Busulfan (BU) Plus Fludarabine Vs Intravenous BU Plus Cyclophosphamide as Conditioning Regimens Prior Allogeneic Hematopoetic Stem Cells Transplant (HSCT) in AML
Condition: Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this prospective phase III, open-label, randomized multicenter study is to
      evaluate whether Acute Myeloid Leukemia (AML) elderly patients in Complete Remission (CR)
      undergoing allogeneic hematopoietic stem cell transplantation after a reduce toxicity
      conditioning regimen (I.V. BuFlu) as compared to the conventional I.V.

      BuCy2 program will experience:

        1. A lower transplant-related mortality (TRM) at 1 year after Hematopoietic Stem Cells
           Transplant (HSCT)

        2. A similar anti-leukemic activity and a similar or better safety profile, in terms of:

             -  Early and/or late graft rejection

             -  Hematopoietic and immunologic recovery

             -  Chimerism

             -  Toxicity and incidence of Veno-occlusive Disease (VOD)

             -  Acute (aGvHD) and chronic graft-versus-host disease (cGvHD)

             -  Cumulative incidence of TRM at +100 days and 2 years after transplant

             -  Cumulative incidence of relapse by 1 and 2 years after transplant

             -  Event-free (EFS) and overall survival (OS) by 1 and 2 years after transplant
    

Detailed description: 
      Hematopoietic stem-cell transplantation (HSCT) is a potentially curative treatment modality
      for patients with Acute Myelogenous Leukemia (AML).

      An effective conditioning regimen is based on the association of oral Busulfan 4 mg/kg daily
      in 4 doses, each of 1 mg/kg, on each of 4 successive days (total dose, 16 mgkg), followed by
      CY 60 mg/kg intravenously on each of 2 successive days (BuCy2). The antileukemic activity of
      this latter program was tested and confirmed in most large randomized clinical trials
      conducted in AML and Chronic Myeloid Leukemia (CML) patients in which the BU-CY regimen was
      associated with survival and relapse probabilities that compare favourably with the CY-Total
      Body Irradiation (TBI) regimen. The BuCy2 program is considered a golden standard preparative
      regimen for allogeneic transplantation in AML patients.

      Nonetheless, for many years the treatment related toxicities of all these full myeloablative
      conditioning regimens has substantially limited the overall applicability of the transplant
      procedure to young patients with a good performance status (PS). The observation that
      allogeneic stem cell transplants have a potentially curative graft-versus-leukemia (GVL)
      effect in addition to the antileukemic action of myeloablative conditioning regimens was a
      major stimulus for the development of reduced-intensity conditioning (RIC) regimens, aimed
      primarily at securing engraftment to provide the GVL effect, while minimizing regimen-related
      toxicity.

      The observation that allogeneic stem cell transplants have a potentially curative
      graft-versus-leukemia (GVL) effect in addition to the antileukemic action of myeloablative
      conditioning regimens was a major stimulus for the development of reduced-intensity
      conditioning (RIC) regimens, aimed primarily at securing engraftment to provide the GVL
      effect, while minimizing regimen-related toxicity. As a consequence reduced-intensity
      conditioning (RIC) regimens might give possibility to extend access to allogeneic
      transplantation to patients who would not have previously been considered reasonable
      candidates because of their age and for the presence of comorbidities. However, after a lot
      of initial enthusiasm, it has become clear that a more intensive conditioning is associated
      with a reduced risk for relapse after HSCT. Therefore, while it is clear that RIC transplants
      have opened the way to using allogeneic SCT in patients several years older than the upper
      age limit of 60, the superiority of the RIC approach cannot be assumed even in this subgroup
      of patients. This is why, more recently, investigators are looking for conditioning programs
      that while better tolerated still might retain a strong ability of inducing a direct ablation
      of the leukemic hematopoiesis. This has led to the new concept of reduced toxicity rather
      than reduced intensity conditioning programs. One of such a program is based on the
      association of a myeloablative dose of intravenous Busulfan (0.8 mg/kg/d for 4 days), with
      Fludarabine (30 mg/m2/d for 4 days) which has been reported as highly effective in patients
      with AML. In elderly patients with this disease, this program might lead to an overall
      outcome at least as good as that following conventional myeloablative programs such as those
      based on Cyclophosphamide combined to the same dose of IV Busulfan or the TBI. In fact, when
      compared to these latter programs, the Busulfan Fludarabine regimen was found associated with
      lower non relapse mortality although a higher relapse rate was still documented, but not in
      all published experiences. In all, outcomes for standard transplant regimens have generally
      improved and these newer myeloablative regimens of Fludarabine with full-dose intravenous
      Busulfan achieve 1 year TRM below 10%. So, based on these considerations, protocol
      GITMO-AML.R2 has been designed to compare intravenous Busulfan plus Fludarabine (BuFlu)
      versus Busulfan (I.V. Bu; Busilvex®) plus Cyclophosphamide (BuCy2) as conditioning regimens
      prior to allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) in patients (aged
      between 40 and 65 years) with Acute Myeloid Leukemia (AML) in Complete Remission (CR).

