Childhood Acute Lymphoblastic Leukemia Research Articles

Prediction of tumor lysis syndrome in childhood acute lymphoblastic leukemia based on machine learning models: a retrospective study.

Tumor lysis syndrome (TLS) often occurs early after induction chemotherapy for acute lymphoblastic leukemia (ALL) and can rapidly progress. This study aimed to construct a machine learning model to predict the risk of TLS using clinical indicators at the time of ALL diagnosis. This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data were collected from pediatric ALL patients diagnosed between December 2008 and December 2021. Four machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. The study included 2,243 pediatric ALL patients, and the occurrence of TLS was 8.87%. A total of 33 indicators with missing values ≤30% were collected, and 12 risk factors were selected through LASSO regression analysis. The CatBoost model with the best performance after feature screening was selected to predict the TLS of ALL patients. The CatBoost model had an AUC of 0.832 and an accuracy of 0.758. The risk factors most associated with TLS were the absence of potassium, phosphorus, aspartate transaminase (AST), white blood cell count (WBC), and urea levels. We developed the first TLS prediction model for pediatric ALL to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200060616). https://www.chictr.org.cn/, identifier ChiCTR2200060616.

Non-homologous End-joining Genotype, mRNA Expression, and DNA Repair Capacity in Childhood Acute Lymphocytic Leukemia.

The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature on the involvement of NHEJ-related genes in childhood acute lymphocytic leukemia (ALL). Our study aimed to elucidate the impact of polymorphisms of X-ray repair cross-complementing group 4 (XRCC4) (rs6869366, rs2075685, rs2075686, rs28360071, rs3734091, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and DNA ligase IV (LIG4) rs1805388, on the odds of childhood ALL. Genotypes NHEJ-related genes of 266 cases and 266 controls were determined, and the genotype-phenotype correlation was investigated by examining mRNA transcript expression and the capacity for overall and precise NHEJ repair. The variant genotypes of XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 were significantly associated with increased odds of childhood ALL. Further analysis based on susceptibility genotypes showed no significant differences in mRNA transcript expression levels among childhood ALL cases with various putative high-risk genotypes, except XRCC6 rs5751129. Moreover, the overall NHEJ repair capacity was similar among carriers of different XRCC4, XRCC5, and XRCC6 genotypes. However, it is worth noting that individuals carrying the variant C allele at XRCC6 rs5751129 exhibited lower precise NHEJ repair capacity compared to those with the wild-type T allele. Our study identified significant associations between XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 genotypes and childhood ALL. Notably, lower transcriptional expression and reduced precise NHEJ repair capacity were observed in patients carrying the C allele of XRCC6 rs5751129. Further investigations are required to gain deeper insights into childhood ALL development.

Predictive factors for L-asparaginase hypersensitivity in pediatric acute lymphoblastic leukemia.

L-Asparaginase is a crucial component of acute lymphoblastic leukemia (ALL) treatment. However, hypersensitivity is a common adverse event. This study aimed to identify risk factors for L-asparaginase hypersensitivity in childhood ALL. Children treated for ALL at Chiang Mai University Hospital, Thailand, between 2005 and 2020 were included. Demographic data, clinical characteristics, and factors related to L-asparaginase were retrospectively reviewed. L-Asparaginase hypersensitivity was observed in 24 of 216 children with ALL (11.1%). All patients received native L-asparaginase intramuscularly, and events occurred exclusively during the post-induction phase without concurrent corticosteroid use. Univariable analysis showed that relapsed ALL, higher accumulated doses, increased exposure days, and longer interval between drug administrations were potential risk factors. In multivariable logistic regression analysis, interruption of L-asparaginase administration for ≥ 52weeks and exposure duration of ≥ 15days were independent risk factors, with adjusted odds ratio of 16.481 (95% CI 3.248-83.617, p = 0.001) and 4.919 (95% CI 1.138-21.263, p = 0.033), respectively. Children with ALL who require re-exposure to L-asparaginase after 52-week interruption or who have received L-asparaginase for ≥ 15 exposure days are at risk of developing L-asparaginase hypersensitivity. Further management strategies in this setting should be evaluated.

Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset

BackgroundAcute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced.MethodsWe assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables.ResultsThere were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0–3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures.ConclusionsOur more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.

Hepatic Dysfunction during Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma and Its Effects on Subsequent Therapy and Outcome

Abstract Introduction The overall survival rate for childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) has shown tremendous growth in the recent years. Hepatic dysfunction is one of the complications seen during therapy and can add to the underlying morbidity of the disease, delay in chemotherapy, modification of drugs, and rarely fulminant hepatic failure. Objective This article aims to find out the prevalence of hepatic dysfunction during induction chemotherapy for ALL and LBL. Materials and Methods This was a retrospective study, where the data of all children between 1 and 18 years of age with ALL and LBL treated at our center as per the UK-ALL 2003 protocol between December 2013 and December 2021 have been included from the medical records. Hepatic dysfunction was defined as grade 3 and 4 alanine transaminase (ALT) and aspartate transaminase (AST) levels as per Common Terminology Criteria for Adverse Events v5.0 and hyperbilirubinemia as ≥ 1.4 mg/dL as the chemotherapy modification begins at this cutoff. Data from children with hepatic dysfunction was compared with those without hepatic dysfunction using chi-squared test and Student's t-tests. Those variables with a p-value of &lt; 0.2 were analyzed with multivariate regression analysis. Kaplan–Meier survival estimates were used to calculate the event-free survival (EFS). Results A total of 142 children were included in the study. Thirty-one (21.8%) children developed hepatic dysfunction, 14 (9.9%) of them with ALT/AST elevation and 27 (19%) with bilirubin elevation. Weight (mean 25 ± 13.5, p 0.01), body surface area (mean 0.87 ± 0.29, p 0.02), and National Cancer Institute high risk (p 0.005) were associated with hepatic dysfunction in univariate analysis but none of them were significant in multivariate regression analysis. Treatment modification was required in 14/31 children with hepatic dysfunction. Death in induction was more among children with hepatic dysfunction (p &lt; 0.001). There was no significant impact on minimal residual disease outcomes. Five-year EFS (death or relapse) was 59.93 ± 9% in children with hepatic dysfunction as opposed to 72 ± 5.0% in those without hepatic dysfunction (95% confidence interval, p = 0.07). Conclusion One in five children with ALL and LBL on induction therapy developed hepatic dysfunction. Almost half of those with hepatic dysfunction required chemotherapy modifications.

Changes in the Concentrations of Proangiogenic Cytokines in Human Brain Glioma and Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) and glioma are some of the most common malignancies, with ALL most often affecting children and glioma affecting adult men. Proangiogenic cytokines and growth factors play an important role in the development of both of these tumors. Glioma is characterized by an extremely extensive network of blood vessels, which continues to expand mainly in the process of neoangiogenesis, the direct inducers of which are cytokines from the family of vascular endothelial growth factors, i.e., vascular endothelial growth factor (VEGF-A) and its receptor vascular endothelial growth factor receptor 2 (VEGF-R2), as well as a cytokine from the fibroblast growth factor family, fibroblast growth factor 2 (FGF-2 or bFGF). Growth factors are known primarily for their involvement in the progression and development of solid tumors, but there is evidence that local bone marrow angiogenesis and increased blood vessel density are also present in hematological malignancies, including leukemias. The aim of this study was to examine changes in the concentrations of VEGF-A, VEGF-R2, and FGF-2 (with a molecular weight of 17 kDa) in a group of patients divided into specific grades of malignancy (glioma) and a control group; changes of VEGF-A and FGF-2 concentrations in childhood acute lymphoblastic leukemia and a control group; and to determine correlations between the individual proteins as well as the influence of the patient's age, diet, and other conditions that may place the patient in the risk group. During the statistical analysis, significant differences in concentrations were found between the patient and control groups in samples from people with diagnosed glioma and from children with acute lymphoblastic leukemia, but in general, there are no significant differences in the concentrations of VEGF-A, VEGF-R2, and FGF-2 between different grades of glioma malignancy. Among individuals treated for glioma, there was no significant impact from the patient's gender and age, consumption of food from plastic packaging, frequency of eating vegetables and fruit, smoking of tobacco products, the intensity of physical exercise, or the general condition of the body (Karnofsky score) on the concentrations of the determined cytokines and receptor. The listed factors do not bring about an actual increase in the risk of developing brain glioma.

