Factor In Acute Lymphoblastic Leukemia Research Articles

Clonal evolution defines risk stratification for central nervous system leukemia in adult acute lymphoblastic leukemia.

It is well established that central nervous system leukemia (CNSL) is an adverse prognostic factor in acute lymphoblastic leukemia (ALL), yet whether prognostic heterogeneity reside in CNSL is less addressed. Therefore, we aimed to develop potential risk classification for CNSL. We retrospectively analyzed a study in PDT-ALL-2016 pediatric-inspired cohort (N = 494). Flow cytometry (FCM) and next-generation sequencing (NGS) were tested on bone marrow (BM) and cerebrospinal fluid (CSF). The 5-year OS of 437 non-CNSL patients was 62.3% and 33.7% in 57 CNSL patients (P < 0.001). 57 CNSL including 16 primary CNS involvement and 41 CNS relapse patients were divided into 3 groups. The 5-year OS was 48.9% in patients with concordant FCM and NGS between BM and CSF, which were defined as non-clonal evolutionary CNSL, a standard-risk subgroup, while the 5-year OS was 30.2% in patients with discordant FCM or NGS between BM and CSF and isolated CNS relapse (P < 0.05), which were defined as clonal evolutionary CNSL, a high-risk subgroup. Furthermore, the mean times of lumbar punctures to achieve complete remission (CR) in CSF was 4.14 in clonal evolutionary CNSL, comparing to 1.62 in non-clonal evolutionary CNSL (P < 0.05). Based on the evidence of clonal evolution, we develop a risk stratification for CNSL for the first time.

Assessment of measurable residual disease after induction chemotherapy in acute lymphoblastic leukemia patients in a tertiary care hospital

Background: Measurable residual disease (MRD) is a crucial prognostic factor in acute lymphoblastic leukemia (ALL), influencing treatment outcomes and long-term survival. This study investigates the prevalence of MRD post-induction chemotherapy and its association with clinical, demographic, and biochemical markers in ALL patients at a tertiary care hospital. Methods: This observational cross-sectional study was conducted at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, from August 2021 to July 2022. A total of 22 newly diagnosed ALL patients underwent induction chemotherapy and MRD evaluation using flow cytometry. Clinical signs, demographic data, and laboratory findings, including serum creatinine, uric acid, and BCR-ABL1 status, were recorded. Statistical analyses assessed the relationships between MRD status and various predictors. Results: Of the 22 patients, 7 (31.82%) remained MRD positive after induction chemotherapy. Anaemia was prevalent, affecting 20 participants (90.91%). MRD positive patients had higher serum creatinine (mean 1.23±0.31 mg/dl) and uric acid levels (mean 7.09±1.62 mg/dl) compared to MRD negative patients. None of the MRD positive patients tested positive for BCR-ABL1. Six of the 7 MRD positive patients were male (85.71%). Bone marrow analysis showed 5 MRD positive patients (71.43%) achieved complete remission. Risk stratification did not significantly correlate with MRD status. Conclusions: MRD is a critical prognostic tool in ALL management, correlating with higher biochemical markers of tumor burden and a distinct clinical profile. These findings support integrating MRD assessment with detailed clinical and laboratory evaluations to refine treatment strategies and improve patient outcomes in ALL.

Prognostic impact of IL7R mutations on acute myeloid leukemia.

