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

Alternate Title

Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	Under 22	NCI	COG-2961 CCG-2961, NCT00002798

Objectives

1. Increase the remission induction rate to greater than 85% in children with untreated acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) by replacing daunorubicin (DNR) with idarubicin (IDA) in intensively timed DCTER chemotherapy (dexamethasone, cytarabine (ARA-C), thioguanine, etoposide, and daunorubicin) in the first 4 days of each course.
2. Increase the remission rate further by comparing the efficacy of consolidation chemotherapy with intensively timed IDA DCTER/DCTER vs fludarabine (FAMP), ARA-C, and IDA in maintaining remission and in achieving remission in patients with M2 disease (5%-29% blasts in marrow) at the end of induction chemotherapy.
3. Compare overall survival, event-free survival, and disease-free survival in patients who receive consolidation with IDA DCTER/DCTER vs FAMP, ARA-C, and IDA.
4. Compare overall survival, event-free survival, and disease-free survival in patients receiving intensification with the Capizzi II regimen (high-dose ARA-C and asparaginase) vs those receiving a matched-related allogeneic bone marrow transplantation.
5. Compare overall survival, event-free survival, and disease-free survival in patients treated with interleukin-2 (IL-2) vs standard follow up care after Capizzi II intensification.
6. Determine whether multichannel flow cytometry detection of residual AML on a companion biologic study protocol CCG-B942 predicts outcome, and determine whether any of these treatment regimens eliminates minimal residual disease more effectively than another.
7. Register all patients with MDS treated or followed at CCG institutions and capture their biologic, historical and outcome data.
8. Determine, on a companion biologic study protocol CCG-B972, whether levels of IL-2 soluble receptor (sIL-2R) and absolute lymphocyte count (ALC) before, during, and after therapy correlates with outcome.

Entry Criteria

Disease Characteristics:

• Histologically confirmed previously untreated acute myeloid leukemia (AML) in patients 1 month to 21 years of age
  • Infants under 1 month with progressive disease eligible
    • Supportive care may be given to confirm that the leukemia is not regressing prior to entry
  • No acute promyelocytic leukemia (FAB M3)
  • No acute undifferentiated leukemia (FAB M0)
• Histochemical verification of AML required by the following stains:
  • Wright or Giemsa
  • Peroxidase
  • PAS
  • Chloroacetate esterase
  • Sudan black
  • Nonspecific esterase (NSE) with and without fluoride (NaF) inhibition
  • Combined NSE/NaF and butyrate inhibition or diagnosis of megakaryoblastic leukemia (FAB M7) should be supported by one of the following:
    • CD41 reactivity
    • Glycoprotein 1b reactivity
    • Factor VIII-related antigen reactivity
    • Platelet peroxidase on electron microscopy
• The following are also eligible:
  • Myelodysplastic syndromes, including:
    • Refractory anemia (RA) *
    • RA with ringed sideroblasts (RARS) *
    • RA with excess blasts (RAEB)
    • RAEB in transformation (RAEBt)
    • Chronic myelomonocytic leukemia (CMML)
  • AML with monosomy 7
  • Granulocytic sarcoma (chloroma) with or without marrow involvement
  • Mixed lineage leukemia with 2 morphologically defined populations provided the predominant population is myeloid
• No Downs syndrome
• No juvenile chronic myelogenous leukemia
• No Fanconi's anemia
• No secondary AML

 [Note: * RA and RARS may be registered and observed until treatment deemed necessary]

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior anticancer chemotherapy

Endocrine therapy:

• Prior topical or inhaled steroids for nonmalignant conditions allowed

Radiotherapy :

• No prior anticancer radiotherapy

Surgery:

• Not specified

Other:

• No prior antileukemic therapy

Patient Characteristics:

Age:

• Under 22

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoeitic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Expected Enrollment

Approximately 880 patients with de novo acute myelogenous leukemia will be accrued for this study within 4 years. It is expected that 178 patients per year will be randomly assigned for consolidation, that 39 patients per year will undergo allogeneic bone marrow transplantation while 120 patients per year will receive chemotherapy as intensification, and that 102 patients per year will be randomly assigned for polychemotherapy immunomodulation. An additional 80 patients with myelodysplastic syndromes will be accrued for this study.

Outline

This is a randomized, multicenter study. Patients are stratified according to center, diagnosis (acute myelogenous leukemia vs other), and response to induction (partial vs complete remission). After induction, patients with M1/M2 marrow are randomized to arm I or II. Patients in complete remission after consolidation who have an HLA-identical or 1-antigen mismatched sibling or parent donor are nonrandomly assigned to the allogeneic bone marrow transplantation (AlBMT) regimen; all others in complete remission are nonrandomly assigned to the Capizzi II regimen, then are randomly assigned to arms III or IV. Patients with refractory anemia (RA) or RA with ringed sideroblasts with indolent disease may be registered and followed. Other patients with myelodysplastic syndromes may receive 2961 chemotherapy or go directly to AlBMT. Patients with chloromas (granulocytic sarcomas) receive optional radiotherapy on arm V.

• Induction: Patients receive idarubicin IV over 30 minutes on days 0-3, cytarabine and etoposide IV continuously on days 0-3, and oral thioguanine twice a day and oral dexamethasone 3 times a day on days 0-3. Patients then begin course 2, which consists of cytarabine, etoposide, thioguanine, and dexamethasone on days 10-13, daunorubicin IV continuously on days 10-13, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 16 and continuing until blood counts recover. Patients also receive CNS prophylaxis/therapy consisting of cytarabine intrathecally (IT) on days 0 and 14 (if no CNS disease at entry) or on days 0, 5, and 7 (if CNS disease present at entry).