Role of neurotrophic growth factors in vincristine polyneuropathy in children with acute lymphoblastic leukemia

Vincristine-induced peripheral neuropathy (VIPN) is one of the frequent toxic complications in the treatment of acute lymphoblastic leukemia in children. The pathogenesis of peripheral nerve damage is not fully understood; however, recent studies have demonstrated the involvement of neurotrophic factors. The purpose of the study: to evaluate the level of plasma neurotrophic growth factors in children with acute lymphoblastic leukemia (ALL) and determine their association with the VIPN formation. Materials and methods: 131 newly diagnosed ALL patients aged 3 to 17 years receiving chemotherapy according to the ALL–MB 2015 protocol participated in a single-center prospective study. Depending on the development of VIPN, the patients were divided into two groups: the study group (n=106) — children with VIPN and the comparison group (n=25) — children without VIPN. The plasma level of neurotrophic growth factors (NGF-β and BDNF) was determined using multiparametric immunofluorescence analysis.Results: during the follow-up period, 80.9 % of the children (n=106) developed VIPN against the background of chemotherapy. In most cases, neurotoxic disorder manifested at the induction stage of treatment — in 84.9 % (n=90) of the patients. The clinical phenotype of VIPN was characterized by a combination of neurological disorders in 67.9 % (n=72) of the patients, with the predominance of sensory and motor symptoms. The comparative analysis of plasma neurotrophic growth factors in the groups of children with ALL depending on the VIPN formation showed that in the patients with VIPN, a statistically significant increase in brain-derived neurotrophic factor (BDNF) was noted at the consolidation stage of chemotherapy (study 1–284.3 (97.4÷628.3) pg/mL; study 2–281.7 (178.9÷679.2) pg/mL; study 3–980.2 (454.3÷2,005.9) pg/mL; p1-2=0.424 and p1-3=0.009). However, in the children without VIPN, an increase in this growth factor was observed during the induction phase (study 1–370.5 (95.4÷463.8) pg/mL; study 2–683.0 (362.4÷1,486.3) pg/mL; study 3–674.6 (394.8÷2,584.0) pg/mL; p1-2=0.043 and p1-3=0.021). In addition, in the study group patients with the early debut of VIPN, the level of nerve growth factor-β (NGF-β) before the administration of chemotherapy was significantly lower in contrast to the patients with its development in later terms (22.7 (10.9÷22.7) pg/mL and 24.7 (22.7÷91.5) pg/mL, respectively; p=0.045). When assessing the clinical value of this indicator, the diagnostic sensitivity was 88 %, specificity — 71 %, and the integral index characterizing the accuracy of the test was 0.81. Conclusion. The increase in plasma growth factor (BDNF) in earlier terms in children without VIPN probably reflects the mechanisms aimed at preventing the realization of VIPN. The established low concentration of plasma NGF-β and optimal diagnostic characteristics of the factor in children with early VIPN onset allow considering it as a prognostic biomarker.