Interleukin-7 receptor (IL7R) mutation has been demonstrated to be an adverse prognostic factor in acute lymphoblastic leukemia (ALL) patients. However, the effects of the IL7R mutation on acute myeloid leukemia (AML) have rarely been reported. Here, we investigated IL7R mutations and their effects on AML patients. A total of 346 newly diagnosed AML patients from January 2017 to July 2020 at Nanfang Hospital were analyzed in this study. A genomic panel of 167 gene targets was detected by next-generation sequencing. Among 346 patients, 33 (9.5%) AML patients carried IL7R mutations. With a median follow-up of 50.7 months (95% confidence interval (CI) 17.3-62.2), the 5-year overall survival (OS) rates were 51.5% (95% CI 37.0%-71.0%) and 72.2% (95% CI 67.4%-77.3%; p = 0.008), the 5-year event-free survival (EFS) rates were 36.1% (95% CI 23.2%-57.1%) and 58.1% (95% CI 52.9%-63.8%; p = 0.005), the 5-year non-relapse mortality (NRM) were 21.4% (95% CI 8.5%-38.2%) and 6.2% (95% CI 3.7%-9.5%; p = 0.004) in the IL7R mutant (IL7R MUT ) group and non-IL7R mutant (IL7R WT ) group, respectively. There is no significant difference in the disease-free survival (75.1% vs 73.5%, p = 0.885) and cumulative incidence of relapse (25.7% vs 25.2%, p = 0.933) between IL7R MUT and IL7R WT group. Furthermore, patients who underwent hematopoietic stem cell transplantation (HSCT) still had more adverse outcomes in the IL7R MUT group than in the IL7R WT group (5-year OS: 61.9% vs 85.3%, p = 0.003). In the TET2 (p = 0.013) and DNA methyltransferase 3A (DNMT3A; p = 0.046) mutation subgroups, the presence of IL7R mutations was associated with worse OS than in AML patients without IL7R mutations. Our study demonstrated that the IL7R mutation is associated with an inferior prognosis for AML patients. Patients with IL7R mutations have higher NRM, shorter OS, and EFS than patients without IL7R mutations, even patients who have undergone HSCT. Future larger and multicentric prospective studies will be explored.

Phase Angle and Body Composition As a Prognostic Factor in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukaemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stage of differentiation that can invade bone marrow, blood, and extramedullary sites. Age specific incidence is highest in children aged 1-4 years, then drops sharply through childhood (5-14 years), adolescence and young adulthood (AYA) (15-39 years), reaching the lowest point between 25 years and 45 years. Bioelectrical impedance analysis (BIA) is a method used to estimate body composition and cell membrane integrity. BIA is a useful tool as it is non-invasive, relatively inexpensive, can be performed on nearly any patient, does not expose the patient to ionizing radiation, is painless, and has both high intra and inter observer precision (coefficient of variation = 2.7%-4.0%). Phase angle (PhA) is obtained by BIA and is associated with cellular function. It is considered a reliable marker of malnutrition. PhA has been shown to predict survival in solid malignancies and hematopoietic stem cell transplant patients. To date, no studies have evaluated the usage of PhA in ALL patients. Therefore, this retrospective study sought to establish the prognostic significance of baseline PhA and lean mass index on OS and LFS in newly diagnosed ALL patients receiving intensive chemotherapy. Retrospective, cross-section, observational and descriptive study. The records of patients who received intensive chemotherapy from January 2019 to January 2023 were reviewed. Statistical analysis The qualitative variables were studied in frequencies and proportions, the quantitative variables were grouped into medians and ranges. OS and LFS were determined using Kaplan-Meier survival curves with log-Rank with a significant p &amp;lt;0.05 value. Statistical analysis was performed with SPSS version 25 and GraphPad Prism version 9.5.0. Results 85 patients were included, 56.7% (48) men and 43.5% (37) women. 79 patients with ALL-B and 6 patients ALL-T. The mean age was 25 years. 68 were AYA population and 17 not-AYA. The CR was 89%, ND MRD was 57%. The chemotherapy for AYA was CALGB 10403, and not AYA was Hyper-CVAD. Relapse was documented in 38%. The mean body mass index was 26.98±5.27 kg/m 2. The mean PhA was 4.547±0.9983°. The mean lean mass index was 17.8 (12.9-35.5) kg/m 2. The mean fat mass index was 9.195±4.425 kg/m 2. The mean OS was 86% at 1 year and OS at 3 years was 64.5%. The results that were statistically significant in LFS compared by Kaplan Meier curves were: male vs female p=0.0344, PhA &amp;gt;4, p=0.0235, lean mass index ≥16, p=0.0111. Conclusions In conclusion, our findings suggest that in newly diagnosed ALL patients undergoing intensive induction chemotherapy, PhA may provide important prognostic information for LFS and OS. PhA is an objective, repeatable, high-precision measure in ALL patients and, unlike other prognostic factors in this population, is potentially subject to intervention. Future studies of PhA in ALL patients should address the content validity of phase angle while further exploring the promising findings of the effect of strength training and nutritional supplementation on PhA and patient outcomes.

