Extended vs Short-term Abatacept Dosing for Graft Versus Host Disease Prophylaxis

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). Donorsmay have a single mismatch (i.e. be a 7/8) and this mismatch may be at the allele orantigen level; however, donors with allele level disparity should be givenpreference over those with antigen level disparity. Patients for whom a donor isavailable with disparity only in the host versus graft direction (because ofrecipient homozygosity), will not be eligible, since this mismatching does notincrease 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 betweendonors 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 informedconsent. Assent, when appropriate, will be obtained according to institutionalguidelines.

4. Must have a hematologic malignancy treatable by HCT (except for those stipulatedbelow under study Exclusion Criteria), which is in remission by standard testing (nopatients in relapse will be included).

5. Patients with an inherited predisposition to leukemia or otherwise hematologicmalignancies that have not been associated with predisposition to transplantmorbidities 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/studycommittee must be contacted to determine eligibility.

Exclusion Criteria:

1. Patients with the following hematologic malignancies will be excluded: ChronicLymphocytic 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 testingperformed 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 asstandard of practice at the treating institution, patients with any MRD status areeligible 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 studyenrollment.

8. HIV infection.

9. Serious psychiatric disease including schizophrenia, bipolar disorder and severedepression.

10. Prisoners or others who are compulsorily detained.

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

12. Patients with a known inherited or constitutional predisposition to transplantmorbidities, including, but not limited to Fanconi Anemia, DyskeratosisCongenita, Shwachman-Diamond Syndrome and Down Syndrome will be excluded.

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

14. Patients with active non-hematological malignancies (except non-melanoma skincancers) or those with non-hematological malignancies (except non-melanoma skincancers) who have been rendered with no evidence of disease, and are disease freefor <2 years.

15. Incompletely treated active tuberculosis Infection.

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

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

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

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

20. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected forhemoglobin) or requiring supplemental oxygen. Children who are developmentallyunable to perform pulmonary function testing will be assessed solely on their needfor supplemental oxygen.

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

22. Patients who have developed severe AGVHD, severe CGVHD or relapse will be excludedat the time of randomization.

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

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

25. If any clinical events occur that preclude further dosing of abatacept, thosepatients will be deemed ineligible for randomization