ObjectiveThis study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children.MethodsClinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted.ResultsThe proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain (SPTB)gene (NM_001355436.2) and a missense mutation, c.292G>A (p.Ala98Thr), in the lipoprotein lipase (LPL) gene (NM_000237.3). The SPTB c.6005G>A (p.Trp2002*) mutation was inherited from the mother, who exhibited mild anemia, jaundice, and splenomegaly. The LPL c.292G>A (p.Ala98Thr) mutation was inherited from the father, who had hypertriglyceridemia. The SPTB c.6005G>A (p.Trp2002*) mutation is extremely rare in the general population.ConclusionThe heterozygous mutations SPTB c.6005G>A (p.Trp2002*) and LPL c.292G>A (p.Ala98Thr) are the pathogenic causes in this family and provide a basis for clinical management and genetic counseling. Based on the HGMD, 1000G, and ExAC databases, the SPTB c.6005G>A (p.Trp2002*) mutation is reported here for the first time, enriching the mutation spectrum of the SPTB gene.

Background: Leukemia is the most prevalent malignancy in children and a major contributor to pediatric cancer-related mortality. Clinical risk stratification for pediatric ALL has been progressively developed over recent decades. Accurate risk prediction is crucial for identifying high-risk patients needing intensive treatment and protecting low-risk patients from unnecessary therapies. By using clinical characteristics to assess risk, it helps minimize adverse drug reactions, optimize treatment, and improve outcomes while reducing long-term morbidity.Predicting risk levels based on clinical characteristics can help prevent adverse drug reactions and optimize treatment planning. Methods: This retrospective cohort study was conducted across 20 hospitals in southern China between March 1, 2012, and December 31, 2023. Patients were selected from each center for inclusion. The primary endpoints of the study included ALL risk levels, treatment duration, overall survival (OS), and prednisone drug sensitivity. Seven machine learning (ML) methods were used to predict a patient's response to prednisone after eight days of treatment, and five ML methods to identify changes in minimum residual disease after 33 days to help clinically assess drug tolerance and subsequent risk stratification. The effects of different clinical factors on the survival rate between the groups were analyzed. Findings: A total of 2,981 children diagnosed with acute lymphoblastic leukemia (ALL) were included in the study, with minimal missing data observed during quality control. Univariate and multivariate regression analyses were conducted to identify potential clinical risk factors for pediatric ALL, which may inform future clinical management. The external validation set was filtered to exclude samples with missing MRD and prednisone data. The 2,259 patients from 20 hospital centers were divided into a Training cohort (n=1,583), Internal cohort 1 (n=339), and Internal cohort 2 (n=337). The machine learning (ML) model with the best internal validation performance was then used to develop prediction models for MRD and prednisone response. The external validation set was further divided into a Training set (n=1,479), External validation cohort 1 (n=561), and External validation cohort 2 (n=219) by hospital. The maximum AUC for the external validation cohorts reached 84.2 and 98.5, respectively. Survival analysis showed significant differences in survival among patient groups based on clinical factors, including bleeding, fever, bone pain, and immune phenotype. Interpretation: Our model accurately predicts prednisone drug sensitivity and MRD in pediatric leukemia patients based on clinical factors, providing a foundation for risk stratification and reducing the likelihood of adverse drug reactions. Furthermore, survival analysis, along with univariate and multivariate regression analyses, helps to clarify clinical risk factors for pediatric leukemia, offering valuable guidance for treatment decisions—especially in rural areas with limited access to specialized expertise.