The causal relationship between gut microbiota and leukemia: a two-sample Mendelian randomization study

BackgroundThe association between gut microbiota and leukemia has been established, but the causal relationship between the two remains unclear.MethodsA bidirectional two-sample Mendelian randomization (MR) was used to analyze the causal relationship between gut microbiota and leukemia. Microbiome data (n = 14,306) and leukemia (n = 1,145) data were both sourced from European populations. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on several criteria. We employed various MR methods, such as the inverse variance weighted (IVW) method, to evaluate the causal effect between exposure and outcomes and conducted sensitivity analyses to validate the heterogeneity and pleiotropy of the instrumental variables.Results5,742 qualified instrumental variables were included. In the primary MR results, a total of 10 gut microbial taxa were associated with leukemia risk. Genus Blautia and genus Lactococcus are risk factors for acute lymphoblastic leukemia [genus Blautia odds ratio (OR): 1.643, 95% confidence interval (CI): 1.592 ~ 1.695, Adjusted p &amp;lt; 0.001; genus Lactococcus OR: 2.152, 95% CI: 1.447 ~ 3.199, Adjusted p = 0.011]. Genus Rikenellaceae RC9 gut group, genus Anaerostipes, genus Slackia, and genus Lachnospiraceae ND3007 group are risk factors for acute myeloid leukemia [genus Rikenellaceae RC9 gut group OR: 1.964, 95% CI: 1.573 ~ 2.453, Adjusted p &amp;lt; 0.001; genus Anaerostipes OR: 2.515, 95% CI: 1.503 ~ 4.209, Adjusted p = 0.017; genus Slackia OR: 2.553, 95% CI: 1.481 ~ 4.401, Adjusted p = 0.022; genus Lachnospiraceae ND3007 group OR: 3.417, 95% CI: 1.960 ~ 5.959, Adjusted p = 0.001]. Genus Ruminococcaceae UCG011 and genus Ruminococcaceae UCG014 were risk factors for chronic myeloid leukemia (genus Ruminococcaceae UCG011 OR: 2.010, 95% CI: 1.363 ~ 2.963, Adjusted p = 0.044; genus Ruminococcaceae UCG014 OR: 3.101, 95% CI: 1.626 ~ 5.915, Adjusted p = 0.044). Genus Slackia was a protective factor for acute lymphoblastic leukemia (genus Slackia OR: 0.166, 95% CI: 0.062 ~ 0.443, Adjusted p = 0.017). Family Acidaminococcaceae was a protective factor for acute myeloid leukemia (family Acidaminococcaceae OR: 0.208, 95% CI: 0.120 ~ 0.361, Adjusted p &amp;lt; 0.001). Genus Desulfovibrio was a protective factor for chronic lymphoblastic leukemia (genus Desulfovibrio OR: 0.581, 95% CI: 0.440 ~ 0.768, Adjusted p = 0.020). Sensitivity analysis revealed no heterogeneity or pleiotropy between SNPs.ConclusionThis study revealed the causal relationship between the gut microbiota and leukemia, and identified potential pathogenic bacteria and probiotic taxa associated with the onset of leukemia. This research may aid in the early detection of various types of leukemia and offer a new direction for the prevention and treatment of leukemia.

Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children’s Study

AbstractOccupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

Clinical characteristics and risk factors of acute lymphoblastic leukemia in children with severe infection during maintenance treatment.

Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05). Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti-infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections.

Chemotherapy De-Escalation Factors in Acute Lymphoblastic Leukemia

Chemotherapy De-Escalation Factors in Acute Lymphoblastic Leukemia

Minimal Residual Disease Detection Using Gene Scanning Analysis, Fluorescent Fragment Analysis, and Capillary Electrophoresis for IgH Rearrangement in Adult B-Lineage Acute Lymphoblastic Leukemia: A Cross-Sectional Study.

Minimal residual disease (MRD) is considered the greatest prognostic factor in acute lymphoblastic leukemia (ALL). MRD is a valuable tool for anticipating impending relapse and treatment response assessment. The objective of the present study was to investigate whether the detection of IgH gene rearrangement using polymerase chain reaction (PCR)-based GeneScan analysis could be a complementary method to monitor MRD along with the quantitative realtime PCR (qPCR). In this cross-sectional study, we valued the MRD levels, based on the GeneScanning analysis (GSA), and then compared the data with quantitative real-time polymerase chain reaction at different time points in peripheral blood (PB) samples of adult B-lineage ALL patients (n=35). The specific polymerase chain reaction (PCR) primers for IGH gene FR-1 and fluorescence-labeled J-primer were used and analyzed by capillary gel electrophoresis on a sequencer. The results of this study were compared with the previously reported MRD results obtained by the IGH rearrangements allele-specific oligonucleotide (ASO) -qPCR methods. The total concordance rate was 86.7%, with a P<0.001. MRD results obtained by GSA and ASO-qPCR methods were concordant in all diagnostic samples and samples on the 14th and 28th days of induction therapy. The results of these 2.5 years' follow-ups demonstrated a significant correlation between the two techniques (r=0.892, P<0.001). It seems that the PCR-based GeneScan analysis of IGH gene rearrangement detection may be a valuable molecular technique to distinguish monoclonality from polyclonality. And also, it may be a precise tool to detect the residual leukemic DNA in the PB follow-up samples of patients.

MiR-128-3p as blood based liquid biopsy biomarker in childhood acute lymphoblastic leukemia

BackgroundMinimal residual disease (MRD) is one of the most valuable independent prognostic factors in acute lymphoblastic leukemia (ALL). Bone marrow (BM) aspiration, however, is an invasive process. Previous studies have shown that microRNAs (miR) and extracellular vesicle (EV)-related miRs show different expression profiles at the presence of malignant cells compared to healthy controls. In our previous project, we have reported that two miRs previously described to be overexpressed in blasts were significantly decreased over the first week of the therapy of patients with ALL in the platelet free plasma fraction (PFP) of peripheral blood samples (PB). The aim of the current study was to assess the relation between day 15 flow cytometry (FC) MRD and expression of miR-128-3p and miR-222-3p miRs in exosome-enriched fraction (EEF) of PFP to evaluate whether their expression in EEF correlates with day 15 FC MRD more precisely. MethodsPB was collected from 13 patients diagnosed with pediatric pre-B ALL at 4 time points. Expression of miR-128-3p and miR-222-3p was measured by qPCR in PFP and EEF. ResultsPositive correlation was found between changes of miR-128-3p expression in EEF or PFP by day 8 of chemotherapy and day 15 FC MRD (rEEF = 0.99, pEEF = 1.13E-9 and rPFP = 0.99, pPFP = 4.75E-9, respectively). Furthermore, the decrease of miR-128-3p in EEF by day 15 of treatment also showed a positive correlation with day 15 FC MRD (rEEF = 0.96; pEEF = 4.89E-5). ConclusionOur results show that circulating miRs are potential biomarkers of ALL MRD, asmiR-128-3p level both in PFP and EEF predicts day 15 FC MRD. In addition, the assessment of the EEF gave a more promising result.

