Addition of Daclizumab to Standard Graft-Versus-Host Disease Prophylaxis in Patients with Thalassemia Major Undergoing Transplantation from Alternative Donor Hematopoietic Stem-Cell Transplantation: A Single-Center Retrospective Analysis from China

Background: Previous studies have confirmed that the incidence of Graft-versus-host disease (GvHD) remained very high in patients with thalassemia major (TM) undergoing alternative donor hematopoietic stem-cell transplantation (HSCT), which seriously affected patients' overall survival (OS), thalassemia-free survival (TFS) and thalassemia-GvHD-free survival (TGFS), especially acute GvHD (aGvHD). This study aimed to investigate whether administering Daclizumab at a dose of 1 mg/kg on days +7, +14, +28, and +42, in addition to standard GvHD prophylaxis (tacrolimus [FK506], methotrexate [MTX], and mycophenolate mofetil [MMF]), reduces the incidence of GvHD in TM patients undergoing alternative donor HSCT.

Methods: We retrospectively analyzed data of consecutive TM patients who underwent alternative donor HSCT at the First Affiliated Hospital of Guangxi Medical University in China from March 2021 to March 2024. TM patients in the Daclizumab group received GvHD prophylaxis that included Daclizumab at a dose of 1 mg/kg on days +7, +14, +28, and +42, in addition to standard GvHD prophylaxis (FK506 at 0.03 mg/kg/day, MTX at 15 mg/m² on day +1 and 10 mg/m² on days +3, +6, and +11, and MMF at 250 mg/day for 90 days). Patients in the control group received standard GvHD prophylaxis only. The conditioning regimen for all patients included busulfan (Bu, 1mg/kg i.v. 4x daily on days -9 to -6), cyclophosphamide (Cy, 50mg/kg i.v. once daily, days -5 to -2), fludarabine (Flu, 50mg/m² i.v. once daily from days -12 to -10), and anti-thymocyte globulin (ATG, 2.5mg/kg i.v. once daily, days -4 to -1). Sixty-six (39.05%) patients received letermovir in prophylaxis of cytomegalovirus (CMV) infection, including 65 in the Daclizumab group and 1 in the control group. The primary endpoint was the cumulative incidence of grade 3-4 aGVHD on day +100. Secondary endpoints included OS, TFS, TGFS, Epstein–Barr virus (EBV), CMV, bacterial, fungal infections and Veno-occlusive disease (VOD), hemorrhagic cystitis (HC), post-transplant lymphoproliferative disease (PTLD).

Results: We evaluated the transplantation data of 169 patients. The baseline characteristics between the 85 (50.3%) patients in the Daclizumab group and the 84 (49.7%) in the control group were balanced, including age at transplantation, gender, serum ferritin, organ iron deposition, genotypes, and donor-recipient gender types. The median age was 9 years old (IQR, 6-11 years). The median follow-up period was 15 months (9-25 months). The median days for neutrophil engraftment were +12 (11-15) and +12 (11-14) in the Daclizumab and control groups, respectively (p=0.186). Platelet engraftment days were +14 (11-18.5) and +13 (12-17) in the two groups, respectively (p=0.482). The cumulative incidence of grades 2-4 aGvHD was 24.7% in the Daclizumab group and 38.1% in the control group (hazard ratio [HR], 0.651; 95%CI, 0.372-1.138; p=0.061). The cumulative incidence of grades 3-4 aGvHD was significantly lower in the Daclizumab group compared to the control group, at 5.9% and 20.2% (HR, 0.306; 0.111-0.842; p=0.006), respectively. Prompt initiation of robust therapeutic measures upon GvHD occurrence helps reduce patient mortality. Patients in the Daclizumab group had similar OS rates at 2 years compared to those in the control group (94.7% vs 94.0%; p=0.985) and comparable TFS rates at 2 years (94.7% vs 94.0%; p=0.985). Moreover, TGFS was significantly improved in the Daclizumab group compared to the control group at 2 years (86.6% vs 70.8%; HR, 0.366; 0.170-0.791; p=0.003). A notable decrease in the CMV reactivation rate was observed in the Daclizumab group compared to the control group (23.5% vs 44.0%; p=0.005). The cumulative incidence rates of EBV infection, bacterial infection, fungal infection, septicemia, HC, and VOD in the Daclizumab group were similar to the control group. No patients developed post-transplant PTLD.

Conclusions: This is the first clinical study report on the addition of Dalizumab to the standard GvHD prevention regimen for GvHD prophylaxis in thalassemia transplantation. The use of Daclizumab significantly reduced clinically relevant grade 3-4 aGvHD without increasing severe infections or transplant related complications, also improved post-transplant TGFS. The addition of Daclizumab is highly effective and safe for alternative donor transplantation in patients with TM.