Childhood Acute Lymphoblastic Leukemia Research Articles

A comparison of hypersensitivity reactions between intravenous and intramuscular applications of native E. coli asparaginase in children with acute lymphoblastic leukemia.

Asparaginase is an indispensable drug in treating childhood acute lymphoblastic leukemia (ALL). Hypersensitivity reactions (HSR) are the most common side effects and interfere with the antineoplastic activity of the drug. This study aims to compare the intramuscular (IM) and intravenous (IV) administration routes of Native Escherichia coli Lasparaginase (L-ASNase) in terms of hypersensitive reactions. L-ASNase was randomly administered IV or IM to newly diagnosed ALL patients and HSR was monitored in all patients for 1 h following the end of the IV infusion and for 2 h following the end of the IM administration of L-ASNase. Based on a retrospective review of clinical charts, reactions were identified. In order to determine the severity of each allergic reaction, we used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for allergic reactions. A total of 1032 doses of L-ASNase were administered to 85 patients (42 males and 43 females) during the study period. Among 85 patients, 30 reactions were recorded, which means that 35% of the patients reacted. According to the CTCAE, twenty-nine out of 30 reactions (97%) were grade 2, while one (3%) was grade 4. In terms of individual doses, there was a non-significant trend toward increased incidence of reactions with IV administration (3.8% versus 0.9%, p = 0.064). The rate of reactions was higher in patients who received all IV doses (n: 60) as compared to those who received all IM doses (n: 25) (31.7% vs. 3.5%; chi-square= 8.415, p value=0.04). Based on the risk groups and HSR incidence, it was found that high risk group (HRG) patients were significantly more likely to develop HSR compared to the standart risk group (SRG) and intermediate risk group (MRG) patients (chi-square p = 0.003, CI: 95%; odds ratio: 3.12 and 5.91, respectively). In conclusion, IM administration of L-ASNase causes significantly less HSR to L-ASNase than the IV route. Patients with HRGALL have a higher risk of HSR. Since L-ASNase is still used in many developing countries and there are problems in the supply of Erwinia chrysanthemi ASNase (Erwinia), LASNase can be administered IM to reduce the frequency of HSR.

Commentary: Association between the miR-146a rs2910164 polymorphism and childhood acute lymphoblastic leukemia susceptibility in an Asian population.

GENERAL COMMENTARY article Front. Genet., 20 March 2023Sec. Statistical Genetics and Methodology Volume 14 - 2023 | https://doi.org/10.3389/fgene.2023.1134659

Vincristine and Dexamethasone Pulses in Addition to Maintenance Therapy Among Pediatric Acute Lymphoblastic Leukemia(GD-ALL-2008): an Open-label, Multicentre, Randomized, Phase III Clinical Trial.

The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial, which was conducted at nine major medical centers in Guangdong province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n=384) or the VCR/DEX pulse (treatment group, n=375). When limited to the SR cohort, 10-year EFS was 82.6% (95%CI: 75.9-89.9) in the control group and 80.7% (95%CI:74-88.1) in the treatment group (Pnon-inferiority =0.0002). Similarly, patients with IR also demonstrated that non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6%[95%CI: 67.6-80] vs 77.6%[95%CI: 71.8-83.9]); Pnon-inferiority =0.005). Among the HR cohort, compared with the control group, patients in the treatment group experienced significant benefit in terms of 10-year EFS (61.1%[95%CI:47.7-78.2] vs 72.6%[95%CI:55.6-94.7, P=0.026) and a trend towards higher 10-year OS (73.8%[95%CI:61.6-88.4] vs 87.9% [95%CI:579.2-97.5, P=0.068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs 100%, P=0.033; 37.5% vs 60%, P=0.036). Conversely, the total prevalence of chemotherapy induced thrombocytopenia were higher for patients in the treatment group than in the control group (88.9% vs 40%, P=0.027). Pediatric acute lymphoblastic leukemia with high-risk are suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses. This article is protected by copyright. All rights reserved.

Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia

Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL.

Treatment outcomes in childhood acute lymphoblastic leukemia: 40-year experience from a single tertiary center in Thailand

Studies on the long-term treatment outcomes of childhood acute lymphoblastic leukemia (ALL) in resource-limited countries are scarce. The purpose of this study was to assess the evolution of survival outcomes of pediatric ALL in a tertiary care center in Thailand over a 40-year period. We retrospectively reviewed the medical records of pediatric patients who were diagnosed with ALL and treated at our center between June 1979 and December 2019. We classified the patients into 4 study periods depending on the therapy protocol used to treat the patients (period 1: 1979–1986, period 2: 1987–2005, period 3: 2006–2013, and period 4: 2014–2019). The Kaplan–Meier method was used to determine overall and event-free survival (EFS) for each group. The log-rank test was used to identify statistical differences. Over the study period, 726 patients with ALL were identified, 428 boys (59%) and 298 girls (41%), with a median age at diagnosis of 4.7 years (range: 0.2–15 years). The study periods 1, 2, 3, and 4 had 5-year EFS rates of 27.6%, 41.6%, 55.9%, and 66.4%, and 5-year overall survival (OS) rates of 32.8%, 47.8%, 61.5%, and 69.3%, respectively. From periods 1 to 4, both the EFS and OS rates increased significantly (p <. 0001). Age, study period, and white blood cell (WBC) count were all significant prognostic indicators for survival outcomes. The OS of patients with ALL treated in our center improved significantly over time from 32.8% in period 1 to 69.3% in period 4.

Melatonin protects against methotrexate hepatotoxicity in young rats: Impact of PI3K/Akt/mTOR signaling.

With the improvement in children's acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of children's ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity.

The relationship of bone marrow fibrosis at diagnosis with prognosis and survival in childhood acute lymphoblastic leukemia

Objectives: Our aim in this study is to investigate the effect of fibrosis at diagnosis on treatment and survival in childhood acute lymphoblastic leukemia (ALL). Methods: This study is retrospective. We evaluated the relationship between patients' age, white blood cell count at diagnosis, morphological blast percentage and flow cytometric blast percentage at diagnosis, day 15th and day 33th, absolute blast count in peripheral smear on day 8th, and the degree of fibrosis in bone marrow biopsy at diagnosis in 36 pediatric patients. The fibrosis degree in biopsy on the thirty-third day after induction therapy was measured. Results: Twenty-eight (77.8%) cases were diagnosed B-ALL and 8 T-ALL (22.2%). There was no statistically significant difference between the groups with and without fibrosis in terms of any parameter measured at the time of diagnosis, 8th day, 15th day, and 33th day. No significant difference was found between the groups according to overall survival (OS): the mean OS was 50.22 ± 5.44 months in the fibrosis group and 49.70 ± 3.96 months in the non-fibrosis group (p = 0.557). Conclusions: There is a high detection rate of bone marrow fibrosis in ALL pediatric cases at the time of diagnosis. Nevertheless, fibrosis does not affect survival.

Impact of minimal residual disease on relapse in childhood acute lymphoblastic leukemia: Lessons learnt from a tertiary cancer center in India