Background: Despite high cure rates in pediatric B-cell acute lymphoblastic leukemia (B-ALL), relapse remains a major challenge. Current risk stratification systems fail to identify a subset of occult high-risk (HR) patients. Transferrin receptor 1 (CD71), a key regulator of iron uptake, is often overexpressed in aggressive tumors; however, its independent prognostic value in pediatric B-ALL has not been fully elucidated. Objectives: To evaluate the independent prognostic significance of CD71 expression in a large cohort of pediatric B-ALL patients and to determine its utility in identifying HR subgroups. Design: A retrospective, multicenter cohort study. Methods: We analyzed 1207 pediatric B-ALL patients treated under the South China Children’s Leukemia Group-ALL-2016 protocol between January 2016 and June 2023 across 20 centers in Southern China. CD71 expression was assessed by flow cytometry at diagnosis, with positivity defined as ⩾20% expression on blast cells. We analyzed associations between CD71 status, clinical characteristics, and survival outcomes using Kaplan–Meier methods and multivariate Cox regression models. Results: CD71 positivity was rare in B-ALL (1.0%) compared to T-ALL (15.6%). Clinically, CD71-positive B-ALL patients presented with significantly lower initial white blood cell (WBC) counts (median 4.0 vs 10.0 × 10 9 /L, p = 0.015). Despite this lower peripheral tumor burden, CD71 positivity was associated with extremely poor outcomes. The 5-year cumulative incidence of relapse (CIR) was significantly higher in the CD71-positive group compared to the negative group (39.4% vs 10.1%, p = 0.004). Multivariate analysis confirmed that CD71 positivity is an independent risk factor for relapse (hazard ratio (HR) = 5.94, p = 0.003) and adverse events (HR = 4.868, 95% confidence interval: 1.512–15.671, p = 0.008), irrespective of age, WBC, genetic subtype, or minimal residual disease status. Conclusion: CD71 expression identifies a rare but biologically distinct B-ALL subgroup characterized by aggressive behavior despite low initial WBC counts. These findings indicate that the inclusion of CD71 in diagnostic panels may help to optimize current risk stratification systems, serving as a critical tool to recognize occult HR patients who might otherwise be under-stratified by conventional prognostic markers. Clinical trial registration: The trial is registered with the Chinese Clinical Trial Registry (Chi-CTR; https://www.chictr.org.cn/ ; number ChiCTR2000030357; Registration date: February 29, 2020).

Hemoglobin H (HbH) disease is a subtype of α-thalassemia typically caused by genetic defects in three out of four α-globin genes. To date, the genetic factors contributing to the highly heterogeneous clinical severity of HbH disease remain largely unknown. In this study, we perform targeted long-read sequencing (T-LRS) on a cohort of 591 HbH patients, aiming to profile the genomic variants and their haplotypes within the α/β-globin gene clusters and key erythroid genes. Phenotypic analysis confirms that non-deletional HbH patients generally exhibit more severe clinical manifestations compared to deletional ones. Moreover, we identify the co-inheritance of β-thalassemia mutations to be a mitigating factor for HbH patients, as reflected by higher hemoglobin levels and lower serum ferritin, suggesting the less imbalanced synthesis of α/β-globin among these patients. Furthermore, through haplotype phasing using long-sequencing reads, we find a haplotype of HS40 associated with milder clinical symptoms of HbH patients, validated by reporter gene assay, and that functional mutations in erythroid transcription factors BCL11A and MYB-HBS1L exert significant effects on β-thalassemia but not on HbH patients. This study presents the largest T-LRS study for α-thalassemia patients, which may provide insight into precise clinical diagnosis and phenotyping of HbH diseases.

Platelets act as a crucial indicator for monitoring hypercoagulability and thrombosis and a key target for pharmacological intervention. Genotype-phenotype association studies have confirmed that platelet traits are quantitatively regulated by multiple genes. However, there is currently a lack of genetic studies on the heterogeneity of platelet traits in β-thalassemia under a hypercoagulable state. Here, we studied the phenotypic heterogeneity of platelet count (PLT) and mean platelet volume (MPV) in a cohort of 1020 β-thalassemia patients. We further performed a functionally informed whole-genome sequencing (WGS) association analysis of common variants and rare variants for PLT and MPV in 916 patients through integrative analysis of WGS data and functional annotation data. Extreme phenotypic heterogeneity of platelet traits was observed in β-thalassemia patients. Additionally, the common variant-based gene-level analysis identified RNF144B as a novel gene associated with MPV. The rare variant analysis identified several novel associations in both coding and noncoding regions, including missense rare variants of PPP2R5C associated with PLT and missense rare variants of TSSK1B associated with MPV. In conclusion, this comprehensive and systematic whole-genome scan of platelet traits in the β-thalassemia cohort reveals the specific genetic regulation of platelet traits in the context of β-thalassemia, providing potential targets for intervention.

