Analysis of efficacy and prognostic factors in transfusion-dependent thalassemia following allogeneic hematopoietic stem cell transplantation using the ‘gx-07-tm’ regimen

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for transfusion-dependent thalassemia (TDT). Our center has performed over 1,000 transplants using the GX-07-TM regimen, a myeloablative protocol developed for TDT. This study evaluated the regimen's efficacy, compared survival across donor types, and identified key prognostic factors. Methods: We retrospectively analyzed 1,010 consecutive TDT patients who underwent Allo-HSCT using GX-07-TM between July 2007 and June 2024. Myeloablative conditioning consisted of fludarabine (Flu), busulfan (BU), cyclophosphamide (Cy), and anti-thymocyte globulin (ATG). GVHD prophylaxis involved calcineurin inhibitors (CNI), mycophenolate mofetil (MMF), and methotrexate (MTX). Primary endpoints were 2-year overall survival (OS), transplant-free survival (TFS). Transplant donors shifted over time: matched sibling donors (MSDs) predominated before 2020, whereas alternative donors (ADs) became dominant after that. Donor types included matched sibling donors (MSDs), unrelated donors (MUDs), and haploidentical donors (HIDs). A TFS prediction model was constructed using multivariable Cox regression. Results: Of the 1,010 patients (62.2% male, median age 7 years), 601 received grafts from MSDs, 243 from MUDs, and 166 from HIDs. The median follow-up duration was 65(5-208) months, 443 transplants performed after 2020. Median age was 7 years (2–20), with 628 males (62.2%) and 382 females (37.8%). Neutrophil and platelet engraftment occurred at median day +11 (10–14) and +14 (12–21), respectively. The cumulative 2-year OS, TFS, and graft-versus-host disease and relapse-free survival (GRFS) were 93.9%, 93.3%, and 84.0%, respectively. Outcomes improved after 2020 (OS: 95.7% vs 92.6%; TFS: 95.4% vs 91.7%). There were 62 deaths (6.1%), with 5.7% transplant-related mortality (TRM) and 0.8% graft failure (GF), mainly due to pneumonia. In the MSD group, 2-year OS, TFS, and GRFS were 94.3%, 94.0%, and 87.7%, with significant improvements after 2020 (OS: 97.8% vs 92.9%, p=0.02). Among 409 AD recipients (MUDs and HIDs), the 2-year OS, TFS, and GRFS were 93.2%, 92.3%, and 78.5%. Propensity score matching showed no significant differences between ADs and MSDs for OS (HR 2.47, 95% CI: 0.64–9.54) or TFS (HR 3.2, 95% CI: 0.87–11.83). However, inverse probability weighting indicated AD transplantation as a risk factor for TFS (HR 2.95, 95% CI: 1.15–7.57). Multivariable Cox regression was used to identify risk factors and construct a TFS prediction model. Independent risk factors for inferior TFS included age over 9 years (HR 2.11, 95% CI:1.23–3.60), pneumonia (HR 6.60, 95% CI:3.74–11.67), grade 2–4 aGVHD (HR 2.06, 95% CI:1.19–3.59), and umbilical cord blood grafts use (HR 6.59, 95% CI:1.37–31.78), while transplantation after 2020 was protective (HR 0.42, 95% CI:0.23–0.77). A TFS prediction model incorporating age, graft type, CD34+ cell dose, hepatomegaly, pneumonia, and acute GVHD was developed. Conclusions: This long-term, large-sample, retrospective study demonstrates that the ‘GX-07-TM’ regimen achieves excellent OS and TFS after allo-HSCT in patients with TDT using MSDs and ADs. AD transplantation is a viable frontline option for patients without MSDs. This is the first post-transplant survival prediction model in thalassemia, supporting early intervention and personalized monitoring.