Graphical abstract
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for transfusion-dependent thalassemia (TDT). Since the first HSCT for thalassemia performed by Thomas et al. [1], outcomes have improved substantially. A long-term survival comparison between human leukocyte antigen (HLA)-matched related donor (MRD) and matched unrelated donor (MUD) HSCT versus standard transfusion plus iron chelation in TDT children and adults revealed no significant difference in 30-year overall survival (OS; 82.6% vs. 85.3%) [2]. HSCT-related mortality (13.8%) was comparable to cardiovascular-related mortality (12.2%) in the transfusion group. In another retrospective analysis of 1,493 TDT patients; 91% under 18 years old (European Society for Blood and Bone Marrow Transplantation; EBMT Hemoglobinopathy Registry, 2000−2010), the 2-year OS was 88% and event-free survival (EFS) was 81% [3]. These findings underscore HSCT as a viable curative option for TDT when an HLA-matched donor is available, although pre-HSCT risk factors still affect outcomes. HSCT success in TDT is influenced by multifactorial factors such as age, clinical status before HSCT, donor type, HLA compatibility, and stem cell source. The Pesaro risk assessment [4]—which considers liver size, fibrosis, and iron chelation adherence—stratifies patients into risk classes, with higher mortality in classes II and III. This model has limitations, including the invasiveness of liver biopsy and varying definitions of adequate chelation. Furthermore, studies have identified higher-risk patients with poorer HSCT outcomes, such as those who are older, have severe iron overload or hepatomegaly, or exhibit alloimmunization from chronic transfusions [5-8].
In Thailand, the first successful HSCT for TDT was performed in 1988 at Siriraj Hospital. Multiple centers subsequently adopted HSCT for TDT patients. Here, we present a 30-year multicenter analysis of Thai patients younger than 20 years who underwent HSCT for TDT. The study aims to evaluate contributing factors affecting survival outcomes and complications which provide insights into HSCT evolution of TDT, to guide future practice in developing countries.
Methods
1. Study design
We conducted a multicenter retrospective study of HSCT in TDT patients who underwent related or unrelated HSCT at 5 major transplant centers in Thailand: Faculty of Medicine Siriraj Hospital and Ramathibodi Hospital, Mahidol University; Faculty of Medicine, Chulalongkorn University; Phramongkutklao Hospital and Phramongkutklao College of Medicine; and Faculty of Medicine, Prince of Songkla University. The study included transplants performed from January 1988 to December 2016, with follow-up until December 2021. Haploidentical HSCT procedures were excluded. Lucarelli risk classification was not feasible because liver biopsy was not performed in most cases. Instead, high-risk patients were identified based on age ≥10 years and hepatomegaly, as reported elsewhere [5,6,8].
2. Ethics approval
This study was approved by the Institutional Review Board of the Faculty of Medicine Siriraj Hospital (Si 658/2015), in accordance with the Declaration of Helsinki (1975) and its subsequent revisions. The protocol was registered in the Thai Clinical Trial Registry (TCTR20220905001).
3. Data collection
Collected data included demographic details, thalassemia type, liver and spleen size, transfusion history, serum ferritin (SF) levels, pre-HSCT splenectomy, HSCT complications, chimerism data, and outcomes. Histocompatibility was determined by serologic or DNA-based testing. Beginning in 2000, typing methods advanced from intermediate to high resolution and from 6−8 to 8−10 loci.
4. HSCT supportive care
The majority of patients received oral gentamicin before 2000 and ciprofloxacin thereafter for gut decontamination. Prophylactic antifungal therapy was administered during the first 100 days after HSCT, using oral nystatin or itraconazole before 2000, and fluconazole or posaconazole thereafter. Antifungal prophylaxis was extended beyond day 100 in patients who required additional immunosuppressive therapy for graft-versus-host disease (GVHD). Trimethoprim-sulfamethoxazole prophylaxis was initiated after stable engraftment and continued for 3 months after discontinuation of immunosuppressive therapy. After 2000, post-HSCT monitoring enhancements included DNA chimerism monitoring, cytomegalovirus surveillance, and refined GVHD prophylaxis with mycophenolate mofetil for most unrelated donor procedures. From 2010 onward, all centers adopted intravenous busulfan instead of oral busulfan, using a nomogram to guide dosing as previously described [9]. Most patients underwent pharmacokinetic monitoring for dose optimization.
5. Periods of analysis
To evaluate outcome patterns, data were categorized into 3 time periods based on the year of transplantation: P1 (1988−1999), P2 (2000−2009), and P3 (2010−2016).
