Risk Factors For Acute Myeloid Leukemia Research Articles

Prevalence, Risk Factors, and Prognostic Value of Anxiety and Depression in Acute Myeloid Leukemia

Introduction: Limited studies report anxiety and depression prevalence and their correlations with prognosis in acute myeloid leukemia (AML). Even worse, their risk factors for AML remained unclear. This study aimed to investigate the prevalence, risk factors, and prognostic value of anxiety and depression in AML patients. Methods: Totally, 132 de novo AML patients, 60 non-malignant hematological disease patients (as disease controls), and 60 healthy controls were enrolled. Anxiety and depression status were evaluated by the Hospital Anxiety and Depression Scale (HADS) in all participants. Results: HADS-anxiety score (8.2 ± 3.2 vs. 6.1 ± 2.9 vs. 4.7 ± 2.8), anxiety rate (48.5% vs. 25.0% vs. 10.0%), HADS-depression score (7.8 ± 3.0 vs. 5.8 ± 3.0 vs. 4.0 ± 2.8), and depression rate (43.2% vs. 23.3% vs. 8.3%) were highest in AML patients, followed by disease controls, and the lowest in healthy controls (all p p = 0.002, odds ratio [OR] = 0.240), smoking (p = 0.043, OR = 2.474), education duration (p = 0.024, OR = 0.889), and NCCN high-risk stratification (p = 0.008, OR = 2.347), while those independently associated with depression were age (p = 0.005, OR = 1.055), single/divorced/widowed status (p = 0.014, OR = 3.149), NCCN high-risk stratification (p = 0.002, OR = 3.077), and white blood cell (WBC) (p p = 0.012) and overall survival (p = 0.041) in AML patients, whereas anxiety was not. Conclusions: Anxiety and depression are prevalent, among which depression is associated with poor survival profile, but anxiety is not; moreover, age, male, education, single/divorced/widowed status, smoking, NCCN high-risk stratification, and WBC were independent related factors of anxiety and depression in AML patients.

Molecular Epidemiology of Acute Myeloid Leukemia (AML): Novel Association of Clinical Epidemiologic Exposures with Unique Mutation Groups on Exome Sequencing of Leukemia DNA in the Mayo Clinic AML Epidemiology Cohort

