Evaluation of Allogeneic Hematopoietic Stem Cell Transplantation with Azacitidine Versus Conventional Chemotherapy in High-Risk Myelodysplastic Syndromes

The primary objective of this study is to evaluate the **feasibility** of hematopoietic stem cell transplantation (**HSCT**) in patients with higher-risk myelodysplastic syndromes (**HR-MDS**). This evaluation is stratified based on the proportion of bone marrow blasts, specifically comparing patients with less than 10% blasts to those with 10% or more. This distinction is clinically relevant as it may influence treatment outcomes and guide therapeutic decisions in HR-MDS management.

Secondary objectives include:

• Overall survival in the intention-to-treat (ITT) population.
• Event-free survival in the ITT population, considering relapse, progression, or death from any cause.
• Assessment of safety.
• Changes in the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) at the time of HSCT compared to enrollment.
• Pattern of relapse or progression post-HSCT.
• Translational studies involving mutational, methylation, and cytofluorimetric analysis pre- and post-treatment.
• Quality of life assessment at enrollment, before HSCT, and six months post-HSCT.
• Pharmacoeconomic evaluation in terms of hospitalization duration.

The clinical trial involves participants diagnosed with **higher-risk myelodysplastic syndromes** (HR-MDS). The study population includes both male and female subjects, aged between 18 and 70 years, who have not previously received treatment for HR-MDS. Participants are required to have a life expectancy of at least three months and an Eastern Cooperative Oncology Group Performance Status Grade of 0-2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial population was selected based on their eligibility for hematopoietic stem cell transplantation (HSCT) and their consent to participate, as per ICH/EU/GCP and national local laws. The sponsor has not provided the total number of participants involved in the study. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria focus on patients with newly diagnosed higher-risk MDS, specifically those classified as IPSS Intermediate-2 and high, and IPSS-R intermediate to very-high. The sponsor has not disclosed additional lifestyle considerations or exclusion criteria.

The clinical trial is designed to evaluate the feasibility of hematopoietic stem cell transplantation (HSCT) in patients with **higher-risk myelodysplastic syndromes** (HR-MDS). This is a prospective, randomized, double-blind, controlled study. The trial aims to compare the outcomes of HSCT performed upfront versus HSCT preceded by azacitidine or conventional chemotherapy, based on the proportion of bone marrow blasts. The study is expected to run from November 27, 2020, to September 30, 2031, with participant involvement lasting up to 42 days, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-70 years), newly diagnosed HR-MDS, and HSCT eligibility. The inclusion visit will also involve obtaining informed consent. Following randomization, participants will attend follow-up visits to monitor treatment response and safety, including assessments of overall survival, event-free survival, and adverse events. Translational studies involving mutational and cytofluorimetric analysis will be conducted at enrollment, before HSCT, and six months post-HSCT. Quality of life assessments and pharmacoeconomic evaluations will also be performed at these time points.

The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the primary endpoint of HSCT feasibility and secondary endpoints such as survival rates and safety profiles. Participants may be terminated early from the study if they experience significant adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial will utilize **cytarabine**, **azacitidine**, **daunorubicin hydrochloride**, **fludarabine phosphate**, **thiotepa**, and **busulfan** as part of the treatment regimen, administered via intravenous or subcutaneous routes, depending on the specific drug and treatment protocol.

The clinical trial involves the administration of several **experimental medications** and standard treatments. **Cytarabine** is utilized in the form of a powder for solution for injection. It is administered via **intravenous infusion** with a maximum daily dose of 200 mg/m² and a total dose not exceeding 4200 mg/m² over a treatment period of up to 21 days. Participant compliance is monitored through regular assessments of dosing schedules and infusion records.

**Azacitidine Accord** is provided as a 25 mg/mL powder for suspension for injection. This medication is administered **subcutaneously** with a maximum daily dose of 75 mg/m² and a total dose of 3150 mg/m² over a period of 42 days. Compliance is ensured by tracking the administration schedule and dosage adherence.

**Daunorubicin Hydrochloride** is supplied as a powder and solvent for solution for injection. It is administered **intravenously** with a maximum daily dose of 60 mg/m² and a total dose of 495 mg/m² over a 9-day treatment period. Monitoring of participant compliance is conducted through infusion logs and dosage verification.

**Fludarabine Phosphate** is available as a concentrate for solution for injection/infusion. It is administered **intravenously** with a maximum daily and total dose of 160 mg/m², limited to a single day of treatment. Compliance is monitored by ensuring accurate dosing and administration records.

**Thiotepa** is provided as a powder for concentrate for solution for injection/infusion. It is administered **intravenously** with a maximum daily and total dose of 10 mg/kg, restricted to a single day of treatment. Participant compliance is tracked through detailed administration logs.

**Busulfan** is administered as a concentrate for solution for injection. It is given **intravenously** with a maximum daily and total dose of 12.8 mg/kg, also limited to a single day of treatment. Compliance is monitored by maintaining accurate dosing records and administration schedules.

Throughout the trial, participant compliance is closely monitored through systematic documentation of dosing schedules, administration routes, and adherence to the prescribed treatment regimens. This ensures the integrity of the trial data and the safety of the participants. No placebo or comparator treatments are utilized in this study, as the focus is on the feasibility of allogeneic stem cell transplantation in higher-risk myelodysplastic syndromes.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the feasibility of **hematopoietic stem cell transplantation (HSCT)**, evaluated using a non-inferiority design. This will be determined by the proportion of patients who successfully receive HSCT out of the total number of randomized participants. Patients who undergo HSCT will be classified as "successes," while those who do not will be considered "failures." Sensitivity analyses will be conducted to adjust the treatment comparison based on prognostic factors.

Secondary endpoints include overall survival and event-free survival, which encompasses relapse, progression, or death from any cause. Safety will be monitored through the assessment of adverse events (AEs) and serious adverse events (SAEs). Additional analyses will involve the pattern of relapse or progression post-HSCT, translational studies with mutational and cytofluorimetric analysis, and quality of life assessments. These assessments will occur at enrollment, before HSCT, and six months after HSCT. A pharmacoeconomic evaluation will also be conducted, considering factors such as the duration of hospitalization and red blood cell transfusions.