6. Definitions and outcomes
TDT was defined as thalassemia patient who required regular blood transfusions every 2−5 weeks to maintain a pretransfusion hemoglobin (Hb) level 9−10 g/dL. GVHD and hepatic veno-occlusive disease (VOD) were defined according to established criteria [10-12]. Neutrophil engraftment was the first of 3 consecutive days with an absolute neutrophil count > 500/mm3. Platelet engraftment was the first of 7 consecutive days with a platelet count >20 000/mm3 without transfusions. Red blood cell transfusion independence was recorded as the first day on which no transfusions were required. The median time to neutrophil and platelet engraftment applies to patients who achieved primary engraftment, excluding cases of graft failure or pre-engraftment mortality. Chimerism status was defined as full and mixed donor chimerism (DC), corresponding to >95 and 5%–95% donor DNA, respectively. OS was defined as the time from HSCT to death from any cause, with patients alive at the last follow-up censored at the last contact date. EFS was defined as the time from HSCT to the first event, including graft failure, graft rejection, thalassemia recurrence, or death; patients without events were censored at the last follow-up date. Patients who lost to follow up were censored at their last known contact date. Graft failure was defined as the failure of primary neutrophil or platelet engraftment. Graft rejection was the loss of a previously successful engraftment, characterized by a progressive decline and loss of DC. Thalassemia recurrence was defined by the reestablishment of a thalassemia disease with transfusion-dependent state after HSCT.
7. Statistical analyses
Descriptive statistics were calculated using PASW Statistics ver. 18.0 (SPSS Inc., USA). Fisher exact test or Pearson chi-square test (as appropriate) was applied to compare parameters across the different HSCT groups. Missing data were handled using complete-case analysis, with the denominators (N) reported for each comparison in the table.
Kaplan-Meier survival analysis was performed to evaluate selected variables, and statistical significance was determined using the log-rank test. Univariate and multivariate Cox proportional hazards regression models were employed to determine the effect of potential covariates on OS and EFS. Univariate and multivariate logistic regression analyses were performed to identify factors significantly and independently associated with long-term endocrine side effects. Statistical significance was defined as a P value ≤0.05.
Results
A total of 266 HSCTs were performed in 249 TDT patients. The 5-year OS and EFS for the entire cohort was 91.3% and 81.0%, respectively. Survival did not differ significantly by stem cell source or donor type. Of these, 31 experienced thalassemia recurrence; 17 patients proceeded to a second HSCT (6.4% of all transplants). Most HSCTs (75.9%) had Hb E/β-TDT, and HLA-MRD transplants were most common (71.8%). Bone marrow (BM) remained the primary stem cell source (69.5%), although the use of peripheral blood stem cell (PBSC) increased significantly in P2 and P3 (P<0.01). Table 1 summarizes patient characteristics and HSCT details across each study period. The median age at HSCT was 6.9 years, and 14 HSCTs (5.3%) were performed at age >15 years. Patients transplanted after 1999 were significantly older (P<0.001), with a greater proportion of patients aged >10 years in P3 > P2 > P1 (P=0.03). Pre-HSCT splenectomy was performed in 38 patients (14.3% of HSCTs), except for 1 patient who underwent the procedure before a second HSCT.
Most patients (92.5%) received regular transfusions, and 70.2% had iron chelation therapy before HSCT, with a median SF of 1,728 ng/mL. The proportion of patients on regular transfusions and iron chelation increased significantly over time (P<0.01). There were no significant differences in liver size, pre-HSCT SF, or CD34+ cell doses across the 3 periods. The majority of patients received busulfan-based myeloablative conditioning (MAC) regimens without radiation. High-risk patients were identified in 33 HSCTs (12.4%). Beginning in 2000, these patients received pre-HSCT immunosuppressive therapy with hydroxyurea and/or azathioprine plus or minus 1−2 courses of fludarabine and dexamethasone. Thirty-two high-risk patients (12%) underwent reduced-intensity conditioning (RIC) with fludarabine, busulfan, and anti-thymocyte globulin, as previously reported [8]. These patients received PBSC targeting a CD34+ dose of 5−10×106 cells/kg. Cyclosporine and methotrexate were the most common GVHD prophylaxis (72.1% of HSCTs). Mycophenolate mofetil was added in most MUD and mismatched unrelated donor (MMUD) transplants (62.6% in P2 and 64.5% in P3).