Background: Serum ferritin (SF) monitors secondary iron overload in beta-thalassemia (b-thalassemia). Transferrin (TRF) has been shown to reverse iron accumulation in experimental models, but its role in transfusion-dependent beta-thalassemia (TDT) patients remains unclear. This study aims to explore the relationship between TRF and SF in TDT patients and to reveal the unique connection between specific genotypes and iron metabolism, providing potential therapeutic targets for clinical practice. Methods: This cross-sectional study includes 817 TDT patients (b0/b0 genotype: n=560; b0/b+ genotype: n=257). We use genotype-phenotype analysis and employ logistic regression and restricted cubic spline (RCS) curves to assess the association between TRF and SF. Results: Significant differences were observed between the b0/b0 and b0/b+ genotypes in terms of age at first transfusion, transfusion requirements, chelation initiation age, reticulocyte count, red blood cell count, red cell distribution width-coefficient of variation (RDW-CV), fetal haemoglobin (HbF) level, splenomegaly, and SF. b0/b0 patients presented with more severe clinical phenotypes. SF was significantly associated with TRF, HbF, RDW-CV, and chelation therapy. RCS analysis revealed a dose-response relationship with a negative linear correlation between TRF and SF (OR=0.26, P<0.001), indicating that higher TRF levels are linked to lower SF risk. Conclusions: This study systematically confirms for the first time a significant negative correlation between high TRF levels and high SF risk in TDT patients. This new finding may help clinicians more effectively manage iron overload, especially in patients with different genotypes.

Background:This study aimed to develop an efficient survival model for predicting event-free survival (EFS) in patients with Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL). Methods:Data related to Ph-like ALL were collected from the South China Children's Leukemia Group (SCCLG) multicenter study conducted from October 2016 to July 2021. A model for predicting the survival of patients with Ph-like ALL was built using Cox proportional hazards regression, random forest, extreme gradient boosting, and gradient boosting machine techniques. By integrating indicators including the concordance index (C-index), 1-, 3-, and 5-year area-under-the-receiver operating characteristics curve (AUROC), Brier score, and decision curve analysis, the predictive capabilities of each model were compared. Results:The random forest algorithm demonstrated the most robust predictive performance. In the test set, the C-index of the random forest model was 0.797 (95% CI: 0.736-0.821; P < 0.001). The AUROCs for 1, 3, and 5 years were 0.787 (95% CI: 0.62-0.953; P < 0.001), 0.797 (95% CI: 0.589-1; P < 0.001), and 0.861 (95% CI: 0.606-1; P < 0.001), respectively. The Brier scores for 1, 3, and 5 years were 0.102 (95% CI: 0.032-0.173; P < 0.001), 0.126 (95% CI: 0.063-0.19; P < 0.001), and 0.121 (95% CI: 0.051-0.19; P < 0.001), respectively. Conclusion:The random forest model effectively predicted the survival outcomes of patients with Ph-like ALL, which can aid clinicians to conduct personalized prognosis assessments in advance. Based on a web-based calculator, using random forest prediction models to calculate the prognosis of Ph-like ALL (https://songxiaodan03.shinyapps.io/RFpredictionmodelforPHlikeALL/) could facilitate healthcare professionals in carrying out clinical evaluation.

