Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Condition: Disorder Related to Bone Marrow Transplantation; Leukemia; Transplantation Infection
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes
Intervention: Fludarabine; Clofarabine; Busulfan; Thymoglobulin; Stem Cell Infusion; Tacrolimus; Methotrexate
Intervention description: Flu + Bu Group: 40 mg/m2 by vein on Days -6 through -3.
Flu +Clo + Bu Group: 10 mg/m2 by vein on Days -6 through -3.; 30 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, and infused on Days -6 through -3.; Busulfan systemic exposure dose of 6000 µMol-min in normal saline over three (3) hours by vein every twenty-four (24) hours for four (4) consecutive days (days -6 to -3), starting immediately after the completion of Clofarabine. The dose on day -6 to -3 based on pharmacokinetic analysis of target AUC of 4,000 µMol-min ± 5% for 61-70 years of age (without Pharmacokinetics alternate dose 130 mg/m2).; Both groups who receive a graft from an unrelated donor:
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.0 mg/kg on day -1. On day -3, administered after the chemotherapy is complete.; Cryopreserved bone marrow or peripheral blood progenitor cells infused on day 0.; Starting dose: 0.015 mg/kg (ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml. Changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) present.; 5 mg/m2 by vein on Days 1, 3, 6 and 11 post transplant.
Intervention MeSH terms: Methotrexate; Fludarabine phosphate; Clofarabine; Fludarabine; Busulfan; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 256.0
Sex: All
Minimum age: 3 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Blood And Marrow Transplantation; Leukemia; Allogeneic hematopoietic stem cell transplantation; Acute myeloid leukemia; AML; Myelodysplastic syndrome; MDS; Progression free survival; Rate of engraftment; Toxicity; Relapse rate; Graft-vs-host disease; GvHD; Progression-free survival; PFS; Overall survival; OS; Fludarabine; Fludarabine Phosphate; Fludara; Clofarabine; Clofarex; Clolar; Busulfan; Busulfex; Myleran; Thymoglobulin; ATG; Antithymocyte Globulin; Methotrexate; Tacrolimus; Prograf

Summary:

      The goal of this clinical research study is to learn if combining busulfan with clofarabine
      and fludarabine can help control the disease better than the previous standard method (using
      busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination
      therapy will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have one of the following hematologic malignancies: a) Acute myeloid
             leukemia (AML) any stage and cytogenetic risk-group with the only exception being that
             patients with AML and favorable cytogenetics (t(8;21, inv 16, or t(15;17) who achieve
             complete remission with one course of induction chemotherapy are not eligible .
             Patients with treatment related AML are eligible. b) Myelodysplastic syndromes (MDS)
             with intermediate or high risk International Prognostic Scoring System score (IPSS
             scores) or treatment related MDS. Patients with low risk MDS are eligible if they fail
             to respond to hypomethylating agent therapy such as azacitidine or decitabine.

          2. Age 3-70 years old. Eligibility for pediatric patients will be determined in
             conjunction with an MDACC pediatrician.

          3. Performance score of >/= 60 by Karnofsky or PS 0 to 2 (ECOG) (age > 12 years), or
             Lansky Play-Performance Scale >/= 60 or greater (age <12 years).

          4. Negative Beta HCG test in a woman with child bearing potential, defined as not
             post-menopausal for 12 months or no previous surgical sterilization. Women of child
             bearing potential must be willing to use an effective contraceptive measure while on
             study.

          5. Adequate major organ system function as demonstrated by: Left ventricular ejection
             fraction of at least 40%.

          6. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50%
             predicted. For children </=7 years of age who are unable to perform PFT, oxygen
             saturation >/=92% on room air by pulse oximetry.

          7. Creatinine < 1.5 mg/dL. If question about renal function discuss with study chairman
             and do 24 hour creatinine clearance (clearance should be >50 ml/min).

          8. Bilirubin < to 2.0 x normal (except Gilbert's Syndrome). SGPT (ALT) < 200. No evidence
             of chronic active hepatitis or cirrhosis.

          9. Histocompatible stem cell donor: Patients must have an HLA matched related or
             unrelated donor (HLA A, B, C and DR) willing to donate for allogeneic hematopoietic
             transplantation. High resolution allele level typing is required for donors other than
             genotypically identical siblings.

         10. No uncontrolled infection. Protocol PI or designé will be final arbiter if there is
             uncertainty regarding whether a previous infection is controlled on appropriate
             (antibiotic) therapy.

         11. Patient or patient's legal representative, parent(s) or guardian able to sign informed
             consent.

        Exclusion Criteria:

          1. Positive for HIV, HBsAg, HCV or other viral hepatitis or cirrhosis from any cause.

          2. Prior allogeneic or autologous stem cell transplant using a myeloablative busulfan or
             total body radiation containing conditioning regimen defined as busulfan-based using a
             total dose of >/=12 mg/kg given by mouth or >/=10 mg/kg given IV; or a total-body
             irradiation (> 4 Gy).

          3. Active or prior CNS leukemia, unless in complete remission for at least 3 months.

          4. Previous therapeutic XRT to the liver as part of involved-field radiation.

          5. History of serious chronic mental disorder or drug-abuse accompanied by documented
             problems of compliance with therapeutic programs.

          6. Lack of care-giver for the early (100-day) post-transplant period.