A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies
Condition: Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Biphenotypic Leukemia; Pre-leukemic Syndromes; Monosomy 7; Bone Marrow Clonal Malformations; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndromes; Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematologic Neoplasms; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome; Monosomy
Study type: Interventional
Phase: Phase 2

Summary: 
      There is no curative therapy once acute leukemia patients relapse after transplant. Patients
      who develop clinically significant graft versus host disease (GVHD) have a lower rate of
      relapse than those who do not develop GVHD. We are initiating this study of post-transplant
      fast withdrawal of immunosuppression and donor lymphocyte infusions, with a goal of achieving
      full donor chimerism in children with hematologic malignancies. If our hypothesis that full
      donor chimerism results in leukemia-free survival is correct, using immune modulation to
      achieve full donor chimerism should decrease relapse rate and thus increase survival. The
      goal of this Phase II study is to identify if achieving full donor chimerism in whole blood
      CD3+ and leukemia-specific (CD14/15+, CD19+, CD33+ and CD34+) subset may decrease the risk of
      relapse of patients undergoing allogeneic transplant for hematologic malignancy.
    

Detailed description: 
      The goal of this Phase II study is to identify if achieving full donor chimerism in whole
      blood, CD3+, and leukemia-specific subset (CD3+, CD14/15+, CD19+, CD33+ and CD34+ subset) may
      decrease the risk of relapse of patients undergoing allogeneic transplant for hematologic
      malignancy.

      We estimate that total of 50 recipient patients will need to be enrolled. Of these 50
      recipient patients an observation group and an intervention group will be formed. We want to
      enroll 25 recipient patients in the intervention group, this group will receive study
      intervention and their outcomes will be the focus of statistical analysis for this study.
      Intervention will involve fast withdrawal of immunosuppression following transplant and donor
      lymphocyte infusion (DLI) until full donor chimerism is achieved. Chimerism is a genetic test
      that measures the proportion of donor's and recipient's cells in blood or bone marrow. Twenty
      five patients will undergo fast withdrawal of immunosuppression and 33 -50% of them (8-13)
      will undergo DLI following fast withdrawal of immunosuppression.

      Patients will have peripheral blood (PB) chimerism tested upon engraftment. A confirmatory
      test from PB and bone marrow (BM) will be done on day 45±7. Minimal residual disease (MRD)
      will be examined by immunoflow, FISH, cytogenetics or PCR. Patients with positive MRD will be
      on a faster schedule of immune intervention than patients with negative MRD. Interventions
      will be carried on until 1 year post transplant. If confirmatory testing shows no evidence of
      MRD and full donor chimerism is present in all subsets, the patient will be part of the
      "observation" group and be observed until 2 years post transplant. Chimerism will be repeated
      at 12 and 24 months post transplant. If the patient has mixed chimerism on both confirmatory
      tests (PB and BM), the patient will be part of the "intervention" group and fast withdrawal
      of immunosuppression will be initiated. If the patient has mixed chimerism on one of the
      confirmatory tests (PB or BM), the test will be repeated in 2 weeks and the patient will
      proceed with either observation or intervention, based on the result of the repeated test.
      Patients will be followed for the incidence of acute and chronic Graft Versus Host Disease
      (GVHD) and relapse until 2 years post transplant. The study will be considered successful if
      the relapse rate at 2 years post transplant is ≤20% for the entire study or ≤ 40% for the
      intervention group.
    

Intervention name(s): Withdrawal of immunosuppression and donor lymphocyte infusion
Intervention type(s): Other
Intervention description(s): Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hematologic; Malignancy; Leukemia; Pre-leukemic; Allogeneic; Transplant; Pediatric