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Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders

This study has been completed.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of California, San Francisco Identifier:
First received: March 9, 2006
Last updated: May 15, 2013
Last verified: May 2013

RATIONALE: Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell, 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 cyclosporine together with methotrexate and methylprednisolone may stop this from happening.

PURPOSE: This phase II trial is studying how well giving alemtuzumab together with fludarabine and busulfan works when given before donor stem cell transplant in treating young patients with hematologic disorders.

Condition Intervention Phase
Congenital Amegakaryocytic Thrombocytopenia
Diamond-blackfan Anemia
Myelodysplastic Syndromes
Severe Congenital Neutropenia
Biological: alemtuzumab
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: methotrexate
Drug: methylprednisolone
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Procedure: umbilical cord blood transplantation
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Evaluation of Fludarabine, Busulfan and Alemtuzumab as a Reduced Toxicity Ablative Bone Marrow Stem Cell Transplant Regimen for Children With Stem Cell Defects, Marrow Failure Syndromes, or Myelodysplastic Syndrome (MDS)/Leukemia

Resource links provided by NLM:

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation [ Time Frame: 6 weeks post-transplant ]
    Peripheral blood chimerism studies were performed by quantitative real time polymerase chain reaction (qPCR) evaluation of differential short tandem repeat DNA sequences

Secondary Outcome Measures:
  • Treatment-related Mortality at 100 Days and 1 Year Post Transplantation [ Time Frame: 100 days and 1 year ]
  • Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation [ Time Frame: 1 year post-transplantation ]
  • Cytomegalovirus (CMV) Viral Infection and Disease Symptoms [ Time Frame: Up to one year post-transplant ]
    polymerase chain reaction testing for presence of CMV weekly until at least day +100 then every 2 weeks until T-cell reconstitution as defined by cluster of differentiation 4 (CD4) > 200 cells/mm3. Median time to T-cell reconstitution was 6 months.

  • Disease-free Survival With Correction of Disease at One Year Post Transplantation [ Time Frame: 1 year post-transplantation ]
    Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation

Enrollment: 35
Study Start Date: January 2005
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single arm - conditioning and transplant
Alemtuzumab 0.5 mg/kg (maximum 15 mg) daily for 3 days; Busulfan i.v. every 6 hours from day -9 to day -6 for 16 total doses; Fludarabine phosphate from day -5 for 4 days at 1.3 mg/kg (if patient was less than 12 kg) or 40 mg/m*2 per dose; Cyclosporine continuous infusion 3 mg/kg/Day beginning day -1 for GVHD prophylaxis; Methotrexate at 15 mg/m*2 on day +1, 10 mg/m*2 on days +3, +6, and (only for MUDs) day +11 also for GVHD prophylaxis; Methylprednisolone only as required for GVHD prophylaxis; allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation or peripheral blood stem cell transplantation or umbilical cord blood transplantation.
Biological: alemtuzumab Drug: busulfan Drug: cyclosporine Drug: fludarabine phosphate Drug: methotrexate Drug: methylprednisolone Procedure: allogeneic bone marrow transplantation Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Procedure: umbilical cord blood transplantation

Detailed Description:



  • Determine the engraftment rate with reduced toxicity ablative conditioning regimen comprising alemtuzumab, fludarabine, and busulfan followed by allogeneic stem cell transplantation in pediatric patients with stem cell defects, marrow failure syndromes, hemoglobinopathy, severe immunodeficiency syndromes (nonsevere combined immunodeficiency disorders), myelodysplastic syndromes, or myeloid leukemia.


  • Determine the acute reactions, incidence of infections, and rate of immune reconstitution in patients treated with this regimen.

OUTLINE: This is a multicenter study.

  • Conditioning regimen: Patients receive alemtuzumab IV over 6 hours on days -12 to -10, high-dose busulfan IV over 2 hours 4 times daily on days -9 to -6, and fludarabine IV over 30 minutes on days -5 to -2.
  • Allogeneic stem cell transplantation: Two days after the completion of conditioning regimen, patients undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
  • Graft-vs-host disease (GVHD) prophylaxis:

    • Most transplantations (bone marrow or peripheral blood stem cell transplantation): Patients receive cyclosporine IV continuously beginning on day -1 until at least day 50 followed by a taper at either 2 months, 9 months, or 1 year in the absence of GVHD. Patients also receive methotrexate on days 1, 3, and 6.
    • Umbilical cord blood transplantation: Patients receive cyclosporine as in most transplantations, and methylprednisolone IV twice daily on days 0-21 followed by a weekly taper.

