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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

Phase 3
21 Years
Not Enrolling
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Thank you

Trial Information

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


- 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

- 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.

Inclusion Criteria


- 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

- 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



- See Disease Characteristics

- 21 and under

Performance status:

- Not specified

Life expectancy:

- Not specified


- See Disease Characteristics


- See Disease Characteristics


- Not specified


- 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)


Biologic therapy:

- Not specified


- Prior chemotherapy for TMD allowed

- No prior chemotherapy for malignancy

Endocrine therapy:

- Concurrent topical or inhaled steroids for other conditions allowed


- No prior radiotherapy for malignancy


- Not specified


- No prior antileukemic therapy

- Prior enrollment on this study for TMD allowed

Type of Study:


Study Design:

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

Outcome Measure:

Event Free Survival

Outcome Time Frame:

Length of study

Safety Issue:


Principal Investigator

Alan S. Gamis, MD, MPH

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Mercy Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

June 1999

Completion Date:

April 2012

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • 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
  • Neoplasms
  • Down Syndrome
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases



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