Effect of allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease in children: A multicentre, retrospective cohort study in China.

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0-16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9-79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

Cord Blood Transplantation for Very Early-Onset Inflammatory Bowel Disease Caused by Interleukin-10 Receptor Deficiency.

PURPOSE: Interleukin-10 receptor (IL-10R) deficiency can result in life-threatening very early-onset inflammatory bowel disease (VEO-IBD). Umbilical cord blood transplantation (UCBT) is a curative therapy for patients with IL-10R deficiency. This study aimed to investigate the efficacy of UCBT in treating IL-10R deficiency and develop a predictive model based on pre-transplant factors. METHODS: Eighty patients with IL-10R deficiency who underwent UCBT between July 2015 and April 2023 were retrospectively analyzed. Cox proportional hazards regression and random survival forest were used to develop a predictive model. RESULTS: Median age at transplant was 13.0 months (interquartile range [IQR], 8.8-25.3 months). With a median follow-up time of 29.4 months (IQR, 3.2-57.1 months), the overall survival (OS) rate was 65.0% (95% confidence interval [CI], 55.3%-76.3%). The engraftment rate was 85% (95% CI, 77%-93%). The cumulative incidences of acute and chronic graft-versus-host disease were 48.2% (95% CI, 37.1%-59.4%) and 12.2% (95% CI, 4.7%-19.8%), respectively. VEO-IBD-associated clinical symptoms were resolved in all survivors. The multivariate analysis showed that IL-6 and stool occult blood were independent prognostic risk factors. The multivariate Cox proportional hazards regression model with stool occult blood, length- or height-for-age Z-score, medical history of sepsis, and cord blood total nucleated cells showed good discrimination ability, with a bootstrap concordance index of 0.767-0.775 in predicting OS. CONCLUSION: Better inflammation control before transplantation and higher cord blood total nucleated cell levels can improve patient prognosis. The nomogram can successfully predict OS in patients with IL-10R deficiency undergoing UCBT.

Outcome of infants with acute lymphoblastic leukemia treated with the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia 2015 study protocol.

Not available.

Immunophenotype of lymphocytes and real-world outcome of COVID-19 infection in children with hematology and oncology.

BACKGROUND: Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. METHODS: In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. RESULTS: A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P < 0.0001), long duration of symptom (P < 0.0001), low lymphocytes count (P = 0.095), low CD3 + and CD8 + T cell count (P = 0.013, P = 0.022), high percentage of CD4 + TCM (P = 0.016), and low percentage of transitional B cells (P = 0.045) were high risk factors for severe COVID-19 infection. Cox regression model showed that the absolute lymphocytes count (P = 0.027) and long duration of symptom (P = 0.002) were the independent factors for severity. Patients with CD8 + dominant and B cell depletion subtype wasn't related with severity, but had higher percentage of CD8 + effector memory T cells (TEM) and terminally differentiated effector memory T cells (TEMRA) (P < 0.001, P < 0.001), and a longer COVID-19 duration (P = 0.045). CONCLUSION: The severity was relatively mild in children with immunodeficiencies in the third year of COVID-19 pandemic. Low lymphocyte count and long duration of symptom were the independent risk factors with COVID-19 severity. Delays in cancer care remain a major concern and the long outcome is pending.

Molecular Evolution and Increasing Macrolide Resistance of Bordetella pertussis, Shanghai, China, 2016-2022.

Resurgence and spread of macrolide-resistant Bordetella pertussis (MRBP) threaten global public health. We collected 283 B. pertussis isolates during 2016-2022 in Shanghai, China, and conducted 23S rRNA gene A2047G mutation detection, multilocus variable-number tandem-repeat analysis, and virulence genotyping analysis. We performed whole-genome sequencing on representative strains. We detected pertussis primarily in infants (0-1 years of age) before 2020 and older children (>5-10 years of age) after 2020. The major genotypes were ptxP1/prn1/fhaB3/ptxA1/ptxC1/fim2-1/fim3-1 (48.7%) and ptxP3/prn2/fhaB1/ptxA1/ptxC2/fim2-1/fim3-1 (47.7%). MRBP increased remarkably from 2016 (36.4%) to 2022 (97.2%). All MRBPs before 2020 harbored ptxP1, and 51.4% belonged to multilocus variable-number tandem-repeat analysis type (MT) 195, whereas ptxP3-MRBP increased from 0% before 2020 to 66.7% after 2020, and all belonged to MT28. MT28 ptxP3-MRBP emerged only after 2020 and replaced the resident MT195 ptxP1-MRBP, revealing that 2020 was a watershed in the transformation of MRBP.

