Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor Hematopoietic Stem Cell Transplant

Acute Graft versus Host Disease (aGvHD) is the most deadly complication facing children who
have allogeneic hematopoietic stem cell transplant (HSCT). aGvHD occurs, in large part,
because the T cells in the bone marrow graft do not "accept" the presence of the transplant
recipient's cells, and mount a severe, debilitating, and often deadly attack against the
recipient, striking the skin, the liver, and the gastrointestinal track, most prominently.
For patients receiving bone marrow from an unrelated donor, the rate of aGvHD can reach as
high as 80%, with up to half of patients dying from this complication. These serious outcomes
occur despite our best efforts at aGvHD prevention. Given the lack of success in preventing
aGvHD with current therapies, novel therapies to prevent this disease are desperately needed.

In this study, we plan to test a novel drug to prevent aGvHD. This drug, known as abatacept,
specifically blocks the activation pathway critical to T cell function known as "T cell
costimulation." In particular, it blocks the CD28-mediated costimulation pathway that is
critical for optimal T cell activation and proliferation. My research group has done
extensive pre-clinical work with this compound. Our work has demonstrated its efficacy in
inducing immune tolerance after transplantation in both mouse models and primate models. In
addition, patient trials have demonstrated that blocking CD28-directed T cell costimulation
can prevent T cell-mediated diseases, including rheumatoid arthritis and psoriasis, and can
improve solid organ transplant acceptance. Abatacept is currently FDA approved for use in
rheumatoid arthritis. Given this drug's safety and efficacy profile, we have been granted an
IND-exemption from the FDA for the inclusion of abatacept in a GvHD-prevention strategy.

This is a safety and tolerability study of the addition of abatacept to a GvHD-prophylaxis
regimen. Thus, the primary objective of the study is to determine the safety and tolerability
of the addition of abatacept to aGvHD prophylaxis in transplants for malignant hematologic
disease using unrelated donor bone marrow or peripheral blood stem cell grafts.

Three secondary objectives will also be addressed:

1. We will estimate the incidence and severity of aGvHD in patients receiving the
abatacept-based protocol.

2. We will determine the immune phenotype of donor cells in patients receiving abatacept.

3. We will determine the ability of donor T-cells in patients receiving abatacept to
respond to both polyclonal and recipient-specific immune stimulation.

These secondary objectives will allow us to determine the impact of abatacept-containing GvHD
prevention on both T cell alloreactivity and on T cell-mediated protective immunity.

This study is for patients older than 12 who have been diagnosed with high-risk leukemia and
for whom an unrelated bone marrow transplant is planned. We plan to enroll 10 patients on the
study, over a 1-year period from the opening of the trial. Of these ten patients, at least
five will be pediatric patients; the other five may be from adult patients taken care of by
Winship Cancer Center physicians. All clinical study coordination and biologic studies will
be performed by CHOA personnel.

Participants will receive one of two standard myeloablative conditioning regimens for their
stem cell transplant, and will receive an aGvHD prophylaxis regimen including cyclosporine,
methotrexate, and abatacept. They will have immunologic analysis for 1 year after transplant
and clinical analysis for 3 years after transplant.

Inclusion Criteria:

1. Patients with AML, with or without a history of myelodysplastic syndrome in one of the
following categories.

(a) Patients in first complete remission with high-risk features

2. Patients with ALL, in either of the following categories:

1. In 2nd or greater complete remission (complete remission is defined as > 5%
blasts in marrow)

2. Delayed 1st CR-Failure to achieve complete remission after a single round of
induction therapy

3. Patients with undifferentiated or biphenotypic leukemia in 1st or greater complete
remission.

4. Patients with Myelodysplastic Syndrome(s) with an IPSS score of >1.5 and <10% blasts
in the bone marrow at the time of transplant. These conditions will include:

1. Refractory anemia

2. Refractory anemia with ringed sideroblasts

3. Refractory cytopenia with multilineage dysplasia

4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts

5. Refractory anemia with excess blasts-1 (5-10% blasts)

6. Refractory anemia with excess blasts-2 (10-20% blasts)

7. Myelodysplastic syndrome, unclassified

8. MDS associated with isolated del (5q)

9. Patients diagnosed with AML in CR1 after an initial diagnosis of MDS.

5. Age 12 years or older.

6. No prior allogeneic transplant

7. Karnofsky performance score or Lansky Play-Performance of at least 80.

8. Signed informed consent for adults and for minors the provision of pediatric assent
and parental permission.

Exclusion Criteria:

1. Age <12 years old.

2. Patients requiring >2 courses of induction chemotherapy to achieve remission status.

3. HIV infection

4. Tuberculosis Infection

5. Chronic Obstructive Pulmonary Disease

6. Pregnancy (positive serum b-HCG) or breastfeeding

7. Creatinine clearance or nuclear medicine GFR of < 50 mL/min

8. Cardiac ejection fraction < 50%

9. bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved
veno-occlusive disease.

10. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected for
hemoglobin) or O2 saturation <92% on room air.

11. Karnofsky performance score or Lansky Play-Performance Scale <80

12. Uncontrolled viral, bacterial, or fungal infection at the time of study enrollment

13. Availability of a willing and fully MHC-matched related donor.

14. Positive cytotoxic recipient-donor cross-match or positive HLA antibody screen against
donor-disparate antigens.

15. Any active infection.

16. Unable to obtain informed consent.