Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
Condition: Bone Marrow Failure Syndrome; Thalassemia; Sickle Cell Disease; Diamond Blackfan Anemia; Acquired Neutropenia in Newborn; Acquired Anemia Hemolytic; Acquired Thrombocytopenia; Hemophagocytic Lymphohistiocytoses; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; Common Variable Immunodeficiency; X-linked Lymphoproliferative Disease; Severe Combined Immunodeficiency; Hurler Syndrome; Mannosidosis; Adrenoleukodystrophy
MeSH terms: Adrenoleukodystrophy; Anemia; Anemia, Sickle Cell; Thrombocytopenia; Thalassemia; Neutropenia; Bone Marrow Failure Disorders; Pancytopenia; Granulomatous Disease, Chronic; Lymphohistiocytosis, Hemophagocytic; Lymphoproliferative Disorders; Anemia, Diamond-Blackfan; Wiskott-Aldrich Syndrome; Severe Combined Immunodeficiency; Mannosidase Deficiency Diseases; Mucopolysaccharidosis I; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency; Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      In this study, the investigators test 2 dose levels of thiotepa (5 mg/kg and 10 mg/kg) added
      to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte
      globulin (rATG) to determine the minimum effective dose required for reliable engraftment for
      subjects undergoing hematopoietic stem cell transplantation for non-malignant disease.
    

Detailed description: 
      Hematopoietic stem cell transplantation is the only curative choice for a number of inherited
      bone marrow failure syndromes, hemoglobinopathies, metabolic disorders and primary immune
      deficiencies. While survival of these patients is typically better than survival of patients
      with malignancies, toxicities of conditioning regimens and failure of engraftment remain
      challenges. Most children with non-malignant disorders present with normocellular or even
      hypercellular bone marrow, posing a barrier to engraftment and requiring intensive
      conditioning. Commonly used backbone of busulfan and fludarabine, although well tolerated,
      results in variable engraftment, in particular with mismatched unrelated donors and cord
      blood recipients. In this study, the investigators test 2 dose levels of thiotepa (5 mg/kg
      and 10 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and
      rabbit anti-thymocyte globulin (rATG) in order to determine the minimum effective dose
      required for reliable engraftment. Subjects are stratified in groups A and B based the risk
      of graft failure.
    

Intervention name(s): Thiotepa--single daily dose; Thiotepa--escalated dose
Intervention type(s): Drug; Drug
Intervention description(s): Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.; Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
Intervention MeSH terms: Thiotepa
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: The study builds in rules for escalation of thiotepa dose based on graft failure by day 42. Patients are stratified in two groups A (lower risk of graft failure) and B (higher risk of graft failure). Patients undergoing 10/10 HLA matched bone marrow and peripheral blood transplants are assigned to Group A, and patients receiving <10/10 matched bone marrow or peripheral blood, or receiving cord blood, even if fully matched, are assigned to Group B.
If criteria for thiotepa dose escalation are met first in Group A, which has a lower risk of graft failure, thiotepa dose will be escalated for all subjects (Groups A and B). If criteria for thiotepa dose escalation are met first in Group B, dose will be escalated only in Group B and Group A will continue enrolling patients at a lower dose level.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: human leukocyte antigen (HLA)