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG-ALL-2015: A multicenter study.

BACKGROUND: Contemporary risk-directed treatment has improved the outcome of patients with acute lymphoblastic leukemia (ALL) and TCF3::PBX1 fusion. In this study, the authors seek to identify prognostic factors that can be used to further improve outcome. METHODS: The authors studied 384 patients with this genotype treated on Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015 and December 31, 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk arm without prophylactic cranial irradiation; those with high minimal residual disease (MRD) ≥1% at day 46 (end) of remission induction were candidates for hematopoietic cell transplantation. RESULTS: The overall 5-year event-free survival was 84.4% (95% confidence interval [CI], 80.6-88.3) and 5-year overall survival 88.9% (95% CI, 85.5-92.4). Independent factors associated with lower 5-year event-free survival were male sex (80.4%, [95% CI, 74.8-86.4] vs. 88.9%, [95% CI, 84.1-93.9] in female, p = .03) and positive day 46 MRD (≥0.01%) (62.1%, [95% CI, 44.2-87.4] vs. 87.1%, [95% CI, 83.4-90.9] in patients with negative MRD, p < .001). The presence of testicular leukemia at diagnosis (n = 10) was associated with particularly dismal 5-year event-free survival (33.3% [95% CI, 11.6-96.1] vs. 83.0% [95% CI, 77.5-88.9] in the other 192 male patients, p < .001) and was an independent risk factor (hazard ratio [HR], 5.7; [95% CI, 2.2-14.5], p < .001). CONCLUSIONS: These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indicators for new molecular therapeutics or immunotherapy in patients with TCF3::PBX1 ALL.

Nomogram for Predicting Early Mortality after Umbilical Cord Blood Transplantation in Children with Inborn Errors of Immunity.

PURPOSE: Pediatric patients with inborn errors of immunity (IEI) undergoing umbilical cord blood transplantation (UCBT) are at risk of early mortality. Our aim was to develop and validate a prediction model for early mortality after UCBT in pediatric IEI patients based on pretransplant factors. METHODS: Data from 230 pediatric IEI patients who received their first UCBT between 2014 and 2021 at a single center were analyzed retrospectively. Data from 2014-2019 and 2020-2021 were used as training and validation sets, respectively. The primary outcome of interest was early mortality. Machine learning algorithms were used to identify risk factors associated with early mortality and to build predictive models. The model with the best performance was visualized using a nomogram. Discriminative ability was measured using the area under the curve (AUC) and decision curve analysis. RESULTS: Fifty days was determined as the cutoff for distinguishing early mortality in pediatric IEI patients undergoing UCBT. Of the 230 patients, 43 (18.7%) suffered early mortality. Multivariate logistic regression with pretransplant albumin, CD4 (absolute count), elevated C-reactive protein, and medical history of sepsis showed good discriminant AUC values of 0.7385 (95% CI, 0.5824-0.8945) and 0.827 (95% CI, 0.7409-0.9132) in predicting early mortality in the validation and training sets, respectively. The sensitivity and specificity were 0.5385 and 0.8154 for validation and 0.7667 and 0.7705 for training, respectively. The final model yielded net benefits across a reasonable range of risk thresholds. CONCLUSION: The developed nomogram can predict early mortality in pediatric IEI patients undergoing UCBT.

Molecular characteristics of carbapenem-resistant gram-negative bacilli in pediatric patients in China.