BACKGROUND:Chronic myeloid leukemia (CML) is rare in children and often shows more aggressive features than in adults. Real-world data on the efficacy and safety of frontline nilotinib in pediatric CML in chronic phase (CML-CP) remain limited. METHODS:This prospective multicenter real-world study evaluated the efficacy, safety, and pharmacokinetics of frontline nilotinib in newly diagnosed pediatric CML-CP across 26 hospitals in China between January 2023 and April 2025. Patients received nilotinib 230 mg/m2 twice daily. Primary end points were complete cytogenetic response (CCyR) at six cycles and major molecular response (MMR) at 12 cycles. Secondary end points included time to MMR, event-free survival (EFS), and safety. RESULTS:Among 59 enrolled patients (median age, 10.6 years), 71.8% (28/39) achieved MMR at 12 cycles and all achieved CCyR at six cycles. Median time to MMR was 6.2 (3.3, 12.2) months, and 2-year EFS was 93.3% (84.4%-100%). Nilotinib trough concentrations (Ctrough) correlated negatively with BCR::ABL1 transcript levels at cycles 6 and 12. Patients with Ctrough >950 ng/mL were three to five times more likely to reach MMR, whereas those with Ctrough ≥1500 ng/mL had a 6.5-fold higher risk of hyperbilirubinemia. CONCLUSIONS:Frontline nilotinib thus shows strong efficacy and manageable safety in pediatric CML-CP. Higher drug exposure predicts deeper molecular responses but increases toxicity, supporting the potential role of therapeutic drug monitoring.

Pediatric hemophagocytic lymphohistiocytosis (HLH) lacks reliable risk models for personalized treatment. We aimed to develop a survival nomogram to address this gap. We retrospectively analyzed 404 pediatric HLH patients from multiple centers. Independent prognostic variables identified by Cox regression were incorporated into a nomogram. Five predictors of mortality were identified: central nervous system involvement, gastrointestinal bleeding, WBC < 2.3 × 10⁹/L, Hb < 80 g/L, and IL-10 > 69pg/mL. The nomogram demonstrated strong predictive accuracy, with validation cohort AUCs of 0.83, 0.78, and 0.79 for 1-, 2-, and 3-year overall survival (OS). Calibration and decision curve analysis confirmed accuracy. Using an X-tile-determined cutoff of 261, patients were stratified into low- and high-risk groups with significantly different 3-year OS (training cohort: 94.0

BACKGROUND:Prednisone response (PR) remains a key early treatment indicator in pediatric acute lymphoblastic leukemia (ALL). However, its independent prognostic significance has waned with the advent of minimal residual disease (MRD)-guided risk assessment. Evaluating the enduring biological and clinical significance of PR, especially in high-risk subtypes, could enhance the precision of therapeutic approaches. METHODS:This retrospective study analyzed clinical data from 2,979 pediatric patients primarily diagnosed with acute lymphoblastic leukemia (ALL) and enrolled in the South China Children's Leukemia Group (SCCLG-ALL)-2016 Collaborative Group between October 2016 and June 2023. Patients were categorized into "good prednisone response" (GPR) and "poor prednisone response" (PPR) groups based on their response to prednisone. Clinical characteristics were compared between groups using the chi-square test. Logistic regression was employed to analyze the correlation between prednisone response and early minimal residual disease (MRD). Survival analysis was performed using Kaplan-Meier curves, and prognostic factors were evaluated using Cox regression models. RESULTS:Among the 2,979 patients, 2,649 were categorized as GPR and 330 as PPR. Children in the PPR group exhibited multiple high-risk clinical features and had a poorer prognosis than those in the GPR group. However, multivariate Cox regression analysis revealed that days 15 and 33 MRD had a stronger predictive value than prednisone response. Notably, PR showed strong predictive value for MRD positivity on both Day 15 and Day 33. CONCLUSIONS:In this large real-world Chinese cohort, PR was not an independent prognostic marker but was strongly associated with early MRD burden. These findings support the contextual use of PR as a practical surrogate for MRD in resource-limited settings, and highlight the need to reconsider its role in modern risk-adapted treatment strategies.

