Sequential Conditioning in Haploidentical Transplantation for Refractory Acute Myeloid Leukemia
Condition: Refractory Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional

Summary: 
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option
      with a significant chance of healing in acute myeloid leukemia (AML) or refractory multiple
      relapses after chemotherapy. However, all patients with an indication of allo-HSC can not
      benefit because of two limitations: the toxicity of the treatment and graft shortage
      available.
    

Detailed description: 
      The goal is to evaluate the efficacy and safety of the combination of an SET followed by
      haploidentical transplant with post-transplant immune modulation by prophylactic DLI in
      patients with refractory acute myeloid leukemia or relapsed. The main objective is to assess
      overall survival at 2 years in these patients.

      Secondary objectives:

        1. To evaluate the efficacy of this therapeutic strategy in terms of remission of disease,
           incidence of relapse and relapse-free survival

        2. To evaluate the non-relapse mortality

        3. To evaluate the incidence of acute and chronic graft against host disease (GVHD)

        4. To assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)

        5. To analyze the post-transplant immune reconstitution

      Secondary endpoints:

        1. partial or complete remission rate by standard criteria at 90 days and then 6, 12 and 24
           months after transplantation.

           Relapse incidence and death related to the disease 90 days 6, 12 and 24 months after
           transplantation Leukemia-free survival at 1 year and 2 years after transplantation

        2. Cumulative incidence of death not related to relapse at 90 days, 1 year and 2 years
           after transplantation

        3. Cumulative incidence of acute and chronic graft against host disease (GVHD)

        4. Number of patients for whom pDLI was possible and number of pDLI / patient; incidence,
           severity and treatment of possible secondary GVHD in these patients

        5. Study of immune reconstitution post-transplant in the peripheral blood 30, 90 and 180
           days after transplantation (CD4 lymphocyte levels, CD8, T regulators, Natural Killer
           cells and B cells)

      Methodology, experimental design:

      Multicenter study in routine care, prospective

      All patients will receive, as part of the marketing authorization of the products used, the
      following regimen:

      1- sequential Packaging (SET):

        1. sequential chemotherapy:

             -  Thiotepa 5 mg / kg / day for 1 day (D-13)

             -  Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)

             -  Etoposide 100 mg / m² / day for 4 days (J-12 to J-9)

        2. Rest days J-8 and J-6

        3. Reduced-intensity conditioning (RIC)

             -  Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)

             -  Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)

             -  Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2)

                2 Graft transfusion: the day D0. A graft of peripheral stem cells is preferred.

                3- Prevention of GVHD:

             -  Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5

             -  Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)

             -  Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6)

                4- Care supports: according to the protocols of each center

                5- lymphocyte injection of prophylactic donor (pDLI): according to the protocols of
                each center. The following scheme is proposed:

             -  In the absence of clinical contraindication(GVHD), tapering MMF between days D + 35
                and D + 56, then tapering CSA between D + 62 and D + 90

             -  pDLI: 3 injections from the D + 120 in patients who discontinued immunosuppressive
                therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade> II.

                6. Feedback: at baseline and 1, 3, 6, 12 and 24 months after transplant
                (engraftment, disease response, immune reconstitution, chimerism, GVHD, infection,
                quality of life).

      The treatments evaluated in this strategy are all used in the usual care of patients and
      follow-up will not be changed.
    

Intervention name(s): Sequential Packaging (SET); Transfusion graft; Prevention of GVHD; Care supports; Lymphocyte injection of prophylactic donor (PDLI)
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Sequential chemotherapy:
Thiotepa 5 mg / kg / day for 1 day (D-13)
Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)
Etoposide 100 mg / m² / day for 4 days (J-12 to J-9) Repos days J-8 and J-6 Reduced-intensity conditioning (RIC)
Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)
Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)
Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2); Graft of peripheral stem cells is preferred at D0; Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5
Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)
Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6); According to the protocols of each center; According to the protocols of each center. In the absence of clinical indication against-disease (GVHD), phasing MMF between days D + 35 and D + 56, then phasing APF between D + 62 and D + 90
- PDLI: 3 injections from the D + 120 patients who discontinued immunosuppressive therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade> II
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Allogenic cell stem transplant, Sequential chemotherapy Haploidentical transplant