The median follow-up time for this cohort was 102 months (range, 5 days−359 months). Among the 266 HSCTs, thalassemia recurrence occurred in 11.6%, with the highest rate in P1. The cumulative incidence of thalassemia recurrence at 5-year post-HSCT was 12.3%. Outcomes by transplant period are summarized in Table 2. The overall mortality rate was 9.0%. A total of 24 patients died, of whom 16 (66.7%) succumbed to infections, primarily Gram-negative sepsis. Bleeding was the second most common cause of death (20%), including 3 cases of pulmonary hemorrhage and 2 cases of intracerebral hemorrhage. VOD occurred in 12.4% of transplants, mostly mild or moderate. Acute GVHD developed in 26.7%, and chronic GVHD in 14.7% of patients. Incidence of acute and chronic GVHD was significantly higher in P2 and P3 than in P1. Three patients died from infections during chronic GVHD, and one died during acute GVHD.
1. MRD- versus MUD-HSCT
Given that MUD-HSCT was introduced in P2, and patients in P2 and P3 were significantly older, the comparison of MRD versus MUD outcomes was restricted to these later periods (194 HSCTs in total). There were no significant differences between MRD- and MUD-HSCT regarding stem cell source, patient age at HSCT, engraftment time, mortality, or thalassemia recurrence rates. However, acute complications, particularly VOD (P=0.015) and acute GVHD (P<0.001), were significantly more common in MUD-HSCT. The characteristics and outcomes of MRD- versus MUD-HSCT are shown in Table 3.
2. Survival by type of donors
Among those receiving HLA-MRD versus MUD transplants, 5-year OS was 91.5% and 88.0%, respectively (P=0.52), and 5-year EFS was 82.0% versus 76.2%, respectively (P=0.45). All 9 patients who underwent mis-MRD transplants survived, although 2 experienced graft rejection, yielding a 5-year EFS of 77.8%. In contrast, all 7 patients who received MMUD-HSCT survived and achieved thalassemia-free status. Figs. 1 and 2 illustrate OS and EFS for all related donor versus unrelated donor transplants.
4. Prognostic factors for transplant outcomes
From Univariate analysis, patients who underwent HSCT at age ≤10 years or with pre-HSCT SF ≤2,500 ng/mL had significantly better 5-year OS and EFS. Figs. 5 and 6 illustrate these outcomes stratified by age (≤10 vs. >10 years). Notably, a significant benefit of younger age was observed only in P1, not in P2 or P3. Pre-HSCT splenectomy was significantly associated with worse 5-year OS, whereas oral busulfan was linked to poorer 5-year EFS compared with intravenous busulfan (P value was marginally significant at P=0.08). However, the type of conditioning regimens (MAC vs. RIC) did not affect OS or EFS. Furthermore, patients receiving low CD34+ cell doses (≤3×106 cells/kg for BM or PB, and ≤3×105 cells/kg for cord blood) had significantly worse OS and EFS. Univariate analysis of these pre-HSCT variables affecting survival is summarized in Table 4. The subsequent multivariate analysis of these factors showed statistically significant adverse effects for the following 3 variables. Pre-HSCT SF > 2,500 ng/mL emerged as a negative predictor for both OS (hazard ratio [HR], 2.82; 95% confidence interval [CI], 1.04−7.61; P=0.04) and EFS (HR, 3.06; 95% CI, 1.40−6.70; P<0.01). A low CD34+ cell dose was significantly detrimental to EFS (HR, 4.17; 95% CI, 1.82−9.09; P=0.01). Oral busulfan was also significantly associated with worse EFS (HR, 2.86; 95% CI, 1.16−7.14; P=0.02).
For factors affecting thalassemia recurrence, univariate (data not shown) and multivariate analyses were conducted, including age at HSCT, pre-HSCT spleen and liver size, splenectomy, pre-HSCT SF, donor type, stem cell source, oral versus intravenous busulfan, types of conditioning regimen, and CD34+ cell dose. Only a low CD34+ cell dose (BM and PB ≤3×106 cells/kg, cord blood ≤3×105 cells/kg) significantly increased recurrence risk (odds ratio, 4.74; 95% CI, 1.81−12.44; P=0.002). We analyzed DC results collected at 1, 3, 6, and 12 months post-HSCT. Only the mixed DC status at 1 and 3 months was significantly correlated with the risk of graft rejection leading to thalassemia recurrence (HR [95% CI], 54.26 [6.77−434.74], P<0.001 and 13.84 [2.53−75.56], P=0.002, respectively). Donor lymphocyte infusions were administered to 21 patients with mixed chimerism, ranging from 1−11 times.