The clinical-genetic characteristics of ETV6-RUNX1-like acute lymphoblastic leukemia (ALL) is still unclear in pediatrics. Therefore, we conducted Fluorescent In Situ Hybridization (FISH), Polymerase Chain Reaction(PCR) and Whole Transcriptome Sequencing (WTS) on 2171 B-lineage ALL cases and identified 49 (2.3%) ETV6-RUNX1-like and 406 (18.7%) ETV6-RUNX1 cases. We found that: i) ETV6-RUNX1-like patients were characterized by ETV6 abnormalities and enrich for PAX5, KRAS, CDKN2A/2B, CRLF2, IKZF1, PTTN11, NRAS, FLT3. ii) Genes affecting of transcription factor regulation, RAS signal pathway, cell cycle regulation, JAK/STAT signal pathway and epigenetic modification were significantly frequent in ETV6-RUNX1-like ALL. iii) Four hub genes, ETV6, CDKN2A, ABL1 and MYC, were identified among ETV6-RUNX1-like ALL. The clinical characteristics highlighted that: i) ETV6-RUNX1-like patients had higher minimal residual disease (MRD) persistence at day 15 (D15 MRD) than ETV6-RUNX1 patients (P = 0.023). ii) 5-year event-free survival (EFS) and overall survival (OS) of ETV6-RUNX1-like patients were both significantly worse than ETV6-RUNX1 patients (65.8 ± 15.4% vs. 95.7 ± 1.0%, P < 0.001 and 91.3 ± 4.2% vs 98.2 ± 0.7%, P = 0.006). iii) ETV6-RUNX1-like positive was the risk factor for EFS (HR 3.25 (95% CI, 1.23–8.61); P = 0.018). Therefore, it is important to discern ETV6-RUNX1-like patients early and opt for more intensive chemotherapy for these patients.

Despite the well-documented mutation spectra of β-thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long-read sequencing (T-LRS) is demonstrated to capture 20 genes/loci in 1,020 β-thalassemia patients. This panel permits not only identification of thalassemia mutations at 100% of sensitivity and specificity, but also detection of rare structural variants (SVs) and single nucleotide variants (SNVs) in modifier genes/loci. The highly homologous regions of α-/β-globin gene clusters are then phased and 3 novel haplotypes in HBG1/HBG2 region are reported in this population of β-thalassemia patients. Furthermore, one of the haplotypes is associated with ameliorated symptoms of β-thalassemia. Similarly, 5 major haplotypes are identified in HBA1/HBA2 homologous region while one of them is found highly linked with deletional α-thalassemia mutations. Finally, rare mutations in erythroid transcription factors in DNMT1 and KLF1 associated with increased expression of fetal hemoglobin and reduced transfusion dependencies are identified. This study presents the largest T-LRS study for β-thalassemia patients to date, facilitating precise clinical diagnosis and haplotype phasing of globin gene clusters.

BACKGROUND:IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS:A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS:The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS:Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

The next-generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T-ALL and B-ALL. In B-ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co-occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3-year RFS rates for the RAS signaling pathway mutation-positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation-positive. RAS signaling pathway mutation is an important biomarker for poorer relapse-free survival in pediatric B-ALL patients despite good early MRD levels.

Anti-myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) associated disorder (MOGAD) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disorder that has been widely recognized in recent years. It is distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which are separate disease spectrums. Here we report the case of a 5-year-old boy who was admitted for 3 days with fever, headache, and vomiting. Magnetic resonance imaging revealed abnormal hyperintensity in the left thalamus and positive serum IgM for M. pneumoniae. After treatment with azithromycin, the headache gradually disappeared, but paralysis and urinary retention occurred on the 6th day after admission. MRI re-examination showed that the original abnormal signal in the left thalamus was significantly weakened, but new abnormal signals appeared in the brain and cerebrospinal cord, and the serum MOG-IgG was positive. After treatment, the child has fully recovered and is still receiving follow-up care. We believe that this is a case of MOGAD in a child with a biphasic ADEM phenotype secondary to M. pneumoniae infection, which has potential value in elucidating the pathophysiology of MOGAD.

