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

Alternate Title

Comparison of Combination Chemotherapy Regimens in Treating Children With Previously Untreated Acute Myeloid Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed under 21 NCI POG-9421 POG-9421

Objectives

I.  Assess complete response rates and event free survival (EFS) in childhood 
acute myeloid leukemia (AML) treated with high vs standard dose cytarabine 
(ARA-C) in the DAT (daunorubicin/ARA-C/thioguanine) induction regimen.

II.  Compare EFS in childhood AML following 3 courses of consolidation 
chemotherapy with vs without the multidrug resistance (MDR) modulator 
cyclosporine (CYSP).

III.  Compare the EFS of patients with available donors who undergo allogeneic 
bone marrow transplantation vs those without donors who receive consolidation 
chemotherapy.

IV.  Correlate EFS with various clinical and laboratory factors, e.g., 
cytogenetics and MDR expression.

V.  Confirm that, compared to other patients, Down syndrome patients have a 
superior response to standard induction chemotherapy and non-CYSP-containing 
consolidation chemotherapy.

VI.  Assess specific biologic and ARA-C pharmacokinetic characteristics of 
Down syndrome patients, including cytarabine incorporation into leukemic 
cells, folate pools, and intracellular dCTP levels.

Entry Criteria

Disease Characteristics:

Newly diagnosed acute myeloid leukemia (AML)

Abnormal marrow without usual AML diagnostic criteria eligible only with:
  Karyotype t(8;21) or inv16 OR
  Unequivocal presence of megakaryoblasts

Isolated granulocytic sarcoma eligible

No FAB M3 leukemia (consider protocol POG-9220)
No myelodysplastic syndrome until overt leukemia develops
No AML secondary to therapy 
No pre-existing Fanconi anemia

Prior/Concurrent Therapy:

No prior therapy except leukapheresis for WBC greater than 100,000/mm3

Patient Characteristics:

Age:
  Under 21

Performance status:
  Not specified

Hepatic:
  Not specified

Renal:
  Creatinine no greater than 1.5 mg/dL
  BUN no greater than 8.0 mg/dL
  Patients with hyperuricemia or azotemia may be eligible after appropriate
   control measures are undertaken

Cardiovascular:
  Patients on pressor support eligible only with approval of protocol chairman

Pulmonary:
  Patients on ventilatory assistance eligible only with approval of
  protocol chairman

Other:
  No proven or suspected sepsis, pneumonia, or meningitis until:
     Appropriate therapeutic measures instituted OR
     Systemic signs are no longer life threatening

  Trisomy 21 (Down syndrome) must be registered concurrently on protocol
  POG-9481

Expected Enrollment

A total of 600 patients (560 without and 40 with Down syndrome) will be 
accrued for this study over 4 years.  Of the 560 without Down syndrome it is 
anticipated that about 80 will be induction failures, 360 will be randomized 
for consolidation chemotherapy, and 120 will be potential candidates for BMT 
(80 are expected to receive a transplant).

Outline

This is a randomized, multicenter study. Patients are stratified according to 
center, eligible sibling bone marrow donor (yes vs no), presence of trisomy 21 
(yes vs no), cytologic classification (M0 vs M1 vs M2 vs M4 vs M5 vs M6 vs M7 
vs granulocytic sarcoma), gender, and race (Caucasian vs African-American vs 
Hispanic). Patients with Down syndrome are nonrandomly assigned to Arms I and 
III. Other patients are initially randomized to Arms I and II as induction I, 
then all patients receive induction II. Following induction II, patients with 
M1 or M2a marrow who have an HLA-matched sibling donor receive allogeneic bone 
marrow transplant on regimen B, while all others are randomized on arms III or 
IV for consolidation chemotherapy.

Induction I:

 Arm I: Patients receive daunorubicin IV over 15 minutes on days 1-3,
 cytarabine IV continuously on days 1-7, oral thioguanine on days 1-7, and
 cytarabine intrathecally (IT) on day 1.

 Arm II: Patients receive daunorubicin and thioguanine as in arm I plus high
 dose cytarabine IV over 1 hour every 12 hours on days 1-7.

Induction II: Patients receive cytarabine IV over 1 hour every 12 hours for 10 
doses.

 Patients with positive CSF also receive cytarabine IT on day 15 of induction
 I and II. Patients with symptomatic disease (cranial nerve palsies,
 intracranial or epidural chloromas) undergo radiotherapy on days 1-3 of
 induction.

 Patients with M1 or M2a marrow without an appropriate marrow donor are
 randomized to arm III or IV; others proceed to regimen B.

Consolidation: 

 Arm III: 
  Consolidation I: Patients receive mitoxantrone IV over 30 minutes on days 1-
  4, etoposide IV over 45-60 minutes on days 1-5, and cytarabine IT on day 1.

  Consolidation II: Patients receive cytarabine IV over 1 hour every 12 hours
  for 10 doses, beginning after recovery from consolidation I.

  Consolidation III: Patients receive therapy as in consolidation I, beginning
  after recovery from consolidation II.

 Arm IV: 
  Consolidation I: Patients receive cyclosporine IV for 100 hours.
  Chemotherapy begins 2 hours after cyclosporine begins and consists of
  mitoxantrone IV over 30 minutes on days 1-4, etoposide IV over 45-60 minutes
  on days 1-5, and cytarabine IT on day 1.

  Consolidation II:  Same as arm III, consolidation II.

  Consolidation III: Same as arm IV, consolidation I.

Regimen B: Patients begin therapy within 8 weeks of beginning induction II. 
Patients receive total body irradiation twice a day on days -7 to -4 and 
etoposide IV on day -3. Allogeneic bone marrow is infused on day 0. 

O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008.[PUBMED Abstract]

Brown P, McIntyre E, Rau R, et al.: The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 110 (3): 979-85, 2007.[PUBMED Abstract]

Becton D, Dahl GV, Ravindranath Y, et al.: Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 107 (4): 1315-24, 2006.[PUBMED Abstract]

Lacayo NJ, O'Brien M, Jain S, et al.: Gene expression profiling predicts outcome in de novo acute myeloid leukemia (AML) with normal karyotype: results of Childrens Oncology Group (COG) study POG #9421. [Abstract] Blood 108 (11): A-1915, 2006.

O'Brien M, Taub J, Stine K, et al.: Excessive cardiotoxicity despite excellent leukemia-free survival for pediatric patients with Down syndrome (DS) and acute myeloid leukemia (AML): results from POG (Pediatric Oncology Group) protocol 9421. [Abstract] Blood 108 (11): A-559, 2006.

Kuo DJ, Lacayo NJ, Hoang D, et al.: Array CGH discovers novel genomic signatures in de novo acute myeloid leukemia (AML): results of Children’s Oncology Group (COG) study POG #9421. [Abstract] Blood 106 (11): A-2771, 2005.

Lacayo N, Meshinchi S, Raimondi S, et al.: Gene expression profiling and FLT3 status correlate with outcome in de novo acute myeloid leukemia (AML) with normal karyotype: results of Children’s Oncology Group (COG) study POG #9421. [Abstract] Blood 106 (11): A-2372, 2005.

Kuo DJ, Lacayo NJ, Buck S, et al.: Gene expression profiling identifies genes associated with in vitro resistance to daunorubicin and cytarabine in children with de novo acute myelogenous leukemia (AML) from the Pediatric Oncology Group (POG) study # 9421. [Abstract] Blood 104 (11): A-1130, 2004.

Lacayo NJ, Meshinchi S, Raimondi SC, et al.: FLT3 mutations determine the clinical outcome in children with de novo acute myelogenous leukemia (AML) and normal karyotype: Pediatric Oncology Group (POG) study # 9421. [Abstract] Blood 104 (11): A-570, 2004.

Stine K, Becton D, Dahl GVH, et al.: Genetic randomization to allogeneic bone marrow transplant in first remission pediatric acute myeloid leukemia patients, Pediatric Oncology Group 9421 (now Childrens Oncology Group). [Abstract] Blood 104 (11): A-616, 2004.

Taub JW, Huang X, Matherly LH, et al.: Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 94 (4): 1393-400, 1999.[PUBMED Abstract]

Taub JW, Matherly LH, Stout ML, et al.: Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87 (8): 3395-403, 1996.[PUBMED Abstract]

LaFiura KM, Edwards H, Taub JW, et al.: Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group. Oncogene 27 (36): 4933-42, 2008.[PUBMED Abstract]

Brown P, McIntyre E, Rau R, et al.: Incidence and clinical significance of nucleophosmin mutations in childhood AML: a Childrens Oncology Group study. [Abstract] Blood 108 (11): A-221, 2006.

Loew TW, Gamis A, Smith FO, et al.: Down syndrome patients with relapsed acute myelogenous leukemia. [Abstract] Blood 104 (11): A-4526, 2004.

Loew TW, Gamis A, Smith FO, et al.: Induction therapy failures in Down Syndrome patients with acute myelogenous leukemia. [Abstract] Blood 104 (11): A-4527, 2004.

Trial Contact Information

Trial Lead Organizations

Pediatric Oncology Group

David Becton, MD, Protocol chair		Ph: 501-364-5650