patient Characteristics:

Age

• 1 to 21 at time of relapse

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Cardiovascular

• Shortening fraction at least 28% by echocardiogram
• Ejection fraction at least 50% by MUGA

Other

• No active fungal infection
• No prior invasive filamentous fungal infection
• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 63-126 patients will be accrued for this study within 14 months.

Outline

This is a randomized, multicenter study. Patients are stratified according to risk (high-vs low), Philadelphia chromosome (Ph) status (negative vs positive), CNS relapse (yes vs no), and duration of first complete remission (less than 36 months vs at least 36 months). Patients without CNS relapse are randomized to arms I or IIa. Patients with CNS relapse are assigned to arm IIb.

• The following strata are used:
  • Stratum 1.1: High risk, Ph negative, with or without non-CNS extramedullary site relapse
  
  
  
  • Stratum 1.2: High risk, Ph negative, CNS combined relapse
  
  
  
  • Stratum 1.3:High risk, Ph positive, with or without non-CNS extramedullary site relapse
  
  
  
  • Stratum 1.4: High risk, Ph positive, CNS combined relapse
  
  
  
  • Stratum 2.1: Low risk, Ph negative, with or without non-CNS extramedullary site relapse
  
  
  
  • Stratum 2.2: Low risk, Ph negative, CNS combined relapse
  
  
  
  • Stratum 2.3: Low risk, Ph positive, with or without non-CNS extramedullary site relapse
  
  
  
  • Stratum 2.4: Low risk, Ph positive, CNS combined relapse
  
  
  



• Arm I (Strata 1.1, 1.3, 2.1, and 2.3):
  • Treatment Block 1: Patients receive cytarabine intrathecally (IT) on day 1 and methotrexate IT on days 15 and 29. Patients also receive vincristine IV on days 1, 8, 15, and 22; oral prednisone twice or thrice daily on days 1-29; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; and doxorubicin IV over 15 minutes on day 1. Ph-positive patients also receive oral imatinib mesylate on days 1-14.
  
  
  
  • Treatment Block 2: Patients receive methotrexate IT on days 1 and 22, cyclophosphamide IV over 30 minutes and etoposide IV over 2 hours on days 1-5, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Patients also receive methotrexate IV over 24 hours on day 22 followed by leucovorin calcium IV every 6 hours on days 24 and 25. Ph-positive patients receive oral imatinib mesylate on days 1-14.
  
  
  
  • Treatment Block 3a (Ph-negative patients): Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9, asparaginase IM on days 2 and 9, and G-CSF SC beginning on day 10 and continuing until blood counts recover.
  
  
  
  • Treatment Block 3b (Ph-positive patients): Patients receive cytarabine IV over 3 hours every 12 hours on days 1 and 2, asparaginase IM on day 2, and G-CSF SC beginning on day 3 and continuing until blood counts recover. Patients also receive oral imatinib mesylate on days 1-14.
  
  
  



• Arm IIa (Strata 1.1, 1.3, 2.1, and 2.3 only): Patients receive therapy as in arm I except in the following order: block 1, block 3, and block 2.



• Arm IIb (Strata 1.2, 1.4, 2.2, and 2.4 only):
  • Treatment Block 1: Patients receive cytarabine IT on day 1 and then methotrexate, cytarabine and hydrocortisone IT (triple intrathecal therapy; TIT) on days 8, 15, 22, and 29. Vincristine, prednisone, pegaspargase, doxorubicin, and imatinib mesylate are administered as in arm I.
  
  
  
  • Treatment Block 3: Patients receive cytarabine, asparaginase, G-CSF, and imatinib mesylate as in arm I.
  
  
  
  • Treatment Block 2: Patients receive TIT on days 1 and 22. Patients then receive cyclophosphamide, etoposide, G-CSF, methotrexate IV, leucovorin calcium, and imatinib mesylate as in arm I.

    After each block is completed, disease is assessed. The next block is started on day 36 if blood counts have recovered and marrow during block 1 is at least M2/M3. Patients are removed from protocol therapy if disease progresses, unacceptable toxicity occurs, marrow is M2/M3 at day 15 of the second administered block of treatment, or cerebrospinal fluid blasts persist after 6 weekly doses of TIT.

  
  
  

Patients are followed for at least 4 months.

Raetz EA, Borowitz MJ, Devidas M, et al.: Reinduction platform for children with first marrow relapse in acute lymphoblastic lymphoma. J Clin Oncol 26 (24): 3971-8, 2008.[PUBMED Abstract]

Raetz EA, Borowitz MJ, Devidas M, et al.: Outcomes of children with first marrow relapse: results from Childrens Oncology Group (COG) study AALL01P2. [Abstract] Blood 108 (11): A-1871, 2006.

Borowitz MJ, Devidas M, Hunger SP, et al.: Minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) in relapse. A Children's Oncology Group (COG) study. [Abstract] Blood 104 (11): A-324, 2004.

Bhojwani D, Kang H, Moskowitz N, et al.: Biological pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. [Abstract] Blood 108 (2): 711, 2006.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Elizabeth Raetz, MD, Protocol chair		Ph: 212-241-7022 Email: elizabeth.raetz@mssm.edu

Registry Information
Official Title		Intensive Induction Therapy For Children With Acute Lymphoblastic Leukemia (ALL) Who Experience A Bone Marrow Relapse
Trial Start Date		2003-01-27
Registered in ClinicalTrials.gov		NCT00049569
Date Submitted to PDQ		2002-09-20
Information Last Verified		2006-01-03
NCI Grant/Contract Number		U10-CA13539

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