BMT 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=20). 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:

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.