Childhood Acute Lymphoblastic Leukemia Research Articles

Clinical Profile, Toxicities, and Survival Outcome of MCP841 in Pediatric Acute Lymphoblastic Leukemia in Current Era: A Retrospective Study from Eastern India

Abstract Introduction: The overall survival in pediatric acute lymphoblastic leukemia (ALL) ranges from 45 to 81% in India. Aggressive chemotherapy protocols like MCP841 have improved the outcome and it can be delivered with minimal supportive care. This study retrospectively analyses the clinical profile and overall survival of patients treated by this protocol. Objective: This single-center study aims to estimate the event-free survival of patients treated accordingly to the MCP841 protocol with high-dose cytarabine (HDAC) at 2 g/m2 as the backbone, along with the risk-stratified incidence and cause of mortality in childhood ALL. Material and Methods: Records of 156 patients aged 1 to 19 years, newly diagnosed with ALL from June 2009 to August 2013 who were treated according to the forementioned protocol were analyzed. Risk stratification for both precursor B-cell ALL (B-ALL) and T-cell ALL (T-ALL) was done, followed by an analysis of the correlation of risk-stratified groups with mortality and survival outcomes. Result: Precursor B-ALL was found in 70% patients (including 69.7% [n = 76] standard risk, 20.1% [n = 22] intermediate risk, and 10% [n = 11] high risk), while 30% had T-ALL (including 74.4% [n = 35] standard risk and 25.5% [n = 12] high risk). Death during induction occurred in 0.04% (n = 5) precursor B-ALL and 23% (n = 11) T-ALL patients. The causes were infection in 62.5%, hemorrhage in 25%, and cortical venous thrombosis in 12.5%. Among those who attained remission (89.7%, n =140), relapse occurred in 26% (n = 27) precursor B-ALL and 28% (n = 10) T-ALL patients. Approximately 31% patients died in the postinduction phase, with progressive disease due to relapse being the most common cause and bone marrow the most common site. Event-free survival at 168 months for overall population, precursor B-ALL, and T-ALL was 59, 62.4, and 51.1%, respectively. Conclusion: A comparable survival outcome in par with similar centers in developing countries with the MCP841 protocol was found. Infections are a major cause of mortality during treatment, especially when associated with malnourishment. Relapsed disease and poor salvage rates remain a major hurdle to achieving better survival in developing countries; however, better supportive care and infection control measures along with implementing risk-stratified high-dose chemotherapy protocols might improve outcome in the future.

Glucocorticoid Sensitivity Among Young Survivors of Childhood Acute Lymphoblastic Leukemia: What Does It Matter?

The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors.

Disparities in Acute Lymphocytic Leukemia Outcomes Among Young Adults.

Age is a strong prognostic factor in acute lymphocytic leukemia (ALL), with children doing better than adults with the same disease. One hypothesis for this age-based disparity is differences in treatment regimens. Optimizing care for adolescents and young adults (AYA) with ALL has not been well defined and disparities in care exist. We conducted a retrospective study of all veterans with ALL diagnosed between the ages of 18 and 45 since the year 2000 to evaluate disparities among prognostication methods, treatment regimens, and accrual to clinical trials with regard to age and race/ethnicity and how these factors influence overall survival. Electronic medical record data from the VA Informatics and Computing Infrastructure (VINCI) were used to identify 6,724 patients with an ICD-9 or 10 code for ALL. All patients were chart checked to confirm an ALL diagnosis between the ages of 18 and 45 and excluded if they were diagnosed before 2000, had childhood ALL, or if induction protocol was not recorded. A total of 252 patients were included in the final analysis. Multivariate analysis was performed with controls for age, ALL subtype (B, T, mixed phenotype), Ph status, cytogenetic risk (based on modified Medical Research Council-Eastern Cooperative Oncology Group (MRC-ECOG) study), obesity (body mass index (BMI) > 30), and race. Patients treated with pediatric regimens, including pediatric-inspired regimens, have statistically significant (P = 0.009) survival gains, with a hazard ratio (HR) of 0.52 after controlling for age, obesity, ALL subtype, cytogenetic risk and race. White patients had significantly improved OS compared to people of color (HR 0.57, P = 0.02) after controlling for the aforementioned covariates. Black patients were far less likely (23%) to receive a transplant than non-Black patients (46%). Only 7% of patients were treated on a clinical trial. These data demonstrate that treatment with a pediatric regimen significantly improves overall survival in patients up to the age of 45 and suggests ongoing shortcomings in treatment for young adults with ALL, especially 30 to 45 years old, including persistently high use of adult induction regimens, low rates of referral to clinical trials, and significant racial disparities in bone marrow transplants for Black patients.