Targeting TNF/IL-17/MAPK pathway in hE2A-PBX1 leukemia: effects of OUL35, KJ-Pyr-9, and CID44216842.

t(1;19)(q23;p13) is one of the most common translocation genes in childhood acute lymphoblastic leukemia (ALL) and is also present in acute myeloid leukemia (AML) and mixed-phenotype acute leukemia (MPAL). This translocation results in the formation of the oncogenic E2A-PBX1 fusion protein, which contains a trans-activating domain from E2A and a DNA-binding homologous domain from PBX1. Despite its clear oncogenic potential, the pathogenesis of E2A-PBX1 fusion protein is not fully understood (especially in leukemias other than ALL), and effective targeted clinical therapies have not been developed. To address this, we established a stable and heritable zebrafish line expressing human E2A-PBX1 (hE2A-PBX1) for high-throughput drug screening. Blood phenotype analysis showed that hE2A-PBX1 expression induced myeloid hyperplasia by increasing myeloid differentiation propensity of hematopoietic stem cells (HSPC) and myeloid proliferation in larvae, and progressed to AML in adults. Mechanistic studies revealed that hE2A-PBX1 activated the TNF/IL-17/MAPK signaling pathway in blood cells and induced myeloid hyperplasia by upregulating the expression of runx1. Interestingly, through high-throughput drug screening, three small molecules targeting the TNF/IL-17/MAPK signaling pathway were identified, including OUL35, KJ-Pyr-9, and CID44216842, which not only alleviated the hE2A-PBX1-induced myeloid hyperplasia in zebrafish but also inhibited the growth and oncogenicity of human pre-B ALL cells with E2A-PBX1. Overall, this study provides a novel hE2APBX1 transgenic zebrafish leukemia model and identifies potential targeted therapeutic drugs, which may offer new insights into the treatment of E2A-PBX1 leukemia.

Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.

Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.

A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC). A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained. A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed. The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.

QTc intervals at rest and during exercise assessed by group correction formulas in survivors of childhood acute lymphoblastic leukemia

IntroductionEarly signs of subclinical cardiac damage must be identified before they turn into clinical manifestations. Tailoring a formula is relevant for precise QTc evaluation in childhood acute lymphoblastic leukemia (ALL) survivors considering they are at risk of long-term cardiac problems. Therefore, we aim to develop group heart rate correction formulas for QT intervals in childhood ALL survivors at rest and during exercise, and to assess the applicability of these methods across a variety of risk groups exposed to diverse chemotherapy dosages. MethodsTwo hundred and fifty childhood ALL survivors in the PETALE study were classified into 3 groups depending on their prognostic risk group. ECG measurements (QT and RR intervals) were made at rest and during a cardiopulmonary exercise test. QT correction for heart rate was applied using 5 different formulas, which included 2 previously published formulas and 3 group-specific formulas for each sex. ResultsThe QT/RR relation showed 2 different curves between rest and during exercise, which was worse for females. Group-specific QTc formulas allowed adequate heart rate-corrected QT interval, independently of the cumulative dose of doxorubicin received during treatment. Group-specific formulas showed significantly shorter QTc intervals than QTc from Bazett's formula. QTc (Bazett's formula) values surpassed the established clinical norm in 22 males (11%) and 22 females (11%), with a majority occurring during exercise, affecting 15 males (7.5%) and 10 females (5%). ConclusionThis study shows the applicability of personalized group correction of QT/RR data in childhood ALL survivors. Our comprehensive assessments (spanning rest, exercise, and recovery) is an effective approach for risk stratification of cardiac complications in childhood ALL survivors.

Treatment of Pediatric Acute Lymphoblastic Leukemia: A Historical Perspective.