5. Cohort of long-term survivors
We evaluated 211 patients who remained thalassemia-free for more than 2-year post-HSCT. The median follow-up time was 10.5 (range, 2−30) years. Of these, 48 (22.7%) experienced at least 1 late complication and 17 (8.1%) had mixed DC. The lowest DC observed in these survivors was 29.65% at 9-year post-HSCT. This patient was ex-Hb E/beta-thalassemia post MUD-HSCT. At the last follow-up, her Hb level was 8.8 g/dL without transfusion. Hb typing revealed Hb A 72.2, F 7.8, and E 13.5%.
Endocrine dysfunction was the most frequent late effect (28 patients, 58.3%), with a significantly higher incidence in P2 and P3 compared to P1 (18.4% vs. 13% vs. 2.6%) (P=0.01). The major endocrine manifestations included gonadal insufficiency (17 patients, 35.4%), hypothyroidism (10 patients, 20.8%), diabetes mellitus (4 patients, 8.3%), Hashimoto thyroiditis (1 patient), and toxic goiter (1 patient). Three patients developed 2 endocrine complications, and one had three. In the univariate analysis, patients with endocrine dysfunction were significantly older at HSCT, and those aged >10 years had a higher risk for these complications. RIC and acute GVHD grades 2–4 also showed a significant correlation with a higher risk of endocrine complications. The univariate analyses of pre-HSCT predictors for endocrine outcomes are summarized in Table 5. However, the subsequent multivariate analysis revealed that only acute GVHD grades 2–4 was significantly correlated with the risk of long-term endocrine complications (HR, 2.84; 95% CI, 1.13−7.15; P=0.027).
Late effects attributed to chronic GVHD occurred in 8 patients (16.7%). Bronchiolitis obliterans was the most common manifestation (5 patients, 10.4%), followed by scleroderma (3 patients, 6.3%), eye irritation, and esophageal stricture with malnutrition (1 patient each). Two patients presented with late-onset chronic GVHD symptoms.
Five patients (10.4%) developed autoimmune disorders, including autoimmune hemolytic anemia (2 patients), autoimmune hypothyroidism (2 patients), and Hashimoto thyroiditis (1 patient). Their HSCT types comprised 2 MRDs, 2 MUDs, and 1 MMUD. Three patients had full DC, and chimerism data were unavailable for the remaining 2. No malignancies were observed among ex-thalassemia survivors in this cohort.
Discussion
This study provides a comprehensive analysis of 266 HSCT outcomes in 249 pediatric TDT patients in Thailand over 30 years. The data concerning some of these HSCT cases were previously reported [8,13-15]. Our analysis revealed no significant difference between MRD-HSCT and MUDHSCT, with 5-year OS and EFS around 90% and 80%, respectively. This finding aligns with prior observations that, with stringent HLA matching, pre-HSCT immunosuppression and appropriate conditioning intensity in high-risk patients, and improved supportive care, MUD-HSCT can approximate MRD-HSCT outcomes [7,8,16-18]. The Thalassemia International Federation also recommends HLA-MUDs if MRDs are unavailable and emphasizes the importance of stringent HLA class I and II compatibility criteria to optimize outcomes [19]. A Chinese study supports this notion, reporting excellent outcomes in 48 children (aged 2−11 years) with TDT who underwent MUD-PB HSCT using cyclophosphamide/fludarabine/intravenous busulfan/antithymocyte globulin. All achieved donor engraftment, with OS and EFS of 100% at a median follow-up of 14 months, and the incidence of grades II−IV acute GVHD and chronic GVHD was 8.3% each [20]. Similarly, a South Indian study of 264 children with thalassemia major who underwent MRD- (78%) and MUD-HSCT (22%) reported a median follow-up of 65 months, with 93% receiving a MAC regimen comprising treosulfan/thiotepa/fludarabine and 61% receiving PBSC. In that study, the EFS and OS for MUD-HSCT were 84% and 87%; and matched sibling donor-HSCT were 94% and 95%, respectively. However, acute GVHD and chronic GVHD rates were high in MUD-HSCT (60% and 41%, respectively), likely reflecting PBSC predominance [21].