Posterior Reversible Encephalopathy Syndrome Associated with L-Asparaginase Treatment in Children: Literature Review and Six Case Reports.

L-asparaginase (L-ASNase) is an enzyme that shows targeted activity against Acute Lymphoblastic Leukemia (ALL) and similar lymphoid neoplasms by facilitating the breakdown of asparagine into L-aspartic acid, thereby reducing L-asparagine levels in leukemic cells. However, its therapeutic potential is hindered by its associated toxicity, leading to complications, such as thrombosis, hemorrhage, thrombocytopenia, fibrinolysis, hypersensitivity reactions, and the development of Posterior Reversible Encephalopathy Syndrome (PRES). This review compiles documented cases of PRES linked to treating B and T cell acute lymphoblastic leukemia in children using L-ASNase. Although this pathology is rare, understanding its management is crucial within ASNase-based chemotherapy protocols. As PRES lacks a specific treatment, focusing on symptomatic management becomes pivotal. Therefore, comprehending the underlying causes during L-ASNase treatment for acute lymphoblastic leukemia is essential. Understanding the etiology and clinical symptoms of this illness is critical for early diagnosis and treatment. The cases of PRES described in this review include instances in which this syndrome has appeared after the administration of L-ASNase in children. In some cases, PRES developed during induction therapy, while in others, it occurred during the reinduction phase. These cases resolved days after discontinuation of L-ASNase. The findings suggest a close relationship between drug administration and the appearance of brain lesions, as evidenced by the disappearance or decrease of these lesions when the drug was eliminated from the bloodstream.

The safety and efficacy of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia in children

To explore the safety and efficacy of blinatumomab in the treatment of CD19 positive (CD19+) B-cell acute lymphoblastic leukemia (B-ALL) in children. A retrospective analysis was conducted on the clinical data of pediatric B-ALL patients who received blinatumomab treatment from Hematology & Blood Diseases Hospital of Chinese Academy of Medical Sciences from August 2021 to October 2023. Based on their disease status, the patients were divided into refractory/relapsed(RR) group, minimal residual disease clearance (MC) group, and chemotherapy intolerance (IC) group. Clinical data of the children were collected to evaluate the adverse drug reactions, therapeutic efficacy and survival of the children. In total, 35 patients were included, with 20 males and 15 females, aged from 0.6 to 16.4 (9.9±4.2) years old. There were 10 cases in the RR group, 20 cases in the MC group and 5 cases in the IC group. A total of 56 cycles of infusion were completed, with one cycle in 24 cases, two cycles in 5 cases, three cycles in 2 cases and four cycles in 4 cases. The median infusion time [M (Q1, Q3)] from the first to the fourth cycle was 14 (14, 28) days, 28 (28, 28) days, 28 (28, 28) days and 28 (26, 28) days, respectively. In terms of adverse reactions, the incidence of grade 1-2 cytokine release syndrome(CRS) was 57.1% (32/56), with grade 1 CRS accounting for 84.4% (27/32). The incidence rate of immune effector cell-associated neurotoxicity syndrome(ICANS) (grade 4) was 1.8% (1/56). In the RR group, 6 cases were treated effectively, and minimal residual disease(MRD) turned negative, before treatment, MRD levels were all less than 20%. Among them, 3 cases had MRD turning positive again 14 to 42 days after discontinuation of Belintoumab. Four cases were treated ineffectively, with MRD >20% before treatment. All MRD positive cases in MC group turned negative and all MRD negative cases in the IC group remained negative after treatment. The median follow-up time of RR group was 5.7 (3.8, 9.4) months, and 1 year median survival rate and event-free survival rate were 40.0%±21.9% and 33.3%±19.2%, respectively. The median follow-up time for MC and IC group patients was 6.7 (5.2, 12.5) months and 7.1 (5.1, 7.6) months, respectively, with an event free survival rate of 100%. The safety and efficacy of using belintoumab in partial RR, MRD clearance, and chemotherapy intolerance are good.