Acute lymphoblastic leukemia (ALL) is the most common disease in pediatric oncology. The history of developmental therapeutics for ALL began in the 1960s with the repetition of "unreliable" medical interventions against this lethal disease. By the 1990s, the development of multi-agent chemotherapy and various types of supportive care rendered ALL treatable. Highly sophisticated, molecular, diagnostic techniques have enabled highly accurate prediction of the relapse risk, and the application of risk-adapted treatments has increased the survival rate in the standard-risk group to nearly 100% in most European nations and North America. Incorporation of state-of-the-art, molecularly targeted agents and novel treatments, including cell and immunotherapy, is further improving outcomes even in the high-risk group. On the other hand, the financial burden of treating children with ALL has increased, imperiling the availability of these diagnostic and treatment strategies to patients in low- and middle-income countries (LMICs). The fundamental treatment strategy, consisting of corticosteroid and classical cytotoxic therapy, has achieved fairly good outcomes and should be feasible in LMICs as well. The present review will discuss the history of developmental therapeutics for childhood ALL in various countries through an extensive literature review with the aim of proposing a model for a treatment backbone for pediatric ALL. The discussion will hopefully benefit LMICs and be useful as a base for future clinical trials of novel treatments.

Movement efficiency in survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude lifetime cohort study.

Movement efficiency, a measure of neuromuscular biomechanics, may be modified by physical activity. We aimed to assess the risk of and risk factors for low movement efficiency in survivors of childhood acute lymphoblastic leukemia (ALL). Participants underwent an assessment of activity energy expenditure (AEE) with actigraphy, and the gold standard doubly labeled water, where the differences between elimination rates of oxygen and hydrogen from body water are evaluated over a week. Movement efficiency was assessed using the raw residuals of a linear regression between AEEs from accelerometers and doubly labeled water. Elastic-net logistic regressions were used to identify demographic, treatment, and functional variables associated with movement efficiency. The study cohort included 256 non-cancer controls and 302 ALL survivors (48% female), categorized as efficient (N = 24), normal (N = 245), or inefficient (N = 33) based on their movement efficiency. There was no difference in the odds for poor movement efficiency between survivors (n = 33, 10.9%) compared to controls (n = 23, 9.0%, odds ratio [OR]: 1.19, 95% confidence interval [CI]: 0.67, 2.10; p = 0.55). In survivors, neuropathy was associated with a higher risk of being inefficient compared to efficient (OR 4.30, 95% CI 1.03-17.96), while obesity (≥ 30kg/m2) had a protective association (OR 0.18, 95% CI 0.04-0.87). Neuropathy was associated with a higher risk of poor movement efficiency in survivors of childhood ALL. These results further highlight impairments associated with treatment-induced neuropathy in survivors of childhood ALL.

Clinical Analysis of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Children

To explore the clinical characteristics, molecular characteristics, treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with a therapeutic target. A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021. The data of age, gender, white blood cell (WBC) count at initial diagnosis, genetic characteristics, molecular biological changes, chemotherapy regimen, different targeted drugs were given, and minimal residual disease (MRD) on day 19, MRD on day 46, whether hematopoietic stem cell transplantation (HSCT) were retrospective analyed, and the clinical characteristics and treatment effect were summarized. Survival analysis was performed by Kaplan-Meier method. The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients, 10 patients were treated with targeted drugs during treatment, and 3 patients were bridged with HSCT, 1 patient died and 2 patients survived. Among the 24 patients who did not receive HSCT, 1 patient developed relapse, and achieved complete remission (CR) after treatment with chimeric antigen receptors T cells (CAR-T). The 3-year overall survival, 3-year relapse-free survival and 3-year event-free survival rate of 27 patients were (95.5±4.4)%, (95.0±4.9)% and (90.7±6.3)% respectively. Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children, combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor, and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.

Survival and Treatment Outcomes of Childhood Acute Lymphoblastic Leukemia in a Low-Middle Income Country: A Single-Center Experience in West Java, Indonesia.

