Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor

Phase 3Not Yet RecruitingNCT06083129

Assistance Publique - Hôpitaux de Paris324 enrolled

Overview

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most of the patients requiring an allo-HSCT are above 50 years of age and are transplanted with a reduced intensity conditioning (RIC) regimen. The optimal RIC and Graft Versus Host Disease (GVHD) prophylaxis regimen allowing a good control of the disease while preventing GVHD remains to be determined for elderly patients. A phase III trial comparing the conventional RIC fludarabine-busulfan 2 days to fludarabine-treosulfan demonstrated an advantage for the flu-treosulfan arm in terms of event free survival (EFS), that should therefore be considered as the new standard of RIC regimen for AML and MDS. GVHD prevention has a crucial role in post-transplant outcomes by potentially interfering with the graft-versus-leukemia (GVL) effect and immune reconstitution. Anti-thymocyte globulins (ATG) are recommended to reduce the risk of acute and chronic GVHD in transplants performed with matched unrelated donors. However, the optimal type of ATG between the 2 approved brands (ATG-thymoglobulin and ATLG-grafalon) displaying distinct characteristics and the optimal dose of ATG are still unknown. In a retrospective study of patients transplanted mainly with RIC with matched related and unrelated donors for haematological malignancies, we observed that Anti-T lymphocyte globulin (ATLG) was associated with a reduction of grade II-IV acute GVHD in comparison to ATG without increasing the incidence of relapse. In this phase III randomised study, we propose to compare GVHD prevention with ATG versus ATLG in AML and MDS patients above 50 years of age transplanted with a matched unrelated donor following a fludarabine-treosulfan RIC, with the hypothesis that ATLG would better control GVHD in this population of patients thus limiting the risk of morbidity and mortality of the procedure.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Eligibility

Sex: ALLMin age: 50 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 50 and ≤ 70 years 2. Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score ≥2) 3. AML requiring allogeneic stem cell transplantation (intermediate or high-risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS≥ 1.5 or IPSS-R \> 4.5 or IPSS-R \> 3-4.5 with risk features \[rapide blast increase, life-threatening neutropenia (\<0.3 G/L) or thrombopenia (\<30G/L) or high transfusion needs (\>2/month for 6 months)\] 4. Without an HLA matched related donor 5. Having an identified matched HLA 10/10 unrelated donor 6. With usual criteria for HSCT: 1. ECOG performans status ≤ 2 2. No severe and uncontrolled infection 3. Cardiac left ventricular ejection fraction ≥50% 4. Lung DLCO \> 40% 5. Adequate organ function: ASAT and ALAT ≤ 3N, total bilirubin ≤ 2N, creatinine clearance ≥ 50 mL/min (except if those abnormalities are linked to the hematological disease) 7. With health insurance coverage 8. Having signed a written informed consent 9. Contraception methods must be prescribed during all the duration of the research NB: The authorized contraceptive methods are: * For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal releasing system (IUS), sexual abstinence (only if this the preferred and usual lifestyle of the participants). * For man in absence of permanent sterilization: sexual abstinence, condoms Exclusion Criteria: 1. Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) 2. Uncontrolled infection 3. Seropositivity for HIV or HTLV-1 or active hepatitis B or C 4. Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation 5. Heart failure according to NYHA (II or more) or Left ventricular ejection fraction \< 50%. 6. Lung DLCO ≤ 40% 7. Preexisting acute hemorrhagic cystitis 8. Renal failure with creatinine clearance \< 50ml / min 9. Pregnancy (β-HCG positive) or breast-feeding 10. Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol 11. Patient under state medical aid 12. Patient under legal protection (protection of the court, or in curatorship or guardianship). 13. For Grafalon: Hypersensitivity to the active substance or to any of the excipients 14. For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients 15. Participation in other interventional clinical trials 16. Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan

Outcomes

Primary Outcomes

Incidence of grade II-IV acute Graft Versus Host Disease (GVHD) according to the Mount Sinai Acute GVHD International Consortium (MAGIC) classification

Acute GVHD MAGIC classification permit to diagnose and score the severity of acute GVHD. MAGIC score varies from Grade 0 to Grade 4. The higher the score the more severe the damage.

Time frame: At day 100 post-transplantation

Secondary Outcomes

Number of patients with at least 3 consecutive days with neutrophils > 0.5 G/L and platelets > 20 G/L

Hematopoietic recoveries

Time frame: Up to 24 months

T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood

Immune reconstitution

Time frame: 1 month after transplantation

T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood

Immune reconstitution

Time frame: 100 days after transplantation

T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood

Immune reconstitution

Time frame: 6 months after transplantation

T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood

Immune reconstitution

Time frame: 12 months after transplantation

T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood

Immune reconstitution

Time frame: 24 months after transplantation

Percentage of chimerism

Time frame: 1 month after transplantation

Percentage of chimerism

Time frame: 100 days after transplantation

Percentage of chimerism

Time frame: 6 months after transplantation

Percentage of chimerism

Time frame: 12 months after transplantation

Incidence of grade I acute GVHD

Treatments for acute GVHD will be described : first line treatment, response to steroids, treatment courses for refractory acute GVHD

Time frame: Up to 24 months

Incidence of chronic GVHD

Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.

Time frame: 12 months after transplantation

Incidence of chronic GVHD

Time frame: 24 months after transplantation

Incidence of relapse

Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).

Time frame: 12 months after transplantation

Incidence of relapse

Time frame: 24 months after transplantation

Progression free survival

Time frame: 12 months after transplantation

Progression free survival

Time frame: 24 months after transplantation

Number of severe infections

Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events

Time frame: 100 days after transplantation

Number of severe infections

Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events

Time frame: 12 months after transplantation

Incidence of CytoMegaloVirus (CMV) reactivation

Time frame: 100 days after transplantation

Incidence of CytoMegaloVirus (CMV) reactivation

Time frame: 6 months after transplantation

Incidence of CytoMegaloVirus (CMV) reactivation

Time frame: 12 months after transplantation

Incidence of Ebstein Barr Virus (EBV) reactivation

Time frame: 100 days after transplantation

Incidence of Ebstein Barr Virus (EBV) reactivation

Time frame: 6 months after transplantation

Incidence of Ebstein Barr Virus (EBV) reactivation

Time frame: 12 months after transplantation

Non-relapse mortality

Time frame: 6 months after transplantation

Non-relapse mortality

Time frame: 12 months after transplantation

Non-relapse mortality

Time frame: 24 months after transplantation

Overall survival

Time frame: 12 months after transplantation

Overall survival

Time frame: 24 months after transplantation

GVHD and relapse free survival (GRFS)

Defined by being alive without disease relapse and without having developed acute grade III-IV or severe chronic GVHD

Time frame: Up to 24 months after transplantation

Health-related Quality of life

Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.

Time frame: At inclusion

Health-related Quality of life

Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.

Time frame: 100 days after transplantation

Health-related Quality of life

Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.

Time frame: 6 months after transplantation

Health-related Quality of life

Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.

Time frame: 12 months after transplantation

Number of days of hospitalization for the transplant and after the hospitalization for transplantation related complications

Time frame: Up to 12 months after transplantation

Incidence and severity of veino-occlusive disease (VOD)

Time frame: 100 days after transplantation

Lymphocyte counts on standard blood counts before conditioning

Time frame: 7 days before transplantation

Number of late acute GvHD, overlap syndromes and chronic GvHD

Time frame: from day 100 to day 120 after transplantation

Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts