Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of radiation delivered via 131I-BC8 antibody
(iodine I 131 monoclonal antibody BC8) when combined with the non-myeloablative regimen of
fludarabine (fludarabine phosphate), 2 Gy total-body irradiation (TBI) + cyclosporine
(CSP)/mycophenolate (MMF) in elderly patients with advanced acute myeloid leukemia (AML) or
high risk myelodysplastic syndromes (MDS).

II. To determine the rates of donor chimerism resulting from this combined preparative
regimen, and to correlate level of donor chimerism with estimated radiation doses delivered
to hematopoietic tissues via antibody.

III. To determine, within the limits of a phase I study, disease response and duration of
remission.

IV. To assess dose-limiting toxicity (DLT) at the estimated maximum tolerated dose (MTD) of
131I-BC8 (24 Gy) in order to gain more confidence that the DLT rate is acceptable at this
level.

OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.

CONDITIONING REGIMEN: Patients receive iodine I 131 monoclonal antibody BC8 intravenously
(IV) on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo total-body
irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on
day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV twice daily (BID) on days
-3 to 56 with taper to day 80 (for patients with a related donor) OR days -3 to 100 with
taper to day 177 (for patients with an unrelated donor) in the absence of graft-versus-host
disease (GVHD). Patients also receive mycophenolate mofetil PO or IV thrice daily (TID) on
days 0 to 27 (for patients with a related donor) OR on days 0 to 40 with taper to day 96 (for
patients with an unrelated donor) in the absence of GVHD.

After completion of study treatment, patients are followed up at 6, 9, and 12 months, every 6
months for 1 year, and then yearly thereafter.

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 [Note: classification removed under
current World Health Organization [WHO] classification system]), refractory cytopenia
with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or
chronic myelomonocytic leukemia (CMML)

- Patients in relapse must have documented cluster of differentiation (CD)45 expression
by their myelodysplastic or leukemic cells to be studied and treated with 131I-labeled
BC8 antibody; patients in remission do not require phenotyping and may have leukemia
previously documented to be CD45 negative

- Patients should have a circulating blast count of less than 10,000/mm^3 (control with
hydroxyurea or similar agent is allowed)

- Patients must undergo a 24-hour urine collection with documented creatinine clearance
> 50 ml/min

- 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 a human leukocyte antigen (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) 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 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; PBSC is the
only permitted hematopoietic stem cell (HSC) source

- DONOR: Donors must meet HLA matching criteria as outlined above as well as standard
Seattle Cancer Care Alliance (SCCA) and/or NMDP 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 marrow or PBSC transplantation