Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission

Sponsor

University of California, San Francisco (Other)

Overall Status

Completed

CT.gov ID

NCT00305708

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as busulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. A donor peripheral blood, bone marrow , or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving antithymocyte globulin before the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of busulfan, antithymocyte globulin, and fludarabine when given together with a donor stem cell transplant in treating young patients with blood disorders, bone marrow disorders, chronic myelogenous leukemia in first chronic phase, or acute myeloid leukemia in first remission.

Condition or Disease	Intervention/Treatment	Phase
Congenital Amegakaryocytic Thrombocytopenia Diamond-blackfan Anemia Fanconi Anemia Leukemia Severe Congenital Neutropenia Thrombocytopenia	Biological: anti-thymocyte globulin Drug: busulfan Drug: fludarabine phosphate Procedure: allogeneic bone marrow transplantation Procedure: peripheral blood stem cell transplantation Procedure: umbilical cord blood transplantation Radiation: radiation therapy	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

Determine the efficacy, in terms of graft rejection at 4 weeks, of a conditioning regimen comprising busulfan, anti-thymocyte globulin, and fludarabine followed by donor stem cell transplantation (SCT) in children with stem cell defects, marrow failure syndromes, chronic myelogenous leukemia in first chronic phase, or acute myeloid leukemia in first remission.
Determine the pharmacokinetics of busulfan in children undergoing donor SCT.

Secondary

Determine the toxicity of this regimen in these patients.
Determine engraftment at 3, 6, 9, and 12 months and mixed chimerism in patients treated with this regimen.
Determine overall and disease-free survival of patients treated with this regimen.

OUTLINE: Patients receive one of the following cytoreductive regimens:

Regimen 1 (patients with an HLA genotypic matched sibling donor): Patients receive busulfan IV over 2 hours every 6 hours on days -9 to -6, fludarabine IV on days -5 to -2, and anti-thymocyte globulin (ATG) IV over 10 hours on days -3 to -1.
Regimen 2 (patients with an HLA closely matched related [not genotypic] or unrelated donor): Patients receive busulfan and fludarabine as in regimen 1, and ATG IV over 10 hours on days -4 to -1.
Regimen 3 (patients with Fanconi's anemia or severe aplastic anemia with genotypic matched sibling donor): Patients receive fludarabine as in regimen 1 and ATG as in regimen 2.
Regimen 4 (patients with Fanconi's anemia who have a closely matched related [not genotypic] or unrelated donor): Patients undergo thoracoabdominal irradiation on day -6 and receive fludarabine as in regimen 1 and ATG as in regimen 2.

All patients undergo allogeneic bone marrow, umbilical cord blood, or peripheral blood stem cell transplantation on day 0.

After the completion of study treatment, patients are followed periodically for 20 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Bone Marrow Stem Cell Transplantation for Children With Stem Cell Defects, Marrow Failure Syndromes, or Myeloid Leukemia in 1Remission

Study Start Date :

Aug 1, 2000

Actual Primary Completion Date :

Jul 1, 2004

Actual Study Completion Date :

Jul 1, 2004

Outcome Measures

Primary Outcome Measures

Graft rejection measured by ANC < 500 with no evidence of donor cells in blood or marrow from transplantation to week 4 post transplantation []

Secondary Outcome Measures

Toxicity grades 3 or 4 assessed from conditioning through 1 year post transplantation []
Engraftment at 1, 3, 6, 9, and 12 months post transplantation []
Mixed chimerism at 1, 3, 6, 9, and 12 months post transplantation []
Survival measured from the day of first dose of conditioning []
Disease-free survival measured from the day of first dose of conditioning []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of one of the following hematopoietic disorders:
Severe aplastic anemia with marrow aplasia (i.e., absolute neutrophil count < 500/mm^3, platelet and/or red blood cell transfusion dependent), meeting 1 of the following criteria:
Closely matched related donor
Unresponsive to immunosuppressive therapy within 3 months after follow-up AND alternative matched unrelated donor available
Congenital marrow failure syndrome, including any of the following:
Primary red blood cell aplasia (Diamond-Blackfan syndrome)
Congenital neutropenia (Kostmann's syndrome)
Amegakaryocytic thrombocytopenia
Hemoglobinopathy including any of the following:
β-thalassemia major
Sickle cell anemia
Severe immunodeficiency disease including any of the following:
Chediak-Higashi disease
Wiskott-Aldrich syndrome
Combined immunodeficiency disease (Nezelof's)
Hyperimmunoglobulin M syndrome
Bare lymphocyte syndrome
Other stem cell defects (e.g., osteopetrosis)
Chronic myelogenous leukemia in first chronic phase
Not eligible for other ongoing phase II/III studies
Acute myeloid leukemia in first remission
Not eligible for other ongoing phase II/III studies
Inborn errors of metabolism
No severe combined immunodeficiency disorder
Available donor, meeting 1 of the following criteria:
Related donor matched by high resolution DNA typing at both HLA Drβ1 alleles and ≤ 1 mismatch at the 4 HLA-A and -B alleles
Unrelated donor, meeting one of the following criteria:
Bone marrow matched by high resolution DNA typing at both HLA Drβ1 alleles and ≤ 1 mismatch by high resolution DNA typing at the 4 HLA-A and -B alleles
Umbilical cord blood matched at 4/6 HLA-A, -B, and Drβ1 alleles by high resolution typing with ≥ 1 Drβ1 match and ≥ 3 X 10^7 cells/kg body weight of recipient