A RANDOMIZED DOUBLE-BLIND TRIAL OF ABATACEPT EXTENDED DOSING VERSUS ABATACEPT SHORT-TERM DOSING FOR GRAFT VERSUS HOST DISEASE PROPHYLAXIS: ABA3

This is a multicenter randomized, double blind, Phase 2 trial for patients receiving
transplants from 7 of 8 HLA matched donors, in which an extended dosing regimen of abatacept,
and a short-term dosing regimen + placebo, when added to standard calcineurin inhibitor +
methotrexate-based prophylaxis, will be compared for their ability to improve outcomes in
patients with a minimum follow-up of one year post-transplant. All patients will receive 4
doses of abatacept (Days -1, +5, +14, +28). Prior to the fifth dose, patients will be
randomly assigned to the 4-dose abatacept arm and receive 4 doses of placebo or 8-dose
abatacept arm and receive 4 more doses of abatacept. The primary endpoint of the study will
be severe AGVHD-free, severe CGVHD-free, relapse-free survival (SGRFS). The study will end
when the last patient has reached 2 years after transplant. Results will first be calculated
and the study unblinded when the last patient has reached one year post-transplant.

Inclusion Criteria:

1. Must be at least 2 years old and weigh 10 kg.

2. Must have a willing unrelated adult donor (bone marrow or peripheral blood). Donors
may have a single mismatch (i.e. be a 7/8) and this mismatch may be at the allele or
antigen level; however, donors with allele level disparity should be given preference
over those with antigen level disparity. Patients for whom a donor is available with
disparity only in the host versus graft direction (because of recipient homozygosity),
will not be eligible, since this mismatching does not increase the risk for GVHD.
Centers may perform extended typing (e.g. DQB1 and DPB1) according to institutional
practices and use these results in selecting donors; however, it is recommended that
this extending typing be used only to select between donors who are equally well
matched with the recipient at the A, B, C and DRB1.

3. 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.

4. Must have a hematologic malignancy treatable by HCT (except for those stipulated below
under study Exclusion Criteria), which is in remission by standard testing (no
patients in relapse will be included).

5. Patients with an inherited predisposition to leukemia or otherwise hematologic
malignancies that have not been associated with predisposition to transplant
morbidities or non-hematologic cancers.

6. Karnofsky performance score or Lanskey Play-Performance Scale score >/= 80.

- If the patient does not meet defined eligibility requirements, the PI/study
committee must be contacted to determine eligibility.

Exclusion Criteria:

1. Patients with the following hematologic malignancies will be excluded: Chronic
Lymphocytic Leukemia, Myeloma and Primary Myelofibrosis.

2. Active Relapse (>5% blasts) of their primary malignancy.

3. For patients with Acute Lymphocytic Leukemia (ALL) with pre-transplant MRD testing
performed as standard practice at the treating institution, patients with MRD >0.01%
will be ineligible.

4. For patients with Acute Myeloid Leukemia (AML) with pre-transplant MRD testing as
standard of practice at the treating institution, patients with any MRD status are
eligible and should be enrolled at the discretion of provider.

5. For patients with MDS, those with >5% blasts will be excluded.

6. Prior allogeneic HCT.

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

8. HIV infection.

9. Serious psychiatric disease including schizophrenia, bipolar disorder and severe
depression.

10. Prisoners or others who are compulsorily detained.

11. Any patient with a known or suspected inherited predisposition to cancer should be
discussed with the study team prior to screening for eligibility.

1. Patients with a known inherited or constitutional predisposition to transplant
morbidities, including, but not limited to Fanconi Anemia, Dyskeratosis
Congenita, Shwachman-Diamond Syndrome and Down Syndrome will be excluded.

2. Patients with known inherited or constitutional predisposition to non-hematologic
cancers including, but not limited to Li-Fraumeni syndrome, BRCA1 and BRCA2
mutations will be excluded.

12. Patients with active non-hematological malignancies (except non-melanoma skin cancers)
or those with non-hematological malignancies (except non-melanoma skin cancers) who
have been rendered with no evidence of disease, and are disease free for <2 years.

13. Incompletely treated active tuberculosis Infection.

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

15. Estimated GFR of < 50 mL/min/1.73m2.

16. Cardiac ejection fraction < 50 (using M-Mode if assessment is done by ECHO)

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

18. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected for
hemoglobin) or requiring supplemental oxygen. Children who are developmentally unable
to perform pulmonary function testing will be assessed solely on their need for
supplemental oxygen.

19. Presence of antibodies to a mismatched donor HLA antigen (please refer to Section
3.4.g).

20. Patients who have developed severe AGVHD, severe CGVHD or relapse will be excluded at
the time of randomization.

21. Exclusion Criteria Prior to Randomization (prior to 5th dose of abatacept/placebo):

1. Severe allergic reaction during the first 4 doses of abatacept

2. If any clinical events occur that preclude further dosing of abatacept, those
patients will be deemed ineligible for randomization