In our series, MUD-HSCT showed significantly higher rates of VOD and acute GVHD (Table 3). In addition, P2 and P3—which increased use of MUD, mismatched donors, and PBSC—also had higher incidences of VOD, acute GVHD, and chronic GVHD despite optimized GVHD prophylaxis for most MUD procedures; yet, these periods showed a lower rate of thalassemia recurrence (Tables 1 and 2). The elevated VOD incidence was likely due to the higher intensity conditioning and immunosuppressive drugs employed in MUD, mismatched donor, and PBSC settings. However, the higher incidence of GVHD may have been beneficial by mitigating the risk of thalassemia recurrence from graft rejection. Our 5-year OS and EFS are comparable to the multicenter EBMT hemoglobinopathy registry in 2000-2010 which results 2-year OS 88% and EFS 81% [3] and the Italian sibling cohorts which reported long-term 20-year OS 89.2% and EFS 85.7% [22]. Notably, our HLA-mis-MRD- and MMUD-HSCT outcomes (5-year OS and EFS) were more favorable than a prior report [7], possibly because our mismatched cases were few and involved only a single antigen or allele mismatch.
Older age at HSCT, commonly defined as ≥7 to ≥10 years, has been repeatedly associated with poorer outcomes in Asian, EBMT, and Italian studies. This is often attributed to a higher pre-HSCT transfusion load, a greater iron burden, and subsequent organ damage [3,5-8,21]. Our findings confirm this association in patients older than 10 years who underwent HSCT during the early period (P1), where younger recipients (≤10 years) showed significantly better 5-year OS and EFS. However, this age-related effect was not statistically significant in P2 and P3 (Table 4), highlighting an important observation that the negative impact of older age at the time of HSCT has become less pronounced in more recent periods. This supports the continuous evolution of risk models beyond fixed age cutoffs. Although MUD-HSCT was first introduced in P2 and the proportion of older children receiving transplants rose during P2 and P3, there was also a concomitant increase in the proportion of patients receiving regular transfusions and iron chelation which were known favorable factors for HSCT outcome. Furthermore, our study showed a decrease in pre-HSCT splenectomy over time. This reduction likely reflects our improvements in medical management, including early and adequate blood transfusions to minimize spleen enlargement. Additional advances after 2000 included refinements in HLA typing, widespread adoption of intravenous busulfan, greater use of fludarabine-based RIC and pre-HSCT immunosuppression for high-risk patients, and more robust post-HSCT supportive care. These collective improvements likely attenuated the adverse effect of older age observed in P1, resulting in more favorable outcomes for older children in the 2 later periods and better survival gains despite higher GVHD rates.
Irregular iron chelation has been identified as an independent prognostic factor in HSCT [4-6,19]. SF levels can serve as a noninvasive indicator of iron overload, although the optimal pre-HSCT cutoff remains uncertain. In our study, SF ≤ 2,500 ng/mL was significantly associated with better 5-year OS and EFS (Table 4), underscoring the importance of effective iron chelation and suggesting that SF ≤ 2,500 ng/mL may be an appropriate pre-HSCT target.
Although pre-HSCT splenectomy correlated with significantly lower OS in our study, this association did not reach statistical significance in multivariate analysis. A study by Mathews et al. [23] reported higher rates of peritransplant infectious deaths, lower EFS, and reduced OS in β-thalassemia major patients undergoing pre-HSCT splenectomy. Since no clear survival benefit emerged, routine pre-HSCT splenectomy for TDT is not recommended. Instead, increasing pretransfusion Hb levels to suppress ineffective erythropoiesis and reduce spleen size appears more beneficial.
Our findings also highlight the importance of CD34+ cell dose. Low CD34+ counts (≤3 ×106 cells/kg in BM or PB) were associated with worse EFS, stressing the need for adequate stem cell yields. The optimal target depends on various factors, including patient risk level, stem cell source, HSCT type, and conditioning regimen [8,14,24]. Our study underscores the critical importantance of monitoring early mixed DC during the first 3 months post-HSCT, as it correlates with thalassemia recurrence. This result supports previous research [25] showing that the progressive loss of DC in the initial 2 months is a vital signal for initiating pre-emptive interventions, including the tapering of immunosuppressive drugs or donor lymphocyte infusion. Nevertheless, ex-thalassemia patients who maintain persistent mixed DC beyond 2 years post-HSCT can establish reciprocal donor-recipient tolerance [26]. This allows for the production of sufficient Hb, leading to transfusion independence, similar to our survivor patients.
