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

Sponsor

Association for Training, Education, and Research in Hematology, Immunology, and Transplantation (Other)

Overall Status

Completed

CT.gov ID

NCT03035422

Collaborator

(none)

Enrollment

Location

Arm

47.1

Actual Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Refractory Acute Myeloid Leukemia	Drug: Sequential Packaging (SET) Drug: Transfusion graft Drug: Prevention of GVHD Drug: Care supports Drug: Lymphocyte injection of prophylactic donor (PDLI)	N/A

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:

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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

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

Actual Study Start Date :

Jan 15, 2018

Actual Primary Completion Date :

Dec 18, 2021

Actual Study Completion Date :

Dec 18, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: Patients with primary refractory acute myeloid leukemia Patients with primary refractory acute myeloid leukemia	Drug: 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) 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) Drug: Transfusion graft Graft of peripheral stem cells is preferred at D0 Drug: 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) Drug: Care supports According to the protocols of each center Drug: Lymphocyte injection of prophylactic donor (PDLI) 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

Arm

Intervention/Treatment

Other: Patients with primary refractory acute myeloid leukemia

Patients with primary refractory acute myeloid leukemia

Drug: 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) 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)

Drug: Transfusion graft

Graft of peripheral stem cells is preferred at D0

Drug: 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)

Drug: Care supports

According to the protocols of each center

Drug: Lymphocyte injection of prophylactic donor (PDLI)

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

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [2 years after transplantation]
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.

Secondary Outcome Measures

Partial or complete remission rate by standard criteria Relapse incidence and death related to the disease [90 days and then 6, 12 and 24 months after transplantation]
To evaluate the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse
Cumulative incidence of death not related to relapse [90 days and then 12 and 24 months after transplantation]
Assess not related to relapse mortality
Cumulative incidence of acute and chronic graft against host disease (GVHD) [100 days and then 12 and 24 months after transplantation]
To evaluate the incidence of acute and chronic graft against host disease (GVHD)
Number of patients for whom pDLI was possible. [2 years after transplantation]
Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)
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 [90 days and then 6, 12 and 24 months after transplantation]
Study the post-transplant immune reconstitution
Leukemia free survival [90 days and then 6, 12 and 24 months after transplantation]
Relapse-free survival
Number of pDLI / patient; incidence, severity and treatment of possible secondary GVHD in these patients [90 days and then 6, 12 and 24 months after transplantation]
Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Service d'hématologie Clinique Hôpital Saint Antoine	Paris		France	75012

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

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

ClinicalTrials.gov Identifier:

NCT03035422

Other Study ID Numbers:

2016-A00862-49

First Posted:

Jan 30, 2017

Last Update Posted:

Jul 25, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Association for Training, Education, and Research in Hematology, Immunology, and Transplantation

Allogenic cell stem transplant, Sequential chemotherapy Haploidentical transplant

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Study Results

No Results Posted as of Jul 25, 2022