Efficacy and Influencing Factors of Allogeneic Hematopoietic Stem Cell Transplantation in Treatment of 71 Children with Leukemia
Leukemia is a malignant proliferative disease that has become the most common malignancy in children, accounting for 40.5% of malignant cancers in this population. Although chemotherapy can effectively treat many children with leukemia, some patients with high-risk and relapsed acute lymphoblastic leukemia (ALL) and acute myelocytic leukemia (AML) fail to achieve long-term remission. For these patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often the best treatment option. However, the efficacy of allo-HSCT can be influenced by numerous factors. This study retrospectively analyzed the clinical data of 71 children with leukemia who underwent allo-HSCT to evaluate the clinical efficacy and identify the factors that may influence the outcomes.
Patient Characteristics and Treatment Protocols
The study included 71 patients aged 1 to 14 years (median age: 9 years), comprising 46 boys and 25 girls. The primary diseases included ALL (34 patients), AML (32 patients), chronic myelocytic leukemia (4 patients), and juvenile myelomonocytic leukemia (1 patient). The patients were treated with two main conditioning regimens: a busulfan-cyclophosphamide-based (Bu/Cy-based) regimen and a total body irradiation-cyclophosphamide-based (TBI/Cy-based) regimen. Specifically, 55 patients received the Bu/Cy-based regimen, which consisted of busulfan (0.8 mg/kg every 6 hours for 4 days) and cyclophosphamide (40 to 60 mg/kg for 2 days). The remaining 16 patients received the TBI/Cy-based regimen, which included total body irradiation (4 to 5 Gy for 2 days) and cyclophosphamide (40 to 60 mg/kg for 2 days).
For graft-versus-host disease (GVHD) prophylaxis, patients with matched sibling donors (MSD) received cyclosporine A (CsA) and short-course methotrexate (MTX), while those with alternative donors (AD) received CsA, MTX, mycophenolate mofetil (MMF), and rabbit anti-human thymocyte immunoglobulin (ATG). CsA plasma concentrations were monitored twice weekly and maintained at 200 to 400 ng/mL. To prevent complications, all patients were administered alprostadil to prevent hepatic vein occlusion disease (HVOD), and hydration and alkalization of urine were performed to prevent hemorrhagic cystitis. During transplantation, all blood products were irradiated before infusion, and patients began receiving granulocyte colony-stimulating factor (5 mg/kg) from day +5 until white blood cell and neutrophil counts returned to normal.
Engraftment and Survival Definitions
Neutrophil engraftment was defined as the first day of three consecutive days with an absolute neutrophil count greater than 0.5 x 10^9/L. Platelet engraftment was defined as the first of seven consecutive days with a platelet count greater than 20 x 10^9/L, without transfusion support for at least seven days. After hematopoietic reconstitution, bone marrow samples were obtained to confirm engraftment using quantitative PCR for short tandem repeat gene signatures or sex chromosome analysis. Overall survival (OS) was defined as the length of time from HSCT to death from any cause or the last follow-up. Disease-free survival (DFS) was defined as the length of time from HSCT to the last follow-up or the first event (relapse or death from any cause).
Outcomes and Influencing Factors
The study found that 70 out of 71 patients (98.6%) successfully achieved hematopoietic reconstitution, with one patient experiencing early graft rejection and severe infection. The median time to neutrophil and platelet engraftment was 13 days (range: 9–26 days) and 14 days (range: 9–46 days), respectively. The median follow-up time was 16 months (range: 1.5–106 months). During the follow-up period, 50 patients (70.4%) developed acute GVHD (aGVHD), and 21 patients (29.6%) developed chronic GVHD (cGVHD). Grade II-IV aGVHD was observed in 36 patients (37%). No cases of HVOD were reported. At the end of the observation period, 19 patients had relapsed, and 31 patients had died. Among the deaths, 22 patients (31%) died from transplant-related complications, including severe infection (14 patients), cerebral hemorrhage (3 patients), hemorrhage of the digestive tract (2 patients), severe GVHD (2 patients), and cardiac insufficiency (1 patient).