Background: Clinical epidemiologic risk factors associated with leukemia development are prevalent, and can be identified in over 90% of AML patients. We previously demonstrated an association of clinical exposures with cytogenetic risk group and outcome after therapy, but the molecular impact of such exposures is unclear, and specifically it is not known whether specific epidemiologic exposures are associated with unique genetic lesions. We therefore performed Exome Sequencing in 98 patients from our clinical epidemiology cohort to determine whether there was an association of clinically relevant AML risk factors and exposures with unique deleterious non-synonymous (nonsyn.) mutations.Methods: The Mayo Clinic AML Epidemiology cohort comprises a highly annotated series of n=295 unselected and consecutive patients diagnosed and treated at Mayo Clinic Florida & Arizona [Cancer Epidemiol 39:1084, 2015]. We obtained AML DNA from remnant diagnostic cytogenetic pellets identified in 98 patients in the cohort, and performed Exome Sequencing [ExSeq] using standard techniques. The ~100 million paired-end 100bp reads from each sample were mapped to human genome build hg19 using BWA-MEM 1. The single nucleotide variants (SNVs) and small INDELs in the exome capture regions were identified using Mayo Clinic in-house developed analytic pipeline GenomeGPS 4.0.1 following Broad GATK 2 variant discovery best practices of alignment, realignment and recalibration, haplotype caller, and multi-sample joint genotyping. The variants passed the GATK's Variant Quality Score Recalibration (VQSR) quality control were kept. Since no patient matched normal were sequenced, SNVs and INDELs were filtered using both germline whole exome and whole genome sequencing of ~1200 Mayo Clinic Biobank samples and the public germline variant databases of 1000 genome project, 6500 individuals sequenced in the exome sequencing project (ESP), and HapMap phase 3. The remaining variants were annotated using ANNOVAR 3, and potential functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. We evaluated the association of unique mutations occurring in 10 or more patients and in TP53, and also gene categories according to algorithm of Lindsley et al (Blood 125:1367, 2015) with relevant clinical and epidemiology exposures identified in our prior analysis. Risk factors and exposures were compared between patients with and without a mutation in different genes of interest using Fisher's exact test.Results: The read quality was excellent, and results from 97 evaluable samples were included in analysis. Results are noted in Table. We found a strong and significant association of prior history of immunosuppressive therapy (IST) or solid organ transplantation (SOT) with RUNX1 mutation (p=0.0001), and of regular Statin use with ASXL1 mutation (p=0.008). Statin use was also associated with mutations in genes involved in DNA methylation (p=0.036) and in Chromatin Modifier genes (p=0.049). We identified a novel inverse association of obesity - the most prevalent AML risk factor - with spliceosome mutation (p=0.010), and of IST/SOT with mutations in Myeloid Transcription Factors (TF, p=0.015) and Activated Signaling pathways [RAS, FLT3, KIT, CBL, NF1] (p=0.026). We confirm the association of secondary AML [sAML] with spliceosome mutation (p=0.018), observed as expected most strongly for Antecedent Hematologic Disorder (p=0.008, not shown). Other borderline associations (p≤0.10) are noted in Table. We did not identify any association of family history [FHx] of hematologic malignancy or of smoking [TOB] with unique mutations, nor did we identify clinical exposures associated with TP53 mutation.Conclusion: For the first time (apart from sAML) we have identified a unique leukemia genotype associated with some common clinical and epidemiologic exposures. Some mutations groups (Cohesin, TP53) were not associated with any clinical exposures, suggesting alternate mechanisms of leukemogenesis. ExSeq was for the first time successfully performed on archived diagnostic cytogenetic cell pellets, we believe a novel source of leukemia DNA. These results will guide a planned prospective study to determine frequency and mechanism of leukemogenesis after exposures, and development of strategies for prediction of leukemia risk and ultimately prevention. [Display omitted] DisclosuresCerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering .

Highlighting the Prognostic Importance of Measurable Residual Disease Among Acute Myeloid Leukemia Risk Factors

Objective:The optimal timing of measurable residual disease (MRD) evaluation in acute myeloid leukemia (AML) patients has not been well defined yet. We aimed to investigate the impact of MRD in pre- and post-allogeneic hematopoietic stem cell transplantation (AHSCT) periods on prognostic parameters.Materials and Methods:Seventy-seven AML patients who underwent AHSCT in complete morphological remission were included. MRD analyses were performed by 10-color MFC and 10-4 was defined as positive. Relapse risk and survival outcomes were assessed based on pre- and post-AHSCT MRD positivity.Results:The median age of the patients was 46 (range: 18-71) years, and 41 (53.2%) were male while 36 (46.8%) were female. The median follow-up after AHSCT was 12.2 months (range: 0.2-73.0). The 2-year overall survival (OS) in the entire cohort was 37.0%, with a significant difference between patients who were MRD-negative and MRD-positive before AHSCT, estimated as 63.0% versus 16.0%, respectively (p=0.005). MRD positivity at +28 days after AHSCT was also associated with significantly inferior 2-year OS when compared to MRD negativity (p=0.03). The risk of relapse at 1 year was 2.4 times higher (95% confidence interval: 1.1-5.6; p=0.04) in the pre-AHSCT MRD-positive group when compared to the MRD-negative group regardless of other transplant-related factors, including pre-AHSCT disease status (i.e., complete remission 1 and 2). Event-free survival (EFS) was significantly shorter in patients who were pre-AHSCT MRD-positive (p=0.016). Post-AHSCT MRD positivity was also related to an increased relapse risk. OS and EFS were significantly inferior among MRD-positive patients at +28 days after AHSCT (p=0.03 and p=0.019).Conclusion:Our results indicate the importance of MRD before and after AHSCT independently of other factors.