BACKGROUND: Carbapenem-resistant gram-negative bacilli (CR-GNB) have been increasingly reported in China. However, dynamic monitoring data on molecular epidemiology of CR-GNB are limited in pediatric patients. RESULTS: 300 CR-GNB isolates (200 Carbapenem-resistant K. pneumoniae (CRKP), 50 carbapenem-resistant A.baumannii (CRAB) and 50 carbapenem-resistant P. aeruginosa (CRPA)) were investigated. The predominant carbapenemase gene was blaNDM-1 (73%) and blaKPC-2 (65%) in neonates and non-neonates. Meanwhile, the predominant STs were ST11 (54%) in neonates and ST17 (27.0%) and ST278 (20.0%) in non-neonates. Notably, a shift in the dominant sequence type of CRKP infections from ST17 /ST278-NDM-1 to ST11-KPC-2 was observed during the years 2017-2021 and KPC-KP showed relatively higher resistance to aminoglycosides and quinolones than NDM-KP.BlaOXA-23 was isolated from all the CRAB isolates while only one isolate expressing blaBIC and 2 isolates expressing blaVIM-2 were found in CRPA isolates. ST195 (22.0%) and ST244 (24.0%) were the most common in CRAB and CRPA isolates and all the STs of CRAB belonged to CC92 while CRPA presents ST types with diversity distribution. CONCLUSION: CRKP showed different molecular phenotypes in neonates and non-neonates and was changing dynamically and high-risk clone of ST11 KPC-KP should be paid more attention. Most CRKP and CRAB strains shared the same CCs, suggesting that intrahospital transmission may occur, and large-scale screening and more effective measures are urgently needed.

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).

Causes of death and treatment-related mortality in newly diagnosed childhood acute lymphoblastic leukemia treatment with Chinese Children's Cancer Group study ALL-2015.

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014).

Shift in the dominant sequence type of carbapenem-resistant Klebsiella pneumonia infection from ST278-NDM-1 to ST11-KPC-2 in neonatal patients in a children's hospital in Shanghai, China, 2017-2021.

OBJECTIVES: To investigate the clinical characteristics and molecular epidemiology of CRKP infection in neonatal patients in a children's hospital in China from 2017 to 2021. METHODS: Species identification and antibiotic susceptibilities were tested with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and VITEK 2 systems. The clinical data were collected from medical records. Carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates were investigated by antimicrobial susceptibility testing, carbapenemase genes and multilocus sequence typing. RESULTS: Six kinds of resistant genes and 23 STs were detected. BlaNDM-1 (n=83, 55.3%) was the predominant carbapenemase gene, followed by blaKPC-2 (n=45, 30.0%), blaNDM-5 (n=7, 4.7%), blaIMP-38 (n=6, 4.0%). BlaNDM-1 was predominant in 2017 and 2018, whereas blaKPC-2 increased in 2019 and became the predominant gene from 2020 to 2021. ST11 accounted for most infections (n=35, 23.3%), followed by ST278 (n=23, 15.3%), ST17 (n=17, 11. 3%) and ST2735 (n=16, 10.7%). ST278 and ST17 were predominant in 2017 and 2018, whereas ST11 increased in 2019 and became the predominant sequence type from 2020 to 2021. Compared with blaNDM-1, the CRKP strains producing blaKPC-2 were characterized by high resistance to gentamicin, amikacin and levofloxacin and the change trend of drug resistance rate before and after COVID-19 was consistent with that of blaNDM-1 and blaKPC-2. CONCLUSIONS: The main sequence type of CRKP infection changed dynamically from ST278-NDM-1 to ST11-KPC-2 during the years 2017-2021 in the newborns. Antibiotic exposure and the prevalence of COVID-19 since 2020 may have led to changes in hospital population and lead to the changes.

Clinical features and treatment outcomes of Castleman disease in children: a retrospective cohort in China.

Castleman disease (CD) is a rare lymphoproliferative disorder of undetermined etiology. Unicentric CD (UCD) and multicentric CD (MCD) are two phenotypes of CD diagnosed by the histopathology of lymph nodes. We attempted to describe a pediatric CD cohort to optimize the management of this disease. We reviewed the medical records of pediatric patients diagnosed with CD between April, 2004, and October, 2022, at the Children's Hospital of Fudan University. Prognosis information was collected in January, 2023, by telephone inquiry. Twenty-two patients with UCD and 2 patients with MCD were identified, all with hyaline vascular (HV) type. The median ages at diagnosis were 10.75 years (IQR 8, 12.81) for UCD and 14.42 years (IQR 13.42, 15.42) for MCD. The most common lesion location of UCD was the neck (9/22, 40.91%) and abdomen (9/22, 40.91%). Systematic symptoms occurred on 10/22 (45.45%) patients with UCD and 1/2 (50%) patients with MCD, and abnormal laboratory indexes were detected in both. Resection and biopsy were performed on all patients. One out of two patients with MCD also received rituximab for upfront therapy. After a median of 4 years (IQR 1.5, 6) of follow-up time, the overall survival was 100% and the complete remission rate in UCD was 63%. There was no relapse or progression. CONCLUSIONS: Our series demonstrated that HV-UCD was the most common type in children. Resection and biopsy were used for both deterministic diagnoses and treatments. Despite the high possibility to develop systematic inflammation, children with CD showed promising outcomes. WHAT IS KNOWN: • Castleman disease is a rare lymphoproliferative disorder with limited cohort studies, especially in pediatrics. • The ubiquity of delayed confirmations and misdiagnoses points to a lack of knowledge about etiology and characteristics, which is a prerequisite for novel therapeutics. WHAT IS NEW: • We retrospectively reviewed and analyzed the clinical and pathological symptoms, laboratory and imaging features, and treatment outcomes of a Chinese pediatric cohort with Castleman disease. • Our work may improve the recognition and optimize the management of this rare disease in children.

