A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched Bone Marrow for Patients with Hematologic Malignancies
Primary objective of this protocol: To estimate the incidence of graft rejection and severe graft versus-host disease (GVHD) following myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies. Secondary objectives include: 1) To obtain estimates of overall survival (OS), relapse, non-relapse mortality (NRM), and event-free survival (EFS) in patients receiving myeloablative conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives; 2) To characterize additional hematologic and non-hematologic toxicities of myeloablative haploidentical BMT; 3) To characterize donor hematopoietic chimerism in peripheral blood at days ~30 and ~60 after BMT; 4) To characterize the relationship between KIR mismatch and relapse, OS, progression free survival (PFS), engraftment and GVHD; 5) To characterize the effects of post-transplantation cyclophosphamide on the immune reconstitution of T cells, B cells, and NK cells; 6) To assess the incidence of HLA specific antibodies developed after HLA mismatched, allogeneic partially HLA-mismatched bone marrow transplantation.
1) The patient is NOT eligible for BMT from an HLA- matched, sibling donor or from an HLA-matched, unrelated donor (unrelated donor not identified or length of time to identify a potential unrelated donor is an issue) but has an HLA-mismatched, related donor (3/6 to 5/6). 2)The patient has met medical criteria for myeloablative BMT as listed in the Sidney Kimmel Comprehensive Cancer Center BMT Policy and Procedure Manual. 3)The patient is NOT eligible for or has refused autologous or standard allogeneic BMT. 4)The patient is between the ages of 0.5 years and 65 years 5)The patient does NOT have indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT). 6)The patient does NOT have a positive leukocytotoxic crossmatch. 7)The patient had a prior autologous transplant, is less than 18 years of age and greater than 1 year has elapsed since autologous BMT. 8)The patient has at least one of the following very high-risk diagnoses: (I)For patients greater than or equal to 21 years of age: a)Refractory leukemia (primary refractory or refractory disease after standard or salvage chemotherapy) b)Secondary AML c)Therapy-related AML and NOT eligible for BMT CTN protocol 0603 d)MDS: RAEB with greater than 5% and less than 20% bone marrow blasts e)Chronic myelogenous leukemia beyond 1st chronic phase f)CMMoL g)Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high- grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy) h)Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease. i)Follicluar Lymphoma, Grade 3. j)Transformed indolent lymphomas (II)For patients less than or equal to 21 years of age: a)Refractory leukemia (primary refractory or refractory disease after standard or salvage chemotherapy) b)Any leukemia patient in CR greater than 2 except for late relapsed ALL ( greater than 36 months from diagnosis) c)High-risk acute leukemia in greater than CR 1;Bilineage leukemia, AML: unfavorable cytogenetics, and ALL d)Secondary AML e)MDS: RAEB with greater than 5% and less than 20% bone marrow blasts f)Chronic myelogenous leukemia beyond 1st chronic phase g)JMML h)Chemotherapy-resistant Hodgkins Lymphoma or intermediate or High grade non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy) i)The patient has performance status of ECOG 0, 1, 2, or Karnofsky/Lansky greater than 70. j)The patient has adequate physical functions; Renal, Cardiac, and Pulmonary
Treatment Arm A: Prior to infusion with unmanipulated BM, patients will undergo Busulfan 0.8 mg/kg/dose q 5-6 hrs for 4 days, followed by Cyclophosphamide 50 mg/kg/day for 2 days. Following BMT, patients will receive Cyclophosphamide 50 mg/kg/day for two days with Mesna 40 mg/kg/day. Patients will receive MMF 15 mg/kg though Day 35, and FK-506 through Day 180. Chimerism will be assessed in peripheral blood, and disease status evaluated through followup up to 2 years. Treatment Arm B (ALL, or Lymphoblastic Lymphoma): Prior to TBI cGy with infusion of unmanipulated bone marrow, patients will received Cyclophosphamide 50 mg/kg/day for two days with Mesna, followed by TBI 300 cGY once a day for 3 days.
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