  Disease is reassessed on day 28-42. Patients with M1 or M2 marrow proceed to consolidation while those with M3 marrow or progressive disease go off study.

• Consolidation:
  • Arm I: Patients receive treatment as in induction therapy, plus G-CSF SC beginning on day 16 and continuing until blood counts recover. If CSF is clear by day 10 of induction, patients receive cytarabine IT on days 0, 10, and 35. If CSF is not clear, patients receive triple intrathecal therapy (TIT; cytarabine, hydrocortisone, methotrexate) on days 0 and 10.
  • Arm II: Patients receive fludarabine IV over 24 hours on days 0 and 1, cytarabine IV over 72 hours on days 2-4, and idarubicin IV over 15 minutes on days 0-2. G-CSF begins on day 6 and continues until blood counts recover. Patients also receive TIT on days -1 and 7, if CSF is not clear on day 10 of induction.

    Patients on both arms are reassessed on day 35. Those patients with M1 marrow proceed to intensification; all others are removed from the study.

• Intensification:
  • Capizzi II regimen: Course 1: Patients receive cytarabine IV over 3 hours every 12 hours on days 0, 1, 7, and 8 and asparaginase IM on days 1 and 8. Course 2: Patients also receive cytarabine IT or TIT on days 0, 7, and 14.
  • AlBMT regimen: Therapy begins within 2-8 weeks of hematologic recovery. Patients may receive interim therapy consisting of oral thioguanine for about 2 weeks. Patients then receive oral busulfan every 6 hours on days -9 to -6 and cyclophosphamide IV over 1 hour on days -5 to -2. AlBMT is infused over 4 hours beginning 36-48 hours after the last dose of cyclophosphamide.

    Patients in complete remission after completing the Capizzi II regimen proceed to maintenance therapy on arm III.

  • Arm III: Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.
  • Arm IV: No further treatment.
  • Arm V: Patients undergo radiotherapy to the chloroma 5 days a week for 2 weeks. Patients are followed monthly for 18 months, every 3 months for 1 year, and then every 6 months until 5 years from diagnosis.

Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008.[PUBMED Abstract]

Lange BJ, Gerbing RB, Feusner J, et al.: Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293 (2): 203-11, 2005.[PUBMED Abstract]

Lange BJ, Smith FO, Dinndorf PA, et al.: Outcomes in CCG-2961, a Children’s Cancer Group Phase III trial for untreated acute myeloid leukemia (AML). [Abstract] Blood 106 (11): A-169, 2005.

Bhatla D, Gerbing RB, Alonzo TA, et al.: Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia. Br J Haematol 144 (3): 388-94, 2009.[PUBMED Abstract]

Ho PA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 113 (26): 6558-66, 2009.[PUBMED Abstract]

Bhatla D, Gerbing RB, Alonzo TA, et al.: DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group. Leukemia 22 (2): 265-72, 2008.[PUBMED Abstract]

Horan JT, Alonzo TA, Lyman GH, et al.: Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 26 (35): 5797-801, 2008.[PUBMED Abstract]

Mehta PA, Gerbing RB, Alonzo TA, et al.: FAS promoter polymorphism: outcome of childhood acute myeloid leukemia. A children's oncology group report. Clin Cancer Res 14 (23): 7896-9, 2008.[PUBMED Abstract]

Meshinchi S, Stirewalt DL, Alonzo TA, et al.: Structural and numerical variation of FLT3/ITD in pediatric AML. Blood 111 (10): 4930-3, 2008.[PUBMED Abstract]

Sung L, Alonzo TA, Gerbing RB, et al.: Respiratory syncytial virus infections in children with acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 784-6, 2008.[PUBMED Abstract]

Barbaric D, Alonzo TA, Gerbing RB, et al.: Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961. Blood 109 (6): 2314-21, 2007.[PUBMED Abstract]

Pollard J, Alonzo T, Gerbing R, et al.: Prevalence and prognostic significance of c-KIT mutations in pediatric CBF AML patients enrolled on serial CCG/COG protocols. [Abstract] Blood 110 (11): A-1442, 2007.

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.

Aplenc R, Alonzo TA, Gerbing RB, et al.: Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group. Blood 108 (1): 74-80, 2006.[PUBMED Abstract]

Loh ML, Reynolds MG, Vattikuti S, et al.: PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. Leukemia 18 (11): 1831-4, 2004.[PUBMED Abstract]

Perentesis JP, Alonzo TA, Gerbing R, et al.: Polymorphism in folate metabolism and outcomes of therapy in children with AML with and without Down Syndrome. [Abstract] Blood 102 (11 Pt 1): A-479, 2003.

Sievers EL, Lange BJ, Alonzo TA, et al.: Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group Study of 252 acute myeloid leukemia patients. [Abstract] 2003 Pediatric Academic Societies' Annual Meeting, May 3-6, Seattle, Washington. A-1528, 2003. Available online Last accessed August 30, 2005.

Sievers EL, Lange BJ, Alonzo TA, et al.: Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood 101 (9): 3398-406, 2003.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Beverly Lange, MD, Protocol chair		Ph: 215-590-2249 Email: Lange@email.CHOP.edu

Registry Information
Official Title		A PHASE III STUDY IN CHILDREN WITH UNTREATED ACUTE MYELOGENOUS LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)
Trial Start Date		1996-08-30
Registered in ClinicalTrials.gov		NCT00002798
Date Submitted to PDQ		1996-08-30
Information Last Verified		2002-10-01
NCI Grant/Contract Number		CA13539

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