Marrow Stem Cell Defects Treatment Options

For many patients with marrow failure syndromes who have a closely-matched related donor or who fail immunosuppressive chemotherapy, an allogeneic bone marrow transplant (BMT) can result in 80 percent to 90 percent disease-free survival. These syndromes include:

  • Primary red cell aplasia
  • Severe congenital neutropenia or Kostmann's syndrome
  • Red cell aplasia or diamond-blackfan syndrome
  • Amegakaryocytic thrombocytopenia
  • Severe aplastic anemia
  • Fanconi's anemia

In addition, 75 percent to 90 percent of children with thalassemia major or sickle cell disease who have a human leukocyte antigen (HLA) matched relative can be cured of their hemoglobinopathy with a BMT.

For children with most inherited severe immunodeficiency diseases, such as Wiskott-Aldrich disease, Chediak-Higashi syndrome and chronic granulomatous disease, the only known cure -- and therefore the treatment of choice -- is an allogeneic bone marrow transplant in which up to 90 percent may be cured.

The goals of this protocol are to determine:

  • The efficacy and toxicity of a fludarabine-based conditioning regimen in children with marrow failure syndromes, hemoglobinopathies or severe immunodeficiency diseases other than severe combined immunodeficiency disease (SCID)
  • The pharmacokinetics of an intravenous (IV) preparation of busulfan in children undergoing BMT

Improving Engraftment

Two of the major causes of failure of BMT for these diseases are:

  • Graft rejection due to an inadequate preparative regimen
  • Organ damages caused by the conditioning regimen

The standard conditioning regimens for all of these non-malignant disorders, except for severe aplastic anemia or Fanconi's anemia, consists of busulfan, cyclophosphamide and anti-thymocyte globulin. Busulfa is an alkylating agent that until recently could only be taken by mouth. A limitation of using busulfan in children is the significant variability in its absorption and clearance. Techniques are available for monitoring the pharmacology of busulfan that have improved its efficacy to reduce graft rejection. However, the use of busulfan in combination with cyclophosphamide also is associated with an increased incidence of liver damage in the form of veno-occlusive disease and bladder damage resulting in hemorrhagic cystitis. The good news is that an IV preparation of busulfan has become commercially available which should improve the administration and pharmacokinetics in children and may reduce these negative side effects. To learn more, please see Busulfan Pharmacokinetics.

Using Fludarabine

Recently, a chemotherapy drug called fludarabine has been used in conditioning regimens, replacing cyclophosphamide as a potent immunosuppressive agent. Fludarabine is a purine analogue that has major effects on resting and activated T and B lymphocytes. It has been associated with minimal side effects, such as nausea, vomiting and neurotoxicity.

Fludarabine has primarily been associated with opportunistic infections, called lymphopenia, and there have been a limited number of reports of autoimmune hemolytic anemia or thrombocytopenia. Fludarabine has been used in combination with busulfan or cyclophosphamide to prepare children with a variety of marrow stem cell disorders. It has been used alone in a limited number of patients with Fanconi's anemia.


Patients with the following are eligible for this protocol if they have a closely matched related or unrelated donor available:

  • Severe aplastic anemia who are unresponsive to immunosuppressive therapy within three months follow-up and have an alternative matched unrelated donor
  • Congenital marrow failure syndrome with closely matched relative or unrelated donor, including the following syndromes:
    • Primary red cell aplasia or diamond-blackfan syndrome
    • Congenital neutropenia or Kostmann's syndrome
    • Amegakaryocytic thrombocytopenia
    • Other congenital and acquired cytopenias unresponsive to conventional therapy
  • Hemoglobinopathy with closely matched relative or unrelated donor, including:
    • Thalassemia major
    • Sickle cell anemia
  • Severe immunodeficiency disease including:
    • Chediak-Higashi disease
    • Wiskott-Aldrich Syndrome
    • Combined immunodeficiency disease or Nezelof's
    • Hyper IgM syndrome
    • Bare lymphocyte syndrome
    • Chronic granulomatous disease
    • Other stem cell defects, such as osteopetrosis>/li>
    • Chronic myelogenous leukemia in the first chronic phase
    • Acute myelogenous leukemia in first remission
    • Myelodysplastic syndrome


Reviewed by health care specialists at UCSF Benioff Children's Hospital.

Related Information

UCSF Clinics & Centers

Blood & Marrow Transplant

Blood and Marrow Transplant Program
1975 Fourth St., Sixth Floor
San Francisco, CA 94158
Phone: (415) 476-2188
Fax: (415) 502-4867

Blood & Marrow Transplant Clinic
1825 Fourth St., Sixth Floor
San Francisco, CA 94158
Phone: (415) 353-2986
Fax: (415) 502-4867

Patient Experiences

Our Experts

Morton J. Cowan
Dr. Morton J. Cowan,
pediatric immunologst and bone marrow transplant specialist
Christopher Dvorak
Dr. Christopher Dvorak,
pediatric hematologist and oncologist
Robert E. Goldsby
Dr. Robert E. Goldsby,
pediatric hematologist and oncologist
James Huang
Dr. James Huang,
pediatric hematologist