Prognostic significance of steroid response in pediatric acute lymphoblastic leukemia: The CCCG-ALL-2015 study.

Whether steroid response is an independent risk factor for acute lymphoblastic leukemia (ALL) is controversial. This study aimed to investigate the relationship between response to dexamethasone and prognosis in children with ALL. We analyzed the data of 5,161 children with ALL who received treatment in accordance with the Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015, and December 31, 2018, in China. All patients received dexamethasone for 4 days as upfront window therapy. Based on the peripheral lymphoblast count on day 5, these patients were classified into the dexamethasone good response (DGR) and dexamethasone poor response (DPR) groups. A peripheral lymphoblast count ≥1× 109/L indicated poor response to dexamethasone. The age, white blood cell counts, prevalence of the BCR/ABL1 and TCF3/PBX1 fusion genes, and rates of recurrence in the central nervous system were higher in the DPR than in the DGR group (P<0.001). Compared to the DPR group, the DGR group had a lower recurrence rate (18.6% vs. 11%) and higher 6-year event-free survival (73% vs. 83%) and overall survival (86% vs. 92%) rates; nevertheless, subgroup analysis only showed significant difference in the intermediate-risk group (P<0.001). Response to dexamethasone was associated with an early treatment response in our study. In the intermediate-risk group, dexamethasone response added a prognostic value in addition to minimal residual disease, which may direct early intervention to reduce the relapse rate.

The Interplay of Cesarean-Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia.

Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been associated with early-life exposures, including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and restrain later dysregulated immune responses that can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development. Cases comprised 1,126 children (0-12 years) with ALL (BCP-ALL: 78.5%) from the EMiLI study group in Brazil (2002-2020). Age- and sex-matched controls (n = 2,252) were randomly selected from healthy children whose mothers participated in the National Placental and Umbilical Cord Blood Bank donation. Multiple logistic regression was run fitted and adjusted for selected covariates models. C-section delivery was associated with increased risk for ALL [odds ratio (OR) ALL: 1.10; 95% confidence intervals (CI), 1.04-1.15; ORBCP-ALL: 1.09; 95% CI, 1.03-1.14], as well as being the firstborn child. Interaction analysis showed a significant effect of first birth on the observed C-section associations (P < 0.0001). Indeed, high-risk children, namely, firstborn children delivered via C-section were at increased risk for ALL (OR: 2.33; 95% CI, 2.40-4.84) compared with non-first, vaginally born children. An increased risk was found for firstborn children delivered by C-section and non-breastfed with ALL (ORALL: 2.32; 95% CI, 1.27-4.24; ORBCP-ALL: 2.37; 95% CI, 1.18-4.76). Our observations are in accord with the prediction that exposures determining microbiome composition and adrenal pathway in infancy contribute to the risk of BCP-ALL. These findings encourage the exploration of potential preventive interventions. See related commentary by Wiemels and Gallant, p. 292.

