Comparison of ATG-Thymoglobulin Versus ATLG-Grafalon for GVHD Prophylaxis in Elderly AML or MDS Patients Undergoing Allogeneic HSCT with Reduced Intensity Conditioning

The primary objective of this Phase III study is to compare the incidence of grade II-IV acute **graft-versus-host disease (GVHD)** at day 100 post-transplantation in patients with **acute myeloid leukemia (AML)** or **myelodysplastic syndrome (MDS)**. These patients are transplanted with a 10/10 matched unrelated donor following a reduced intensity conditioning regimen with fludarabine-treosulfan. The comparison is between patients receiving GVHD prophylaxis with ATG-thymoglobulin versus ATLG-grafalon. This objective is clinically relevant as it aims to determine the most effective prophylactic treatment to reduce the incidence of acute GVHD, a significant complication that can affect transplant outcomes and patient survival.

Secondary objectives include evaluating the effect of the two GVHD prophylaxis regimens on various clinical outcomes: - Engraftment and graft failure - Incidence of grade I acute GVHD and chronic GVHD - Incidence of infections - Progression-free survival - Relapse incidence - Non-relapse mortality - Overall survival - GVHD and relapse-free survival (GRFS) - Health-related quality of life (FACT BMT) - Chimerism - Immune reconstitution (T, B, NK, regulatory T cell levels in peripheral blood) - Days of hospitalization during the first 12 months post-transplantation - Incidence and severity of veno-occlusive disease (VOD) - Prognostic factors associated with the primary endpoint for each prophylaxis arm - Incidence of late acute GVHD (after day 100), overlap syndromes, and chronic GVHD.

The clinical trial involves participants diagnosed with **myelodysplastic syndrome (MDS)** or **acute myeloid leukemia (AML)**. The study population includes both male and female subjects aged between 50 and 70 years. Participants aged 50 to 55 years must be unfit for myeloablative conditioning. The trial does not involve a vulnerable population. Participants are required to have a 10/10 matched unrelated donor for transplantation and meet specific health criteria, including an ECOG performance status of ≤ 2, no severe uncontrolled infections, and adequate organ function. Lifestyle considerations include the use of prescribed contraception methods throughout the study duration. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants have no HLA matched related donor and have signed informed consent, with health insurance coverage being mandatory.

The clinical trial is designed to evaluate the efficacy of **GVHD** prophylaxis using ATG-thymoglobulin compared to ATLG-grafalon in elderly patients diagnosed with **acute myeloid leukemia** (AML) or **myelodysplastic syndrome** (MDS) undergoing allogeneic hematopoietic stem cell transplantation. This is a Phase III, randomized, double-blind, controlled trial. The study aims to compare the incidence of grade II-IV acute GVHD at day 100 post-transplantation between the two treatment groups. The trial is expected to run from October 2023 to September 2028, with participant involvement lasting until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease status, and donor matching. Following successful screening, participants will be randomized to receive either ATG-thymoglobulin or ATLG-grafalon as part of their conditioning regimen. The study includes multiple follow-up visits at key time points: day 100, month 6, month 12, and month 24 post-transplantation. These visits are designed to monitor hematopoietic recovery, immune reconstitution, chimerism, and the incidence of GVHD and other complications. The end-of-study visit will occur at month 24, marking the conclusion of participant involvement.

Participant involvement is expected to last up to 24 months, with conditions for early termination including severe adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and meet the inclusion criteria, which include age between 50 and 70 years, absence of an HLA matched related donor, and adequate organ function. The study will utilize both oral and intravenous administration routes for the investigational products, with dosages tailored to individual patient needs and monitored throughout the trial duration.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Mycophenolate mofetil** is provided in the form of a coated tablet, administered orally. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 30 mg/kg and a total maximum dose of 1350 mg/kg over a treatment period of 45 days. Compliance with the dosing schedule is monitored throughout the trial.

**Thymoglobuline**, a rabbit anti-human thymocyte immunoglobulin, is administered as a solution for infusion. The pharmaceutical form is a powder for solution for infusion, with a concentration of 5 mg/ml. The maximum daily dose is 2.5 mg/kg, with a total maximum dose of 5 mg/kg over a 2-day treatment period. The route of administration is intravenous infusion, and participant compliance is closely monitored.

**Ciclosporin** is provided in capsule form and administered orally. The dosage is 3 mg/kg per day, with a total maximum dose of 540 mg/kg over a 6-week period. The administration schedule is designed to ensure consistent therapeutic levels, and adherence is tracked throughout the study.

**Fludarabine** is administered as a powder for solution for infusion, with a dosage of 30 mg/m² per day and a total maximum dose of 150 mg/m² over a 5-day period. The route of administration is intravenous infusion, and compliance with the dosing regimen is monitored.

**Grafalon**, an anti-T lymphocyte immunoglobulin for human use derived from rabbits, is administered as a solution for infusion. The maximum daily dose is 10 mg/kg, with a total maximum dose of 30 mg/kg over a 3-day period. The administration is via intravenous infusion, and participant adherence is tracked.

**Treosulfan** is provided as a solution for infusion, with a dosage of 10000 mg/m² per day and a total maximum dose of 30000 mg/m² over a 3-day period. The route of administration is intravenous infusion, and compliance with the treatment protocol is monitored.

Efficacy in this clinical trial will be assessed primarily by evaluating the incidence of grade II-IV acute **Graft-versus-Host Disease (GVHD)** at day 100 post-transplantation, as classified by the MAGIC criteria. This primary endpoint will provide a direct measure of the effectiveness of the GVHD prophylaxis being tested. Secondary endpoints will include a comprehensive set of parameters to further evaluate efficacy and patient outcomes. These include hematopoietic recovery, defined as at least 7 consecutive days with neutrophils greater than 0.5 G/L and platelets greater than 20 G/L, and immune reconstitution, which will be assessed by analyzing T, B, NK, regulatory T cell, and gammaglobulin levels in peripheral blood at multiple timepoints: month 1, day 100, month 6, month 12, and month 24 post-transplantation.

Additional secondary endpoints will include chimerism at month 1, day 100, month 6, and month 12, as well as the incidence of grade I acute GVHD and chronic GVHD at month 12 and month 24, using the NIH classification. The trial will also monitor relapse incidence, progression-free survival, severe infections, and incidences of CMV and EBV reactivations at specified intervals. Non-relapse mortality, overall survival, and GVHD and relapse-free survival (GRFS) will be evaluated at month 6, month 12, and month 24. Health-related quality of life will be assessed using the FACT-BMT-v4 questionnaire at inclusion and at day 100, month 6, and month 12 post-transplantation. The number of days of hospitalization for the transplant and related complications until month 12 will also be recorded. The incidence and severity of VOD at day 100, lymphocyte counts before conditioning, and late acute GVHD, overlap syndromes, and chronic GVHD at day 120 will be documented to provide a comprehensive assessment of the trial's efficacy outcomes.