Risk Of Leukemia Research Articles

Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of femaleindividuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose femaleindividuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Pediatric Carotid Injury after Blunt Trauma and the Necessity of CT and CTA-A Narrative Literature Review.

Background: Blunt carotid injury (BCI) in pediatric trauma is quite rare. Due to the low number of cases, only a few reports and studies have been conducted on this topic. This review will discuss how frequent BCI/blunt cerebrovascular injury (BCVI) on pediatric patients after blunt trauma is, what routine diagnostics looks like, if a computed tomography (CT)/computed tomography angiography (CTA) scan on pediatric patients after blunt trauma is always necessary and if there are any negative health effects. Methods: This narrative literature review includes reviews, systematic reviews, case reports and original studies in the English language between 1999 and 2020 that deal with pediatric blunt trauma and the diagnostics of BCI and BCVI. Furthermore, publications on the risk of radiation exposure for children were included in this study. For literature research, Medline (PubMed) and the Cochrane library were used. Results: Pediatric BCI/BCVI shows an overall incidence between 0.03 and 0.5% of confirmed BCI/BCVI cases due to pediatric blunt trauma. In total, 1.1-3.5% of pediatric blunt trauma patients underwent CTA to detect BCI/BCVI. Only 0.17-1.2% of all CTA scans show a positive diagnosis for BCI/BCVI. In children, the median volume CT dose index on a non-contrast head CT is 33 milligrays (mGy), whereas a computed tomography angiography needs at least 138 mGy. A cumulative dose of about 50 mGy almost triples the risk of leukemia, and a cumulative dose of about 60 mGy triples the risk of brain cancer. Conclusions: Given that a BCI/BCVI could have extensive neurological consequences for children, it is necessary to evaluate routine pediatric diagnostics after blunt trauma. CT and CTA are mostly used in routine BCI/BCVI diagnostics. However, since radiation exposure in children should be as low as reasonably achievable, it should be asked if other diagnostic methods could be used to identify risk groups. Trauma guidelines and clinical scores like the McGovern score are established BCI/BCVI screening options, as well as duplex ultrasound.

TP53 mutation screening for patients at risk of myeloid malignancy.

6546 Background: Cellular therapy is a promising approach for many diseases but is associated with a risk of subsequent myelodysplastic syndrome and/or acute myeloid leukemia, also known as therapy-related myeloid neoplasms (tMN). This phenomenon has recently been described with allogeneic hematopoietic cell transplantation (HCT) and gene therapy for sickle cell disease (SCD). Mutation(s) in functional domains of TP53 are often associated with the development of tMN but currently no prospective screening or monitoring technology is available. Methods: A next-generation sequencing (NGS) assay with unique molecular identifiers (UMI) and bioinformatic noise-suppression was designed to discover somatic mutations at a variant allele frequency (VAF) 1% throughout the TP53gene. The background error profile at each base position was calculated using blood genomic DNA from healthy donors. The minimal detectable allele fraction with 95% confidence (MDAF) was calculated for all reported known AML/tMN TP53 hotspots. Orthogonal validation was performed using droplet digital PCR (ddPCR). Results: The median error corrected sequencing depth at 62 known TP53 hotspot regions was 14,512 (95% CI: 14,769 – 15,430) with a theoretical median de novo NGS variant discovery limit of 0.058% (range: 0.037% - 0.13%). Experimental evidence of assay performance characteristics was produced using serial dilutions of 4 missense, 2 splicing, and 1 frameshift TP53 variants with 100% discovery specificity observed (lowest detected VAF range: 0.05 – 0.12%). High correlation was observed in quantification using NGS discovery and ddPCR validation ( r = 0.958, p<0.0001). Pre- and post-HCT clinical samples from 19 patients with SCD, 11 of which had graft failure including 4 who developed tMN, were screened for TP53 mutations. In all tMN cases, the AML-associated TP53 variant was detectable at least 6 months and up to 2.5 years prior to clinical diagnosis of myeloid malignancy. In contrast, no pathogenic TP53 variants were detected in 15 SCD patients who underwent HCT but did not develop tMN. Conclusions: This study provides generalizable evidence that ultra-sensitive discovery of TP53 mutations prior to cellular therapy is possible and could be a potentially valuable clinical tool to screen for tMN risk.

Risk of secondary leukemias in patients with germline PALB2 pathogenic variants after chemotherapy exposure.

