Hematopoietic Bone Marrow Transplantation for Patients With High-risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using Related HLA-Mismatched Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined With Immunosuppression Before and After Transplantation
Hematopoietic Bone Marrow Transplantation for Patients With High-risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using Related HLA-Mismatched Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined With Immunosuppression Before and After Transplantation
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.
PRIMARY OBJECTIVES:
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.
Inclusion Criteria:
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):
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 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
Exclusion Criteria: