Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia
Condition: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Neoplasm Metastasis; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Recurrence
Intervention: total-body irradiation; allogeneic hematopoietic stem cell transplantation; cyclophosphamide; mycophenolate mofetil; busulfan; cyclosporine; fludarabine phosphate; peripheral blood stem cell transplantation; nonmyeloablative allogeneic hematopoietic stem cell transplantation; laboratory biomarker analysis; cytogenetic analysis; flow cytometry; fluorescence in situ hybridization; pharmacological study; polymorphism analysis; tacrolimus; methotrexate
Intervention description: Radiation; Undergo allogeneic transplantation; Given IV; Given orally; Given IV or orally; Given IV or orally; Given IV; Undergo transplantation; Undergo allogeneic transplantation; Correlative studies; Correlative studies; Correlative studies; Correlative studies; Correlative studies; Correlative studies; Given IV or orally; Given IV
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Busulfan; Methotrexate; Fludarabine; Fludarabine phosphate; Tacrolimus; Cyclosporins
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      RATIONALE: Giving chemotherapy, such as fludarabine phosphate, busulfan, and
      cyclophosphamide, and total-body radiation therapy before a donor peripheral stem cell
      transplant helps stop the growth of cancer cells. It may also stop the patient's immune
      system from rejecting the donor's stem 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. It is not yet known whether low-dose chemotherapy
      and total-body radiation therapy is more effective than high-dose chemotherapy in treating
      patients with myelodysplastic syndrome or acute myeloid leukemia.

      PURPOSE: This phase III trial is studying low-dose conditioning to see how well it works
      compared to high-dose conditioning followed by peripheral blood stem cell transplant in
      treating patients with myelodysplastic syndromes or acute myeloid leukemia
    

Eligibility criteria:

        Inclusion Criteria:

          -  Myelodysplastic syndrome (MDS) or transformed acute myelogenous leukemia (transformed
             from MDS)

          -  De novo acute myelogenous leukemia (AML) beyond first remission

          -  Intermediate or high risk de novo AML in first complete response (at FHCRC unrelated
             donor recipients only)

          -  Chemotherapy required prior to HCT for all patients:

          -  A) Interval between start of a cycle of cytoreductive chemotherapy and infusion of
             donor stem cells must be at least 30 days; chemotherapy received for disease
             maintenance will be allowed during this time period

          -  B) All patients must have < 5% myeloblasts based on marrow morphology performed within
             21 days prior to start of conditioning regimen and at least 3-4 weeks after the start
             of pre-transplant cytoreductive chemotherapy

          -  C) All patients must have no circulating peripheral blood myeloblasts present based on
             morphologic analysis

          -  Age 65 years or under for patients with related donors; age 60 years or under for
             patients with unrelated donors

          -  HCT-Specific Comorbidity Index Score (HCT-CI) < 3

          -  Related donor (age > 12 years, nonsyngeneic) or unrelated donor, HLA phenotypically or
             genotypically identical at the allele level at A,B,C,DRQ1, and CBQ1

          -  DONOR: Related or unrelated donors who are genotypically or phenotypically matched by
             high resolution HLA typing (HLA-A, B, C, DRB1, and DQB1); class 1 single allele
             mismatch allowed

          -  DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft
             rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and
             the donor is A*0201, and this type of mismatch is not allowed

          -  DONOR: A positive anti-donor cytotoxic crossmatch or flow cytometric assay is an
             absolute donor exclusion at FHCRC/SCCA

          -  DONOR: Age >= 12 years

          -  DONOR: Donors must consent to PBSC mobilization with G-CSF and leukaphereses; bone
             marrow as a source of stem cells will not be allowed

          -  DONOR: Donor must have adequate veins for leukaphereses or agree to placement of
             central venous catheter (femoral, subclavian)

        Exclusion Criteria:

          -  HIV seropositivity

          -  Fungal infections with radiographic progression after appropriate therapy for greater
             than one month

          -  Organ dysfunction

          -  Symptomatic coronary artery disease or ejection fraction < 35%

          -  DLCO < 65%, FEV1 < 65% or receiving supplementary continuous oxygen

          -  Liver function abnormalities: Patients with clinical or laboratory evidence of liver
             disease will be evaluated for the cause of liver disease, its clinical severity in
             terms of liver function, histology, and the degree of portal hypertension; patients
             with fulminant liver failure, cirrhosis with evidence of portal hypertension or
             bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding
             esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic
             dysfunction evidenced by prolongation of the prothrombin time, ascites related to
             portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic
             viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
             will be excluded

          -  Karnofsky Performance Score < 70

          -  Lansky-Play Performance Score < 70 for pediatric patients

          -  Life expectancy severely limited (< 2 years) by disease other than MDS/AML

          -  Fertile men and women unwilling to use contraceptive techniques during and for 12
             months following treatment

          -  Patients with active non-hematological malignancies except:

          -  A) Patients with follicular or low grade lymphoma will be eligible as long as they
             have not and do not require active treatment for control of their disease

          -  B) Patients with localized non-melanoma skin malignancies

          -  Patients with poorly controlled hypertension who are unable to have blood pressure
             stabilized below 150/90 mm Hg on standard medication

          -  Females who are pregnant or breastfeeding

          -  Patients with systemic, uncontrolled infections

          -  Active CNS disease as identified by positive CSF cytospin

          -  DONOR: Identical twin

          -  DONOR: Age < 12 years

          -  DONOR: Pregnancy

          -  DONOR: HIV seropositivity

          -  DONOR: Inability to achieve adequate venous access

          -  DONOR: Known adverse reaction to G-CSF