Prognostic predictive value of end of induction minimal residual disease (EOI-MRD) is well established in acute lymphoblastic leukemia (ALL). We evaluated the factors likely to affect EOI-MRD positivity (>0.01%) by flow cytometry and relapse in different BFM-95 (Berlin–Frankfurt–Munich) risk groups among children and adolescents. In this retrospective study, data of 223 newly diagnosed patients with ALL was analyzed. Association between demographic and pretreatment characteristics with EOI-MRD was assessed. Risk factors for relapse were analyzed using univariate and multivariate Cox regression. Proportion of the SR (standard risk), MR (moderate risk), and HR (high risk) patients was 18.8%, 60.9%, 20.3%, respectively. Positive EOI-MRD among these risk groups was observed in 11.9%, 18.3%, and 55.5% patients respectively (p value <.01%). MRD positivity was more likely to be associated with older age (>10 years) and BFM-HR patients (p value .0008 and <.0001). Thirty-four (15.2%) patients relapsed in the whole cohort. On univariate analysis, statistically significant factors for RFS (relapse-free survival) included hyperleukocytosis, high-risk cytogenetics, NCI (National Cancer Institute) high risk, poor day-8 prednisolone response, BFM–HR and positive EOI-MRD status. Of all these only EOI-MRD retained its impact by multivariate analysis. Positive EOI-MRD significantly predicted relapse in BFM-MR with 5-year RFS of 88.0% and 68.4% (p value .02). Five-year RFS of EOI-MRD negative and positive groups were 86.4% and 65.5%, respectively (p value .004). EOI-MRD is a powerful tool to predict relapse in children and adolescent with ALL especially in BFM-MR. Application of MRD in HR patients needs to be redefined in conjunction with other variables.

PPARG, GNG12, and CD19 are potential independent predictors of central nerve recurrence in childhood acute lymphoblastic leukemia

ABSTRACTObjectiveTo identify biomarkers that can predict the recurrence of the central nervous system (CNS) in children with acute lymphoblastic leukemia (ALL).Materials and MethodsThe transcriptome and clinical data of ALL in children were downloaded from the TARGET database. Transcriptome data were analyzed by bioinformatics method to identify core (hub) genes and establish a risk assessment model. Univariate Cox analysis was performed on each clinical data, and multivariate Cox regression analysis was performed on the obtained results and risk score. The children ALL phase I samples from TARGET database were used for validation.ResultsUnivariate multivariate Cox analysis of 10 hub genes identified showed that PPARG (HR = 0.78, 95%CI = 0.67–0.91, p = 0.007), CD19 (HR = 1.15, 95%CI = 1.05–1.26, p = 0.003) and GNG12 (HR = 1.25, 95%CI = 1.04–1.51, p = 0.017) had statistical differences. The risk score was statistically significant in univariate (HR = 3.06, 95%CI = 1.30–7.19, p = 0.011) and multivariate (HR = 1.81, 95%CI = 1.16–2.32, p = 0.046) Cox regression analysis. The survival analysis results of the high and low-risk groups were different when the validation dataset was substituted into the model (p = 0.018). Then, we constructed a Nomogram which had a concordance index of survival prediction of 0.791(95%CI= 0.779-0.803). In addition, the CNS involvement grading status at first diagnosis CNS3 vs. CNS1 (HR = 5.74, 95%CI = 2.01–16.4, p = 0.001), T cell vs B cell (HR = 1.63, 95% CI = 1.06-2.49, p = 0.026) were also statistically significant.ConclusionsPPARG, GNG12, and CD19 may be predictors of CNS relapse in childhood ALL.

Translational advances in the treatment of childhood acute lymphoblastic leukemia: narrative review of current and emerging molecular and immunotherapies.

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy of lymphoid origin in children. The prognosis for newly diagnosed ALL in the pediatric population is generally favorable, with a 5-year overall survival rate of more than 90%. Though conventional therapy has led to meaningful improvements in cure rates for new-onset pediatric ALL, one-third of patients still experience a relapse or refractory disease, contributing to a significant cause of pediatric cancer-related mortality. An extensive literature review was undertaken via various databases of medical literature, focusing on both results of larger clinical trials, but also with evaluation of recent abstract publications at large hematologic conferences. Remission is achievable in most of these patients by re-induction with currently available therapies, but the long-term overall survival rate is deemed suboptimal and remains a therapeutic challenge. As part of never-ceasing efforts to improve pediatric ALL outcomes, newer modalities, including targeted molecular therapies as well as immunotherapy, and chimeric antigen receptor (CAR) T-cell therapy, are currently being employed to increase treatment effectiveness as well as lessen the side effects from conventional chemotherapy. These approaches explore the use of early genome-based disease characterization and medications developed against actionable molecular targets. Additional clinical research is nonetheless required to learn more about the potentially harmful effects of targeted therapies and investigate the possibility of these agents replacing or decreasing the use of conventional chemotherapy in treating pediatric ALL.

