Abatacept as GVHD Prophylaxis Phase 2
Condition: Graft vs Host Disease; Malignancy
MeSH terms: Graft vs Host Disease
Intervention: Abatacept; placebo
Intervention description: Arm B-investigational prophylaxis with abatacept, a calcineurin inhibitor and methotrexate
Intervention MeSH terms: Abatacept
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 186.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No

Summary:

      This is a phase II multi-center, randomized, double blind, placebo-controlled trial.

      The investigators are doing this study to see if a new drug, abatacept, can be used together
      with a calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate to provide better
      protection against Acute Graft versus Host Disease (aGvHD) without causing more infections.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Must be at least 6 years old and weigh 20 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. The use of mismatched donors in which
             disparity is only in the host versus graft direction (because of recipient
             homozygosity) is discouraged because of the potentially heightened risk for graft
             rejection. 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 high risk hematologic malignancy as defined below:

               1. Acute myeloid leukemia (AML).

               2. Myelodysplastic syndrome

             (i) Adult patients (≥21 years) must meet criteria for intermediate, high or very
             high-risk disease based on the World Health Organization classification based
             prognostic scoring system.

        Intermediate risk (2 points), high risk (3-4 points), very high risk (4-5 points)

          -  RA = refractory anemia, RARS = refractory anemia with ringed sideroblasts, RCMD =
             refractory cytopenia with multilineage dysplasia, RCMD-RS = refractory cytopenia with
             multilineage dysplasia and ringed sideroblasts, RAEB-1 = refractory anemia with excess
             of blasts-1 (5-9% blasts), RAEB-2 = refractory anemia with excess of blasts-2 (10-19%
             blasts).

          -  *Karyotype: Good = normal, -Y, del(5q), del(20q), Poor = complex (≥ 3 abnormalities),
             chromosome 7 anomalies, Intermediate = other abnormalities.

               -  *RBC transfusion requirement = having ≥ 1 RBC transfusion every 8 weeks over a
                  4-month period.

        (ii) Pediatric patients with MDS, regardless of subtype, will be eligible.

        (c) Acute lymphoblastic leukemia (ALL). (i) Given the poor prognosis of adults (≥21 years)
        with ALL, adults in 1st or greater complete remission will be eligible.. CR is defined as
        an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute
        neutrophil count ≥ 1.0 x 109/L. Complete remissions without platelet recovery (CRp) will be
        considered remissions (ii) Given the generally good prognosis of children (<21 years) with
        ALL, they will have to meet one of the criteria listed below. Additionally, children who
        are enrolled on a COG ALL trial for newly diagnosed or relapsed disease will have to meet
        the criteria for BMT outlined in that trial. CR is defined as an M1 marrow (<5% blasts), no
        evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L.
        Complete remissions without platelet recovery (CRp) will be considered remissions.

          1. In 1st complete remission with a very high risk for relapse.

               1. Haplodiploidy (<44 chromosomes)

               2. >1% residual marrow blasts by flow cytometry at the end of induction.

               3. >0.01% residual marrow blasts by flow cytometry at the end of consolidation.

               4. Early T-Cell Precursor (ETP) phenotype

          2. In 2nd complete remission with B-lineage disease after a marrow relapse occurring less
             than 36 months from diagnosis.

          3. In 2nd complete remission with T-lineage disease or Ph+ disease after a marrow relapse
             occurring at any time.

          4. In a 2nd complete remission with T-lineage disease after an extra-medullary relapse
             occurring less than 18 months from diagnosis.

          5. In 3rd or greater complete remission after a marrow or extramedullary relapse

             (d) Patients with acute undifferentiated, biphenotypic, or bilineal leukemia, which is
             in 1st or greater complete remission (CR) or partial remission (PR). Cr will be
             defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an
             absolute neutrophil count ≥ 1.0 x 109/L. CR without platelet recovery (CRp) will be
             considered complete remissions.) PR will be defined as an M2 marrow (5-19% blasts), no
             evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L.).

             (e) Chronic myelogenous leukemia (CML). (i) Chronic phase with resistance to tyrosine
             kinase inhibitors. (ii) accelerated phase (development of cytogenetic abnormality in
             addition to t(9:22), blood blast percentage ≥10, blood basophil percentage ≥20,
             platelet count <100,000 X 109/L) (iii) blast crisis. (iv) 2nd or greater chronic
             phase.

             (f) Acute Lymphoblastic Lymphoma in 2nd or greater complete remission. Complete
             remission includes confirmed complete response (CR) defined as the disappearance of
             all evidence of disease from all sites for at least 4 weeks. Bone marrow and CSF must
             be normal and any macroscopic nodules in any organs detectable on imaging techniques
             should no longer be present. Imaging should include PET scanning. CR will also include
             unconfirmed complete responses defined as a residual lymph node mass > 1.5 cm in
             greatest transverse diameter that has regressed by > 75% in sum of the products of the
             greatest perpendicular diameters (SPD), or any residual lesions in organs that have
             decreased by > 75%, with a negative PET scan, negative bone marrow and CSF.

             (g) Peripheral T cell lymphoma (PTCL).

             (h) Chronic lymphocytic leukemia (CLL) (i) Newly diagnosed disease with 17p- (ii)
             Disease beyond first CR that has been treated with a fludarabine containing regimen.

             (i) Chronic myelomonocytic leukemia.

             (j) Atypical (BCR-ABL negative) chronic myelogenous leukemia

             (k) Hodgkin lymphoma that has recurred or progressed after an autologous BMT. Disease
             must be chemosensitive; salvage chemotherapy must produce at least a partial response.

             (l) Non-Hodgkin lymphomas that has recurred or progressed after an autologous BMT.

        Exclusion Criteria:

          1. Prior allogeneic HSCT.

          2. The patient is enrolled on a COG trial that uses criteria for unrelated donor HSCT,
             which conflict with our eligibility criteria.

          3. The patient is enrolled on a COG trial that utilizes unrelated donor HSCT and requires
             that patients be transplanted using an approach specified by the protocol that is in
             conflict with the approach specified in this protocol.

          4. Availability of a willing and suitable HLA identical related donor.

          5. Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study
             enrollment.

          6. HIV infection.

          7. Serious psychiatric disease including schizophrenia, bipolar disorder and severe
             depression.

          8. 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.

               3. 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 will not be excluded.

          9. Known inherited or constitutional predisposition to cancer including, but not limited
             to Li-Fraumeni syndrome, Down syndrome and BRCA1 and BRCA2 mutations.

         10. Incompletely treated active tuberculosis Infection.

         11. Pregnancy (positive serum b-HCG) or breastfeeding.

         12. Estimated GFR of < 50 mL/min/1.73m2.

         13. Cardiac ejection fraction < 50.

         14. bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved
             veno-occlusive disease.

         15. 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.

         16. Karnofsky performance score or Lansky Play-Performance Scale score <80

         17. Presence of antibodies to a mismatched donor HLA antigen