Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
Condition: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Neoplasm Metastasis; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Anemia; Myelodysplastic Syndromes; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Syndrome; Recurrence
Intervention: iodine I 131 monoclonal antibody BC8; fludarabine phosphate; total-body irradiation; allogeneic hematopoietic stem cell transplantation; peripheral blood stem cell transplantation; cyclosporine; mycophenolate mofetil; laboratory biomarker analysis
Intervention description: Given IV; Given IV; Undergo TBI; Undergo PBSC transplantation; Undergo PBSC transplantation; Given IV or PO; Given PO; Correlative studies
Intervention MeSH terms: Iodine; Cyclosporine; Mycophenolic Acid; Antineoplastic Agents, Immunological; Fludarabine; Fludarabine phosphate; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: This study will assess the feasibility and safety of patients with advanced AML or high-risk MDS treated with Iodine-131 BC8 antibody at a starting dose of 22 Gy delivered to the normal organ receiving the highest dose combined with fludarabine and 2 Gy total body irradiation (TBI), plus cyclosporine (CSP)/mycophenolate mofetil (MMF), followed by matched related or unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Determination of the maximum tolerated dose (MTD) will be the major study endpoint.
Dose-escalation/de-escalation of radiolabeled BC8 antibody (I-131-BC8) is conducted using a "two-stage" approach. Under this plan, dose levels during the first stage are increased (or decreased) for individual patients until a dose-limiting toxicity (DLT) is observed, at which point the second stage proceeds with each dose level administered to a cohort of four patients.
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 16 Years
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      This phase II trial studies the side effects and best dose of iodine I 131 monoclonal
      antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and
      donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating
      patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other
      places in the body and usually cannot be cured or controlled with treatment. Giving
      chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor
      peripheral blood stem cell transplant helps stop the growth of cancer or abnormal cells and
      helps stop the patient's immune system from rejecting the donor's stem cells. Also,
      radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find
      cancer cells and carry cancer-killing substances to them without harming normal cells. When
      the healthy stem cells from a donor are infused into the patient they may help the patient's
      bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the
      transplanted cells from a donor can make an immune response against the body's normal cells.
      Giving fludarabine phosphate and total-body irradiation before the transplant together with
      cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
      Giving a radiolabeled monoclonal antibody together with donor stem cell transplant,
      cyclosporine, and mycophenolate mofetil may be an effective treatment for advanced acute
      myeloid leukemia or myelodysplastic syndromes.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with advanced AML defined as beyond first remission, primary refractory
             disease, or evolved from myelodysplastic or myeloproliferative syndromes; or patients
             with MDS expressed as refractory anemia with excess blasts (RAEB), refractory anemia
             with excess blasts in transformation (RAEBT), refractory cytopenia with multilineage
             dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic
             leukemia (CMML)

          -  Patients not in remission must have CD45-expressing leukemic blasts or myelodysplastic
             cells; patients in remission do not require phenotyping and may have leukemia
             previously documented to be CD45 negative (because in remission patients, virtually
             all antibody binding is to non-malignant cells which make up >= 95% of nucleated cells
             in the marrow)

          -  Patients should have a circulating blast count of less than 10,000/mm^3 (control with
             hydroxyurea or similar agent is allowed)

          -  Patients must have an estimated creatinine clearance greater than 50/ml per minute
             (serum creatinine value must be within 28 days prior to registration)

          -  Bilirubin < 2 times the upper limit of normal

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times the
             upper limit of normal

          -  Karnofsky score >= 70 or Eastern Cooperative Oncology Group (ECOG) =< 2

          -  Patients must have an expected survival of > 60 days and must be free of active
             infection

          -  Patients must have an HLA-identical sibling donor or an HLA-matched unrelated donor
             who meets standard Seattle Cancer Care Alliance (SCCA) and/or National Marrow Donor
             Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC)
             donation; related donors should be matched by molecular methods at the intermediate
             resolution level at HLA-A, B, C, and developmentally regulated RNA binding protein 1
             (DRB1) according to Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice
             Guidelines and to the allele level at DQB1; unrelated donors should be identified
             using matching criteria that follows the FHCRC Standard Practice Guidelines limiting
             the study to eligible donors that are allele matched for HLA-A, B, C, DRB1, and DQB1
             (grade 1), and accepting up to one allele mismatch as per Standard Practice grade 2.1
             for HLA-A, B, or C

          -  DONOR: Donors must meet HLA matching criteria as well as standard SCCA and/or NMDP or
             other donor center criteria for PBSC donation

        Exclusion Criteria:

          -  Circulating antibody against mouse immunoglobulin (human anti-mouse antibody [HAMA])

          -  Prior radiation to maximally tolerated levels to any normal organ

          -  Patients may not have symptomatic coronary artery disease and may not be on cardiac
             medications for anti-arrhythmic or inotropic effects

          -  Inability to understand or give an informed consent

          -  Patients who are seropositive for human immunodeficiency virus (HIV)

          -  Perceived inability to tolerate diagnostic or therapeutic procedures, particularly
             treatment in radiation isolation

          -  Patients who have previously undergone autologous or allogeneic HSCT