Abatacept for GVHD Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease

Outcomes of hematopoietic stem cell transplantation (HSCT) for children and adolescents with
sickle cell disease (SCD) have improved. Graft versus host disease (GVHD), however, remains a
barrier to success. GVHD accounts for most of the transplant related mortality and much of
the morbidity in this setting-in part through the injury it directly causes and in part
through the deleterious effects of steroids and the other immunosuppressive agents used to
prevent and treat it. The results of pre-clinical studies and a phase I clinical study in
patients with hematologic malignancies suggest that the costimulation blocking agent CTLA4-Ig
may hold promise an agent for GVHD prophylaxis. In the present trial, the investigators are
assessing the tolerability of adding abatacept to standard GVHD prophylaxis-a calcineurin
inhibitor and methotrexate-in pediatric SCD patients receiving early alemtuzumab (completed
by day -18) followed by fludarabine, thiotepa, and melphalan for conditioning. This trial
will provide the foundation for subsequent trials designed to test the long-term hypothesis
that abatacept is a safe, steroid-sparing effective adjunct to standard GVHD prophylaxis in
this setting.

Inclusion Criteria:

1. Patients with hemoglobin (Hgb) SS or SB0 thalassemia between the ages of 3 and 20.99
years who are at least 10 kg getting an human leukocyte antigen (HLA) matched bone
marrow transplant, will be eligible if they are at increased risk for graft versus
host disease (GVHD) and have severe SCD.

(a) Patients falling into one of the following three groups will be considered to be
at increased risk for GVHD:

(i) Are between 10 and 20.99 years and receiving their transplant from an HLA matched
related donor.

(ii) Are between 3 and 9.99 years and receiving their transplant from an HLA matched
related donor who is at least 10 years.

(iii) Are between 3 and 20.99 years and receiving their transplant from an HLA matched
unrelated donor. Donors must be matched at the A, B, C and DRB1 loci at the allele
level.

(b) Patients who meet one of the following criteria will qualify as having severe SCD:

(i) Previous clinical stroke, as evidenced by a neurological deficit lasting longer
than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury
and cerebral vasculopathy.

(ii) Asymptomatic cerebrovascular disease, as evidenced by one the following:

- Progressive silent cerebral infarction, as evidenced by serial MRI scans that
demonstrate the development of a succession of lesions (at least two temporally
discreet lesions, each measuring at least 3 mm in greatest dimension on the most
recent scan) or the enlargement of a single lesion, initially measuring at least
3 mm). Lesions must be visible on T2-weighted MRI sequences.

- Cerebral arteriopathy, as evidenced by abnormal transcranial doppler (TCD)
testing (confirmed elevated velocities in any single vessel of time-averaged
maximum mean velocities (TAMMV) > 200 cm/sec for non-imaging TCD) or by
significant vasculopathy on magnetic resonance angiogram (MRA) (greater than 50%
stenosis of > 2 arterial segments or complete occlusion of any single arterial
segment).

(iii) Frequent ( ≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes
(defined as episode lasting ≥ 4 hours and requiring hospitalization or outpatient
treatment with parenteral opioids). If patient is on hydroxurea and its use has been
associated with a decrease in the frequency of episodes, the frequency should be
gauged from the 2 years prior to the start of this drug.

(iv) Recurrent ( ≥ 3 in lifetime) acute chest syndrome events which have necessitated
erythrocyte transfusion therapy.

(v) Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain
episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its
use has been associated with a decrease in the frequency of episodes, the frequency
should be gauged from the 3 years prior to the start of this drug.

2. All patients and/or their parents or legal guardians must sign a written informed
consent. Assent, when appropriate, will be obtained according to institutional
guidelines.

3. Must have been evaluated and adequately counseled regarding treatment options for
severe SCD by a pediatric hematologist.

4. Because of the elective and non-urgent nature of hematopoietic stem cell
transplantation (HSCT) for SCD, it is important that all patients and families be
counseled regarding fertility preservation measures available to them. All patients
and/or their parents or legal guardians must indicate on the consent and assent forms
that they have received this counseling.

Exclusion Criteria:

1. Bridging (portal to portal) fibrosis or cirrhosis of the liver.

2. Parenchymal lung disease stemming from SCD or other process defined as a diffusing
capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin) or forced
vital capacity of less than 45% of predicted. Children unable to perform pulmonary
function testing will be excluded if they require daytime oxygen supplementation.

3. Renal dysfunction with an estimated glomerular filtration rate (GFR) < 50% of
predicted normal for age.

4. Cardiac dysfunction with shortening fraction < 25%.

5. Neurologic impairment other than hemiplegia, defined as full-scale IQ ≤70,
quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in
decline of Lansky performance score to < 70%.

6. Clinical stroke within 6 months of anticipated transplant.

7. Karnofsky or Lansky functional performance score < 70%.

8. Patient is human immunodeficiency virus (HIV) infected.

9. Donor is HIV infected.

10. Donor has Hgb SS, SC or SB0 thalassemia.

11. Patient with unspecified chronic toxicity serious enough to detrimentally affect the
patient's capacity to tolerate bone marrow transplantation.

12. Patient or patient's guardian(s) unable to understand the nature and risks inherent in
the bone marrow transplant (BMT) process.

13. History of lack of compliance with medical care that would jeopardize transplant
course.

14. Donor who for psychological, physiologic, or medical reasons is unable to tolerate a
bone marrow harvest or receive general anesthesia.

15. Active viral, bacterial, fungal or protozoal infection.

16. Donor is pregnant.

17. Patient is pregnant.