Untargeted metabolomics of newborn dried blood spots reveals sex-specific associations with pediatric acute myeloid leukemia

The etiology of pediatric acute myeloid leukemia (AML) is largely unknown, but evidence for mutations in utero and long latency periods suggests that environmental factors play a role. Therefore, we used untargeted metabolomics of archived newborn dried blood spots (DBS) to investigate neonatal exposures as potential causal risk factors for AML. Untargeted metabolomics profiling was performed on DBS punches from 48 pediatric patients with AML and 46 healthy controls as part of the California Childhood Leukemia Study (CCLS). Because sex disparities are suggested by differences in AML incidence rates, metabolite features associated with AML were identified in analyses stratified by sex. There was no overlap between the 16 predictors of AML in females and 15 predictors in males, suggesting that neonatal metabolomic profiles of pediatric AML risk are sex-specific. In females, four predictors of AML were putatively annotated as ceramides, a class of metabolites that has been linked with cancer cell proliferation. In females, two metabolite predictors of AML were strongly correlated with breastfeeding duration, indicating a possible biological link between this putative protective risk factor and childhood leukemia. In males, a heterogeneous metabolite profile of AML predictors was observed. Replication with larger participant numbers is required to validate findings.

Functional Genetic Variants in ATG10 Are Associated with Acute Myeloid Leukemia.

Simple SummaryAcute myeloid leukemia (AML) is a hematological neoplasm with a very poor survival rate. To date, diagnostic tools to monitor individuals at higher risk of developing AML are scarce. Single nucleotide polymorphisms (SNPs) have emerged as good candidates for disease prevention. AML is characterized by altered autophagy, a vital mechanism to remove and recycle unnecessary or dysfunctional cellular components. ATG10 is one of the autophagy core genes involved in the autophagosome formation. We hypothesize that SNPs located in regulatory regions of the ATG10 gene could predispose individuals to AML development. We therefore genotyped three SNPs within the ATG10 locus. We identified the ATG10rs3734114 as a potential risk factor for developing AML, whereas the ATG10rs1864182 was associated with decreased risk. These findings highlight ATG10 as a key regulator of susceptibility to AML. Furthermore, we believe that ATG10 SNPs could be exploited in the clinical setting as an AML prevention strategy.Acute myeloid leukemia (AML) is the most common acute leukemia, characterized by a heterogeneous genetic landscape contributing, among others, to the occurrence of metabolic reprogramming. Autophagy, a key player on metabolism, plays an essential role in AML. Here, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene, central for the autophagosome formation. We screened a multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs: rs1864182T>G, rs1864183C>T and rs3734114T>C. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells from a cohort of 46 healthy individuals. Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10rs1864182G allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10rs1864182G allele had decreased autophagy when compared to homozygous major allele carriers. Our results uncover the potential of screening for ATG10 genetic variants in AML prevention strategies, in particular for subjects carrying other AML risk factors such as elderly individuals with clonal hematopoiesis of indeterminate potential.

The risk of early mortality in elderly patients with newly diagnosed acute myeloid leukemia.

BackgroundAcute myeloid leukemia (AML) is a common hematologic neoplasm with high incidence and mortality in the elderly. Our aims were to explore risk factors for early mortality in elderly AML patients and develop a new prognostic score.MethodsWe enrolled newly diagnosed AML patients age 60 and above at Taipei Veterans General Hospital between July 2008 and May 2017. The primary endpoint was early mortality, defined as death within two months after AML diagnosis. A multivariate Cox proportional hazards model was used to build a risk‐scoring system incorporating significant risk factors for AML.ResultsThe final cohort included 277 elderly AML patients. The median age was 74 (range 60‐96), and 61.7% were male. The two‐month mortality rate was 29.9%. Age ≥ 80 (adjusted HR 1.88), myocardial infarction (adjusted HR 1.87), ECOG ≥ 2 (adjusted HR 2.10), complex karyotype (adjusted HR 3.21), bone marrow blasts ≥ 70% (adjusted HR 1.88), WBC ≥ 100 × 109/L (adjusted HR 3.31), and estimated glomerular filtration rate (eGFR) < 45 (adjusted HR 2.60) were identified as independent predictors for early mortality in the multivariate analysis. A simplified score incorporating the seven factors was developed with good predictive ability measured by Harrell's C statistic [0.72 (95% CI 0.66‐0.78)].ConclusionsWe identified seven potential risk factors for early mortality and built up a new prognostic score for elderly AML patients. The new score may help clinicians stratify patients and initiate appropriate management. Further validation of our findings on other cohorts is warranted.

Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa, Busulfan, and Fludarabine (TBF): A Retrospective Study.

This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P=.3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P=.8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P=.002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P=.03) and the risk of death (P=.03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P=.006) and there was a trend for improved survival (P=.07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.

Immunophenotypic Detection of Measurable Residual (Stem Cell) Disease Using LAIP Approach in Acute Myeloid Leukemia.

Half of the patients with acute myeloid leukemia (AML), who achieve complete remission after chemotherapy treatment, will ultimately experience a relapse. Measurable residual disease (MRD) is an important post‐treatment risk factor in AML, because it gives additional information about the depth of the remission. Within MRD, the small population of leukemic stem cells (LSCs) is thought to be at the base of the actual relapse. In this protocol, the flow cytometric detection of MRD and LSCs herein is outlined. We give a detailed overview of the sampling procedures for optimal multiparameter flow cytometry assessment of both MRD and LSC, using leukemia associated immunophenotypes (LAIPs) and LSC markers. Moreover, an overview of the gating strategies to detect LAIPs and LSC markers is provided. This protocol serves as guidance for flow cytometric detection of measurable residual (stem cell) disease necessary for proper therapeutic decision making in AML patients. © 2019 The Authors. Basic Protocol 1: Immunophenotypic LAIP detection for measurable residual disease monitoring Basic Protocol 2: Immunophenotypic detection of CD34+CD38− leukemic stem cells

Interleukin-10 (1082G/A) Polymorphism is Associated with Susceptibility of Acute Myeloid Leukemia Patients in Sudanese Population.

Background: Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenicfunctions and may have both tumor-promoting and -inhibiting properties. We examined the association between a single nucleotide polymorphism (SNP) in IL-10 -1082G/A (rs1800896) in Sudanese acute myeloid leukemia (AML) patients and to assess the association between polymorphisms in IL-10 -1082G/A (rs1800896) and the hematological profile in Sudanese patients with AML. Methods:A total of 30 patients with acute myeloid leukemia and 30 control subjects were enrolled in this study. Blood samples were collected from all patients in EDTA containing tubes. Genomic DNA was extracted from all blood samples using salting out method. The genotypic variants of IL-10 (-1082G/A) polymorphism were detected by allele specific-PCR. Results:We found that (36.7%) of patients have homogenous GG genotype, (43.3%) have heterogeneous GA genotype and (20.0%) have AA genotype. GA genotype was significantly associated with higher risk of AML compared with the homozygous Genotypes (GG and AA), there is no association between IL-10 (-1082G/A) polymorphism and AML sub-type, gender, age group, mean of hematological parameters. Conclusion:Our study concluded that GA genotype of IL-10 -1082G/A (rs1800896) polymorphism is a risk factor for AML and G allele is insignificantly higher than A allele in AML patient. No association between IL-10 (-1082G/A) polymorphism and AML sub-type, gender, age group, mean of hematological parameters.

PB1769 INTERLEUKIN‐10 (1082G/A) GENE POLYMORPHISM IS ASSOCIATED WITH RISK OF ACUTE MYELOID LEUKEMIA IN SUDANESE POPULATION

