Bone Marrow Transplant With Abatacept for Non-Malignant Diseases

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only viable cure for children who suffer from a wide variety of rare, serious non-malignant diseases, such as Fanconi Anemia, Hurler syndrome, and hemophagocytic lymphohistiocytosis. A major obstacle to the success of HSCT is morbidity and mortality from graft versus host disease (GVHD), driven by donor T cells recognizing and reacting against disparate host antigens. This trial is being conducted as a step toward testing the long-term hypothesis that the costimulation blockade agent abatacept can be added to a standard post-transplant GVHD prophylaxis regimen, cyclosporine and mycophenolate mofetil, to improve disease-free survival after unrelated hematopoietic stem cell transplantation (HSCT) using reduced intensity conditioning for children with non-malignant diseases (NMD). This study will have the following Specific Aims:

Specific Aim #1: To conduct a multicenter pilot assessing the tolerability of abatacept (n=10). Patients will receive four doses (10 mg/kg IV on days -1, +5, +14 and +28), a schedule well tolerated by adolescents and adults with hematologic malignancies in a previous pilot. Abatacept will be combined with cyclosporine and mycophenolate mofetil.

Specific Aim #2: To examine the immunological effects of abatacept in this setting.

Three reduced intensity conditioning regimens that have been shown to be effective in achieving sustained engraftment in patients with non-malignant diseases are available for use, depending on the patient's disease:

• Patients with Fanconi anemia will receive fludarabine, low dose cyclophosphamide, and anti-thymocyte globulin.
• Patients with severe aplastic anemia will receive low dose total body irradiation, fludarabine, cyclophosphamide, and anti-thymocyte globulin.
• Patients with other NMD will receive either the low dose total body irradiation regimen or an alemtuzumab, fludarabine, thiotepa, and melphalan regimen.

Inclusion criteria

• Must be between the ages of 0-21 years at the time of admission for transplant.
• Must have one of the following diseases:

• Glanzmann thrombasthenia
• Wiskott-Aldrich syndrome or other combined immune deficiency
• Chronic-granulomatous disease
• Severe congenital neutropenia (with resistance to granulocyte-colony stimulating factor (GCSF) or chronic requirement of GCSF doses ≥10 mcg/kg)
• Leukocyte adhesion deficiency
• Shwachman-Diamond syndrome
• Diamond-Blackfan anemia ((transfusion dependent, including steroid failure or inability to wean steroids)
• Thalassemia major
• Fanconi anemia
• Hemophagocytic lymphohistiocytosis (inherited or acquired refractory to therapy or with recurrent episodes of hyperinflammation)
• Dyskeratosis-congenita
• Hurler Syndrome
• Chediak-Higashi syndrome
• Acquired (immune; non-inherited, non-congenital) severe aplastic anemia
• Sickle cell disease (SCD) (Hgb SS or S-Beta 0 thalassemia) will be eligible between ages 3 and 9.99 and with severe disease.
• Other inherited or congenital marrow failure syndromes complicated by severe aplastic anemia
• Other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy.
• Congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years).
• Other inherited or congenital granulocyte disorders resulting in at least three inpatient hospitalizations in the past three years for infection.
• Must have an unrelated adult donor (marrow or PBSC) who is at least a 7/8 match (A, B, C, DRB1; the mismatch can be at an allele or antigen level) or an unrelated cord blood unit that is matched at least seven of eight loci (A, B and C antigen level-DRB1 allele level) and provides a minimum pre-cryopreservation total nucleated cell (TNC) dose of 7.5 x 107 TNC/kg recipient weight. Mismatches at the DRB1 locus may be at an antigen or allele level.

Exclusion criteria

• Human leukocyte antigen (HLA) matched related donor.
• Severe combined immune deficiency.
• Bridging (portal to portal) fibrosis or cirrhosis of the liver.
• Pulmonary: diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume (FEV1) or forced vital capacity (FVC) < 40% of predicted. In child unable to perform pulmonary function testing, a chronic need for supplemental oxygen will serve as the exclusionary criterion.
• Severe renal dysfunction defined as estimated glomerular filtration rate (GFR) of <60 ml/min/1.73m2.
• Severe cardiac dysfunction defined as shortening fraction < 25%.
• Neurologic impairment other than hemiplegia, defined as full-scale intelligence quotient (IQ) less than or equal to 70, quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in decline of Lansky performance score to < 70%.
• Clinical stroke within 6 months of anticipated transplant.
• Karnofsky or Lansky functional performance score < 50%
• HIV infection.
• Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
• Patient or patient's guardian(s) unable to understand the nature and risks inherent in the blood and marrow transplant process.
• History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.
• Patient is pregnant or lactating
• Patients HLA antibody testing demonstrates an antibody directed against a disparate HLA molecule.