10598 Background: Pathogenic variants in germline cancer-predisposing genes (e.g. BRCA1/2, PALB2) confer an increased risk for solid tumors but not de novomyeloid malignancies. Many of these genes are related to DNA repair pathways. It is not known whether exposure to genotoxic therapy increases the risk of secondary hematologic malignancies. Here, we report the incidence of hematologic malignancy after a solid tumor diagnosis among patients with a germline PALB2 pathogenic variant. Methods: Patients were identified at the Massachusetts General Hospital Center for Cancer Risk Assessment among individuals seeking counseling and/or testing for hereditary cancer risk genes. Analyses were conducted using R version 4.2.2 “tidyverse” and “gtsummary” packages. Results: Of the 176 charts reviewed, 102 (57%) had a history of malignancy, of which 68 (66%) received genotoxic chemotherapy. The median follow-up after chemotherapy was 59mo (IQR =17,109). The most common malignancy and chemotherapy were breast cancer (n=76, 75%) and doxorubicin, cyclophosphamide, and paclitaxel (n = 21, 31%). We compared patient outcomes by receipt of chemotherapy or not. There was no difference in race, age at cancer diagnosis, surgery rate, treatment with hormone therapy, or secondary malignancy between the two groups (p > 0.05). There was higher incidence of radiation treatment in those receiving genotoxic therapy compared to those who did not (65% vs 41%, p = 0.024), but no difference Gray or in follow up after radiation. Mortality in the genotoxic therapy group was 15% (n=10) vs. 9% (n=2) in the no genotoxic therapy group (p =0.33). Two subjects developed a hematologic malignancy (one case each of CLL and CML); both had prior chemotherapy and radiation exposure (Table). Conclusions: Cancer survivors with a germline PALB2 pathogenic variant and subsequent exposure to genotoxic therapy appear to have low risk of secondary hematologic malignancy. Although two subjects in the chemotherapy group developed leukemias, given the cases seen it is unlikely that these relate to the treatment exposure. Given the small sample size and retrospective nature of this study, more investigation is necessary to fully quantify the risk of therapy-related myeloid neoplasm in patients with germline PALB2 pathogenic variants. [Table: see text]

IL-15 gene mutation as a molecular risk factor in acute lymphoid leukemia.

The present study investigated the relationship between single nucleotide polymorphisms in the interleukin (IL)-15 gene located (exon 8) on the chromosomal location 4q31.21 and acute lymphoblastic leukaemia (ALL) risk in Iraqi patients. A total of 78 (49 male -29 female) primary ALL (62B-cell, 16 T-cells lineages cases and 30 healthy control subjects (median age 11, age range were 4-21.5), were enrolled at the Nanakaly Hospital of Erbil Province between February 2021 and January 2022. The genotype analysis was performed using polymerase chain reaction (PCR) and Sanger DNA sequencing. The IL15 homozygous rs10833 (100%) and rs2291596 (63.6%) genotypes indicated high frequencies and were associated with a risk of developing ALL, while the remaining 16 novel mutations indicated in low frequency (9.1%) except for the 97270G>GT genotype (18.2%). High expression levels were noted for different clusters of differentiation (CD) biomarkers between both subtypes of ALL, including, CD10, CD19, CD22, CD79a, CD99, terminal deoxynucleotidyl transferase (TdT), and human leukocyte antigen DR (HLA-DR) isotype in B-cells lineages, while, CD2, CD3, CD5, CD7, CD13, CD117 and TdT are more specific to T-cells lineages. On the other hand, significant changes were noted in certain hematological parameters including red blood cells (RBCs), haemoglobin (g/dl), haematocrite (HCt %), red blood cell distribution width (RDW %), and platelet counts (PLT- 109/L) compared with those of healthy subjects. Finally, it was concluded that various novel mutations were recorded with different subtypes of ALL diseases, and mild anemia was observed among patients. Future studies will be towered to associate these mutations with prognosis and therapeutic response of diseases.

Human Health Risk Assessment of Radionuclide Contamination in Drinking Water

This study investigates the human health risks of uranium, radium, radon, and other drinking water radionuclides and their mitigation strategies. It was implemented through literature review, field sampling, and analytical methods. Samples were taken from various sources, including groundwater, surface water, municipal supplies, and private wells. ICPI-MS and liquid scintillation counters were used for radiation measurements. Statistical analysis and risk assessment models were used to measure health risks and treatment effectiveness. Groundwater sources were the main sources of radionuclides, with private wells being the main sources. The elimination efficiencies of reverse osmosis were exceptional, reaching up to 99%. The elderly population (60+ years) were the most likely to have cancer, with the highest risks for bladder cancer, lung cancer, kidney cancer, and leukemia. The frequency of radionuclide contamination in drinking water sources varied, with the U.S. Environmental Protection Agency, Nigerian EPA, and Canada having the strictest schedules. The results emphasize the urgent need for monitoring programs, effective treatment technologies, and targeted risk management strategies to cope with radionuclide contamination. Government advice includes improving the regulatory system, developing advanced treatment methods, long-term epidemiological studies, public awareness, interdisciplinary collaboration, scientific exploration of alternative water sources, and prioritizing interventions for vulnerable populations.

Radon Exposure and Risk of Leukemia: A Protocol of Systematic Review and Meta-Analysis

Introduction: Radon is a naturally occurring radioactive gas that is considered a risk factor for many health problems, including leukemia. Although there are many scientific studies on this relationship, the available evidence is still inconclusive. This review and meta-analysis aims to provide a comprehensive overview of the existing literature to provide a more in-depth understanding of the relationship between radon exposure and leukemia risk. Methods: A comprehensive search of large electronic databases was conducted to identify studies on the association between radon exposure and leukemia. Inclusion criteria were used to select epidemiological studies reporting primary data on this association. Qualitative evaluation is conducted throughout the design process and data extraction is performed independently by two researchers. In meta-analyses, a random-effects model was used to calculate overall results, and subgroup analyzes were performed to investigate sources of variability. Results: The systematic review identified several studies that met the inclusion criteria. Meta-analyses show overall effect sizes and confidence intervals that indicate the nature of the relationship between radon and leukemia. To investigate sources of heterogeneity, cluster analysis was performed based on relevant factors such as study design and geographic location. A sensitivity analysis was performed to assess the robustness of the findings and assess potential reporting bias. Conclusion: The systematic review identified several studies that met the inclusion criteria. Meta-analyses showing overall effect sizes and confidence intervals illustrate the nature of the relationship between radon and leukemia. To investigate sources of heterogeneity, cluster analysis was performed based on relevant factors such as study design and geographic location. A sensitivity analysis was performed to evaluate the effectiveness of the study results and assess the potential for publication bias.

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies.

In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately. To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients. The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach. The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8cm (mean) with 0.5cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7Gy (mean) with 1.0Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2Gy (mean) with 10.8Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4Gy (mean) with 0.4Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient). We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk

Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk

Medically Assisted Reproduction and Risk of Cancer Among Offspring

Cancer is a leading cause of death among children worldwide. Treatments used for medically assisted reproduction (MAR) are suspected risk factors because of their potential for epigenetic disturbance and associated congenital malformations. To assess the risk of cancer, overall and by cancer type, among children born after MAR compared with children conceived naturally. For this cohort study, the French National Mother-Child Register (EPI-MERES) was searched for all live births that occurred in France between January 1, 2010, and December 31, 2021 (and followed up until June 30, 2022). The EPI-MERES was built from comprehensive data of the French National Health Data System. Data analysis was performed from December 1, 2021, to June 30, 2023. Use of assisted reproduction technologies (ART), such as fresh embryo transfer (ET) or frozen ET (FET), and artificial insemination (AI). The risk of cancer was compared, overall and by cancer type, among children born after fresh ET, FET, or AI and children conceived naturally, using Cox proportional hazards regression models adjusted for maternal and child characteristics at birth. This study included 8 526 306 children with a mean (SD) age of 6.4 (3.4) years; 51.2% were boys, 96.4% were singletons, 12.1% were small for gestational age at birth, and 3.1% had a congenital malformation. There were 260 236 children (3.1%) born after MAR, including 133 965 (1.6%) after fresh ET, 66 165 (0.8%) after FET, and 60 106 (0.7%) after AI. A total of 9256 case patients with cancer were identified over a median follow-up of 6.7 (IQR, 3.7-9.6) years; 165, 57, and 70 were born after fresh ET, FET, and AI, respectively. The overall risk of cancer did not differ between children conceived naturally and those born after fresh ET (hazard ratio [HR], 1.12 [95% CI, 0.96 to 1.31]), FET (HR, 1.02 [95% CI, 0.78 to 1.32]), or AI (HR, 1.09 [95% CI, 0.86 to 1.38]). However, the risk of acute lymphoblastic leukemia was higher among children born after FET (20 case patients; HR 1.61 [95% CI, 1.04 to 2.50]; risk difference [RD], 23.2 [95% CI, 1.5 to 57.0] per million person-years) compared with children conceived naturally. Moreover, among children born between 2010 and 2015, the risk of leukemia was higher among children born after fresh ET (45 case patients; HR, 1.42 [95% CI, 1.06 to 1.92]; adjusted RD, 19.7 [95% CI, 2.8 to 43.2] per million person-years). The findings of this cohort study suggest that children born after FET or fresh ET had an increased risk of leukemia compared with children conceived naturally. This risk, although resulting in a limited number of cases, needs to be monitored in view of the continuous increase in the use of ART.