ALL-373 Immunophenotype of MRD Cells as an Additional Prognostic Marker

Measurable residual disease (MRD) is an independent prognostic factor in acute lymphoblastic leukemia (ALL). However, the impact of the immunophenotype of MRD cells on survival has not been studied. To determine the significance of the immunophenotype of MRD cells detected at the end of induction in patients with ALL. This study included data from 2016 to 2022 for 267 patients enrolled in the Russian multicenter study RALL-2016 (NCT03462095). MRD was assessed on day 70 in patients with complete remission. MRD was assessed in 94 B-ALL and 77 T-ALL patients. Analysis of MRD was performed by 6-11-color flow cytometry. CD19, CD34, CD10, CD20, CD38, CD45, and CD58 were analyzed to detect MRD in all B-ALL patients. CD7, CD3surface, CD3cytoplasmic, CD4, CD8, CD5, CD99, and CD45 were analyzed to detect MRD in T-ALL patients. The expression of these antigens was assessed relative to normal bone marrow cells and transformed into a numeric score. A dendrogram was constructed using the "ward.D" method in R 3.4.4. Relapse-free survival (RFS) was estimated by the Kaplan-Meier method, and comparisons were assessed using the log-rank test. MRD was revealed in 37 (39%) B-ALL and 18 (23.4%) T-ALL patients. RFS was lower in MRD-positive patients (54% vs. 90% [p<0.0001] in B-ALL and 59% vs. 83% [p<0.0025] in T-ALL) than in MRD-negative patients. In B-ALL, 3 clusters of MRD cells were detected. Cluster I (n=16) included cases of CD10+MRD, whereas clusters II (n=13) and III (n=8) included CD10-MRD. Expression of CD38 and CD58 was higher in cluster II than in cluster III. RFS rates were 62%, 33%, and 71% (p=0.043) in clusters I, II, and III, respectively. In T-ALL, 3 clusters were also found. Cluster I included 3 CD7- cases, cluster II included 9 CD7+CD5+CD3dim/+ cases, and cluster III included 6 CD7highCD5-/dimCD3- cases. RFS rates were 33%, 49%, and 100% (p=0.015) for clusters I, II, and III, respectively. MRD at the end of induction impaired RFS in patients in the RALL-2016 study. The immunophenotype of MRD cells is associated with RFS and could be an additional prognostic factor.

Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype-genotype study.

White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N=2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρBCP-ALL =-.17, ρT-ALL =-.19; p<3 × 10-4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ=.43, p<<2 × 10-6 ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.

Global burden and attributable risk factors of acute lymphoblastic leukemia in 204 countries and territories in 1990-2019: Estimation based on Global Burden of Disease Study 2019.

To provide a foundational guideline for policy-makers to efficiently allocate medical resources in the context of population aging and growth, the latest spatial distribution and temporal trend of acute lymphoblastic leukemia (ALL) along with attributable risk factors by sex and age were mapped. Based on the Global Burden of Disease Study 2019, estimated annual percentage change (EAPC) was calculated according to the relativity between age-standardized rate and calendar year, to quantify temporal trends in morbidity and mortality of ALL. We used applied Spearman rank correlation to estimate the relationship between the EAPC and potential influence factors. The population attributable fraction of potential risk factors for ALL-related disability-adjusted life years were estimated by the comparative risk assessment framework. As a result, we found that new ALL cases increased significantly by 1.29% worldwide, and the age-standardized incidence rate increased by 1.61% annually. The proportion of elder patients sharply increased, especially within the higher socio-demographic index (SDI) region. Smoking and high body mass index remained the predominant risk factors for ALL-related mortality. Notably, the contribution of high body mass index presented an increasing trend. In conclusion, the global burden of ALL has steadily increased, especially in Middle SDI region. Health measures and new drugs should be taken into consideration to improve the management and treatment of elders with ALL due to an increasing proportion in the higher SDI region. For Low SDI areas, attention should be paid to the environmental problems caused by industrial development.

Clinical Features and Prognosis of Acute Lymphoblastic Leukemia Children with P2RY8-CRLF2 Gene Rearrangement