Risk factors for recurrence of childhood acute lymphoblastic leukemia after treatment with the Chinese Children's Cancer Group ALL-2015 protocol

To investigate the cumulative incidence of recurrence (CIR) in children with acute lymphoblastic leukemia (ALL) after treatment with the Chinese Children's Cancer Group ALL-2015 (CCCG-ALL-2015) protocol and the risk factors for recurrence. A retrospective analysis was conducted on the clinical data of 852 children who were treated with the CCCG-ALL-2015 protocol from January 2015 to December 2019. CIR was calculated, and the risk factors for the recurrence of B-lineage acute lymphoblastic leukemia (B-ALL) were analyzed. Among the 852 children with ALL, 146 (17.1%) experienced recurrence, with an 8-year CIR of 19.8%±1.6%. There was no significant difference in 8-year CIR between the B-ALL group and the acute T lymphocyte leukemia group (P>0.05). For the 146 children with recurrence, recurrence was mainly observed in the very early stage (n=62, 42.5%) and the early stage (n=46, 31.5%), and there were 42 children with bone marrow recurrence alone (28.8%) in the very early stage and 27 children with bone marrow recurrence alone (18.5%) in the early stage. The Cox proportional-hazards regression model analysis showed that positive MLLr fusion gene (HR=4.177, 95%CI: 2.086-8.364, P<0.001) and minimal residual disease≥0.01% on day 46 (HR=2.013, 95%CI: 1.163-3.483, P=0.012) were independent risk factors for recurrence in children with B-ALL after treatment with the CCCG-ALL-2015 protocol. There is still a relatively high recurrence rate in children with ALL after treatment with the CCCG-ALL-2015 protocol, mainly bone marrow recurrence alone in the very early stage and the early stage, and minimal residual disease≥0.01% on day 46 and positive MLLr fusion gene are closely associated with the recurrence of B-ALL.

Clinical characteristics and prognosis of childhood acute lymphoblastic leukemia with CD123 expression

To investigate the expression of CD123 in children with acute lymphoblastic leukemia (ALL) and its effect on the clinical characteristics and prognosis of children with B-lineage acute lymphoblastic leukemia (B-ALL). A retrospective analysis was conducted on the clinical data of 251 children with ALL who were admitted to the Department of Hematology and Oncology, Children's Hospital of Kunming Medical University, from December 2019 to June 2022. According to the expression of CD123 at initial diagnosis, the children were divided into CD123+ group and CD123- group, and the two groups were compared in terms of clinical characteristics and treatment outcome. The factors influencing the prognosis were analyzed. Among the 251 children with ALL, there were 146 children (58.2%) in the CD123+ group. The B-ALL group had a significantly higher positive expression rate of CD123 than the acute T lymphocyte leukemia group (P<0.05). Compared with the CD123- group, the CD123+ group had significantly lower peripheral blood leukocyte count and percentage of juvenile cells and a significantly higher proportion of children with high hyperdiploid karyotype or an age of 1-10 years, with a relatively low proportion of children with E2A-PBX1 fusion gene (P<0.05). The multivariate Cox proportional-hazards regression model analysis showed that compared with the >10 years group, the 1-10 years group had a significantly higher overall survival rate (P<0.05), and compared with the high risk group, the moderate risk group had a significantly higher event-free survival rate in children with B-ALL (P<0.05). CD123 is widely expressed in children with B-ALL, and positive expression of CD123 might be an indicator for good prognosis in children with B-ALL, which is of great significance for evaluating the efficacy of remission induction therapy and survival prognosis of children with B-ALL.

Ocular hypertension in a child of acute lymphoblastic leukemia

Abstract To highlight the case of ocular hypertension in a 9-year-old male who came with fever and swelling in the left eye (LE) for 3 days. He was a known case of acute lymphoblastic leukemia (ALL) on treatment with oral steroids. His best-corrected vision was 6/6 in both eyes (BES). The anterior segment was normal in BES except for mild periorbital edema in the right eye (RE). On applanation tonometry (AT), intraocular pressure (IOP) was 42 mmHg in RE and 36 mmHg in LE. Gonioscopy showed open angles in BEs. Fundoscopy and optical coherence tomogram–retinal nerve fiber layer were normal in BES. He was diagnosed with steroid-induced ocular hypertension in BES and was started on both topical and oral antiglaucoma medications (AGMs). IOP was normal after 2 weeks of treatment. He came after a month of discontinuation of AGMs against medical advice but was still on oral steroids. He was asymptomatic, but his IOP was 28 mmHg in RE and 26 mmHg in LE. Parents were counseled about the disease and need to restart AGMs. Regular follow-up was also emphasized.

Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia.

Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses. In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment. Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up. Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits. Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.

Bone mineral density in childhood acute lymphoblastic leukaemia survivors and factors affecting it

BackgroundLiterature on bone health in childhood acute lymphoblastic leukemia survivors (cALLS) is conflicting with most studies suggesting an adverse effect on bone mineral density (BMD). MethodsThis cross-sectional study enrolled cALLS>7 years of age. BMD was measured using dual-energy x-ray absorptiometry (DEXA) scan [Lumbo-sacral (LS-BMD) and whole-body (WB-BMD)]. Low BMD was defined as an LS-BMD ≤2 z-score. Demographic, anthropometry-related, therapy/disease-related and endocrine factors affecting LS-BMD were noted in two groups: low verses normal BMD. ResultsFifty-nine cALLS were analyzed with a median age of 66 months (range: 6–212) at diagnosis and a median duration postcompletion of therapy for 14 months (range 1–113). Two-thirds were male, and 25/59 (42%) had Tanner staging>1. Low LS-BMD was seen in 15/59 (25%), and a low WB-BMD in 3/59 (5%). The mean therapeutic doses of steroids and methotrexate were comparable in two groups. In univariate analysis, age at diagnosis >10 years was associated with low BMD (p = 0.02), while high adiposity was seen commonly with normal BMD (p = 0.01). On multivariate analysis, high adiposity was the single-most factor associated with normal BMD, with an odds ratio of 5.2. The correlation between LS-BMD and WB-BMD was statistically significant (r = 0.55).The median values of hormonal and mineral assays affecting calcium and vitamin D homeostasis and BMD in the two groups were comparable. ConclusionWe report a high prevalence of low LS-BMD (25%) in our cohort. Out of the studied demographics, therapy-related, disease-related, and endocrine factors; high adiposity as defined by a high body fat percentage, was protective against low BMD. We also found a significant correlation between LS-BMD and WB-BMD.

High ambient temperature in pregnancy and risk of childhood acute lymphoblastic leukaemia: an observational study

High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukaemia is the most common malignancy in children, the incidence is increasing, and in the USA disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood acute lymphoblastic leukaemia. We used data from California birth records (children born from Jan 1, 1982, to Dec 31, 2015) and California Cancer Registry (those diagnosed with childhood cancer in California from Jan 1, 1988, to Dec 31, 2015) to identify acute lymphoblastic leukaemia cases diagnosed in infants and children aged 14 years and younger and controls matched by sex, race, ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. The association between ambient temperature and acute lymphoblastic leukaemia was evaluated per gestational week, restricted to May-September, adjusting for confounders. Bayesian meta-regression was applied to identify critical exposure windows. For sensitivity analyses, we evaluated a 90-day pre-pregnancy period (assuming no direct effect before pregnancy), adjusted for relative humidity and particulate matter less than 2·5 microns in aerodynamic diameter, and constructed an alternatively matched dataset for exposure contrast by seasonality. 6849 cases of childhood acute lymphoblastic leukaemia were identified and, of these, 6258 had sufficient data for study inclusion. We also included 307 579 matched controls. Most of the study population were male (174 693 [55·7%] of the 313 837 included in the study) and of Latino ethnicity (174 906 [55·7%]). The peak association between ambient temperature and risk of acute lymphoblastic leukaemia was observed in gestational week 8, where a 5°C increase was associated with an odds ratio of 1·07 (95% CI 1·04-1·11). A slightly larger effect was seen among Latino children (OR 1·09 [95% CI 1·04-1·14]) than non-Latino White children (OR 1·05 [1·00-1·11]). The sensitivity analyses supported the results of the main analysis. Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood acute lymphoblastic leukaemia. Further replication and investigation of mechanistic pathways might inform mitigation strategies. Yale Center on Climate Change and Health, The National Center for Advancing Translational Science, National Institutes of Health.

