This phase I trial studies the side effects and best dose of iodine I 131monoclonal antibody
BC8 when given together with fludarabine phosphate, cyclophosphamide, total-body
irradiation, and donor bone marrow transplant, and to see how well they work in treating
patients with acute myeloid leukemia or acute lymphoblastic leukemia that has spread to
nearby or other places in the body (advanced), or high-risk myelodysplastic syndrome. Giving
chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, and total-body
irradiation before a donor bone marrow 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 cyclophosphamide together with mycophenolate mofetil and
tacrolimus after the transplant may stop this from happening. Giving a radiolabeled
monoclonal antibody together with donor stem cell transplant, fludarabine phosphate,
cyclophosphamide, mycophenolate mofetil, and tacrolimus may be an effective treatment for
advanced acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes.
I. To estimate the maximum tolerated dose of radiation delivered via 131 I-BC8 antibody
(iodine I 131 monoclonal antibody BC8) when combined with pre- and post-transplant
cyclophosphamide (CY), fludarabine phosphate (FLU), 2 Gy total-body irradiation (TBI),
tacrolimus, mycophenolate mofetil (MMF), and a haploidentical allogeneic hematopoietic
marrow transplant in patients who have advanced acute myeloid leukemia (AML), acute
lymphoblastic leukemia (ALL), or high risk myelodysplastic syndromes (MDS).
II. To estimate rates of immune reconstitution, engraftment, and donor chimerism resulting
from this combined preparative regimen.
III. To determine rates of disease relapse, acute graft-versus-host disease (GVHD), and day
100 disease-free survival in patients receiving 131 I-BC8 antibody (Ab) combined with CY,
FLU, 2 Gy TBI, tacrolimus, MMF, and human leukocyte antigen (HLA)-haploidentical allogeneic
hematopoietic cell transplant (HCT).
OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via
central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU intravenously (IV) over 30 minutes on
days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF
IV or orally (PO) thrice daily (TID) on days 4 to 35, and tacrolimus IV over 1-2 hours or PO
on days 4 to 180 with taper on day 84.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24
months, and then annually thereafter.
- Patients with advanced AML or ALL 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 cytopenia with multilineage dysplasia (RCMD), RCMD with ringed
sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
- Patients not in remission must have cluster of differentiation (CD)45-expressing
leukemic blasts; 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 a creatinine clearance greater than 50/ml per minute by the
following formula (test must be performed within 28 days prior to registration):
- Creatinine clearance (CrCl) = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0
(male)/72 x serum Cr
- 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
- Patients must have a related donor who is identical for one human leukocyte antigen
(HLA) haplotype and mismatched at the HLA-A, -B or class II, DR beta 1 (DRB1) loci of
the unshared haplotype with the exception of single HLA-A, -B or DRB1 mismatches
- DONOR: Related donor who is identical for one HLA haplotype and mismatched at the
HLA-A, -B, or DRB1 loci of the unshared haplotype with the exception of single HLA-A,
-B, or DRB1 mismatches
- Circulating antibody against mouse immunoglobulin (HAMA)
- Prior radiation to maximally tolerated levels to any critical normal organ
- Cross-match positive with donor
- Patients may not have symptomatic coronary artery disease and may not be on cardiac
medications for anti-arrhythmic or inotropic effects
- Left ventricular ejection fraction < 35%
- Corrected diffusion capacity of carbon monoxide (DLCO) < 35% and/or receiving
supplemental continuous oxygen
- Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of
portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy,
uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the
prothrombin time, ascites related to portal hypertension, bacterial or fungal liver
abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
- Patients who are known seropositive for human immunodeficiency virus (HIV)
- Perceived inability to tolerate diagnostic or therapeutic procedures, particularly
treatment in radiation isolation
- Central nervous system (CNS) involvement with disease refractory to intrathecal
chemotherapy and/or standard cranial-spinal radiotherapy
- Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin
positive [b-HCG+]) or breast feeding
- Fertile men and women unwilling to use contraceptives during and for 12 months
- Inability to understand or give an informed consent