To investigate the clinical features and prognostic factors of acute lymphoblastic leukemia (ALL) children with P2RY8-CRLF2 gene rearrangement. A total of 108 children with B-cell ALL (B-ALL) were diagnosed and systematically treated according to Chinese Children's Leukemia Group (CCLG) -ALL 2008 in our hospital from January 2016 to December 2016. The 108 patients were divided into two groups according to the result of mutiplex polymerase chain reaction: group with P2RY8-CRLF2 gene rearrangement and group without P2RY8-CRLF2 gene rearrangement. The ALL children with P2RY8-CRLF2 gene rearrangement were all treated by CCLG-ALL 2008 high-risk group (HR) regimens, and the ALL children in group without P2RY8-CRLF2 gene rearrangement received different intensity chemotherapy according to clinical risk classification. Five (4 male and 1 female) out of 108 patients with B-ALL had P2RY8-CRLF2 gene rearrangement. In the 5 B-ALL patients with P2RY8-CRLF2 gene rearrangement, the median age of the was 4 (2-6) years old and the median WBC count was 26.2 (2.46-525.1)×109/L. These patients presented different immunophenotype, including 3 cases of common B-ALL and 2 cases of pre B-ALL. Four patients carried a normal karyotype and 1 patient carried 46, XY, der (20) [22]/46, XY[2]. For the children with P2RY8-CRLF2 gene rearrangement, 1 patient (20%) could not achieve complete remission (CR), and minimal residual disease (MRD) of 2 patients (40%) was higher than 1% on day 33 of induction chemotherapy; while in group without P2RY8-CRLF2 gene rearrangement, all the patient achieved CR, and MRD in 6 patients (5.8%) was higher than 1% on day 33 of induction chemotherapy. The 3 year event-free survival (EFS) of ALL children in group with P2RY8-CRLF2 gene rearrangement was significantly lower than that in group without P2RY8-CRLF2 gene rearrangement (60.0%±21.9% vs 85.9%±3.9%) (P<0.05). The early treatment response and prognosis of ALL children with P2RY8-CRLF2 gene rearrangement are worse, and more effective protocol is needed for this subtype patients.

Genotype Analysis of ABCC1, NCF4 and CBR3 Polymorphism and the Association With Childhood Acute Lymphoblastic Leukemia in Mexican Childhood Population.

Background: The identification of genetic risk factors for Acute Lymphoblastic Leukemia (ALL), are increasingly urgent and necessary. Objective: The purpose of this study is to determine the association of the genetic polymorphisms ABCC1 rs3743527, NCF4 rs1883112 and CBR3 rs1056892 with ALL. Methods: DNA samples were obtained in 71 children with ALL (from 2 to 18 years) and in 71 controls without ALL, to determine the polymorphisms by real-time polymerase chain reaction (qPCR), using specific TaqMan probes in a StepOne® thermal cycler (Applied Biosystems, United States). Results: The results of the Odds Ratio analysis show that in the rs1883112 polymorphism of the NCF4 gene, the heterozygous allele has a risk effect for ALL (OR = 3.1870, CI = 1.8880–7.9383 and p = 0.0002), in turn the mutated genotype (AA) is associated with a protective effect (OR = 0.26, 0.1248 to 0.5434 and p = 0.0003). On the other hand, the CBR3 rs1056892 polymorphism shows a significant association of risk to ALL, in the presence of the HT genotype (OR = 2.77, IC = 1.3837 to 5.5651 and p = 0.004) and the mutated genotype of this polymorphism has a significant association with protection to ALL in the HM genotype (OR = 0.52, IC = 0.2639 to 1.0304 and p = 0.05). While the inheritance models of the polymorphisms let us see that of the rs1883112 polymorphism of the NCF4 polymorphism; the HT genotype of the codominant model shows a protective effect against ALL (OR = 0.4117, IC = 0.1718 to 0.9866 and p = 0.04), the recessive model shows us and confirms what we already saw in table number 3, being that there is an association with protective effect in the HM genotype (OR = 0.2604, IC = 0.1248 to 0.5434 and p = 0.0003). In the polymorphism rs1056892 of the CBR3 gene, a protection association was found in the heterozygous allele of the codominant model (OR = 0.3448, IC = 0.1375 to 0.8896 and p = 0.0274). In addition, the recessive inheritance model for the HM genotype shows a protective effect to ALL, (OR = 0.52, CI = 0.9919 to 3.8638 and p = 0.05). Conclusion: There is an evident impact of the NCF4 rs1883112 and CBR3 rs1056892 polymorphisms with an increased risk of susceptibility to ALL; Likewise, through the codominant inheritance model, the effect of the variation of the CBR3 rs1056892 gene as a protective factor against ALL was evaluated.

