Sequential Conditioning in Haploidentical Transplantation for Refractory Acute Myeloid Leukemia (SET-HAPLO)

Association for Training, Education, and Research in Hematology, Immunology, and Transplantation

Status

Completed

Conditions

Refractory Acute Myeloid Leukemia

Treatments

Drug: Sequential Packaging (SET)

Drug: Transfusion graft

Drug: Care supports

Drug: Prevention of GVHD

Drug: Lymphocyte injection of prophylactic donor (PDLI)

Study type

Interventional

Funder types

Other

Identifiers

NCT03035422

2016-A00862-49

Details and patient eligibility

About

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.

Full 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:

To evaluate the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse and relapse-free survival
To evaluate the non-relapse mortality
To evaluate the incidence of acute and chronic graft against host disease (GVHD)
To assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)
To analyze the post-transplant immune reconstitution

Secondary endpoints:

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
Cumulative incidence of death not related to relapse at 90 days, 1 year and 2 years after transplantation
Cumulative incidence of acute and chronic graft against host disease (GVHD)
Number of patients for whom pDLI was possible and number of pDLI / patient; incidence, severity and treatment of possible secondary GVHD in these patients
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):

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)
Rest 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)
  
  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.
  1. 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.

Enrollment

24 patients

Sex

All

Ages

18 to 60 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients with a confirmed diagnosis of acute myeloid leukemia after primary induction treatment failure (persistent leukemia after 2 cycles of induction chemotherapy)
Patient age ≥ 18 to <60 years
Cardiac ejection fraction of the left ventricle ≥ 45%
Lung function - free diffusion capacity for carbon monoxide ≥ 50% of predicted value
Creatinine clearance ≥ 50 ml / min depending on the CKD-EPI formula
Availability of an HLA haploidentical donor in the family
Collection of non-opposition

Exclusion criteria

Uncontrolled invasion of CNS
Availability of an HLA identical family donor who agreed to donate hematopoietic stem cells OR non-related donor HLA-compatible 10/10 on HLA-A alleles, B, C, and DRB1 DQB1 available and ready to give in 4 weeks to make a decision allograft
Presence in the patient HLA-specific antibodies directed against an antigen HLA haploidentical donor family
Karnofsky score <70%
Patient HIV positive
Hepatitis B or C or chronic active
Uncontrolled infection at the time of start packing
Contraindication to the use of treatments provided by the Protocol
Previous history of allo-HSC
No beneficiary of a social security scheme.