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

Alternate Title

Chemotherapy in Treating Children With Down Syndrome and Myeloproliferative Disorder, Acute Myelogenous Leukemia, or Myelodysplastic Syndrome

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Completed 21 and under NCI COG-A2971 CCG-A2971, POG-A2971, CCG-29701, A2971, NCT00003593

Objectives

1. Evaluate the efficacy of reduced-dose induction and intensification chemotherapy, in terms of remission rate, disease-free survival rate, and acute morbidity and mortality, in children with Down syndrome and acute myelogenous leukemia or myelodysplastic syndromes.
2. Define the understanding of the natural history of transient myeloproliferative disorder (TMD) in children with Down syndrome.
3. Determine whether there is a reduction of sequelae in long-term survivors after treatment with this regimen.
4. Determine the incidence of subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen.
5. Determine the predictive risk factors for developing subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen.

Entry Criteria

Disease Characteristics:

• Cytogenetically proven Down Syndrome (constitutional trisomy 21) with transient myeloproliferative disorder (TMD), myelodysplastic syndromes (MDS), or acute myelogenous leukemia (AML)
  • Must be confirmed by bone marrow aspirate, cerebrospinal fluid exam, or blood test
  • Trisomy 21 mosaicism allowed



• Group I:
  • Diagnosis of TMD in patients no older than 90 days at initial presentation
  • Must have nonerythroid blasts (any amount) in the peripheral blood and one of the following:
    • Verification with a second sample
    • More than 5% bone marrow blasts
    • Hepatomegaly and/or splenomegaly
    • Lymphadenopathy
    • Cardiac or pleural effusions

    OR

  • Histologically or cytologically proven TMD with blasts in an affected organ or in fluid (pericardial, pleural, or peritoneal)
  • Bone marrow aspirate is required



• Group II (closed to accrual as of 6/24/04):
  • Diagnosis of MDS or AML (except M3 subtype) in patients older than 90 days with more than 29% blasts in bone marrow (with or without history of TMD), or any of the following histologies:
    • Refractory anemia (RA)
    • RA with excess blasts (RAEB)
    • RAEB in transformation
    • RA with ringed sideroblasts (RARS)
    • Primary cytopenia (later confirmed by bone marrow aspirate as due to marrow hypoplasia) defined by one or more of the following:
      • Absolute neutrophil count less than 500/mm³
      • Untransfused platelet count less than 30,000/mm³
      • Untransfused hemoglobin less than 8 g/dL



• The following diagnoses will be observed only:
  • RA with mild cytopenias*
  • RARS with mild cytopenias*
  • Mild primary cytopenias (one or more) without dysplasia (confirmed by hypoplastic bone marrow exam)

   [Note: * Platelet count 30-150,000/mm³, absolute neutrophil count 500-1,499/mm³, and hemoglobin greater than 8 g/dL ]




• Granulocytic sarcoma (chloroma), with or without bone marrow involvement, allowed

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• Prior chemotherapy for TMD allowed
• No prior chemotherapy for malignancy

Endocrine therapy:

• Concurrent topical or inhaled steroids for other conditions allowed

Radiotherapy:

• No prior radiotherapy for malignancy

Surgery:

• Not specified

Other:

• No prior antileukemic therapy
• Prior enrollment on this study for TMD allowed

Patient Characteristics:

Age:

• See Disease Characteristics
• 21 and under

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• See Disease Characteristics

Renal:

• Not specified

Cardiovascular:

• Shortening fraction greater than 27% by echocardiogram*

  OR

• Ejection fraction greater than 47% by radionuclide angiogram*

 [Note: *For patients with MDS and AML (as of 2/24/04, previously diagnosed MDS or AML closed to accrual; MDS or AML that develops (secondary to TMD) after study enrollment or MDS that requires initial observation [with or without subsequent treatment] allowed) ]

Expected Enrollment

A total of 70 patients with acute myeloid leukemia or myelodysplastic syndromes will be accrued for this study within 3.2 years. A total of 88 patients with transient myeloproliferative disorder who enter remission will be accrued for this study within 5 years.

Outline

This is a multicenter study.

• Group I: Patients are observed if their transient myeloproliferative disorder (TMD) does not require intervention. Patients who require therapy for TMD undergo leukapheresis or exchange transfusion for up to 3 consecutive days. If the TMD does not resolve or there is significant organ involvement, patients receive low-dose cytarabine IV continuously on days 0-4. Treatment repeats at least every 2 weeks for up to 4 courses. Patients who experience a recurrence of TMD at least 8 weeks after resolution or have refractory disease may proceed to group II for further treatment.



• Group II (closed to accrual as of 6/24/04 except for patients first enrolled in group I): Patients receive induction therapy comprising cytarabine IV continuously, daunorubicin IV continuously, and oral thioguanine twice daily on days 0-3. Treatment repeats every 28 days for 4 courses. Patients with no CNS disease at diagnosis receive cytarabine intrathecally (IT) on day 0. Patients with CNS disease at diagnosis receive cytarabine IT on days 0, 5, and 7. If CNS disease persists on day 7, patients receive up to 6 courses of cytarabine IT, hydrocortisone IT, and methotrexate IT, twice weekly beginning on day 10.

  Patients who achieve remission after induction therapy receive 2 courses of intensification therapy, for approximately 4 months. During the first course, patients receive cytarabine IV over 3 hours twice daily on days 0, 1, 7, and 8. Patients also receive asparaginase intramuscularly on days 1 and 8. The second course of therapy comprises CNS prophylaxis. Patients with no CNS disease at diagnosis or whose CNS disease resolved by day 7 of induction therapy receive cytarabine IT on days 0, 7, and 14. Patients with persistent CNS disease on day 7 of induction therapy receive cytarabine IT, hydrocortisone IT, and methotrexate IT on days 0, 7, and 14.

Patients are followed monthly for 18 months, every 3 months for 1 year, every 6 months for 2.5 years, and then annually thereafter.

Gamis AS, Alonzo TA, Hilden JM, et al.: Outcome of Down syndrome (DS) children with acute myeloid leukemia (AML) or myelodysplasia (MDS) treated with a uniform prospective clinical trial initial report of the COG trial A2971. [Abstract] Blood 108 (11): A-15, 2006.

Sharma M, Alonzo TA, Sorrell A, et al.: Uniform approach better defines natural history of transient myeloproliferative disorder (TMD) in Down syndrome (DS) neonates: outcomes from Children's Oncology Group (COG) study A2971. [Abstract] Blood 108 (11): A-376, 2006.

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.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Alan Gamis, MD, MPH, Protocol chair		Ph: 816-234-3265

Registry Information
Official Title		Treatment of Children with Down Syndrome (DS) and Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Transient Myeloproliferative Disorder (TMD): A Phase III Group-Wide Study
Trial Start Date		1999-06-30
Registered in ClinicalTrials.gov		NCT00003593
Date Submitted to PDQ		1998-09-25
Information Last Verified		2004-06-24
NCI Grant/Contract Number		CA13539

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