Effect of nutritional status on outcomes in children receiving umbilical cord blood stem cell transplantation.

BACKGROUND AND OBJECTIVES: The impacts of nutritional status on clinical outcomes in children receiving umbilical cord blood stem cell transplantation (UCBT) are not fully described. We evaluated the risk for malnutrition before transplantation admission and influence of weight loss during hospitalization on short-term clinical outcomes in children with UCBT. METHODS AND STUDY DESIGN: We conducted a retrospective study of pediatric patients up to age 18 years who received UCBT and were treated at the Children's Hospital of Fudan University between January 2019 and December 2020. RESULTS: The mean age of the 91 patients was 1.3 years, with 78 (85.7%) men and 13 (14.3%) women (p<0.001). UCBT was performed mostly for primary immunodeficiency disease (PID) (83, 91.2%). The weight loss differences among children with different primary diseases were statistically significant (p=0.003). Children with a large amount of weight loss during hospitalization (n = 24) had higher risks of skin graft-versus-host disease (GVHD) (multivariate OR=5.01, 95% CI: 1.35-18.65), intestinal GVHD (multivariate OR=7.27, 95% CI: 1.74-30.45), a longer median hospital stay (p=0.004), higher antibiotic costs (p=0.008) and higher total hospitalization costs (p=0.004). Malnutrition on admission was significantly positively correlated with longer parenteral nutrition (PN) time (p=0.008). Early nutritional intervention effects on clinical outcomes need further assessment. CONCLUSIONS: Underweight recipient child and excessive weight loss during transplantation increases the length and cost of hospital stay, and is associated with a high incidence of GVHD, which affects the prognosis of transplantation and medical resources consumption.

Extended vincristine and dexamethasone pulse therapy may not be necessary for children with TCF3-PBX1 positive acute lymphoblastic leukaemia.

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.

BACKGROUND: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia. METHODS: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m2) plus oral dexamethasone (6 mg/m2 per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706. FINDINGS: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060). INTERPRETATION: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia. FUNDING: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing.

BACKGROUND: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give rise to ALL remain poorly understood. METHODS: Using next-generation sequencing (NGS) in matched germline and tumor samples from 140 pediatric Chinese patients with ALL, we landscaped the gene mutations and estimated the mutation frequencies in this disease. RESULTS: Our results showed that the top driver oncogenes having a mutation prevalence over 5% in childhood ALL included KRAS (8.76%), NRAS (6.4%), FLT3 (5.7%) and KMT2D (5.0%). While the most frequently mutated genes were KRAS, NRAS and FLT3 in B cell ALL (B-ALL), the most common mutations were enriched in NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) in T cell ALL (T-ALL). These mutant genes are involved in key molecular processes, including the Ras pathway, the Notch pathway, epigenetic modification, and cell-cycle regulation. Strikingly, more than 50% of mutations occurred in the high-hyperdiploid (HeH) ALL existed in Ras pathway, especially FLT3 (20%). We also found that the epigenetic regulator gene KMT2D, which is frequently mutated in ALL, may be involved in driving leukemia transformation, as evidenced by an in vitro functional assay. CONCLUSION: Overall, this study provides further insights into the genetic basis of ALL and shows that Ras mutations are predominant in childhood ALL, especially in the high-hyperdiploid subtype in our research.

[Identification of a novel CHS1/LYST variant in a Chinese pedigree affected with Chediak-Higashi syndrome].