Household Income Disparities in Childhood Acute Lymphoblastic Leukemia Incidence and Mortality: A US Population-Based Analysis between 2000 and 2020

Introduction: Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer with an annual incidence of 3.7-4.9 cases per 100,000. There are no recent reports of the effect of socioeconomic status on pediatric ALL incidence and mortality class. Objective: Assess the association between ALL incidence and mortality and the socioeconomic status in children ages 21 years and younger. Methods: Retrospective analysis was conducted of the Surveillance, Epidemiology and End Results (SEER) database, which represents up to 48% of the general US population. We included patients with ALL up to 21 years of age during 2000-2020. Patients were categorized based on annual household income into three groups: low-income: &lt; $50,000; middle-income: $50,000-$75,000; high-income: &gt;$75,000. Incidence and mortality rates were expressed per 100,000 person-years. Annual Percentage Changes (APCs) were defined as the average year-over-year rate change. Student’s t test was used to determine if APCs were significantly different from zero with a significance level of 0.05. Results: We reviewed 30,852 cases, of which 9%, 54%, and 37% belonged to low-, middle-, or high-income families, respectively, and with incidence rates of 3.2, 3.4, and 3.1 per 100,000 person-years, respectively. Incidence in low-income children showed a statistically significant average increase of 1.1% (p = 0.003) per year during 2000-2020, while it showed a significant increased followed by stable rates since 2007 and 2010 in middle- and high-income children, respectively. ALL mortality was 0.5, 0.4, and 0.4 per 100,000 person-years, in low-, middle-, and high-income children, respectively. Mortality in low-income children has increased 2000-2007 (APC= 25.2%, p = 0.011); it did not significantly change after that. Conclusions: ALL incidence in low-income children has been increasing and remained the highest while mortality improved in middle-income children. Differences in healthcare access may be associated with the findings; further studies are needed to delineate this further.

Identification of a novel MEF2C::SS18L1 fusion in childhood acute B-lymphoblastic leukemia

PurposeLeukemia-associated fusion genes are closely related to the occurrence, development, diagnosis, and treatment of leukemia. DNA microarrays and second-generation sequencing have discovered multiple B-ALL fusion genes. We identified a novel MEF2C::SS18L1 fusion gene in a child diagnosed with B-ALL. This study investigates the oncogenicity and prognosis of this fusion gene in B-ALL.MethodsA child with B-ALL who has a MEF2C::SS18L1 fusion is reported as a newly discovered case. Compared the breakpoints, structural domains, clinical phenotypes, and differential expression genes of MEF2C::SS18L1 and MEF2D::SS18.Using “ONCOFUSE” software, the carcinogenicity of MEF2C::SS18L1 is predicted. Using whole transcriptome sequencing, we analyze the breakpoints and the secondary structure of the fusion protein. Further, we compared the structures, differentially expressed genes, and clinical phenotypes of MEF2D and MEF2C fusion genes by DESeq, GO functional enrichment, and flow cytometry immunophenotyping analysis.ResultsWhole transcriptome sequencing identified a MEF2C::SS18L1 fusion transcript in a 3-year-old child with B-ALL. The MADS box, MEF structural domain, HJURP_C structural domain, and TAD I structural domain of MEF2C, and the QPGY structural domain of SS18L1, make up the fusion protein. “Oncofuse” found a 0.99 Bayesian probability that the fusion gene drives cancer. The breakpoint positions, fusion protein secondary structures, differentially expressed genes, and clinical characteristics of this patient were identical to those with MEF2D::SS18 fusion gene.ConclusionWe identified a novel MEF2C::SS18L1 fusion gene in childhood ALL, which shares similar structural and clinical characteristics with MEF2D::SS18. Further studies with more samples should be conducted in future.

Folate Metabolism and Risk of Childhood Acute Lymphoblastic Leukemia: A Genetic Pathway Analysis from the Childhood Cancer and Leukemia International Consortium.

Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results. We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups. This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination.