Univariate analysis revealed that several factors significantly influenced OS and DFS. Disease status at HSCT (P=0.036), high-risk AML in first complete remission (AML-CR1) (P=0.014), conditioning regimen (P=0.003), donor-recipient ABO compatibility (P=0.018), and cytomegalovirus (CMV) infection (P=0.044) were significant factors affecting OS. Extramedullary infiltration (P=0.047), high-risk AML-CR1 (P=0.048), and conditioning regimen (P=0.028) were significant factors affecting DFS. The 3-year DFS and OS rates were 39.3% and 49.7%, respectively.
Multivariate analysis further identified disease status at HSCT (RR=1.727, 95% CI 1.067–2.795, P=0.026), high-risk AML-CR1 (RR=8.851, 95% CI 1.019–76.884, P=0.048), and conditioning regimen (RR=2.613, 95% CI 1.255–5.439, P=0.01) as significant factors influencing OS. The conditioning regimen (RR=2.123, 95% CI 1.061–4.247, P=0.033) was also a significant factor influencing DFS.
Discussion
Allo-HSCT has become a widely used treatment for leukemia, with significant improvements in efficacy over the years. Studies have reported 5-year OS rates as high as 70% and 5-year DFS rates around 66%. However, transplant-related complications and post-transplant relapse remain significant challenges. The choice of transplantation for patients with ALL in first complete remission (ALL-CR1) and AML in first complete remission (AML-CR1) is still debated. While some patients in CR1 may benefit from consolidation chemotherapy, high-risk patients and those with refractory disease may achieve better outcomes with allo-HSCT.
In this study, patients in CR1 at the time of HSCT had significantly higher DFS compared to those in CR2, CR3, or non-remission (NR), although the difference was not statistically significant (P > 0.05). This may be due to factors such as short follow-up time. Disease status at HSCT and high-risk AML-CR1 were identified as significant factors affecting OS, suggesting that early allo-HSCT may benefit certain patients with improved survival outcomes.
The conditioning regimen is a critical factor in the success of HSCT. This study found that the Bu/Cy-based regimen resulted in significantly higher 3-year OS and DFS rates compared to the TBI/Cy-based regimen. The TBI/Cy-based regimen was also identified as a factor negatively affecting OS. These findings align with previous studies suggesting that Bu/Cy-based regimens may be more effective for children with leukemia.
ABO incompatibility between donor and recipient was found to influence OS in univariate analysis, but this factor did not reach statistical significance in multivariate analysis. Further studies with larger sample sizes and longer follow-up periods are needed to clarify the impact of ABO incompatibility on transplant outcomes.
Infections, particularly pulmonary infections, were a major cause of transplant-related mortality in this study, accounting for 60% of infection-related deaths. Severe infections remain a significant threat to patient survival post-HSCT, highlighting the need for improved infection prevention and management strategies.
Grade II-IV aGVHD was associated with lower OS in some studies, but this effect was not significant in the current study. This discrepancy may be due to differences in disease classification, risk stratification, and follow-up duration. Further research is needed to better understand the impact of GVHD on transplant outcomes.
Conclusion
Allo-HSCT is a safe and effective treatment for children with leukemia, particularly those who have undergone induction chemotherapy. The study identified several factors that influence survival outcomes, including disease status at HSCT, high-risk AML-CR1, extramedullary infiltration, conditioning regimen, donor-recipient ABO compatibility, and CMV infection. The Bu/Cy-based conditioning regimen was associated with better OS and DFS compared to the TBI/Cy-based regimen. Early allo-HSCT may benefit certain high-risk patients, but further research is needed to refine the indications and optimize transplant strategies.
doi.org/10.1097/CM9.0000000000000150
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