Trends in childhood leukemia incidence in urban countries and their relation to environmental factors, including space weather.

Leukemia is the most common cancer in children. Its incidence has been increasing worldwide since 1910th, suggesting the presence of common sources of the disease, most likely related to people's lifestyle and environment. Understanding the relationship between childhood leukemia and environmental conditions is critical to preventing the disease. This discussion article examines established potentially-carcinogenic environmental factors, such as vehicle emissions and fires, alongside space weather-related parameters like cosmic rays and the geomagnetic field. To discern the primary contributor, we analyze trends and annual variations in leukemia incidence among 0-14-year-olds in the United States, Canada, Australia, and Russia from 1990 to 2018. Comparisons are drawn with the number of vehicles (representing gasoline emissions) and fire-affected land areas (indicative of fire-related pollutants), with novel data for Russia introduced for the first time. While childhood leukemia incidence is rising in all countries under study, the rate of increase in Russia is twice that of other nations, possibly due to a delayed surge in the country's vehicle fleet compared to others. This trend in Russia may offer insights into past leukemia levels in the USA, Canada, and Australia. Our findings highlight vehicular emissions as the most substantial environmental hazard for children among the factors examined. We also advocate for the consideration of potential modulation of carcinogenic effects arising from variations in cosmic ray intensity, as well as the protective role of the geomagnetic field. To support the idea, we provide examples of potential space weather effects at both local and global scales. The additional analysis includes statistical data from 49 countries and underscores the significance of the magnetic field dip in the South Atlantic Anomaly in contributing to a peak in childhood leukemia incidence in Peru, Ecuador and Chile. We emphasize the importance of collectively assessing all potentially carcinogenic factors for the successful future predictions of childhood leukemia risk in each country.

Impact of Propofol Exposure on Neurocognitive Outcomes in Children With High-Risk B ALL: A Children's Oncology Group Study.

Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL. This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group. One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment (Z-score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure (P = .03). In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Alternative polyadenylation quantitative trait loci contribute to acute myeloid leukemia risk genes regulation

Acute myeloid leukemia (AML) is a hematopoietic malignancy with a high relapse rate and progressive drug resistance. Alternative polyadenylation (APA) contributes to post-transcriptional dysregulation, but little is known about the association between APA and AML. The APA quantitative trait locus (apaQTL) is a powerful method to investigate the relationship between APA and single nucleotide polymorphisms (SNPs). We quantified APA usage in 195 Chinese AML patients and identified 4922 cis-apaQTLs related to 1875 genes, most of which were newly reported. Cis-apaQTLs may modulate the APA selection of 115 genes through poly(A) signals. Colocalization analysis revealed that cis-apaQTLs colocalized with cis-eQTLs may regulate gene expression by affecting miRNA binding sites or RNA secondary structures. We discovered 207 cis-apaQTLs related to AML risk by comparing genotype frequency with the East Asian healthy controls from the 1000 Genomes Project. Genes with cis-apaQTLs were associated with hematological phenotypes and tumor incidence according to the PHARMGKB and MGI databases. Collectively, we profiled an atlas of cis-apaQTLs in Asian AML patients and found their association with APA selection, gene expression, AML risk, and complex traits. Cis-apaQTLs may provide insights into the regulatory mechanisms related to APA in AML occurrence, progression, and prognosis.

Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study.

