From June 13th to 16th, 2024, the 29th Annual Meeting of the European Hematology Association (EHA) was grandly held in Madrid, the capital of Spain. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from all over the world each year to share and discuss innovative concepts and the latest scientific and clinical research achievements in hematology. At this year's EHA conference, several studies from Professor Xufan Zhu's team at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences were selected. This issue highlights two studies on pediatric bone marrow failure diseases (acquired aplastic anemia and Shwachman-Diamond syndrome) and includes insightful commentary from Professor Zhu.

P831

Clinical Factors Affecting Telomere Length in Pediatric Aplastic Anemia (AA) Patients

Background

Short telomere syndrome (TBD) is a group of clinical syndromes caused by pathogenic germline mutations in genes related to telomere maintenance, leading to premature telomere shortening. Although both TBD and aplastic anemia (AA) can cause bone marrow failure (BMF), their treatments differ significantly, necessitating careful clinical differentiation. Telomere length (TL) can serve as an initial screening tool to exclude hereditary telomere diseases. However, because TL is also shortened in AA patients, there is controversy regarding the specificity of TL measurement and the appropriate cut-off value for distinguishing TBD from AA.

Objective

This study aims to demonstrate the distribution of TL in pediatric AA patients, explore the clinical factors affecting TL, and analyze the differences in TL between AA and TBD patients to aid in differential diagnosis.

Methods

The study used the Southern Blot method to detect TL in 156 pediatric AA patients. A cut-off value of age-adjusted TL < -2.0 was used, and multiple logistic regression was employed to analyze factors related to TL.

Results

The analysis showed that:

1. Approximately 35.9% (56/156) of pediatric AA patients had shortened TL. Multiple logistic regression analysis indicated that disease duration over 24 months [OR=0.142 (0.039-0.445); P=0.00135] and reticulocyte count >60×10^9/L [OR=0.231 (0.075-0.667); P=0.00782] were negatively correlated with age-adjusted TL. Male gender [OR=3.076 (1.220-8.364); P=0.02089] was positively correlated with age-adjusted TL.
2. Considering the relationship between TL and disease duration, patients were divided into newly diagnosed (≤3 months) and long-term (>3 months) groups to explore the influence of clinical characteristics. Results showed: In newly diagnosed patients, severe aplastic anemia (SAA) [OR=0.128 (0.029-0.455); P=0.00281] was negatively correlated with TL. Male gender [OR=4.664 (1.767-1.405); P=0.00316] was positively correlated with age-adjusted TL. Conversely, in long-term patients, disease duration over 24 months [OR=0.142 (0.039-0.445); P=0.00135] and reticulocyte count >60×10^9/L [OR=0.231 (0.075-0.667); P=0.00782] were negatively correlated with TL; male gender [OR=3.076 (1.220-8.364); P=0.02089] was positively correlated with age-adjusted TL.

Conclusion

In newly diagnosed pediatric AA patients, the main factors affecting TL are disease severity and patient gender. In long-term patients, TL is mainly influenced by disease duration, reticulocyte count, and gender, while disease severity does not appear to significantly affect TL.

Expert Commentary

Professor Xufan Zhu: Internationally, telomere research has a certain history, but in China, due to limitations in detection methods, this area has not been well explored. Our team has previously studied the correlation between TL and treatment efficacy in non-severe AA patients. Preliminary results indicate a clear correlation between TL and clinical characteristics in pediatric AA patients, providing some basis for the diagnosis and differential diagnosis of AA.

P815

Clinical Features and Prognosis of Shwachman-Diamond Syndrome (SDS) with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Background

Shwachman-Diamond syndrome (SDS) is a rare hereditary disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, and a high risk of progression to myeloid malignancies. Previous reports indicate poor prognosis for patients who progress to clonal diseases such as MDS or AML.

Objective

This study aims to investigate the clinical characteristics and prognosis of Chinese patients diagnosed with SDS and MDS or AML from 14 medical centers.

Methods

The China Hematology Alliance’s pediatric bone marrow failure disease cohort study is a prospective, multi-center cohort study that collects data from 24 pediatric hematology treatment centers in China. This study retrospectively analyzed medical records and diagnoses of patients diagnosed with SDS and MDS or AML from 14 medical centers between January 1, 2011, and December 31, 2023.

Results

Among 23 patients with SDS and MDS or AML, 10 were male and 13 were female, with a median onset age of 4 years. The median age at progression to MDS or AML was 10.3 years, with 6 adults and 17 children. Of these patients, 82.6% (19/23) had anemia, 60.8% (14/23) had neutropenia, 82.6% (19/23) had thrombocytopenia, and 47.8% (11/23) had pancytopenia.

According to the 2016 WHO criteria and initial complete blood count data, patients were reclassified: 3 were diagnosed with AML, 5 with MDS-EB, 4 with MDS-MLD, and 11 with RCC. Retrospective analysis showed:

• 11 patients had biallelic mutations in SBDS (c.258+2T>C and c.183-184TA>CT), 5 patients (17.5%) had homozygous mutations (c.258+2T>C gene), 3 patients (6.3%) had compound heterozygous mutations (c.258+2T>C and exon 2 deletion), and 3 had c.258+2T>C and other SDS mutations. One patient had biallelic mutations in DNAJC21, with a history of recurrent infections and pancytopenia. Bone marrow smears showed multilineage dysplasia.
• Deep sequencing of TP53 mutations in bone marrow samples from 15 patients revealed TP53 mutations in 10 patients (66.7%), with mutation frequencies ranging from 1.01% to 86.2%. The TP53 mutation rate was 55.6% (5/9) in the RCC/MLD group and 83.3% (5/6) in the EB/AML group. Karyotype analysis of 21 patients showed 10 (47.6%) had normal karyotypes, 7 had complex karyotypes, 3 had 20q deletions, and 1 had a 7q deletion.
• With a median follow-up of 26.6 months, the 5-year overall survival (OS) rate for all patients was 73.3% (95%CI: 55.3%~97.2%). The OS rate was significantly higher in RCC/MLD patients than in EB/AML patients, at 88.9% (95%CI: 70.6%~100%) vs 42.9% (95%CI: 18.2%~100%) (P=0.0054). Nine patients underwent hematopoietic stem cell transplantation (HSCT), with 4 deaths (including 2 transplant-related deaths and 2 from relapse). Among the 14 patients who did not receive HSCT, 2 died from progression to AML. HSCT did not significantly improve OS.

Conclusion

Among patients with clonal progression of SDS, survival rates were significantly lower in EB/AML patients compared to RCC/MLD patients, and HSCT did not improve prognosis.

Expert Commentary

Professor Xiaofan Zhu : This study on the clinical characteristics and prognosis of Shwachman-Diamond syndrome (SDS) after progression to MDS or AML is a prospective, multi-center study led by our center. SDS affects not only the hematopoietic system but also involves pancreatic exocrine dysfunction (digestive system) and growth and developmental abnormalities (endocrine system), making multidisciplinary collaboration (MDT) crucial for the diagnosis and treatment of SDS.

It is worth noting that some SDS patients present with MDS or AML at diagnosis, with poor subsequent outcomes. This cohort study, by including a large sample size of SDS patients and conducting retrospective analysis, aims to identify the appropriate stage for therapeutic intervention to improve long-term survival. It is critical not to wait blindly until progression to myeloid malignancies for intervention. Additionally, the collaborative group is working with international SDS research teams to collect more high-quality data, conduct in-depth analyses, and explore suitable treatment regimens and timings, further advancing research on this rare hereditary disease.