Differential metabolomic pathway analysis in Malaysian childhood acute lymphoblastic leukemia patients treated with high-dose methotrexate

BackgroundMethotrexate (MTX) is the mainstay of the consolidation and maintenance phase of chemotherapy protocol for childhood acute lymphoblastic leukemia (ALL). This study aimed to investigate the altered metabolism associated with high dose-MTX and determine the potential of the metabolic markers and differential pathways involved in MTX therapy. MethodsSerum samples were collected from 38 children with ALL at 2 time points: p-MTX; before induction chemotherapy was initiated, and post-MTX; after completion of the first high-dose MTX. The samples were analyzed using HPLC/MS-QTOF. Data acquisition was performed using Agilent MassHunterTMB.05.00 software for subsequent metabolomics analysis. Differential expressions of metabolites were analyzed using univariate Welch's t-test unequal variance. Compounds were identified using the METLIN Database. Pathways and network analyses were performed using Metaboanalyst 4.0. Potential biomarkers were analyzed using the Receiving Operator Characteristic curve. ResultsMetabolites with AUC between 0.7 and 0.9 include xanthine (0.889), oxoglutaric acid (0.770), and alpha-linolenic acid (ALA) (0.741). Alpha-linolenic acid abundance was detected in ALL patients with remission status, corresponding to a test sensitivity and specificity of 0.77 and 0.87, respectively. ALA has an antineoplastic effect that potentially inhibits the proliferation of leukemic cells by inhibiting caspase activation in the phosphatidylinositol 3-kinase (PI3K) pathway and Bcl-2 inhibition. ConclusionIn this study, ALA was found to be significantly higher in patients treated with high-dose MTX and associated with remission status than in pre-MTX treatment.

Implementation of pharmacogenetics for treatment of patients with acute lymphoblastic leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the most frequent pediatric leukemia; it can be defined according to chromosomic and genomic data. Cytogenetic analyses and determination of chromosomal numbers (such as hypo- or hyperdiploidy) and/or specific chromosomal rearrangements are basic for ALL classification and treatment. Even though cure rates of childhood ALL are at ~95%, pharmacogenetic aspects are of raising importance. Material and Methods: We have analyzed the literature for ALL subtypes, corresponding therapy options, and pharmacogenetic implications. Results: Data for ALL subtypes such as B-ALL, T-ALL, Ph-like ALL, DS-ALL, ETP-ALL, BCR-ABL1-like ALL are presented here. The gene polymorphism which lead to metabolizability of 6-MP are ITPA variants (94C&gt;A) and IVS2+21A&gt;C, in conjunction with TPMT (238G&gt;C, TPMT*3B 460G&gt;A and *3C 719A&gt;G and NUDT15 (415C&gt;T). For methotrexate metabolism gene polymorphisms are found for gene MTHFR as C677T and A1298C. Conclusion: In the last decade in many hospital laboratories, pharmacogenetic aspects gain more and more importance. Application of many molecular biology methods provided progress in treatment and diagnosis of ALL patients. Combination therapy is proposed as an alternative to single drug treatments.

Implementation of plate reader-based indooxine and nessler protocols for monitoring L-asparaginase serum activity in childhood acute lymphoblastic leukaemia

Abstract Background Monitoring the blood serum activity of L-asparaginase in children with acute lymphoblastic leukemia (ALL) has been highly recommended to detect enzyme inactivation that can cause relapse and to avoid unwanted toxicity. Nevertheless, perhaps at least partially due to the lack of clinically approved commercially available kits or standardised and independently reproduced and validated in-house protocols, laboratory assay-based determination of the optimal doses of L-asparaginase is not carried out routinely. Methods In this study we adapted previously published protocols for two plate reader-based colorimetric methods, indooxine and Nessler, to measure asparaginase activity. Mock samples with dilutions of the enzyme for initial optimisation steps, and patient samples were used as a proof of principle and to compare the two protocols. Results For the first time the indooxine and the Nessler methods are adapted for a plate reader and L-asparaginase serum activity levels are compared by both protocols. Passing-Bablok and Bland-Altman statistical analyses found very little difference, strong correlation (r = 0.852), and bias of only 6% between the data from the two methods when used for fresh patient samples. Furthermore, we demonstrate that the Nessler method could also be applied for frozen sera as the results, compared to fresh samples, showed little difference, strong correlation (r = 0.817), and small bias (9%). Conclusions We successfully adapted and validated two methods for measuring of L-asparaginase activity in cALL and provide the most detailed description to date on how to reproduce and implement them in other clinical laboratories.

Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship

Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia.

The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.