BMT for Children with Stem Cell Defects, Marrow Failure Syndromes, or Myeloid Leukemia in 1st Remission

For many patients with marrow failure syndromes including primary red cell aplasia, severe congenital neutropenia (Kostmann's syndrome), red cell aplasia (Diamond-Blackfan syndrome), amegakaryocytic thrombocytopenia, or severe aplastic anemia who have an HLA closely-matched related donor or who fail immunosuppressive chemotherapy, an allogeneic bone marrow transplant can result in 80-90% disease free survival. Seventy-five to 90% of children with thalassemia major or sickle cell disease who have an HLA matched relative can be cured of their hemoglobinopathy with a BMT. Finally, for children with most inherited severe immunodeficiency diseases, the only known cure and, therefore, the treatment of choice is an allogeneic bone marrow transplant in which up to 90% may be cured.

The goals of this protocol are the following:

• 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 SCID
• To assess the pharmacokinetics of an IV preparation of busulfan in children undergoing BMT.

Improving engraftment in children with marrow stem cell defects

Two of the major causes of failure of BMT for these diseases are graft rejection due to an inadequate preparative regimen and organ toxicity from 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. Busulfan 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 is also associated with an increased incidence of liver damage in the form of veno-occlusive disease and bladder damage resulting in hemorrhagic cystitis. Finally, an IV preparation of busulfan has become commercially available which should improve the administration and pharmacokinetics in children and may reduce toxic side-effects.

Using fludarabine in conditioning regimens

Recently, a chemotherapy drug, 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, and little toxicity (nausea, vomiting and neurotoxicity) has been reported. Fludarabine has primarily been associated with lymphopenia, opportunistic infections, and 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.

Eligibility criteria for this protocol

Patients who are eligible for this protocol should have one of the following diagnoses:

• Severe aplastic anemia with marrow aplasia with closely matched related donor or unresponsive to immunosuppressive therapy within 3 months follow-up and an alternative matched unrelated donor.
• Congenital marrow failure syndrome with closely matched relative or unrelated donor:
  • Primary red cell aplasia (Diamond-Blackfan syndrome)
  • Congenital neutropenia (Kostmann’s syndrome)
  • Amegakaryocytic thrombocytopenia
  • Other congenital and acquired cytopenias unresponsive to conventional therapy
• Hemoglobinopathy with closely matched relative or unrelated donor:
  • Thalassemia major
  • Sickle cell anemia
• Severe immunodeficiency disease including:
  • Chediak-Higashi Disease
  • Wiskott-Aldrich Syndrome
  • Combined Immunodeficiency Disease (Nezelof’s)
  • Hyper IgM Syndrome
  • Bare lymphocyte syndrome
  • Chronic granulomatous disease
• Other stem cell defects e.g. osteopetrosis
• Chronic myelogenous leukemia in 1st chronic phase
• Acute myelogenous leukemia in 1st remission