Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) Initial Salvage Therapy for Induction Failure Acute Myeloid Leukemia (AML)
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Busulfan; Fludarabine; Clofarabine; Total Body Irradiation (TBI); Thymoglobulin; Stem Cell Infusion; Cyclophosphamide; Tacrolimus; Mycophenolate mofetil; Decitabine; Cytarabine; Idarubicin
Intervention description: Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3.; Fludarabine 10 mg/m2 by vein on Days -6 to -3.; Salvage Chemotherapy Before Transplant: Clofarabine 15 mg/m2 by vein on Days 6 - 9.
Stem Cell Transplant: Clofarabine 40 mg/m2 by vein on Days -6 to -3.; Total body irradiation (TBI) delivered at 2Gy on Day -2.; Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2.; Fresh or cryopreserved bone marrow or peripheral blood (PB) progenitor cells infused on Day 0. Goal is to infuse 4 X 106 CD34+ cells/kg if PB or >3.0 X 108 marrow mononuclear cells/kg if bone marrow.; Cyclophosphamide 50 mg/kg by vein on Days +3 and +4.; Tacrolimus 0.015 mg/kg/day by vein or mouth on Day +5.; Mycophenolate mofetil 15 mg/kg/dose by vein or by mouth three times a day from Day +5 to Day+100.; 20 mg/m2 by vein on Days 1 - 5.; 1 g/m2 by vein on Days 6 - 10.; 10 mg/m2 by vein on Days 6 - 8.
Intervention MeSH terms: Cytarabine; Mycophenolic Acid; Cyclophosphamide; Busulfan; Fludarabine; Fludarabine phosphate; Decitabine; Idarubicin; Clofarabine; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Leukemia; Acute myeloid leukemia; AML; Refractory; Allogeneic hematopoietic stem cell transplantation; AHSCT; Busulfan; Busulfex; Myleran; Fludarabine; Fludarabine Phosphate; Fludara; Clofarabine; Clofarex; Clolar; Total body irradiation; TBI; XRT; Thymoglobulin; ATG (Rabbit); Rabbit antithymocyte Globulin; Rabbit Antilymphocyte Globulin; Rabbit ATG; rATG; Stem cell infusion; Cyclophosphamide; Cytoxan; Neosar; Tacrolimus; Prograf; Mycophenolate mofetil; MMF; CellCept; Decitabine; Dacogen; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride; Idarubicin; Idamycin

Summary:

      Objectives:

      Primary Objectives:

        1. To determine the safety and feasibility of allogeneic hematopoietic stem cell
           transplantation (AHSCT) as initial salvage treatment for patients with primary induction
           failure (PIF) acute myeloid leukemia (AML).

        2. To determine efficacy of AHSCT following decitabine, clofarabine, idarubicin, and
           cytarabine (DCIA) salvage chemotherapy evaluated by overall response rate (RR), defined
           as complete response (CR) or CR without platelet recovery (CRp) or CR with insufficient
           hematological recovery (CRi).

      Secondary Objectives:

        1. To determine the percentage of patients with PIF AML eligible for AHSCT after up to 2
           courses of induction chemotherapy.

        2. To determine the early treatment-related mortality (TRM) (within first 4 weeks of first
           salvage chemotherapy regimen with DCIA and day 100 TRM after AHSCT.

        3. To determine the efficacy DCIA regimen as salvage chemotherapy for patients with PIF AML
           (% of patients who achieve </=5% bone marrow blasts prior to AHSCT.

        4. To determine the TRM at 1 year, relapse rate (RR), overall survival (OS) and event-free
           survival (EFS) for patients with PIF AML treated with DCIA followed by early AHSCT.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients age 18-60 years.

          2. Patients with diagnosis of AML, judged primary refractory after up to 2 courses of AML
             induction therapy (> 5% blasts on day 21 (+/-7 days) bone marrow aspirate and/or
             biopsy from the beginning of induction chemotherapy, up to 42 days).

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2.

          4. Adequate major organ function:, defined as: a) Serum creatinine </= 3 mg/dL; b) Total
             bilirubin </= 2.5 mg/dL; c) ALT (SGPT) </= 3 x ULN or </= 5 x ULN if related to
             disease; d) Cardiac ejection fraction >/= 40% (by either ECHO or MUGA).

          5. Willingness to have an allogeneic transplant.

          6. Patient or patient's legal representative able to provide written informed consent.

          7. Patients are required to meet the following criteria to proceed to AHSCT:

          8. Donor criteria: Availability of a donor either an HLA matched sibling donor (MSD) or a
             haploidentical (5-9/10 HLA matched); alternatively a 8/8 HLA matched unrelated donor
             (MUD) by high resolution typing is immediately available;

          9. Disease criteria: Day 21 (+/-7 days) bone marrow aspiration or biopsy from the
             beginning of salvage DCIA: a. In complete morphologic remission with <5% bone marrow
             blasts, or b. Aplastic (<10% bone marrow cellularity), and cytopenic with an absolute
             neutrophil count (ANC) less than 1,000/µL, or c. Low disease burden with < 30% BM
             blasts, with recovery of peripheral blood (PB) WBC (ANC>1,000/µL) and <5% circulating
             blasts.

         10. Adequate organ function criteria: a. Serum creatinine clearance >/= 50 ml/min
             (calculated by Cockcroft-Gault formula); b. Total bilirubin </= 2 times upper limit of
             normal (x ULN) (3 x ULN if considered to be due to leukemic involvement or Gilbert's
             syndrome); c. Alanine aminotransferase (ALT) </= 3 x ULN (5.0 x ULN if considered to
             be due to leukemic involvement); d. LVEF >/= 40% on ECHO or MUGA; e. DLCO >/= 50%
             predicted after correction for hemoglobin (must be performed in patients with history
             of smoking or lung disease;); DLCO may be omitted in patients without history of
             pulmonary disease if approved by the Study Chair.

         11. No active infection: Patients should be afebrile. If present, pulmonary infiltrates or
             other sites of infection must be improving on antibiotics. Patients should not require
             oxygen. Study Chair will be the arbiter of this criterion.

        Exclusion Criteria:

          1. HIV positive; active hepatitis B or C.

          2. Uncontrolled active infections (viral, bacterial, and fungal); the Study Chair will be
             the final arbiter of this criterion.

          3. Patients with active secondary malignancy unless approved by the Study Chair.

          4. Liver cirrhosis.

          5. Active CNS involvement within the previous 2 months.

          6. Prior induction therapy with DAC + CIA.

          7. Positive pregnancy test in a woman with child bearing potential defined as not
             post-menopausal for 12 months or no previous surgical sterilization.

          8. Breast feeding women.

          9. Men must agree not to father a child and agree to use a condom if his partner is of
             child bearing potential.

         10. Inability to comply with medical therapy or follow-up.