Background:Acute myeloid leukemia (AML) is a cytogenetically and molecularly heterogeneous diseases, and description of transforming genetic events is becoming increasingly significant. Interleukins (ILs) are a diverse set of small cell signaling protein molecules. Single nucleotide polymorphisms (SNPs) of ILs alter their function, increasing predisposition to different illnesses.Aims:We investigated the association between a single nucleotide polymorphism (SNP) in IL‐10 ‐1082G/A (rs1800896) in Sudanese acute myeloid leukemia patientsMethods:A total of 30 patients with Acute Myeloid Leukemia and 30 control subjects were enrolled in this study. Blood samples were collected from all participants in EDTA containing tubes. Genomic DNA was extracted from all blood samples using salting out method. The genotypic variants of IL‐10(‐1082G/A) polymorphism were detected by allele specific‐PCR.Results:We found that (36.7%) of patients have homogenous GG genotype, (43.3%) have heterogeneous GA genotype and (20.0%) have AA genotype. GA genotype was significantly higher risk of AML compared with the homozygous, there is no association between IL‐10(‐1082G/A) polymorphism and AML sub‐type, gender, age group, mean of hematological parameter (TWBCs, Blast%, Hb and platelet count).Summary/Conclusion:In summary we conclude that GA genotype of IL‐10 ‐1082G/A (rs1800896) polymorphism is a risk factor for AML and G allele is insignificantly higher than A allele in AML patient. No association between IL‐10(‐1082G/A) polymorphism and AML sub‐type, gender, age group, mean of hematological parameter (TWBCs, Blast%, Hb and platelet count).

Analysis of acute myeloid leukemia incidence and geographic distribution in Canada from 1992 to 2010 reveals disease clusters in Sarnia and other industrial US border cities in Ontario.

Several risk factors have been implicated in acute myeloid leukemia (AML) leukemogenesis. However, the epidemiologic distribution and precise triggers for AML in Canada remain poorly understood. In this study, demographic data for AML patients in Canada from 1992 to 2010 were analyzed using 3 independent population-based cancer registries. The AML incidence and mortality rates were examined at the levels of province/territory, city, and forward sortation area (FSA) postal code. In total, 18,085 patients were identified. AML incidence was documented to be 30.61 cases per million individuals per year (95% confidence interval [CI], 30.17-31.06) from 1992 to 2010. Five industrial cities in Ontario were identified where incidence rates were significantly higher than the national average: Sarnia, Sault Ste. Marie, Thunder Bay, St. Catharines, and Hamilton. Analysis at the FSA postal code level identified significant patient clusters of AML in these cities. Specifically, FSA N7V in Sarnia, Ontario had an incidence of 106.81 (95% CI, 70.96-161.86) cases per million individuals per year, which is >3 times higher than the national average. The pollution from local oil refineries and chemical plants in Sarnia may be implicated as a risk factor for AML in that city. Analysis of mortality rates at the province and city levels corroborated the findings from the incidence data. These results provide a comprehensive analysis of AML burden in Canada and reveal striking geographic case clustering in industrial Ontario cities and potentially implicate exposure to materials/pollution from these plants as an important risk factor for developing AML in Canada.

The Effect of 5 µM and 10 µM Benzoquinone on CXCL12 and KITLG Genes Expression in Mesenchymal Stem Cells

Background: Chronic exposure to benzene or its derivative (benzoquinone and hydroquinone) in humans may result in bone marrow damage followed by development of leukemia. Induction of extra cellular signaling pathways in microenvironment of bone marrow of patients with acute myeloid leukemia (AML) may lead to progression of disease and treatment resistance. Mesenchymal stromal cells (MSCs) are a subpopulation of multipotent cells of non-haematopoietic origin. They are increasingly recognized as a central component of the bone marrow (BM) microenvironment that contributes to the structure and function of the BM niche. MSCs play significant roles in regulation of homing, self-renewal, differentiation, and proliferation of hematopoietic stem cells (HSC) through production of various crucial elements in hematopoietic niche. Niches are local tissue microenvironments that maintain and regulate stem cells. Previous studies have shown that benzene is one of the important risk factors for AML. Objectives: This study aimed to evaluate the effect of low doses of benzoquinone on the expression levels of some hematopoietic function related genes including CXCL12 and Kit ligand (KITLG) in MSCs. Methods: MSCs obtained from bone marrow mononuclear cells of healthy volunteer and cultured in the proper medium. After characterization with standard methods, MSCs were exposed to two doses of 5 and 10 micro molar (µM) of benzoquinone; then, the expression of KITLG and CXCL12 genes were evaluated by real time PCR method. Results: The results indicated that the expression of KITLG and CXCL12 genes were increased after treatment with benzoquinone, specifically with 5 µM dose. Conclusions: The results of our study along with well-established role of KITLG/SCF signaling pathways and the CXCL12-CXCL4 axis in maintenance of the niche and cancer development, benzene metabolite, benzoquinone, is among the major factors in causing acute myelogenous leukemia.

