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This clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell transplant works in treating patients with hematologic cancer or bone marrow failure disorders. Giving low doses of chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells or abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect)
Full description
PRIMARY OBJECTIVES:
I. To determine the transplant related mortality (TRM) of this reduced intensity transplantation (RIT) combination in a patient population that is usually not eligible for a full myeloablative allogeneic transplant.
SECONDARY OBJECTIVES:
I. To evaluate engraftment, safety, clinical response, evidence of graft-versus-malignancy effect/graft-versus-host disease (GVHD) and overall outcomes of treatment with our RIT regimen across a variety of hematological conditions.
OUTLINE: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0.
Note: *Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
After completion of study treatment, patients are followed up periodically.
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Inclusion criteria
Diagnosis of a histology documented hematologic malignancy or marrow disorder
Bone marrow failure disorders and other non-malignant hematologic or immunologic disorders:
Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH):
Hereditary bone marrow failure disorders include Fanconi anemia or related chromosomal breakage syndrome dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Kostmann syndrome, congenital amegakaryocytic thrombocytopenia:
Other non-malignant hematologic or immunologic disorders that require transplantation
Acute leukemias:
Chronic Myeloid Leukemia (CML):
Myeloproliferative and myelodysplastic syndromes (MDS):
Lymphoproliferative disease:
Hodgkin disease:
Failed prior autotransplant
Age >= 3 and =< 75 years for blood and bone marrow transplants and age >= 3, < 60 for cord blood transplants
No serious uncontrolled psychiatric illness
No concomitant active malignancy other than non-melanoma skin cancer
Non-pregnant and non-nursing women (women or men with reproductive potential should agree to use an effective means of birth control)
Patients may have received prior autologous bone marrow transplant (BMT) or prior myeloablative allogeneic BMT (at least 60 days have elapsed)
At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery
Informed consent
DONOR: Permissible HLA matching: Related donors- single antigen mismatch at HLA A, B or DRB 1; unrelated donors- a single antigen mismatch at HLA A, B, or C, +/- additional single allele level mismatch at A, B, C or DRB1; cord blood >= 4 out of 6 antigen match at HLA A, B, DRB1)
DONOR: Compatibility at the four most informative HLA loci: A, B, C and DRB1 are important for reducing the risk of GVHD and successful transplant outcomes; the A, B, C and DRB1 loci comprise 8 possible alleles (a haplotype being inherited from each parent); one additional locus, HLA-DQ, is also typed to ascertain haplotypes and assist in the search for a compatible donor; however mismatching at DQ has not been shown to be associated with adverse outcomes; high resolution molecular typing (at the allele level) is now the standard of care for unrelated donor searches and allows greater refinement of the search strategy
DONOR: Matched related donor: a single antigen mismatch at A, B, or the DR transplant from a family member is associated with a higher risk of GVHD but similar overall survival when compared to full identity at these 3 regions; related donor/recipient pairs must be matched at 5 of 6 HLA antigens (A, B, DRBl)
DONOR: Unrelated donor: when evaluating patients for unrelated donor transplant, a higher degree of matching is preferred due to minimize the risk of GVHD; the A, B, C, DRB1 and DQ loci, comprising 10 possible alleles, will be typed routinely for all unrelated transplants; given the higher risk of TRM in mismatched transplants, RIT is often the best way to mitigate the risk; evolving data from the National Marrow Donor Program now makes it possible to estimate the risks of donor-recipient HLA mismatch at the allele or antigen level; the higher risk from HLA-mismatching must be carefully assessed with respect to the clinical urgency and the patient's risk by the transplant physician; antigen level mismatches at DQ are inconsequential to transplant outcomes and are ignored with respect to donor selection for the purposes of this protocol, with matching requirements confined to the 8 loci involving HLA A, B, C and DRB1; for the purpose of this protocol, a single antigen mismatch at HLA A, B, or C, with or without additional single allele level mismatch may participate in this protocol for voluntary unrelated donors (blood or marrow); patients must be at least antigen-level matched at DRB1
DONOR: If a patient has no suitable family donor matched for 5 of 6 HLA antigens (A, B, DRB1) and no suitable unrelated donor is identified or for reasons of urgency, the patient can be considered a candidate for cord blood transplant, provided a cord blood donor is identified with a >= 4 out of 6 antigen match at HLA A, B, DRB1 antigens; the cord blood product must provide a minimum of 2 x 10^7 nucleated cells/kg, test negative for HIV and Hepatitis A, Band C, and sterility assays have no growth; the cord blood products are located through the National Marrow Donor Program, the American Registry, or the Bone Marrow Donor Worldwide or other established registries, and may be stored in the N.Y Placental Cord Blood Bank, the St. Louis Cord Blood Bank, or any of the established, registered International blood and marrow banks
DONOR: Donor must be healthy and have nonreactive test results for all infectious disease assays as required by state and federal regulations; donors who screen seropositive for hepatitis and/or syphilis must be cleared by infectious disease consultation
DONOR: The donor must have no uncontrolled cardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation unsafe
DONOR: The donor must be able to give informed consent for peripheral blood stem cell collection or bone marrow collection
DONOR: Syngeneic donors are not eligible
DONOR: Donors who have poor peripheral venous access, may require central venous line placement for stem cell apheresis
Exclusion criteria
Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)
Karnofsky (adult) or Lansky (for =< 16 years) performance status =< 50%
Diffusing capacity of the lung for carbon monoxide (DLCO) less than 40% predicted, corrected for hemoglobin (Hb) and/or alveolar ventilation
Cardiac: left ventricular ejection fraction less than 40%
Bilirubin >= 3 x upper limit of normal
Liver alkaline phosphatase >= 3 x upper limit of normal
Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) >= 3 x upper limit of normal
Child's class B and C liver failure
Calculated creatinine clearance < 40 cc/min by the modified Cockcroft-Gault formula for adults or the Schwartz formula for pediatrics
Patients who have received maximally allowed doses (given in 2 Gy fractions, or equivalent) of previous radiation therapy to various organs as follows:
Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
Human immunodeficiency virus (HIV) positive
Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening
Females of childbearing potential with a positive pregnancy test
Primary purpose
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62 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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