Low-Dose Cytarabine in Treating Infants With Down Syndrome and Transient Myeloproliferative Disorder

Treatment of Transient Myeloproliferative Disorder (TMD) in Children With Down Syndrome (DS)

RATIONALE: Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. Giving low-doses of cytarabine may be an effective treatment for Down syndrome and transient myeloproliferative disorder. Sometimes the disease may not need treatment until it progresses. In this case, observation may be sufficient.

PURPOSE: This phase III trial is studying low-dose cytarabine to see how well it works in treating infants with Down syndrome and transient myeloproliferative disorder.

Study Overview

• Status: Withdrawn
• Conditions: Leukemia
• Intervention / Treatment: Drug: cytarabine; Procedure: observation

Detailed Description

OBJECTIVES:

Primary

• Determine whether very low-dose cytarabine can improve event-free survival (EFS) rates in infants with high-risk transient myeloproliferative disorder (TMD), using high-risk TMD patients from clinical trial COG-A2971 for historic comparison, and in infants with intermediate-risk TMD, using intermediate-risk TMD patients from clinical trial COG-A2971 for historic comparison.
• Maintain the current high overall EFS rate in low-risk TMD patients.

Secondary

• Assess the toxicity of this regimen in these patients.

OUTLINE: This is a nonrandomized, multicenter, crossover study. Patients are stratified according to disease risk (high or intermediate vs low).

• Group I (patients with high- or intermediate-risk transient myeloproliferative disorder [TMD]): Patients receive very low-dose cytarabine subcutaneously twice daily on days 1-7. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or complete or hepatic clinical remission undergo observation.
• Group II (patients with low-risk TMD): Patients are observed. If symptoms of intermediate- or high-risk disease develop, patients may crossover to group I.

After completion of study treatment, patients are followed periodically for 10 years.

PROJECTED ACCRUAL: A total of 180 patients will be accrued for this study.

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of transient myeloproliferative disorder (TMD)

• Diagnosis of Down syndrome or Down syndrome mosaicism (confirmed by karyotype analysis within the past 3 weeks) AND 1 of the following:

  • Nonerythroid and nonlymphoid blasts (any amount) in the peripheral blood with verification of a second sample
  • Trisomy 21-positive leukemic blasts documented by biopsy of any organ (including > 5% nonerythroid/nonlymphoid blasts documented by bone marrow aspirate or biopsy)
• Immunophenotype characterization required

• High-, intermediate-, or low-risk TMD, as defined by the following:

  • High-risk TMD, meeting 1 of the following criteria:

    • Life-threatening cardio-respiratory compromise due to complications of TMD (e.g., organomegaly or effusions)

      • Life-threatening cardio-respiratory compromise is defined as cardiovascular grade 4 edema, grade 4 pericardial effusions, or grade 4 pleural effusions
    • Hyperleukocytosis, defined as a WBC > 100,000/mm³

    • Any degree of hepatomegaly (palpable on physical exam) combined with life-threatening hepatic dysfunction

      • Life-threatening hepatic dysfunction is defined as grade 4 disseminated intravascular coagulation, grade 4 ascites, grade 4 bilirubin (> 10.0 times upper limit of normal [ULN]), or grade 4 AST or ALT (> 20.0 times ULN)

  • Intermediate-risk TMD, meeting all of the following criteria:

    • Hepatomegaly (palpable on physical exam) combined with non life-threatening hepatic dysfunction (i.e., grade 1-3 hepatic dysfunction [AST or ALT ≤ 2.5 times ULN] and/or a total or direct bilirubin ≤ 1.5 times ULN)
    • No evidence of life-threatening cardiovascular, respiratory, or hepatic compromise due to complications of TMD

  • Low-risk TMD, meeting all of the following criteria:

    • No palpable hepatomegaly on physical exam OR hepatomegaly is present without hepatic dysfunction (i.e., grade 0 hepatic dysfunction)
    • No evidence of life-threatening cardiovascular, respiratory, or hepatic compromise due to complications of TMD

PATIENT CHARACTERISTICS:

• See Disease Characteristics
• No biliary atresia by hepatic ultrasound for patients with bilirubin 3.0-10.0 times ULN

PRIOR CONCURRENT THERAPY:

• No prior antileukemic therapy (except for leukapheresis or exchange transfusion)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group I; Patients receive very low-dose cytarabine subcutaneously twice daily on days 1-7. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or complete or hepatic clinical remission undergo observation.	Drug: cytarabine; Given subcutaneously
Other: Group II; Patients are observed. If symptoms of intermediate- or high-risk disease develop, patients may crossover to group I.	Procedure: observation; No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free survival

Secondary Outcome Measures

Outcome Measure
Overall survival
Disease-related mortality
Percentage of patients experiencing grade 3-4 toxicity
Incidence of subsequent leukemia in patients for whom transient myeloproliferative disorder is resolved

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: April D. Sorrell, MD, Rutgers Cancer Institute of New Jersey; Study Chair: Jeffrey Taub, MD, Children's Hospital of Michigan

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: December 11, 2006
• First Submitted That Met QC Criteria: December 11, 2006
• First Posted (Estimate): December 13, 2006

Study Record Updates

• Last Update Posted (Estimate): September 30, 2015
• Last Update Submitted That Met QC Criteria: September 28, 2015
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: acute myeloid leukemia/transient myeloproliferative disorder
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Congenital Abnormalities; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Intellectual Disability; Leukocyte Disorders; Abnormalities, Multiple; Chromosome Disorders; Leukocytosis; Down Syndrome; Myeloproliferative Disorders; Leukemoid Reaction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: AAML0532; COG-AAML0532 (Other Identifier: Children's Oncology Group); CDR0000518352 (Other Identifier: Clinical Trials.gov)