Clofarabine and High-Dose Melphalan Followed by Donor Stem Cell Transplant in Patients With Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Myelodysplastic Syndromes
Condition: Leukemia; Myelodysplastic Syndromes
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Giving chemotherapy, such as clofarabine and melphalan, before a donor stem cell
      transplant helps stop the growth of cancer or abnormal cells. It also helps 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. Sometimes the transplanted cells
      from a donor can make an immune response against the body's normal cells. Giving cyclosporine
      and mycophenolate mofetil after the transplant may stop this from happening.

      PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine when
      given together with high-dose melphalan followed by a donor stem cell transplant in treating
      patients with acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic
      syndromes.
    

Detailed description: 
      OBJECTIVES:

        -  To determine the maximum tolerated dose and toxicities of clofarabine when administered
           with high-dose melphalan as a conditioning regimen in patients undergoing allogeneic
           stem cell transplantation for acute myeloid leukemia, acute lymphocytic leukemia, or
           myelodysplastic syndromes.

        -  To assess the efficacy of this regimen in facilitating engraftment in these patients.

        -  To perform correlative laboratory studies of engraftment, immune reconstitution, and
           therapeutic outcomes.

      OUTLINE: This is a dose-escalation study of clofarabine. Patients are stratified according to
      age (< 18 years vs ≥ 18 years).

        -  Reduced-intensity conditioning regimen: Patients receive clofarabine IV over 30 minutes
           on days -9 to -5 and high-dose melphalan IV over 30 minutes on day -4.

      Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated
      dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
      of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

        -  Allogeneic stem cell transplantation: Patients undergo allogeneic stem cell
           transplantation on day 0.

        -  Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 10
           hours or orally twice daily beginning on day -1 and continuing until day 90-100,
           followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil
           IV or orally twice daily beginning on day 0 and continuing until day 28, followed by a
           taper in the absence of GVHD.

      Patients undergo blood and/or bone marrow sample collection periodically for correlative
      laboratory studies. Samples are examined for markers of immune reconstitution (i.e., CD8+ T
      lymphocytes, CD4+ T lymphocytes, NK cells, B cells, and monocytes) by flow cytometry and for
      diversity of the reconstituted T-cell repertoire by PCR-based T-cell receptor repertoire
      analysis. Samples are also examined for gene expression of hRRM2 and markers of apoptosis
      (i.e., Bcl-2, Bid, NFkB2, and Bcl-3) by real-time RT-PCR and for markers of ribonucleotide
      reductase inhibition (i.e., dCTP levels in circulating peripheral blood mononuclear cells).

      After completion of study therapy, patients are followed periodically for up to 5 years.
    

Intervention name(s): clofarabine; melphalan; gene expression analysis; reverse transcriptase-polymerase chain reaction; flow cytometry; laboratory biomarker analysis; allogeneic hematopoietic stem cell transplantation
Intervention type(s): Drug; Drug; Genetic; Genetic; Other; Other; Procedure
Intervention description(s): Administered at the appropriate dose level(dose level one = 30 mg/m2, dose level two and three = 40 mg/m2)on days -9 to day -5 from transplant; Administered at the appropriate dose level (dose level one and two = 100 mg/m2, dose level three = 140 mg/m2) on day -4 from transplant; Peripheral blood draw on day -9 and day -4 prior to transplant; Peripheral blood draw on day -9 and day -4 prior to transplant; Bone marrow aspirate and biopsy to confirm diagnosis prior to transplant, day -9 pre-transplant, day 30 post-transplant, day 100 post-transplant, 6 months post-transplant, one year post-transplant, then yearly through year 5 post-transplant; Peripheral blood draw day -9 or earlier pre-transplant, day 14 post-transplant, day 30 post-transplant, day 60 post-transplant, day 100 post-transplant, 6 months and one year post-transplant.; Infusion of allogeneic hematopoietic stem cells on day 0 of transplant
Intervention MeSH terms: Melphalan; Clofarabine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute lymphoblastic leukemia in remission; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; 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); adult acute myeloid leukemia in remission; recurrent adult acute myeloid leukemia; childhood acute myeloid leukemia in remission; recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; childhood myelodysplastic syndromes; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; childhood acute lymphoblastic leukemia in remission