Long-term surveillance of pediatric TDT patients after HSCT has identified multiple late effects—such as chronic GVHD, endocrine dysfunction, growth retardation, autoimmune cytopenia, and secondary malignancies—that can compromise quality of life and increase morbidity and mortality [26-29]. In our cohort, 22.7% of 211 ex-thalassemia patients developed late complications. Endocrine dysfunction was most prevalent, particularly gonadal insufficiency. These findings mirror a previous study [28] that reported gonadal dysfunction (43.9%)—including azoospermia, primary amenorrhea, and secondary amenorrhea—as the most frequent late effect in TDT patients post-HSCT (median follow-up, 30 years). Thyroid disorders affected 18.6% of that population, with hypothyroidism at 10.6%. Potential causes for these endocrine issues include iron-induced tissue toxicity, iron chelator side effects, and conditioning regimens. However, we observed a higher incidence of endocrine late effects in our later cohort (P2 and P3) which was likely due to a greater incidence of acute GVHD during those periods. The correlation between acute GVHD (grades 2–4) and endocrine late effects (HR, 2.84; P=0.027), independent of conditioning regimens or age, suggests that acute, intense inflammatory events and the high-dose steroid treatment used to manage GVHD cause severe and lasting damage. Previous study [29] also indicated that iron overload, conditioning toxicity, and posttransplant complications (such as GVHD and treatment) influence late effects, including endocrinopathies. Our finding emphasizes the importantance of effective acute GVHD prophylaxis and treatment during HSCT and necessitates long-term multidisciplinary surveillance for all survivors. Secondary solid cancer was reported in 1.74%–12.2% of cases in previous studies [22,28], however we observed no malignancies in our cohort, potentially due to our shorter follow-up duration.
Autoimmune cytopenia was noted in 4.4% of post-HSCT TDT patients in a previous series [27], all of whom received MUD-HSCT. In our cohort, 5 cases (2.4%) developed autoimmune disorders, including 2 with autoimmune hemolytic anemia. Unlike the previous report, these cases occurred not only in MUD but also in MRD and MMUD transplants. The proposed mechanism involves disordered immune reconstitution of the newly adopted immune system, leading to aberrant interactions among antigen-presenting cells, T lymphocytes, B cells, and regulatory T cells [27]. These observations underscore the necessity of ongoing multidisciplinary follow-up for early detection and management of complications in ex-thalassemia patients.
Our multicenter HSCT experience in Thai pediatric TDT demonstrated survival rates comparable to international data (e.g., EBMT and Italian studies) [3,4,6,7]. However, resource limitations such as high procedure costs with no coverage from the National health care system, infrastructure constraints, limited national unrelated donor availability (The Thai National Stem Cell Donor Registry was established in 2002)—often necessitating reliance on costly international registries—, and the maintaining high-quality supportive care which is crucial for minimizing transplant-related mortality are challenging. Addressing equity and sustainability of HSCT in developing countries requires a strategic approach: prioritizing curative HSCT as it is more cost-effective than lifelong transfusion and chelation [30], and implementing national policies that secure sustainable funding. Thailand established this policy for thalassemia in 2020. The cost of HSCT for most patients in this cohort was covered by hospital funds.
The retrospective design of this study makes it susceptible to some limitations including incomplete data and the absence of standardized pre- and post-HSCT protocols across centers, which may have introduced variations in outcomes. Furthermore, specific post-HSCT data on growth and iron overload were not collected. Finally, the long-term outcomes are potentially compromised by selection bias due to patient loss to follow-up. Nonetheless, our findings highlight key factors that affect outcomes in pediatric TDT patients undergoing HSCT and suggest practical improvements in clinical care. These enhancements have contributed to the comparable results between MRD- and MUD-HSCT and have mitigated some of the adverse effects of older age at transplantation. Future investigations should employ prospective, multicenter designs with standardized protocols to validate these observations. Recent advances in gene therapy [31] hold promise for achieving transfusion independence in TDT, providing a potential adjunct or alternative to HSCT.
In conclusion, our results broaden the donor pool by demonstrating similar outcomes between MRD and MUD-HSCT. Rigorous pre-HSCT management of iron overload, the use of intravenous busulfan in conditioning, and ensuring adequate stem cell doses are fundamental to optimizing HSCT success. Careful pre-HSCT preparation is essential, particularly adequate blood transfusions to maintain adequate Hb levels to prevent splenomegaly and providing effective iron chelation. In addition, refined conditioning regimens, optimized GVHD prophylaxis, and robust post-HSCT supportive care can lessen the risks associated with older age at transplantation. Finally, a focused approach to monitoring late complications is crucial for long-term well-being in ex-TDT survivors.
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