Randomized Trial Assessing Isatuximab Efficacy in Pure Red Cell Aplasia Post-Allogeneic Hematopoietic Stem Cell Transplantation

The primary objective of this study is to assess the **efficacy** of isatuximab in the treatment of pure red cell aplasia (PRCA) caused by major ABO mismatch following allogeneic hematopoietic stem cell transplantation. The focus is on the reduction in PRCA resolution time, measured in days, when compared to a control group receiving only supportive care. This is clinically relevant as it aims to improve patient outcomes by potentially shortening the duration of PRCA, thereby reducing the need for prolonged supportive care and associated complications.

Secondary objectives include:

• Evaluating clinical and biological outcomes between the two study arms, such as the reduction of red blood cell transfusion needs with isatuximab, evolution of iron overload, and adverse events related to isatuximab in the context of allogeneic stem cell transplantation. Additionally, the study will assess quality of life concerning functional repercussions of chronic anemia, iterative transfusions, and iron overload at various time points post-randomization, as well as overall survival and relapse-free survival at multiple intervals post-transplant.
• Identifying prognostic factors for the spontaneous resolution of PRCA due to major ABO mismatch between day 60 and month 6, considering variables such as donor type, stem cell source, conditioning regimen, and the occurrence of acute or chronic graft-versus-host disease.
• Evaluating the interest in monitoring group hemagglutinins.
• Comparing the cost-effectiveness of the two study arms, including the costs associated with isatuximab treatment, hospitalizations, transfusion support, and chelation treatments.

The clinical trial involves participants diagnosed with **pure cell red aplasia** following a major ABO mismatch after allogeneic hematopoietic stem cell transplantation. The study population includes both male and female subjects aged 15 years and older. Participants are required to have persistent red blood cell transfusion dependence at day 60 post-transplant, with specific hematological criteria, and must not have experienced a relapse or progression of their underlying disease. The trial includes a vulnerable population, and all participants must have health insurance coverage and have provided informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as contraception methods are mandated for women of childbearing age and men during the study treatment period and for a specified duration after the last dose. The trial population was selected based on these criteria to evaluate the efficacy of isatuximab treatment compared to supportive care in reducing the resolution time of pure cell red aplasia.

The clinical trial is designed to evaluate the **efficacy** of the anti-CD38 monoclonal antibody **isatuximab** in the treatment of pure red cell aplasia (PRCA) by major ABO mismatch following allogeneic hematopoietic stem cell transplantation. This is a randomized, prospective, double-blind, controlled trial. The trial is expected to commence on February 20, 2024, and conclude by March 20, 2027. Participants will be randomly assigned to receive either isatuximab or supportive care, with the primary endpoint being the time to achieve transfusion independence. Secondary endpoints include the number of red blood cell transfusions, ferritin levels, adverse events, quality of life assessments, and antibody levels.

The study will involve several visits, beginning with a screening visit to confirm eligibility based on criteria such as age, previous transplantation, and health status. Participants must be 15 years or older, have undergone an allogeneic hematopoietic stem cell transplantation with a major ABO mismatch, and exhibit PRCA as defined by specific clinical parameters. The inclusion visit will ensure informed consent is obtained and that participants meet all inclusion criteria. Follow-up visits will occur at specified intervals, including D60, D100, M6, M9, M12, and M15 post-transplant, to monitor treatment effects and collect data on secondary endpoints. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participant involvement is expected to last until the resolution of PRCA or the end of the study period, whichever comes first. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any protocol violations. The trial will adhere to rigorous ethical standards, ensuring that all participants are treated with the utmost care and respect throughout the study duration.

The clinical trial involves the administration of **SARCLISA** (isatuximab), a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, specifically designed for **intravenous use**. The active substance, isatuximab, is a humanized monoclonal antibody targeting CD38, also known by the synonym SAR650984. The product is manufactured by Sanofi Winthrop Industrie and is authorized under the marketing authorization number EU/1/20/1435/003. The maximum daily dose is 10 mg/kg, with a total maximum dose of 30 mg/kg over a treatment period not exceeding 29 days. The administration schedule and dosing are carefully monitored to ensure participant compliance and safety throughout the trial.

In addition to the experimental treatment, the study includes a control group receiving supportive care only. This comparator treatment serves as a standard-of-care therapy to evaluate the efficacy of isatuximab in reducing the resolution time of pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation. The trial aims to provide a comprehensive assessment of isatuximab's therapeutic potential compared to existing supportive care practices.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the time to obtain transfusion independence for patients with **Pure Red Cell Aplasia (PRCA)**. This is defined as the time interval between randomization, corresponding to the six-month post-transplant mark, and the resolution of PRCA, indicated by the date of resolution of reticulocytopenia. The treatment involves the use of the anti-CD38 monoclonal antibody, isatuximab, compared to a control group receiving supportive care only.

Secondary endpoints include the number of red blood cell transfusions after randomization, ferritin levels at six, nine, and fifteen months post-transplant, and the occurrence of adverse events graded CTC-AE ≥ 2 after randomization. Additionally, quality of life will be assessed using the EORTC QLQ-C30 v3 questionnaire at various timepoints: day 60, day 100, and months six, nine, twelve, and fifteen post-transplant. Other secondary measures include factors associated with spontaneous resolution of PRCA between day 60 and month six post-transplant, antibody levels (anti-A and/or anti-B titers) at specified intervals, and the number of days of hospitalization, transfusion support, and chelation treatments.