bone marrow transplant with abatacept for non-malignant diseases

Conditions: Hurler Syndrome; Fanconi Anemia; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Shwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia; Thalassemia Major; Hemophagocytic Lymphohistiocytosis; Sickle Cell Disease

Summary: this is a single arm, phase i study to assess the tolerability of abatacept when combined with cyclosporine and mycophenolate mofetil as graft versus host disease prophylaxis in children undergoing unrelated hematopoietic stem cell transplant for serious non-malignant diseases as well as to assess the immunological effects of abatacept. participants will be followed for 2 years.

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.

Eligibility criteria:
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: 1. glanzmann thrombasthenia 2. wiskott-aldrich syndrome or other combined immune deficiency 3. chronic-granulomatous disease 4. severe congenital neutropenia (with resistance to granulocyte-colony stimulating factor (gcsf) or chronic requirement of gcsf doses ≥10 mcg/kg) 5. leukocyte adhesion deficiency 6. shwachman-diamond syndrome 7. diamond-blackfan anemia ((transfusion dependent, including steroid failure or inability to wean steroids) 8. thalassemia major 9. fanconi anemia 10. hemophagocytic lymphohistiocytosis (inherited or acquired refractory to therapy or with recurrent episodes of hyperinflammation) 11. dyskeratosis-congenita 12. hurler syndrome 13. chediak-higashi syndrome 14. acquired (immune; non-inherited, non-congenital) severe aplastic anemia 15. sickle cell disease (scd) (hgb ss or s-beta 0 thalassemia) will be eligible between ages 3 and 9.99 and with severe disease. 16. other inherited or congenital marrow failure syndromes complicated by severe aplastic anemia 17. other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy. 18. congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years). 19. 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.

Keywords: non malignant conditions blood and marrow transplant