Pediatric Myelodysplastic Syndromes (MDS) are rare hematologic disorders, with advanced MDS being particularly concerning. At the 29th Annual Meeting of the European Hematology Association (EHA 2024), Professor Xiaofan Zhu's team from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences presented multiple studies, including two key studies on pediatric MDS. These studies delve into crucial issues and provide significant academic references to optimize the diagnosis and treatment of pediatric MDS. In this issue of "Oncology Frontier - Hematology Frontier," we report the results of these studies and feature an exclusive detailed interpretation by Professor Xiaofan Zhu.

Genomic Landscape and Clinical Significance of Pediatric Advanced MDS

First Author: Chenmeng Liu

Corresponding Author: Chief Physician Wenyu Yang

Background

Pediatric advanced MDS is characterized by poor prognosis and high-frequency gene mutations.

Objective

This study aims to assess the clinical significance of genomic features in pediatric advanced MDS.

Methods

The study analyzed bone marrow samples from 72 children with advanced MDS using next-generation sequencing, including 54 cases of refractory anemia with excess blasts (RAEB) and 18 cases of RAEB in transformation (RAEB-T). Target genes were closely related to MDS or other myeloid tumors in adults and children.

Results

Considering only potential functional mutations, 88.9% (64/72) of the children carried gene mutations, including PTPN11 (16 cases, 22.2%), SETBP1 (14 cases, 19.4%), NRAS (12 cases, 16.7%), RUNX1 (10 cases, 13.9%), NF1 (9 cases, 12.5%), FLT3 (8 cases, 11.1%), GATA2 (8 cases, 11.1%), and WT1 (8 cases, 11.1%). Mutations related to the RAS/MAPK signaling pathway were the most common, occurring in 45.8% (33/72) of the cases, including NRAS, KRAS, NF1, CBL, PTPN11, and BRAF. These mutations were associated with a higher proportion of bone marrow (BM) blasts (14.25% vs. 8%, P=0.017). PTPN11 and NF1 mutations tended to co-occur (P=0.003). SETBP1 mutations were frequently detected in children with monosomy 7 (P<0.001). The presence of all genetic variations did not significantly affect overall survival. Although not statistically significant, PTPN11 mutations seemed to be associated with unstable disease progression. Of the seven children who did not receive allogeneic hematopoietic stem cell transplantation (HSCT), one was lost to follow-up three months after diagnosis, and the remaining six died.

Conclusion

Mutations in the RAS/MAPK pathway are the most common genetic variations in pediatric advanced MDS. PTPN11 mutations are associated with unstable disease progression.

Efficacy and Prognosis of Chemotherapy Bridging Transplantation in Pediatric Advanced MDS

First Author: Xingchen Wang

Corresponding Author: Chief Physician Wenyu Yang

Background

MDS is a group of myeloid disorders originating from hematopoietic stem cells, characterized by ineffective hematopoiesis, peripheral blood cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). While MDS predominantly affects the elderly, with an incidence rate of 55.4 per 100,000 in individuals aged 80 and above, pediatric MDS is extremely rare, with an annual incidence of only 1-4 per million, accounting for less than 5% of pediatric hematologic malignancies. Pediatric advanced MDS, including RAEB and RAEB-T, has unique genetic features and poor prognosis, with no standardized chemotherapy regimens.

Objective

This study aims to evaluate the efficacy of different chemotherapy regimens before HSCT and to assess prognosis.

Methods

The study retrospectively analyzed 30 pediatric MDS patients treated between December 2007 and April 2022. All patients received hypomethylating agents or chemotherapy, including:

1. CAG regimen: cytarabine (Ara-C) + aclarubicin (ACM) + recombinant human granulocyte colony-stimulating factor (G-CSF) / HAG regimen: homoharringtonine + Ara-C + G-CSF
2. Decitabine (DAC) monotherapy
3. DAC combined with CAG/HAG
4. AML-like chemotherapy or other regimens.

After chemotherapy, 76.7% (23/30) of the patients underwent allo-HSCT.

Results

The median age of the patients was 8 years (range: 1-15 years). The median percentage of BM blasts was 15.8% (range: 5%-30%), and the median percentage of peripheral blood blasts was 4% (range: 0%-40%). Chromosomal karyotyping was analyzable in 29 patients (96.7%) at diagnosis, with 20 patients (69%) showing cytogenetic abnormalities. Monosomy 7 was the most common chromosomal abnormality, present in 11 patients (37.9%). Among the 30 patients who received chemotherapy, 25 responded to the first course, with an overall response rate (ORR) of 60%. The complete remission/complete remission with incomplete blood count recovery (CR/CRi) rate was 44%, and 16% achieved partial remission (PR), while 8% experienced disease progression (PD), and 32% showed no response (NR). There was no statistically significant difference in ORR among the four regimens (P=0.18). With a median follow-up of 27.5 months (range: 1-172 months), 23 patients underwent HSCT after chemotherapy. Transplanted patients had higher 3-year overall survival (OS) and event-free survival (EFS) rates compared to non-transplanted patients (83% vs. 14%, 78% vs. 14%, P<0.001). Multivariate analysis showed that HSCT, chemotherapy response, and the interval from diagnosis to HSCT were independent predictors of OS.

Conclusion

Chemotherapy bridging HSCT and a shorter interval from diagnosis to HSCT significantly improved the prognosis of pediatric advanced MDS. Therefore, early initiation of HSCT is recommended for children diagnosed with advanced MDS.

Expert Commentary

Professor Xiaofan Zhu: Compared to adults, pediatric MDS is a very rare malignant tumor. These two studies on pediatric MDS are relatively large-scale single-center cohort studies. The genomic landscape study of pediatric advanced MDS provides critical information on disease prognosis, progression, and genomic changes, offering valuable insights into the pediatric hematologic oncology field.

The other study on the efficacy and prognosis of chemotherapy bridging HSCT provides crucial evidence for determining the timing of transplantation and assessing residual disease status. Through this study, we can better judge the optimal timing for treating pediatric advanced MDS, especially in deciding when to proceed with transplantation. The correct timing not only enhances transplant success rates but also reduces post-transplant relapse rates, significantly improving the overall efficacy of hematopoietic stem cell transplantation in pediatric MDS. For pediatric advanced MDS, chemotherapy alone has limited efficacy. However, hematopoietic stem cell transplantation can significantly improve treatment outcomes. This finding has profound implications for guiding future treatment strategies for pediatric MDS.

In summary, these two studies not only reveal the genomic landscape of pediatric advanced MDS and its key role in prognosis and disease progression but also provide important information on the prognosis of chemotherapy bridging transplantation. They undoubtedly lay a solid scientific foundation for future clinical research and treatment strategy formulation for pediatric MDS. In future clinical practice, we hope to translate these research findings into more specific practices to improve the efficacy and survival rate of pediatric MDS, bringing a brighter outlook for these children.