IL16 and factor V gene variations are associated with asparaginase-related thrombosis in childhood acute lymphoblastic leukemia patients.

Aim: We previously conducted exome-wide association study in acute lymphoblastic leukemia patients and identified association of five SNPs with asparaginase-related thrombosis. Here we aimed to replicate these findings in an independent patient cohort and through analyses in vitro. Patients & methods: SNPs located in IL16, MYBBP1A, PKD2L1, RIN3 and MPEG1 genes were analyzed in patients receiving Dana-Farber Cancer Instituteacute lymphoblastic leukemia treatment protocols 05-001 and 11-001. Thrombophilia-related variations were also analysed. Results: IL16 rs11556218 conferred higher risk of thrombosis and higher in vitro sensitivity to asparaginase. The association was modulated by the treatment protocol, risk group and immunophenotype. A crosstalk between factor V Leiden, non-O blood groups and higher risk of thrombosis was also seen. Conclusion: IL16 and factor V Leiden variations are implicated in asparaginase-related thrombosis.

The role of blinatumomab in the treatment of B-cell relapses of acute lymphoblastic leukemia in children: own experience

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Despite remarkable improvements in the treatment of pediatric acute lymphoblastic leukemia over last years, relapse still carries a poor prognosis with considerable morbidity and mortality. New immunotherapeutic approaches will change the way we treated our patients and the results we had. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory B-cell lymphoblastic leukemia. The use of Blinatumomab in relapsed B-cell ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. The therapy results for patients in the high risk group remain far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates the results of our experience of using Blinatumomab in children with the high-risk group relapsed B-cell ALL treated according to the ALL-REZ 2016 protocol. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The efficacy and toxicity of innovational blocks with the use of fludarabine and clofarabine with subsequent Blinatumomab infusion are shown. And we present the efficacy of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy. Also we demonstrate the results of using Blinatumomab for the treatment of patients with refractory to the first line therapy relapsed B-lymphoblastic leukemia and patients with a second relapse of B-cell ALL. The first line therapy in these patients was carried out according to the ALL-REZ 2014 protocol. Our results show an improved reduction in minimal residual disease in patients with refractory relapsed B-cell ALL as well as an increased event free survival in children with the high-risk group relapsed B-cell ALL.

The prognostic significance of cytokine receptor-like factor 2 expression and &lt;i&gt;JAK2&lt;/i&gt; mutation in pediatric B-cell acute lymphoblastic leukemia: A prospective cohort study

