A multi-center clinical trial of allogeneic hematopoietic stem cell transplantation in transfusion-dependent thalassemia

Allogeneic stem cell transplantation (allo-HSCT) has recently been approved as standard therapy for transfusion-dependent thalassemia (TDT) but remains limited to the use of HLA-matched sibling donors (MSDs), due to a lack of large-scale prospective studies evaluating the use of grafts from alternative donors. Here, we report the results of a non-randomised, interventional, phase 4 clinical trial evaluating allo-HSCT from alternative donors for the treatment of TDT. A total of 823 patients with TDT were transplanted with grafts from MSDs (n = 331) or alternative donors, including matched unrelated donors (MUDs; n = 352) and haploidentical related donors (Haplos; n = 140). Conditioning was with busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin. Graft-versus-host disease (GvHD) prophylaxis was cyclosporine, methotrexate (MTX) and mycophenolate mofetil (MMF) for recipients of MSDs and tacrolimus, MTX, MMF for others. The primary endpoints were 2-year overall survival (OS) and event-free survival (EFS). Two-year OS for MSDs, MUDs, Haplos was 97.2% (95% CI, 95.4-99.0), 93.1% (90.5-95.9) and 95.4% (91.9-99.1); EFS was 97.2% (95.4-99.0), 92.9% (90.1-95.7) and 94.7% (90.9-98.6); GvHD-free, relapse-free survival (GRFS) was 91.4% (88.4-94.6), 77.0% (72.6-82.7) and 75.6% (68.5-83.4) respectively. Two-year OS and EFS for MUDs were lower than those for MSDs (both P < 0.05) and were not significantly different with those for Haplos (both P > 0.05). Transplant-related mortality was 4.4% (3.0-5.9) and graft failure rate was 0.5%. The incidence of grades 2-4 acute GvHD and moderate-severe chronic GvHD from alternative donors were higher than those from MSDs (28.9% [24.7-33.2] vs 7.5% [4.9-10.7], P < 0.001; 12.3% [9.2-15.7] vs 5.0% [2.9-7.9], P < 0.01). In summary, these findings may help expand the donor pool for patients with TDT lacking MSDs (ClinicalTrials.gov: NCT04009525). Allogeneic stem cell transplantation (alloHSCT) is approved for the treatment of transfusion-dependent thalassemia but remains limited to the use of matched sibling donors. In this multi-centre, phase-4 prospective clinical trial, the authors evaluate the use of alloHSCT with matched unrelated donors and haploidentical relatives.