Marker Chromosomes Are a New Cytogenetic Adverse Risk Factor in AML after Allo-HCT

[Background]Chromosome analysis is indispensable for the diagnosis and risk classification of acute myeloid leukemia (AML). A marker chromosome (MC) is a fragmented chromosome that cannot be identified as originating from an existing autosomal or sex chromosome. Although often observed, the significance of MC in hematological malignancies is unknown. Recently, MC was found to be the result of chromothripsis (CT). CT is a catastrophic phenomenon by which chromosomes are shattered into tens to hundreds of fragments. Half of all CT cases are related to TP53 mutation. In addition to MC, complex karyotype (CK), monosomal karyotype (MK) and existing sub-clone (SC) have also been noted as the result of CT. Previous studies reported that MC was a poor prognostic factor in AML. These studies included AML patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT). However, the influence of MC on AML after allo-HCT was not clarified.[Purpose]In this study, we evaluated the impact of MC on the outcome of AML patients after allo-HCT.[Method]This retrospective analysis included 166 AML patients who received allo-HCT at Niigata University Hospital (n=129) or Nagaoka Red Cross Hospital (n=37) between 1990 and 2017. The median age of patients at allo-HCT was 38 years old (range 14-67 y). The median follow-up period was 2.0 y (range 0.0-22.2 y). According to the revised Medical Research Council (rMRC) criteria for cytogenetic risk categories, 26 (15.7%), 104 (62.7%) and 36 (21.7%) patients were categorized as favorable, intermediate and adverse-risk, respectively. Myeloablative conditioning was used for 128 (77.1%) and reduced-intensity was used for 38 (22.9%) patients. Donors were related for 83 (59.3%) and unrelated for 57 (40.7%) patients. The Kaplan-Meier method (log-rank test) and Gray's test were used to estimate the probabilities of overall survival (OS) and cumulated incidence of relapse (CIR). The impact of several variables was assessed by multivariate analysis using a Cox regression model and Fine-Gray test with backward stepwise selection based on the p-value. For the comparison of clinical phenotypes, category variables were evaluated by Fisher's exact test.[Results]MC was detected in 14 (8.4%) of 166 patients. Eleven (78.6%) were grouped as adverse-risk by rMRC criteria. CK, MK and SC were observed in 26 (16.3%), 20 (12.0%) and 23 (13.9%) patients, respectively. The median age of AML/MC+ (n=14) and AML/MC-(n=152) patients were similar (38.5 y, range 19-64 y vs 38 y, range 14-64 y, P=0.812). Twelve AML/MC+ patients (85.7%) received allo-HCT at the advanced stage (³3 CR or non-remission) and 10 (71.4%) had primary induction failure (PIF). Compared with AML/MC- patients, those with AML/MC+ had a higher incidence of MK (78.6% vs. 5.9%, p<0.001), sub-clone (64.3% vs. 9.2%, p<0.001) and CK (85.7% vs. 9.9%, p<0.001). On univariate analysis, the 2-y OS and median survival period of AML/MC+ patients were shorter than those of AML/MC- patients (26.8% vs. 61.3% and 0.78 y vs. 4.9 y, p=0.0126). The 2-y CIR of AML/MC+ patients was higher than that of AML/MC- patients (80.4% vs. 37.2%, p<0.01). To further investigate the impact of MC on the outcome, we compared AML patients with/without MC who had the cytogenetic adverse-risk karyotype. The 2-y OS of adverse-risk AML/MC+ patients (n=11) was shorter than that of adverse-risk AML/MC- patients (n=25) (9.1% vs 58.3%, p=0.003). The median survival periods were 0.58 y and 4.0 y, and the 2-y CIR was 89.6% and 44.7% (p=0.002), respectively. The 2-y OS based on the other risk factors in adverse-risk AML patients were as follows: CK+ 33.2%, MK+ 26.9% and SC+ 34.7%. As these results suggested MC to be a poorer risk factor, we performed multivariate analysis for confirmation. In the multivariate analysis adjusted for CK, MK, SC, donor, conditioning and disease stage before allo-HCT, only MC was an independent poor risk factor for OS (HR 3.547, 95%CI: 1.46-8.63, p=0.005) and CIR (HR 3.90, 95%CI: 1.47-10.33, p=0.006) among adverse-risk AML patients using the rMRC criteria.[Conclusion]It is very difficult for AML/MC+ patients to achieve complete remission, leading to a markedly poor prognosis after allo-HCT. The outcome for AML/MC+ was inferior to that for AML with CK, MK, SC or the current adverse-risk karyotype by rMRC. This analysis revealed MC as a new independent factor that further indicates a poor prognosis after allo-HCT, especially in high-risk AML patients. DisclosuresNo relevant conflicts of interest to declare.

