Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

• Incidence of dose-limiting toxicities (DLT) (Grade III/IV Bearman) to determine MTD of radiation delivered to normal organ by pretargeted 90Y-DOTA-biotin [ Time Frame: Within 100 days post-transplant ] [ Designated as safety issue: Yes ]
  Conducted by the "two-stage" approach introduced by Storer. The MTD will be defined as the dose of 90Y-DOTA-biotin used in combination with the non-myeloablative HCT conditioning regimen that is associated with a Grade III/IV regimen related toxicity (RRT) or true DLT rate of 25%.
  
  

• Rates of engraftment, chimerism, and non-relapse mortality [ Time Frame: Days 28 ] [ Designated as safety issue: Yes ]
  Chimerism testing methods will be in accordance with Standard Practice Guidelines, with timing consistent with other non-myeloablative transplant protocols. Mixed or full donor chimerism will be evidence of donor engraftment. Full Chimerism is defined as > 95% donor CD3+ T cells and mixed chimerism is the detection of peripheral blood donor T cells (CD3+) and granulocytes (CD33+) as a proportion of the total peripheral blood T cell and granulocyte population, respectively. The true rate of graft rejection exceeds must be less than 20%.
  
  
• Rates of engraftment, chimerism, and non-relapse mortality [ Time Frame: Day 84 ] [ Designated as safety issue: Yes ]
  Chimerism testing methods will be in accordance with Standard Practice Guidelines, with timing consistent with other non-myeloablative transplant protocols. Mixed or full donor chimerism will be evidence of donor engraftment. Full Chimerism is defined as > 95% donor CD3+ T cells and mixed chimerism is the detection of peripheral blood donor T cells (CD3+) and granulocytes (CD33+) as a proportion of the total peripheral blood T cell and granulocyte population, respectively. The true rate of graft rejection exceeds must be less than 20%.
  
  
• Rate of grades III-IV acute GVHD [ Time Frame: At day +100 ] [ Designated as safety issue: No ]
  Graded according to the established criteria at the FHCRC.
  
  
• Achievement and duration of response [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  Complete remission is defined as complete resolution of all signs of myelodysplasia or leukemia for at least four weeks with normal bone marrow with blasts < 5% with normal cellularity, normal megakaryopoiesis, more than 15% erythropoiesis, and more than 25% granulocytopoiesis; normalization of blood counts; and no extramedullary disease. Partial remission is defined as improvement of hematological parameters in the peripheral blood and 50% decline in marrow blasts from pre-transplant level with > 10% erythropoiesis and 25% granulocytopoiesis.
  
  

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via PRIT using BC8-SA (BC8 antibody-streptavidin conjugate) when combined with fludarabine (FLU), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and allogeneic hematopoietic cell transplant (HCT) in patients who have advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplastic syndromes (MDS).

SECONDARY OBJECTIVES:

I. To estimate rates of immune reconstitution, engraftment, and donor chimerism resulting from this combined preparative regimen.

II. To estimate rates of disease relapse, acute graft-versus-host disease (GvHD), and day-100 disease-free survival in patients receiving PRIT using BC8-SA combined with FLU, 2 Gy TBI, CSP, MMF, and allogeneic HCT.

III. To assess biodistribution, serum half-life, urinary excretion, tissue localization, and clearance of BC8-SA conjugate and DOTA-biotin.

IV. To assess the feasibility of yttrium y 90 (90Y)-DOTA-biotin to bind to BC8-SA conjugate localized to hematolymphoid tissues.

OUTLINE:

Patients undergo pretargeted radioimmunotherapy comprising a test dose of BC8-SA conjugate intravenously (IV) on day -22 and indium In 111(111In)-DOTA-biotin IV on day -20, followed by a therapy dose of BC8-SA conjugate IV on day -14 and 90Y-DOTA-biotin IV on day -12. Patients receive fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and then peripheral blood stem cell transplantation on day 0. Patients with matched related donors receive cyclosporine IV on days -3 to 56 and taper to day 180 and mycophenolate mofetil orally (PO) twice daily (BID) on days 0-27. Patients with matched unrelated donors receive cyclosporine IV on days -3 to 100 and taper to day 180 and mycophenolate mofetil PO thrice daily (TID) on days 0- 40 and taper to day 96.

After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months, and then periodically thereafter.