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Philadelphia (Ph)-like B-cell acute lymphoblastic leukemia (B-ALL) is defined by a gene expression profile similar to Phpositive B-ALL and shows a large number of genetic alterations in the cytokine receptor and kinasesignaling pathway genes that contribute to its aggressive phenotype and frequent disease recurrence – the main cause of death in affected children. Here, we aimed to correlate CRLF2 expression and JAK2 mutations in B-ALL patients with other prognostic factors and the patients’ outcomes as well as to evaluate their prognostic significance. The study was approved by the local institutional review board and written consents were obtained from a parent of each child before their enrolment. We included 54 newly diagnosed B-ALL pediatric patients (median age: 9.0 (2.0–18.0)) who were stratified either into a standard-risk (SR) or high-risk (HR) group and treated according to the modified BerlinFrankfurt-Münster 90 protocol (ALL-BFM 90). Fresh bone marrow samples were used to determine CRLF2 expression as well as to search for the JAK2 V617F mutation. Normal CRLF2 expression was reported in the SR patients much more often than in the HR group, while its overexpression was more common in the HR patients than in the SR ones (22 vs 6 and 18 vs 8, respectively, p &lt; 0.001). CRLF2 was also more often overexpressed in the MRD-positive cases than in the negative ones (17 vs 9, p &lt; 0.001), while normal CRLF2 expression was more common in the MRD-negative patients compared to the MRD-positive ones (24 vs 4, p &lt; 0.001) which supports the unfavorable prognostic value of CRLF2 in relation to MRD positivity at the end of the induction treatment. JAK2 mutation was detected only in 2 patients belonging to the CRLF2 overexpression group which made the assessment of the prognostic significance of this mutation impossible. Notably, none of the patients with normal CRLF2 expression ended up relapsing while 4 patients with overexpressed CRLF2 developed a relapse (p = 0.031). The study subjects were followed up for up to 24 months, and we did not find CRLF2 overexpression to negatively influence overall survival, however, it did have an adverse effect on relapse-free survival. In summary, CRLF2 overexpression was found to be an unfavorable prognostic factor in childhood ALL as it was expressed more in high-risk patients and in those with poor treatment response. The analysis of CRLF2 expression in B-ALL pediatric patients may help in risk stratification and can potentially offer new treatment options based on novel CRLF2 inhibitors.

Childhood ALL: Small Patients, Yet Everbigger Genetic Complexity

Childhood ALL: Small Patients, Yet Everbigger Genetic Complexity

Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells

The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse-in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model.

IKAROS in Acute Leukemia: A Positive Influencer or a Mean Hater?

One key process that controls leukemogenesis is the regulation of oncogenic gene expression by transcription factors acting as tumor suppressors. Understanding this intricate mechanism is crucial to elucidating leukemia pathophysiology and discovering new targeted treatments. In this review, we make a brief overview of the physiological role of IKAROS and the molecular pathway that contributes to acute leukemia pathogenesis through IKZF1 gene lesions. IKAROS is a zinc finger transcription factor of the Krüppel family that acts as the main character during hematopoiesis and leukemogenesis. It can activate or repress tumor suppressors or oncogenes, regulating the survival and proliferation of leukemic cells. More than 70% of Ph+ and Ph-like cases of acute lymphoblastic leukemia exhibit IKZF1 gene variants, which are linked to worse treatment outcomes in both childhood and adult B-cell precursor acute lymphoblastic leukemia. In the last few years, much evidence supporting IKAROS involvement in myeloid differentiation has been reported, suggesting that loss of IKZF1 might also be a determinant of oncogenesis in acute myeloid leukemia. Considering the complicated "social" network that IKAROS manages in hematopoietic cells, we aim to focus on its involvement and the numerous alterations of molecular pathways it can support in acute leukemias.

Clinical Impact of Drug Adherence of Tyrosine Kinase Inhibitors in Children with Ph-Positive Acute Lymphoblastic Leukemia.

This study aimed to explore the impact of ABL1-tyrosine kinase inhibitors (TKIs) adherence on the survival of chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) children and clarify the potential predictors of patients' prognosis from TKIs intake practices. Ninety newly diagnosed Ph+ ALL patients who received TKIs were enrolled. We collected the baseline characteristics and adverse events in all children; moreover, TKIs adherence was measured by an eight-item Morisky medication adherence scale (MMAS-8). Progression-free survival (PFS) and overall survival (OS) analysis were performed, and risk factors for PFS and OS were evaluated. Among all patients, 69 cases were regarded as adherers, while 21 were non-adherers. The median duration of TKIs interruption was significantly prolonged in the non-adherence group than in the adherence group (13 [0-101] vs. 56 [11-128], p < 0.001). Additionally, dose reduction occurred in 55.2% of non-adherers versus 23.0% of adherers (p=0.002). The PFS and OS in adherers were significantly higher versus non-adherers (p=0.020 and p=0.039). MMAS-8 score was an independent risk factor for PFS (p=0.010) and OS (p=0.031). Among non-adherers, the median OS was only 23.1% (4.2%-42%) in patients aged ≤ 10 years versus 54.4% (38.8%-70%) in adolescents. Most of the patients who experienced TKIs non-adherence suffered pancytopenia. TKIs adherence during treatment significantly influenced the survival of pediatric Ph+ ALL patients, and non-adherers with age ≤ 10 years were more vulnerable to TKIs disruption. The cumulative TKIs dose should be especially emphasized to patients with age ≤ 10 years, which may result in an inferior achievement of relevant treatment milestones.