An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

Abstract LB415: Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia

Abstract LB415: Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia

Abstract SY34-02: Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening

Abstract Most BC patients succumb to metastatic relapse years to decades following primary tumor resection due to reactivation of dormant disseminated cancer cells (DCCs). Improved BC patient survival has led to metastatic relapse manifesting in an older patient population. This population carries somatic mosaicism in many organs including bone marrow. Age-specific somatic mutations (e.g., DNMT3A, ASXL1, TET2) in hematopoietic stem and progenitor cells (HSPCs) results in CH, which is associated with increased inflammatory myeloid cells and risk of leukemia and intriguingly with BC-specific mortality. In this presentation I will discuss new data from a team effort to test the hypothesis that CH myeloid cells could shape target organs niches that harbor dormant DCCs to be pro-metastatic. This hypothesis has been explored in clinical trials data where the presence of CH in ER+ and HER2+ metastatic BC patient cohorts (MSK-IMPACT) was associated with the response to first line CDK4/6i/endocrine therapy or taxol/herceptin/pertuzumab, respectively. We also tested whether CH can accelerate dormant DCC awakening in a murine model of CH carrying mutations in DNMT3A (KO or point mutation) and HER2+ mammary cancer. We propose our work may provide unprecedented insights into how a traceable age-related-mosaicism in the bone marrow (CH) may shape distant organs to be drive metastatic relapse. Citation Format: Julio A. Aguirre-Ghiso, Michael Papanicolaou, Pablo Sánchez Vela, Julie Yang, Anton Safonov, Jacqueline Tao, Sebastia Franch Exposito, Vera Tiedje, Erica Dalla, Luis E. Valencia Salazar, Nicole Barth, Merve Sahin, Kevin Chen, Jinae Park, Matthew Wereski, Aishwarya Krishnan, Anthony Martinez Benitez, Ryan Ptashkin, Mark E. Robson, Elisa de Stanchina, Lior Z. Braunstein, Ahmet Zehir, Elizabeth Comen, Larry Norton, Michael Berger, Richard Koche, Pedram Razavi, Ross Levine. Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY34-02.

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial

Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types.A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study – often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

The role of the APE1 Asp148Glu polymorphism on the risk of acute myeloid leukemia in Iraqi patients

ابيضاض الدم النخاعي الحاد هو أكثر أنواع امراض الدم الخبيثة شيوعًا عند البالغين. يعد انتشار الخلايا الطافرة الغير مسيطر عليها للأسلاف النخاعية الغير متمايزة سمة مميزة لهذا المرض. يمكن إصلاح تلف الحمض النووي عن طريق مجموعة متنوعة من الأنظمة الأنزيمية الموجودة في الخلايا حقيقية النواة. تتشكل الخلايا الطافرة عندما لا يمكن إصلاح تلف الحمض النووي بواسطة آليات إصلاح الخلية. إحدى آليات إصلاح الحمض النووي هي مسار إصلاح استئصال القاعدة ، التي تكون المسئولة عن تصحيح الأضرار الصغيرة الناتجة عن التلف ألتأكسدي أو والقلوية أو المثيلة. اشتملت الدراسة على 70 مريضًا مصابًا بسرطان الدم النخاعي الحاد - 37 أنثى و 33 ذكرًا - بالإضافة إلى 30 فردًا سليمًا كمجموعة سيطرة. تم استخدام مجموعة استخلاص الحمض النووي gSYNCTM لاستخراج الحمض النووي من عينات الدم الكاملة من مجموعات الدراسة. تم استخدام طريقة PCR-RFLP لتحديد تعدد الأشكال Asp148 Glu للجين APE1 في التحليل الجيني ، تبين أن الزيادة في النمط الجيني T/T وأليل T في تعدد الأشكال في كودون APE1 148 يلعب دورًا وقائيًا في مرض ابيضاض الدم النخاعي الحادAML ، وأن الزيادة في النمط الجيني G / G يمكن أن تترافق مع خطر الإصابة بسرطان الدم الحاد. . أظهرت النتائج أن النمط الجيني المتغاير لجين APE1 ، Asp 148 Glu (T / G) وأليل G كانت أعلى بشكل ملحوظ (P &lt;0.05) في مرضى AML مقارنة بمجموعة السيطرة . في تسلسل المنطقة التي تم دراستها ، وجد أن هناك موقعًا للتغاير يقع بين GATC و GAGC ، حيث يمثل التغيير في النيوكليوتيدات T إلى G موقع تقييد الإنزيم القاطع. حيث ارتبط النمط الجيني متعدد الأشكال 148 Glu&gt; Asp من جين APE1 مع تطور AML في المرضى العراقيين. أثبتت الدراسة أن حاملي النمط الجيني T / T لديهم مخاطر أقل لتطور مرض ابيضاض الدم النخاعي الحادAML ، في حين أن حاملي الأليلات G لديهم مخاطر متزايدة.

Clinical Risks for Chronic Lymphocytic Leukemia.

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures. Agent Orange and glyphosate herbicides have perhaps the most data to support their role. CLL is preceded by a precursor condition called monoclonal B-cell lymphocytosis (MBL), which could therefore be considered a risk factor, but which itself is likely caused by the same risk factors that ultimately give rise to CLL. Although virtually all people with CLL have a preceding MBL phase, most people with MBL will not develop CLL.