PRO#0118: Decitabine Plus Mini Flu-Bu
Condition: Acute Myeloid Leukemia; Myelodysplastic Syndrome
MeSH terms: Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a single institution study of combining decitabine with fludarabine and busulfan in
      the setting of allogeneic stem cell transplantation. A study population of 20 subjects will
      be enrolled from The John Theurer Cancer Center at Hackensack University Medical Center.
      Subjects who are eligible to receive allogeneic hematopoietic stem cell transplantation
      according to the eligibility criteria will be consented and enrolled. Subjects will receive
      treatment with decitabine followed by reduced intensity fludarabine and busulfan prior to
      allogeneic stem cell transplantation. Subjects will be followed until 1 year post
      transplantation to assess stability of engraftment, toxicity, progression free survival, and
      disease response
    

Detailed description: 
      Aberrant DNA methylation patterns are commonly found in malignant cells. Hypermethylation of
      gene promotes sequences in cancer cells resulting in transcriptional silencing of tumor
      suppressor genes and contributing to malignant transformation. Hypomethylating agents have
      been explored for the treatment of cancers such as acute myelogenous leukemia and
      myelodysplastic syndrome. In vitro inhibition of methylation using azanucleosides results in
      differentiation of transformed myeloid cells. In vivo these agents induce DNA methylation of
      malignant myeloid cells. The most potent DNA methylating agent currently available,
      decitabine, is effective in patients with myelodysplastic syndrome (MDS) and acute
      myelogenous leukemia (AML). About 30% of patients with MDS and an abnormal karyotype will
      have normalization of their karyotype after receiving the drug.

      The myelodysplastic syndromes are a heterogeneous group of clonal hematologic disorders
      characterized by bone marrow failure and proliferation of myeloblastic leukemia cells.
      Patients with MDS develop cytopenias as a result of ineffective hematopoiesis. These
      cytopenias are believed to be a result of an increase in apoptosis resulting in an increase
      in futile cell cycling. In addition, the apparently mature and differentiated hematopoietic
      cells in patients with MDS are functionally impaired. Granulocytes have decreased
      myeloperoxidase activity and platelets have impaired function. Therapy for MDS includes
      supportive care geared mostly to transfusional support. Allogeneic transplantation has been
      shown to offer the possibility of long-term remission and remains the only curative option
      for patients with MDS. The development of reduced intensity conditioning regimens expanded
      the scope of allogeneic transplantation for older patients with MDS. A very large
      retrospective analysis by the European Blood and Marrow Transplantation Group compared the
      outcome of 836 patients with MDS treated with either a reduced-intensity conditioning regimen
      or a conventional regimen before allogeneic transplantation. The 3-year probabilities of
      progression-free and overall survival were similar in both groups, with a 3-year relapse rate
      being significantly higher in the reduced-conditioning group, offset by a significantly
      reduced probability of non-relapse mortality. This demonstrates the importance of the
      preparative regimen in preventing relapse in this setting.

      Acute myeloid leukemia accounts for over 9,000 deaths yearly in the United States. The WHO
      classification of AML incorporates and interrelated morphology, cytogenetics, molecular
      genetics and immunologic markers in an attempt to construct a classification that is
      clinically and prognostically valid. Under this classification the requisite blast percentage
      in the marrow is > 20%. Hematopoietic stem cell transplantation is an established therapeutic
      modality in patients with AML. An alloreactive immunotherapeutic effect of donor cells has
      been demonstrated.

      No other established therapy applied during complete remission offers as strong an
      anti-leukemic effect. Transplant-related morbidity and mortality, however, remain obstacles
      in the successful application of this treatment. More recently, reduced-intensity
      conditioning has been applied as a therapy for AML. Reduced-intensity conditioning, which
      includes potent immunosuppressive agents in addition to anti-leukemic agents, effectively
      permits engraftment of donor hematopoietic stem cells. Several studies have demonstrated that
      the morbidity and mortality are less with these regimens compared to myeloablative
      conditioning. While the reduced intensity of the conditioning regimen has resulted in reduced
      non-relapse mortality in patients with AML, some studies have suggested a concomitant
      increase in relapse as a consequence of lowering the intensity of the cytotoxic agents. New
      conditioning regimen that may increase the anti-leukemic effect while maintaining the
      reduced-intensity regimen toxicity profile are therefore, needed.

      Decitabine is a deoxycytidine analog that rapidly enters into cells by a nucleoside-specific
      transport mechanism. It is then phosphorylated by deoxycytidine kinase and converted to the
      active triphosphate form, 5AZA-dCTP, a substrate for DNA polymerase alpha. 5AZA-dCTP is
      incorporated into DNA and inhibits DNA methylation as inactivating DNA methyltransferase.
      Decitabine is s-phase specific. A recent study randomized 170 patients with MDS to receive
      either decitabine or best supportive care. Patients who were treated with decitabine achieved
      a significantly higher overall response rate (17%) including complete responses (9%),
      compared with supportive care (0%). Responses were durable and were associated with
      transfusion independence. Patients treated with decitabine had a trend toward a longer median
      time to acute myelogenous leukemia (AML) progression or death compared with patients who
      received supportive care alone. Responses in AML have also been demonstrated with 14%
      complete responses and 8% partial responses in one study . Decitabine has been used in
      combination with cyclophosphamide and busulfan as preparative regimen in patients with AML.
      This regimen was associated with a high response rate, with 40% of patients with AML being
      still in remission more than three years after transplantation. The total dose of decitabine
      ranged from 400 mg/m2 to 800 mg/m2. No decitabine dose-limiting toxicity was documented. The
      combination of fludarabine and busulfan has been well established as a transplant regimen and
      is associated with a reduced regimen-related toxicity. The combination of fludarabine and
      busulfan is the current standard of care for AML patients undergoing allogeneic
      transplantation at HUMC. In this study the investigators will be using the combination of
      reduced-intensity fludarabine and busulfan along with decitabine 300 mg/m2.
    

Intervention name(s): Decitabine plus Fludarabine and Busulfan
Intervention type(s): Drug
Intervention description(s): Decitabine will be administered at a dose of 60 mg/m2 IV daily based on adjusted body weight for patient >20% above ideal body weight
Fludarabine will be administered at a dose of 30/mg/m2 IV daily for 5 days starting on transplant day -7.
Busulfan will be administered at a dose of 130 mg/m2 IV daily for 2 days on transplant days -4 and -3.
Patients will also receive rabbit antithymocyte globulin (Thymoglobulin) at a dose of 2 mg/kg IV daily for 3 days on transplant days -4, -3, and -2.
Hematopoietic cells will be infused on day 0.
Intervention MeSH terms: Fludarabine; Busulfan; Decitabine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Bone Marrow Transplant; Stem Cell Transplant