Efficacy and Prognostic Assessment of Chemotherapy-Bridged Transplantation in Pediatric Patients with Advanced Myelodysplastic Syndromes
Authors: Wang Xingchen , Chen Yunlong , Liu Chenmeng , Wan Yang , An Wenbin , Li Xiaolan , Liu Lipeng , Liu Fang , Zhang Li , Zou Yao , Chen Xiaojuan , Chen Yumei , Guo Ye , Zhu Xiaofan , Yang Wenyu 
Published: December 2024

Backgroud: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms originating from hematopoietic stem cells, clinically characterized by dysplastic hematopoiesis, peripheral cytopenia, and a heightened risk of progression to acute myeloid leukemia (AML). MDS in children is exceedingly rare, with an annual incidence of 1-4 cases per million, accounting for less than 5% of pediatric hematologic malignancies. Advanced MDS in children, including refractory with excess blasts (RAEB) and RAEB in transformation (RAEB-T), exhibits unique genetic features, poor prognosis, and a lack of standardized chemotherapy protocols.
Aims: In the present study, we aimed to evaluate the efficacy of different chemotherapy regimens prior to hematopoietic stem cell transplantation (HSCT) and to assess the prognosis.
Methods: We conducted a retrospective analysis of 30 pediatric patients with MDS treated from Dec 2007 to Apr 2022. All patients underwent demethylating treatment or chemotherapy, with regimens including CAG (cytarabine + aclarubicin + granulocyte colony-stimulating factor) /HAG (homoharringtonine + Ara-C + G-CSF), decitabine monotherapy, a combination of decitabine and CAG/HAG, AML-like chemotherapy or other regimens. Post-chemotherapy, 76.7% (23/30) of the patients underwent bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Results: At data cutoff date of April 2022, 30 patients with a diagnosis of advanced MDS were enrolled in this retrospective study (RAEB [n=16] and RAEB-T [n=14] ). The median age of patients was 8 years (range, 1-15), and 23 (77%) were male. The median bone marrow (BM) blast count was 15.8% (range, 5-30) and the median peripheral blood (PB) blast count was 4% (range, 0-40). At study entry, the chromosomal karyotype analysis revealed normal (27%, n=8), monosomy 7 (37%, n=11), and complex karyotype (7%, n=2). Compared to the MDS-RAEB group, MDS-RAEBT group demonstrated a higher percentage of PB blasts (7% vs. 1%; p=.002), a greater proportion of BM blasts (26% vs. 11%; p&lt;.001), and a reduced lymphocyte-monocyte ratio (LMR) (3.48 vs. 7.90; p=.025). All 30 patients underwent chemotherapy or HMA treatment (CAG/HAG [n=7]; HMA therapy [n=8]; decitabine+chemotherapy [n = 11]; AML-like [n = 4]). The median interval from diagnosis to therapy was 11 days (range 1-90) . Among 25 patients evaluable for one cycle of therapy, overall response rate (ORR) was observed in 15 (60%), of which complete remission (CR) and complete remission with incomplete count recovery (CRi) were achieved by 4 (16%) and 7 (28%) patients, respectively. Non-responders included no remission (NR) in 8 (32%) patients and 2 (8%) had progressive disease (PD). There were no significant difference in ORR during different groups (p =.169). With a median follow-up of 27.5 months (range 1-172), 10 (33%) deaths were documented by the time of data cutoff, including 4 (13%) transplant-related mortality (TRM) and 6 (20%) non-transplant-related mortality (NRM). Causes of NRM include serious complications after chemotherapy, or abandonment of treatment for financial reasons. The overall response (OR) and event-free survival (EFS) rates were 67% and 63%. 23 patients received HSCT after chemotherapy, and they had a higher 3-year OS and EFS rate compared to those who did not undergo transplantation (83% vs 14%, 78% vs 14%, p&lt;0.001). There was a trend towards better OS in patients with response (80% vs. 50%, P=.081). There was no significant difference in OS among patients who received HMA treatment, CAG/HAG, DAC plus chemotherapy, and AML-like chemotherapy(75% vs 57% vs 55% vs 100%, p=.40) . Multivariate analysis indicated that HSCT and pre-transplant OR were independent predictors. OS was influenced by HSCT (HR: 0.086; 95%CI: 0.013-0.570; P=.011) and responders (HR: 0.157; 95%CI:0.026-0.961; P=.045).
Conclusion: In conclusion, decitabine combined with chemotherapy and AML-like regimens can serve as an effective pre-transplant bridging therapy. The reduction of tumor burden before transplantation is a critical factor in improving the prognosis of children with advanced MDS.