How I investigate minimal residual disease in acute lymphoblastic leukemia.

Minimal Residual Disease (MRD) is the most important independent prognostic factor in acute lymphoblastic leukemia (ALL) and refers to the deep level of measurable disease in cases with complete remission by conventional pathologic analysis, especially by cytomorphology. MRD can be detected by multiparametric flow cytometry, molecular approaches such as quantitative polymerase chain reaction for immunoglobulin and T-cell receptor (IG/TR) gene rearrangements or fusion genes transcript, and high-throughput sequencing for IG/TR. Despite the proven clinical usefulness in detecting MRD, these methods have differences in sensitivity, specificity, applicability, turnaround time and cost. Knowing and understanding these differences, as well as the principles and limitations of each technology, is essential to laboratory standardization and correct interpretation of MRD results in line with treatment time points, therapeutic settings, and clinical trials. Here, we review the methodological approaches to measure MRD in ALL and discuss the advantages and limitations of the most commonly used techniques.

RISK FACTORS OF VINCRISTINE-INDUCED PERIPHERAL NEUROPATHY IN ACUTE LYMPHOBLASTIC LEUKAEMIA CHILDREN.

Objective : This study analysed Vincristine-induced peripheral neuropathy (VIPN) risk factors in Acute Lymphoblastic Leukaemia (ALL) children. Method : This cross-sectional study design was performed at Dr. Soetomo Hospital, Surabaya, Indonesia, from August to October 2019. It included ALL children, aged 4-18 years, undergoing the 2013 or 2018 ALL Indonesian Protocol of Chemotherapy, with a cumulative vincristine dose ≥ 12 mg / m2. VIPN diagnosis is based on complaints, the Total Neuropathy Score Pediatric Vincristine (TNS-PV), and nerve conduction studies (NCS). The examined risk factors were sex, age, ALL classification, nutritional status, impaired liver function, and cumulative vincristine dose. Results : There were 52 ALL children : median age 7 years, 59.6% boys, 59.6% ALL standard risk, 44.2% experienced impaired liver function at initial ALL diagnosis. Based on a single parameter for diagnosis, 26.9% had VIPN based on complaints, 76.9% had it based on the TNS-PV, and 100% had it based on NCS. VIPN was diagnosed in 25% of children, with predominantly motor impairment and located in lower extremities. Impaired liver function is a risk factor for VIPN in ALL children (p = 0.046, prevalence ratio (PR) 2.84). Conclusion : Impaired liver function is a significant risk factor for VIPN in ALL children. J. Med. Invest. 68 : 232-237, August, 2021.

Fatty acid synthase, a novel poor prognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract

Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL). To evaluate the impact of fatty acid synthase (FASN) on drug resistant ALL, bone marrow samples were collected from 65 pediatric ALLs, including 40 de novo and 25 relapsed patients. 22 non-cancer individuals were chosen as controls. Quantitative RT-PCR showed increased expression levels of FASN in drug resistant patients compared with the therapy responders. Single and combined treatment of malignant cells were analyzed using Annexin-V/PI double staining and MTT assays. Incubation of resistant primary cells with ginger showed simultaneous increased apoptosis rates and reduced FASN expression levels. Furthermore, docking studies demonstrated high affinity bindings between ginger derivatives and FASN thioesterase and ketosynthase domains, compared with their known inhibitors, fenofibrate and morin, respectively. Finally, combined treatment of in-house multidrug resistant T-ALL subline with ginger and dexamethasone induced drug sensitivity and down regulation of FASN expression, accordingly. To the best of our knowledge, this is the first study that introduces FASN upregulation as a poor prognostic factor for drug resistant childhood ALL. Moreover, it was revealed that FASN inhibition may be applied by ginger phytochemicals and overcome dexamethasone resistance, subsequently.