After transplantation, patients are followed periodically for up to 20 years.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.


Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of 1 of the following hematologic conditions:

    • Aplastic anemia with marrow aplasia, meeting all of the following criteria:

      • Absolute neutrophil count < 500/mm^3
      • Platelet and/or red cell transfusion dependent
    • Chronic aplastic anemia, meeting all of the following criteria:

      • Transfusion dependent
      • Unresponsive to immunosuppressive therapy
      • Alternative matched unrelated donor has been identified
    • Congenital marrow failure syndrome, including any of the following (with closely matched related or unrelated donor):

      • Primary red cell aplasia (Diamond-Blackfan syndrome)
      • Congenital neutropenia (Kostmann's syndrome)
      • Amegakaryocytic thrombocytopenia
      • Congenital dyserythropoietic anemias
      • Other severe acquired cytopenias in which a transplantation using a combined busulfan/cyclophosphamide conditioning regimen is indicated
    • Hemoglobinopathy (with closely matched related or unrelated donor)

      • β-thalassemia major
      • Sickle cell anemia
      • Hemoglobin E/β-thalassemia
    • Severe immunodeficiency disease

      • Chediak-Higashi disease
      • Wiskott-Aldrich syndrome
      • Combined immunodeficiency disease (Nezelof's)
      • Hyper immunoglobulin M (IgM) syndrome
      • Bare lymphocyte syndrome
      • Chronic granulomatous disease
      • Familial erythrohemophagocytic lymphohistiocytosis
    • Other stem cell defects (e.g., osteopetrosis)
    • Severe immune dysregulation/autoimmune disorders

      • Achieved a transient response to prior immunosuppressive therapy
    • Chronic myelogenous leukemia

      • Disease in first chronic phase
    • Acute myeloid leukemia

      • Disease in first remission
    • Myelodysplastic syndromes
    • Inborn errors of metabolism
    • Histiocytosis
  • No severe combined immunodeficiency disease
  • Matched related or unrelated donor available by high resolution DNA typing

    • Related donor, meeting both of the following criteria:

      • Matched at both human leukocyte antigen (HLA)-Drβ1 alleles
      • No more than 1 mismatch at the 4 HLA-A and -B alleles
    • Unrelated donor, meeting 1 of the following criteria:

      • Marrow matched at both HLA-Drβ1 alleles AND no more than 1 mismatch at the 4 HLA-A and -B alleles
      • Umbilical cord blood matched at 5/6 HLA-A, -B, and -DRβ1 alleles with at least 1 -DRβ1 match AND there are ≥ 3x10^5 CD34+ (Cluster of differentiation 34-positive) cells per kg body weight of recipient available at the time of cryopreservation


  • Cardiac ejection fraction ≥ 27%
  • Creatinine clearance ≥ 50 mL/min by 24-hour urine collection or glomerular filtration rate
  • DLCO (diffusion capacity of lung for carbon monoxide) ≥ 50% of predicted (corrected for anemia/lung volume)


  • No prior transplantation for leukemia from which patient remains engrafted and alemtuzumab is not needed as part of the conditioning regimen
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Please refer to this study by its identifier: NCT00301834

United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, Wisconsin
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
Madison, Wisconsin, United States, 53792-6164
Sponsors and Collaborators
University of California, San Francisco
National Cancer Institute (NCI)
Study Chair: Morton J. Cowan, MD University of California, San Francisco
  More Information

Responsible Party: University of California, San Francisco Identifier: NCT00301834     History of Changes
Other Study ID Numbers: CDR0000462406
UCSF-04152 ( Other Identifier: UCSF Helen Diller Family Comprehensive Cancer Center )
UCSF-00452 ( Other Identifier: UCSF Helen Diller Family Comprehensive Cancer Center )
UCSF-H411-25738-02 ( Other Identifier: UCSF Committee on Human Research (CHR) )
Study First Received: March 9, 2006
Results First Received: January 31, 2013
Last Updated: May 15, 2013

Keywords provided by University of California, San Francisco:
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
congenital amegakaryocytic thrombocytopenia
Diamond-Blackfan anemia
severe congenital neutropenia
secondary acute myeloid leukemia
chronic phase chronic myelogenous leukemia
childhood myelodysplastic syndromes

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Anemia, Diamond-Blackfan
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Blood Platelet Disorders
Leukocyte Disorders
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Red-Cell Aplasia, Pure
Genetic Diseases, Inborn
Fludarabine phosphate
Methylprednisolone Hemisuccinate
Busulfan processed this record on May 22, 2017