Sequential Conditioning in Haploidentical Transplantation for Hematopoietic Stem Cells in Patients With Relapsed or Refractory Lymphoid Hematological Disorders

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 lymphoid hematological refractory or 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. For patients refractory or in relapses with an indication of allo-HSC, used the combinaison of an SET followed by the reduced-intensity allo-HSC (RIC) has shown some interesting results. A post-transplant immune modulation with prophylactic injections of donor lymphocytes (PDLI) showed its effectiveness to decrease the risk of relapse while having a lower toxicity than chemotherapy

Official Title
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Sequential Chemotherapy Prior Conditioning Reduced Intensity: Study Routine Care in Haploidentical Allogeneic Hematopoietic Stem Cells in Patients With Relapsed or Refractory Lymphoid Hematological Disorders

Conditions
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Refractory or Relapsed Lymphoid Haemopathy

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 an indication of allo-HSC for a lymphoid hematological malignancy like Hodgkin's lymphoma, non hodgkin's lymphoma b cell (mantle follicular, diffuse large cells, marginal zone,MALT) or T (peripheral T whithout specificity, anaplasic, angio-immunoblastic, natural killer cells, gamma / delta T cells, Sezary's syndrome, primitive cutaneous T), prolymphocytic leukemia, chronic lymphocytic leukemia, waldenström's disease and for which a therapeutic strategie combining a sequential chemotherapy followed by the reduced-intensity conditioning(SET RIC + PDLI) is decided Patients at least in partial response (standard criteria) after a rescue treatment the day of evaluation at 1 month before the conditioning Advanced 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: Invasion of uncontrolled 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. life expentancy estimated less than 1 month by investigator

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
Interventional Model Description: Patients with refractory or relaps lymphoid hematological disorders
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Relapsed or refractory lymphoid hematological disorders<br>Patients in refractory or relapses with an indication of allo-HSC used the combination of an SET followed by the RIC with the PDLI | 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 DO<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) | Describe efficacy and safety of the combination of an SET followed by the RIC with post-transplant immune modulation by PDLI in patients with refractory or relaps lymphoid hematological refractory or multiple relapses lymphoid hematological disorders | 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 and free survival | Describe the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse and relapse-free survival | 90 days and then 6, 12 and 24 months after transplantation | 
| Cumulative incidence of death not related to relapse | Describe 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) | Describe 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 and number PDLI / patient ; incidence, severity and treatment of possible secondary GVHD in these patients | Describe the feasibility of prophylactic injections of donor lymphocytes (PDLI) | 2 years after transplantation | 
| Immune reconstitution post-transplantation in the peripheral blood | Immune reconstitution will be determined by CD4 lymphocyte, CD8, T regulators, Natural Killer cells and B cells levels in the peripheral blood | 30, 90 and 180 days after transplantation | 
| Tolerance of this therapeutic strategy | The tolerance will be evaluated by: The cumulative incidence of death not related to relapse at 90 days, 1 year and 2 years after transplantation The cumulative incidence of acute and chronic graft against host disease (GVHD) The incidence of advert events | 90 days and the 6, 12 and 24 month 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