      So, based on these considerations, protocol GITMO-AML.R2 has been designed to compare
      intravenous Busulfan plus Fludarabine (BuFlu) versus Busulfan (I.V. Bu; Busilvex®) plus
      Cyclophosphamide (BuCy2) as conditioning regimens prior to allogeneic Hematopoietic Stem Cell
      Transplantation (alloHSCT) in patients (aged between 40 and 65 years) with Acute Myeloid
      Leukemia (AML) in Complete Remission (CR).

      The principal objective of this trial is the evaluation of one year transplant-related
      mortality (TRM) of AML patients undergoing allogeneic hematopoietic stem cell transplantation
      after a reduced toxicity conditioning regimen (I.V.BuFlu) as compared to the conventional
      I.V. BuCy2 program.

      To this purpose, in the IV BuCy2 arm, reference TRM was assumed to be 25% (range 16-50%)
      while in the IV BuFlu arm and an estimated 12.5% TRM is assumed (range 0-30%). The study is
      designed to demonstrate a relative risk reduction of 50%. For the event-driven two-sided
      test, an alpha-level probability of 0.05 (type I error) and a power of 80% (type II
      error=0.2) has been considered. The ratio between the numbers of patients included in each
      arm is set equal to 1:1. The resulting required sample size is 240 (120 patients in each
      arm). Sample size estimation is based on the intention-to-treat principle.

      The accrual time is 2.5 years, and an additional follow-up of 2 years is planned after the
      last patient entry in the study and before the final analysis.
    

Intervention name(s): Busulphan plus Cyclophosphamide; Busulphan plus Fludarabine
Intervention type(s): Drug; Drug
Intervention description(s): I.V. Bu (Busilvex), 12.8 mg/kg:
Day -9: 0.8 mg/kg/dose x 4 doses Day -8: 0.8 mg/kg/dose x 4 doses Day -7: 0.8 mg/kg/dose x 4 doses Day -6: 0.8 mg/kg/dose x 4 doses Day -5: Rest
Followed by:
Cyclophosphamide, 120 mg/kg iv:
Day -4: 60 mg/kg Day -3: 60 mg/kg; I.V. Bu (Busilvex), 12.8 mg/kg:
Day -6: 0.8 mg/kg/dose x 4 doses Day -5: 0.8 mg/kg/dose x 4 doses Day -4: 0.8 mg/kg/dose x 4 doses Day -3: 0.8 mg/kg/dose x 4 doses plus:
Fludarabine, 4 x 40 mg/m² iv:
Day -6: 40 mg/m² Day -5: 40 mg/m² Day -4: 40 mg/m² Day -3: 40 mg/m²
Other intervention name(s): I.V. BuCy2; I.V. BuFlu
Intervention MeSH terms: Cyclophosphamide; Busulfan; Fludarabine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myeloid Leukemia; Allogeneic hematopoietic stem cell transplantation