A Multi-Center Clinical Trial of Allogeneic Hematopoietic Stem Cell Transplants in Transfusion Dependent Thalassemia

Background: Graft failure (GF) and graft-versus-host disease (GVHD) remain major barriers to successful outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with transfusion dependent thalassemia (TDT). We had reported an encouraging outcome of allo-HSCT in a single center study, which the 3-year event-free survival (EFS) was 97% in patients with TDT transplanted with HLA-matched sibling donors. We aimed to confirm this result and to assess the outcomes of allo-HSCT for TDT patients transplanted with alternative donor.

Methods: A prospective, multicenter, clinical trial was conducted at eighteen hospitals in China from July 2019 to July 2023. Patients with TDT underwent allo-HSCT with matched sibling donors (MSDs), matched unrelated donors (MUDs) and haploidentical related donors (HIDs) using the protocol of GX-07-TM. The conditioning regimen consisted of busulfan (Bu, 16mg/kg), cyclophosphamide (Cy, 200 mg/kg), fludarabine (Flu, 150 mg/m2), and anti-thymocyte (ATG, Thymoglobulin, 10mg/kg). The GVHD prophylaxis was cyclosporine A (CsA), methotrexate (MTX), mycophenolate mofetil (MMF) for patients with matched sibling donors and tacrolimus (Tac), MTX, MMF for patients with matched unrelated donors or haploidentical related donors. The primary end point was the 2-year overall survival (OS) and EFS after allo-HSCT. The study was registered at www.clinicaltrials.gov as NCT04009525.

Results: A total of 823 patients with TDT underwent allo-HSCT were enrolled, including 331 patients with MSDs, 352 patients with MUDs and 140 patients with HIDs. The median age was 8 years (IQR 5-11) and the median follow-up was 23 months (IQR 13–36). The 2-year OS and EFS of all patients were both of 95%. The 2-year TRM was 4.4% and the rate of GF was 0.5%. The 2-year OS and EFS was both 97% for MSDs, both 93% for MUDs and both 95% for HIDs. The 2-year EFS of patients with alternative donors were inferior to patients with MSDs (93% [ 95%CI: 91, 96] vs 97% [95, 99], HR 2.39, 95% CI 1.14–5.01; p=0.022). The 2-year TRM of patients with alternative donors was higher than patients with MSDs (5.8% [3.7, 7.9] vs 2.5% [0.8, 4.2], HR 2.34, 95% CI 1.06–5.14; p=0.035). Grades 2-4 and 3-4 acute GvHD in patients with MSDs were 7.5% [4.9, 11] and 1.9% [0.8, 3.9], which was lower than for patients with MUDs (28% [23, 33] and 15% [11, 19], both p<0.0001) and patients with HIDs (32%[24, 41] and 15%[8.9, 22], both p<0.0001). Total and moderate-severe cGvHD in patients with MSDs were 8.5% [5.7, 12] and 5.0% [2.9, 7.9], which was lower than for patients with MUDs (19% [15, 24] and 11% [7.9, 15], both p<0.001) and patients with HIDs (23% [15, 31] and 15% [8.9, 23], both p<0.05). Patients from HIDs showed higher incidences of pneumonia (49%), CMV (52%) and EBV (33%) reactivation compared to those from MSDs and MUDs. Moreover, rates of bacterial and fungal infections, septicemia, hepatic veno-occlusive disease, and posterior reversible encephalopathy syndrome was similar between groups. In multi-variate analyses，OS and EFS were associated with recipient age > 15 years (HR 3.07, 95%CI 1.06-8.88; and 2.88,1.01-8.23); grade 2-4 acute GvHD (5.24, 2.70-10.20 and 4.56, 2.40-8.69) and previous splenectomy (3.36,1.49-7.54 and 3.15, 1.41-7.02).

Conclusion: We report excellent 2-year OS and EFS after allo-HSCT in children and adolescents with transfusion dependent thalassemia using matched sibling donors or alternative donors. The outcomes were similar between patients with matched unrelated donors and haploidentical related donors. Allo-HSCT with alternative donors can be considered as a frontline option for TDT patients lacking matched sibling donors. Patients receiving alternative donors will also benefit from an improved GvHD-prophylaxis strategy.