Early Allogeneic Blood Stem Cell Transplantation in High-risk Acute Myeloid Leukemia (AML)
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      Karyotype is a major prognostic risk factor in patients with acute myeloid leukemia (AML)
      translating into unfavourable outcome in case of poor-risk cytogenetic aberrations. Several
      studies have shown that allogeneic hematopoietic stem cell transplantation (HSCT) after
      myeloablative conditioning rather than autologous HSCT or consolidation chemotherapy result
      in long-term disease control in this group of patients when achieving a first complete
      remission. Nevertheless, the complete remission rate achievable is significantly lower than
      in patients with a more favourable risk profile. In fact, only the minority of AML patients
      with poor-risk cytogenetics, although having a suitable donor, proceed to HSCT due to
      refractory disease or infectious complications during induction chemotherapy (IC). Further,
      new data show that the course of therapy can be estimated as early as two weeks after the
      initiation of the first course of IC with patients presenting with more than 10 % marrow
      blasts doing significantly worse than those with a better clearance of blasts. As a result,
      the chance to obtain a durable remission is considerably low and most patients with bad-risk
      cytogenetics or failure to achieve blast clearance do not proceed to an allogeneic approach.
      Together these data indicate that early treatment intensification is warranted in order to
      provide the potential curative benefit of allogeneic HSCT to the majority of high-risk AML
      patients.

      We have shown that reduced-intensity conditioning (RIC) followed by allogeneic PBSC applied
      during aplasia after the first cycle of IC in newly-diagnosed high-risk AML patients is
      feasible and can result in a sustained disease control. These data prompted us to further
      evaluate in a prospective trial an early "up-front HSCT" in patients with newly-diagnosed
      high-risk AML defined by karyotype and insufficient blast clearance after the first cycle of
      IC.

      The goal was to provide an allogeneic HSCT as early as possible after diagnosis in AML
      patients.
    

Detailed description: 
      Only patients with newly-diagnosed AML are eligible for this prospective study. An immediate
      donor-search, either within the family or in volunteer donor registries, will be performed at
      diagnosis irrespective of the expected risk profile. All patients will receiv at least one
      cycle of IC. Inclusion criteria for early allogeneic transplantation are either poor risk
      cytogenetics and/or bad response to the first cycle of IC defined by more than 10% marrow
      blasts on day 15. If a patient meets one of those criteria they could enter the early
      allogeneic HSCT trial after providing informed consent. DNA-based HLA-typing of donor and
      recipient will be performed using high resolution (4 digits) for HLA - A, B, DRB1 and DQB1
      and intermediate resolution (2 digits) for HLA- C.

      During IC-induced aplasia after the 1st or 2nd cycle a fludarabine-based reduced intensity
      conditioning therapy will be started if a donor is available. All patients receive
      fludarabine 30 mg/m2 i.v. daily for five days (day- 6 to -2) and melphalan 150 mg/m² on
      day-2. Antithymocyte globulin (ATG Fresenius 10 mg/kg/day day -5 to -2, total dose 40 mg/kg,
      Fresenius, Bad Homburg, Germany) will be applied after transplantation from unrelated or HLA
      mismatched family donors. PBSC grafts will be preferred. As immunosuppression cyclosporin A
      (CsA) is either administered intravenously at a dose of 3 mg/kg/day or given at an
      bioequivalent amount of the oral formulation in two divided doses starting on the day before
      blood stem cell infusion (day -1). The dose of CsA is adjusted to maintain blood levels
      between 150 and 250 ng/ml. Starting on day 50, oral CsA administration will be tapered by 5%
      weekly if GVHD was inactive. Acute and chronic GvHD will be treated with prednisone, CsA or
      tacrolimus.
    

Intervention name(s): Melphalan, ATG, Fludarabine
Intervention type(s): Drug
Intervention description(s): allo Tx during aplasia
Intervention MeSH terms: Fludarabine; Melphalan
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AML, allogeneic transplantation, high-risk, karyotype