Sequential Conditioning in Haploidentical Transplantation for Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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. 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.

Official Title
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Sequential Chemotherapy Prior to Reduced Intensity Conditioning: Interventional Study in Haploidentical Hematopoietic Stem Cells Transplantation for Patients With Refractory Acute Myeloid Leukemia

Conditions
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Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Sequential Packaging (SET)
* Drug: Transfusion graft
* Drug: Prevention of GVHD
* Drug: Care supports
* Drug: Lymphocyte injection of prophylactic donor (PDLI)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients with primary refractory acute myeloid leukemia<br>Patients with primary refractory acute myeloid leukemia | Drug: Sequential Packaging (SET)<br>* 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)<br>Drug: Transfusion graft<br>* Graft of peripheral stem cells is preferred at D0<br>Drug: Prevention of GVHD<br>* 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)<br>Drug: Care supports<br>* According to the protocols of each center<br>Drug: Lymphocyte injection of prophylactic donor (PDLI)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The aim is to describe the efficacy of the combination of a SET followed by haploidentical transplant with post-transplant immune modulation by pDLI in patients with AML. The main objective is to assess overall survival at 2 years in these patients. | 2 years after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial or complete remission rate by standard criteria Relapse incidence and death related to the disease | To evaluate the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse | 90 days and then 6, 12 and 24 months after transplantation | 
| Cumulative incidence of death not related to relapse | Assess not related to relapse mortality | 90 days and then 12 and 24 months after transplantation | 
| Cumulative incidence of acute and chronic graft against host disease (GVHD) | To evaluate the incidence of acute and chronic graft against host disease (GVHD) | 100 days and then 12 and 24 months after transplantation | 
| Number of patients for whom pDLI was possible. | Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI) | 2 years after transplantation | 
| Study of immune reconstitution post-transplant in the peripheral blood will be used:CD4 lymphocyte levels, CD8, T regulators, Natural Killer cells and B cells | Study the post-transplant immune reconstitution | 90 days and then 6, 12 and 24 months after transplantation | 
| Leukemia free survival | Relapse-free survival | 90 days and then 6, 12 and 24 months after transplantation | 
| Number of pDLI / patient; incidence, severity and treatment of possible secondary GVHD in these patients | Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI) | 90 days and then 6, 12 and 24 months after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogenic cell stem transplant, Sequential chemotherapy Haploidentical transplant