This study aimed to determine the survival rates and treatment outcomes of patients with childhood Acute Lymphoblastic Leukemia (ALL) in a single-center study at Indonesia. Factors contributing to the relapse and survival of ALL in Bandung, Indonesia, were evaluated. Data were collected from the medical record and the Indonesian Pediatric Cancer Registry (IPCAR). Subsequently, univariate and multivariate analyses were evaluated using Cox proportional hazard regression and Kaplan Meier was used for survival analysis. An analytic observational study was conducted on newly diagnosed children aged 1-18 with ALL from January 2019 to December 2022. A total of 137 children were included in the analysis, 30 (21,9%) were dropped out during treatment and 60.5% died during the study period. Most of the deaths occurred after relapse in 32 (38.5%) with a high early relapse (70.5%), occurring mainly during the maintenance phase (42.4%). At the one-year mark, the observed overall survival (OS) rate was at 36%, while event-free survival (EFS) was lower, at 19%. Univariate Cox regression analysis showed that the leucocyte counts at diagnosis (p=0.005) and response to induction phase (p < 0.008) was associated with the death of ALL. Furthermore, a response to induction phase was significant [hazard ratio 4.67 (CI 95%: 1.64-13.29); p = 0.004] in the multivariate analysis. In conclusion, this study underscored the persistent challenges of high treatment discontinuation rates and the occurrence of very early relapses in low- to middle-income countries (LMICs), which significantly impacted the OS of children diagnosed with ALL.

Long-term neurotoxicity among childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC Children Leukemia Group studies

Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15–22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971–1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10–17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).

Acute Lymphoblastic Leukemia: About a Case Observed at the Renaissance University Hospital in N'Djamena.

Introduction: Childhood acute lymphoblastic leukaemia is the most common paediatric cancer. The objective of our work is to focus on a haematological manifestation such as pancytopenia inaugurating the picture of acute lymphoblastic leukaemia. Observation: 11-year-old AI, who has been reporting repeated anaemia and haemoglobinuria for 6 months. The clinical examination reveals an alteration of the general condition, severe mucocutaneous pallor, splenomegaly. The initial blood count showed pancytopenia. The diagnosis of acute lymphoblastic leukaemia was confirmed by a myelogram requested in the presence of pancytopenia. Conclusion: Through this observation, we report the clinical and biological manifestations of acute lymphoblastic leukaemia, emphasizing the interest in eliminating haematological malignancy in the face of any pancytopenia.

CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in TCF3::PBX1 ALL.

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression. TCF3::PBX1 subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with TCF3::PBX1 subtype from others. Our results indicated that NUDT21, an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in TCF3::PBX1 ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Association of long non-coding RNAs and ABO blood groups with acute lymphoblastic leukemia in Egyptian children

Acute lymphoblastic leukemia (ALL) is the most prevailing cancer among children. Despite extensive studies, ALL etiology is still an unsolved puzzle. Long non-coding RNAs (lncRNAs) emerged as key mediators in cancer etiology. Several lncRNAs are dysregulated in ALL, leading to oncogenic or tumor-suppressive activities. Additionally, a relation between ABO blood groups and hematological malignancies was proposed. The current study intended to explore the association of lncRNAs, ANRIL and LINC-PINT, and their downstream targets, CDKN2A and heme oxygenase-1 (HMOX1), with the incidence of ALL and treatment response, and to determine the distribution of blood groups across different childhood ALL phenotypes. Blood samples were taken from 66 ALL patients (at diagnosis and at the end of remission induction phase) and 39 healthy children. Whole blood was used for blood group typing. Expression of ANRIL, LINC-PINT and CDKN2A was analyzed in plasma by qRT-PCR. Serum HMOX1 was measured using ELISA. ANRIL and CDKN2A were upregulated, while LINC-PINT and HMOX1 were downregulated in newly diagnosed patients. All of which showed remarkable diagnostic performance, where HMOX1 was superior. HMOX1 was independent predictor of ALL as well. LINC-PINT and HMOX1 were significantly upregulated after treatment. Notably, ANRIL and LINC-PINT were associated with poor outcome. No significant difference in the distribution of ABO blood groups was observed between patients and controls. In conclusion, our results suggested an association of ANRIL and LINC-PINT with childhood ALL predisposition, at least in part, through altering CDKN2A and HMOX1 production. Furthermore, the impact of remission induction treatment was newly revealed.