One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns.

Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0-14 years during 1988-2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo's DNA methylation programming.

Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia.

L-asparaginase, which hydrolyzes asparagine into aspartic acid and ammonia, is frequently used to treat acute lymphoblastic leukaemia in children. When combined with other chemotherapy drugs, the event-free survival rate is 90%. Due to immunogenicity and drug resistance, however, not all patients benefit from it, restricting the use of L-asparaginase therapy in other haematological cancers. To solve the problem of immunogenicity, several L-ASNase variants have emerged, such as Erwinia-ASNase and PEG-ASNase. However, even when Erwinia-ASNase is used as a substitute for E. coli-ASNase or PEG-ASNase, allergic reactions occur in 3%-33% of patients. All of these factors contributed to the development of novel L-ASNases. Additionally, L-ASNase resistance mechanisms, such as the methylation status of ASNS promoters and activation of autophagy, have further emphasized the importance of personalized treatment for paediatric haematological neoplasms. In this review, we discussed the metabolic effects of L-ASNase, mechanisms of drug resistance, applications in non-ALL leukaemia, and the development of novel L-ASNase.

Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children's Oncology Group cohort trials

Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status. Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Children's Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease. Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 [65·6%]), followed by Hispanic patients (4354 [20·6%]), non-Hispanic Black patients (1517 [7·2%]), non-Hispanic Asian (n=1071 [5·1%]), and non-Hispanic other (n=338 [1·6%]). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1%; hazard ratio [HR] 1·37, 95% CI 1·26-1·49; p<0·0001) among Hispanic patients and 81·8% (79·3-84·0; HR 1·45, 1·28-1·65; p<0·0001) among non-Hispanic Black patients. Non-hispanic Asian patients had a 5-year event-free survival of 88·1% (95% CI 85·5-90·3%) and non-Hispanic other patients had a survival of 82·8% (76·4-87·6%). Inferior event-free survival among Hispanic patients was substantially attenuated by disease prognosticators and insurance status (HR decreased from 1·37 [1·26-1·49; p<0·0001] to 1·11 [1·00-1·22; p=0·045]). The increased risk among non-Hispanic Black patients was minimally attenuated (HR 1·45 [1·28-1·65; p<0·0001] to 1·32 [1·14-1·52; p<0·0001]). 5-year overall survival was 93·6% (91·5-95·1%) in non-Hispanic Asian patients, 93·3% (92·8-93·7%) in non-Hispanic White patients, 89·9% (88·7-90·9%) in Hispanic, 89·7% (87·6-91·4%) in non-Hispanic Black patients, 88·9% (83·2-92·7%) in non-Hispanic other patients. Disparities in overall survival were wider than event-free survival (eg, among non-Hispanic other patients, the HR for event-free survival was 1·43 [1·10-1·85] compared with 1·74 [1·27-2·40] for overall survival). Disparities were restricted to patients with B-cell acute lymphocytic leukaemia, no differences in event-free survival or overall survival were seen in the T-cell acute lymphocytic leukaemia group. Substantial disparities in outcome for B-cell acute lymphocytic leukaemia persist by race and ethnicity, but are not observed in T-cell acute lymphocytic leukaemia. Future studies of relapsed patients, access to and quality of care, and other potential aspects of structural racism are warranted to inform interventions aimed at dismantling racial and ethnic disparities. National Cancer Institute and St Baldrick's Foundation.