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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00003593
First received: November 1, 1999
Last updated: June 26, 2013
Last verified: June 2013
  Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase III trial to study the effectiveness of combination chemotherapy in treating children who have Down syndrome and myeloproliferative disorder, acute myelogenous leukemia, or myelodysplastic syndrome.


Condition Intervention Phase
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: methotrexate
Drug: therapeutic hydrocortisone
Drug: thioguanine
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Event Free Survival [ Time Frame: Length of study ] [ Designated as safety issue: No ]

Enrollment: 254
Study Start Date: June 1999
Study Completion Date: April 2012
Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A: TMD patients only
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. patients will continue to be followed for remission induction, EFS, DFS and OS regardless of the type of leukemia that develops.
Drug: cytarabine
Given IT
Other Names:
  • cytosine arabinoside
  • AraC
  • Cytosar
  • NSC #063878
Experimental: Arm B: AML/MDS patients only
(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 hydrochloride 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, therapeutic hydrocortisone IT, and methotrexate IT, twice weekly beginning on day 10. Asparaginase during Intensification 1 day 1 hour 18.
Drug: asparaginase
Given IV
Other Names:
  • Elspar
  • Kidrolase
  • Crasnitin
  • Leunase
  • NSC #109229
Drug: cytarabine
Given IT
Other Names:
  • cytosine arabinoside
  • AraC
  • Cytosar
  • NSC #063878
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • daunomycin
  • DNR
  • Cerubidine
  • NSC #82151
Drug: methotrexate
Given IV
Other Names:
  • MTX
  • amethopterin
  • NSC #000740
Drug: therapeutic hydrocortisone
Given IT
Other Names:
  • Cortef
  • Solu-cortef
  • NSC #010483
Drug: thioguanine
Given IV
Other Names:
  • 6-thioguanine
  • 6-TG
  • NSC # 000752

Detailed Description:

OBJECTIVES:

  • 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.
  • Define the understanding of the natural history of transient myeloproliferative disorder (TMD) in children with Down syndrome.
  • Determine whether there is a reduction of sequelae in long-term survivors after treatment with this regimen.
  • Determine the incidence of subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen.
  • Determine the predictive risk factors for developing subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen.

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.

PROJECTED ACCRUAL: 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.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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/mm^3
        • Untransfused platelet count less than 30,000/mm^3
        • 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

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)

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00003593

  Show 237 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Alan S. Gamis, MD, MPH Children's Mercy Hospital
  More Information

Additional Information:
Publications:
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.

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00003593     History of Changes
Other Study ID Numbers: A2971, COG-A2971, CCG-A2971, POG-A2971, CCG-29701, CDR0000066664
Study First Received: November 1, 1999
Last Updated: June 26, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Oncology Group:
childhood myelodysplastic syndromes
untreated childhood acute myeloid leukemia and other myeloid malignancies
childhood acute myeloblastic leukemia without maturation (M1)
childhood acute myeloblastic leukemia with maturation (M2)
childhood acute myelomonocytic leukemia (M4)
childhood acute erythroleukemia (M6)
childhood acute megakaryocytic leukemia (M7)
refractory anemia
refractory anemia with ringed sideroblasts
refractory anemia with excess blasts
refractory anemia with excess blasts in transformation
de novo myelodysplastic syndromes
childhood acute minimally differentiated myeloid leukemia (M0)
childhood acute monocytic leukemia (M5b)
childhood acute monoblastic leukemia (M5a)
myelodysplastic/myeloproliferative neoplasm, unclassifiable
juvenile myelomonocytic leukemia
chronic myelomonocytic leukemia
secondary myelodysplastic syndromes

Additional relevant MeSH terms:
Neoplasms
Down Syndrome
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Asparaginase
Cytarabine
Daunorubicin
Methotrexate
Thioguanine
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Hydrocortisone

ClinicalTrials.gov processed this record on August 21, 2014