Background: Maintenance therapy is an important part of childhood acute lymphoblastic leukemia (ALL). However, the optimal chemotherapy regimen for maintenance therapy is still controversial. We aimed to evaluate the benefits of the continuous use of 6-mercaptopurine(6-MP) and methotrexate (MTX) with pulses of vincristine (VCR) and dexamethasone (DEX) in maintenance therapy for pediatric ALL.Methods: A total of 3,008 pediatric patients with ALL were enrolled in South China (2008-2022) and assigned to one of three maintenance regimens. Randomly selected subjects (n=2406;80%) and the remaining subjects comprised the development and validation groups, respectively. The overall survival (OS) probability was calculated using a predictor-based nomogram to evaluate maintenance regimens impact on OS in relation to baseline characteristics. Nomogram performance was assessed by the area under the receiver operating characteristic curve (AUC) and the calibration curve with 500 bootstrap resample validations. Decision curve analysis (DCA) was performed to evaluate the clinical utility of the nomogram. Then interaction between predicted OS probability and actual overall mortality in different maintenance regimens was tested.Findings: According to the minimum criteria of non-zero coefficients of Lasso and logistic regression screening, elder age, high risk group, T-cell, higher white blood count cell(WBC), lower platelet(PLT), day-15 minimal residual disease(MRD) and d-33 MRD positive were independently associated with a lower OS. A nomogram model for OS was established based on these predictors. The AUC (C statistic) of the nomogram was 0.788 (95% CI: 0.72–0.856) in the development group and 0.746 (95% CI:0.692-0.846) in the validation group. The calibration curves after 1000 bootstraps displayed a good fit between the actual and predicted probabilities in both the development and validation groups. DCA showed that the model in the development and validation groups had a net benefit when the risk thresholds were 0–0.2 and 0–0.25, respectively. This model was used to predict the 5-year OS probability in different maintenance regimens. When the predicted 5-year OS probability between 75% and 95%, the benefit of continuous use of 6-MP and MTX with pulses of VCR and DEX on OM decreased progressively as predicted OS decreased(P<0.05).Interpretation: We have developed a predictive model that can be used to identify pediatric patients with ALL who benefit from continuous use of 6-MP and MTX with pulses of VCR and DEX in terms of OS. Specifically, patients with worse baseline characteristics appear to benefit the most.Trial Registration: The trial is registered at http://www.clinicaltrials.gov with the identifier NCT00846703, and is registered with the Chinese Clinical Trial Registry (Chi-CTR; https://www.chictr.org.cn/;number ChiCTR2000030357).Funding: This work was supported by the Guangzhou Science and Technology Program key projects (No.201803010032), Bethune Medical Scientific Research Fund Project (No.SCE111DS), Guangdong Medical Scientific Research Foundation(A2024057), Guangzhou Basic and Applied Basic Research Foundation (2024A04J4686), Yat-sen Excellent Young Scientists Fund (2024A03J1185) and Sun Yat-sen Pilot Scientific Research Fund (YXQH202205).Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: Written informed consent with or without assent was obtained from each participant and parent/legal guardian, in accordance with the Declaration of Helsinki. This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, and by ethics committee of other cooperation centers

ObjectivesThe prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children’s Leukemia Group (SCCLG).MethodsA total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction.ResultsThe frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016).ConclusionCNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

Diamond-Blackfan anaemia (DBA) is an inherited marrow failure disorder characterised by selective erythroid aplasia. Herein, we reported a case of DBA caused by a novel GATA1 gene mutation. The proband manifested normocytic normochromic anaemia, while the parents were asymptomatic. Next-generation sequencing identified a novel de novo mutation at GATA1 initiation codon (GATA1:c.3G>A) in the proband. The mutation led to a shortened GATA1 protein (GATA1s), which caused a reduction in full-length functional GATA1 protein (GATA1fl). This is the first report of GATA1-related DBA patient in the East Asian population, which expanded the mutational spectrum of DBA furthering understanding of its pathogenesis.

Objective Even though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL. Method Children with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children’s leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram. Result The parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan–Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated. Conclusion The nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.