OBJECTIVE: To detect pathological variant in two patients with Chediak-Higashi syndrome (CHS) from a consanguineous family and to explore its genotype-phenotype correlation. METHODS: Clinical data was collected for this pedigree. Genomic DNA was prepared from probands' peripheral leukocytes and their relatives' fingernail. Whole exome sequencing and Sanger sequencing were carried out to detect potential variant of the LYST gene. RESULTS: The proband presented with partial oculocutaneous albinism, immunodeficiency and acidophilic inclusion body in bone marrow and blood smears. A novel homozygous nonsense variant c.8782C>T (p.Gln2928*) was identified in exon 34 of the LYST gene in the sib pair. The same variant was found to be in heterozygous status in 6 unaffected individuals from the pedigree. CONCLUSION: Above result enriched the mutational spectrum of CHS and provided a basis for genetic counseling and prenatal diagnosis for this pedigree.

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia With High Tumor Burden Treated With BFM95-based Protocol Combining Rituximab: A Report From Shanghai, China.

In this study we evaluated children with newly diagnosed advanced (stage III and stage IV) mature B-cell non-Hodgkin lymphoma (B-NHL) or mature B-cell acute leukemia (B-AL), who were treated with Berlin-Frankfurt-Münster (BFM)95-based protocol combined with rituximab (R+BFM95). Our study recruited 46 patients who were treated with BFM95 protocol combined with rituximab. There are 23 patients as the historical control treated with BFM90 protocol. Compared with patients treated with BFM90 protocol, the 5-year event-free survival (EFS) rate of patients under R+BFM95 was higher (83.7%±5.7% vs. 69.6%±9.6%; P=0.1062). Among subgroups of our patients, the 5-year EFS of patients with stage III was 87.3%±6.1% vs. 77.8%±9.8% (P=0.2998), stage IV/B-AL was 72.7%±13.4% versus 40.0%±21.9% (P=0.0878) between patients treated with R+BFM95 and BFM90, respectively. Among patients whose lactate dehydrogenase (LDH) level were <500 U/L at diagnosis, R+BFM95 protocol reached 100% survival, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3%±7.4%; P=0.2994). Among patients had LDH≥500 U/L at diagnosis, the 5-year EFS in R+BFM95 group was 77.2%±7.7% (32 patients) and significantly higher than that of BFM90 group (40.0%±15.5%, 10 patients; P=0.0048). We found that rituximab has improved the EFS of childhood B-NHL/B-AL with LDH≥500U/L. Our results require validation from future studies with large cohort.

Identification of a novel susceptibility locus at 16q23.1 associated with childhood acute lymphoblastic leukemia in Han Chinese.

Recently, genome-wide association studies (GWAS) have identified several susceptibility loci for childhood acute lymphoblastic leukemia (ALL) in populations of European descent; only a few loci could be confirmed in Asian populations because of those populations' genetic heterogeneity. To identify genetic factors associated with childhood ALL risk in the Chinese population, we performed a three-stage GWAS of 1184 childhood ALL cases and 3219 non-ALL controls. The combined analysis identified a new locus (rs1121404 in WWOX) at 16q23.1 associated with childhood ALL susceptibility (odds ratio (OR) = 1.38, P = 5.29 × 10-10), especially in the subtype of B-ALL (OR = 1.39, P = 2.47 × 10-9). The functional studies subsequently revealed that the expression of WWOX in ALL bone marrow was significantly lower than that in normal bone marrow. The G allele of rs1121404 displayed significantly decreased levels of mRNA expression of WWOX These results suggest that WWOX plays an important role in the development of childhood ALL and provide new insights into the etiology of childhood ALL.

[Clinical application of minimal residual disease detection in childhood acute leukemia].

In recent years, great progress has been made in the treatment outcome of childhood acute leukemia with the improvement of chemotherapy regimens and the introduction of risk-stratified therapy; however, minimal residual disease (MRD) is still a difficult problem which affects the prognosis of acute leukemia. MRD influences the selection of chemotherapy regimens and recurrence risk stratification, and meanwhile, it can be used for prognostic prediction. At present, flow cytometry and polymerase chain reaction are mainly used for MRD detection. The next-generation sequencing also plays an important role in MRD detection, especially in MRD detection after stem cell transplantation. This article reviews the methodology and significance of MRD detection in childhood acute leukemia.