Polymorphisms of the CYR61 gene in patients with acute myeloid leukemia in a Han Chinese population

It was demonstrated in previous studies that cysteine-rich angiogenic inducer 61 (Cyr61) plays vital roles in hematological disorders, and we have already reported that the Cyr61 protein is a tumor promoter in acute myeloid leukemia (AML). Here, we investigated the association between CYR61 gene polymorphisms and susceptibility to AML.We genotyped 2 single-nucleotide polymorphisms (rs2297141 and rs6576776) in the region of the CYR61 gene by improved multiplex ligase detection reaction genotyping assays in a total of 275 samples, including samples from 137 AML patients and 138 healthy controls. Chi-squared tests and logistic regression analysis were performed to compare the different distributions of the genotypes and alleles between patients and healthy controls.The rs2297141 A allele was associated with lower risk of AML compared with the G allele (odds ratio [OR] = 0.704, 95% confidence interval [CI] = 0.503–0.985, P = .04) in both the dominant (OR = 0.447, 95% CI = 0.22–0.909, P = .025, AA vs GG) and recessive inheritance models (OR = 0.419, 95% CI = 0.23–0.763, P = .004, AA vs GA + GG). Although the distribution of the rs6576776 alleles was not different between patients with AML and normal controls, the CC genotype significantly increased the risk of AML in the dominant inheritance model (OR = 6.064, 95% CI = 1.303–28.216, P = .01, CC vs GG) and the recessive inheritance model (OR = 5.937, 95% CI = 1.291–27.306, P = .01, CC vs GC + GG). Additionally, it was shown that the rs2297141 and rs6576776 genotypes were associated with AML-M5 and AML-M2, respectively.Our findings indicated that genetic polymorphisms in the CYR61 gene may be considered potential AML risk factors in the Han Chinese population.

Correlation of TET2 SNP rs2454206 with improved survival in children with acute myeloid leukemia featuring intermediate-risk cytogenetics.

Single nucleotide polymorphisms (SNPs) may influence the disease course and outcome of hematologic neoplasms. SNP rs2454206 is common in the TET2 gene, which plays a role in epigenetic regulation of myelopoiesis. Few investigations examined the role of TET2 SNP rs2454206 in acute myeloid leukemia (AML) and none of those studies was performed in Chinese populations. Here, we report the prevalence and clinical relevance of TET2 SNP rs2454206 in 254 Chinese patients with childhood AML. Our data demonstrate that TET2 SNP rs2454206AG/GG is associated with improved overall survival and event-free survival in AML patients with intermediate-risk cytogenetics features. The prognostic impact of TET2 SNP rs2454206AG/GG was independent of other common AML risk factors, such as age, white blood cell count, and FLT3-ITD. No difference in TET2 expression levels in AML with TET2 SNP rs2454206AA and TET2 SNP rs2454206AG/GG was detected, indicating that TET2 SNP rs2454206 status does not affect TET2 expression in pediatric AML.

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio (HR), 2.34; p = 0.0039) and overall survival (HR, 2.14; p = 0.036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide post-remission treatment.

Methylation-independent CHFR expression is a potential biomarker affecting prognosis in acute myeloid leukemia.

CHFR acts as a tumor suppressor gene, which is frequently inactivated caused by its promoter hypermethylation in various solid tumors. Although a recent study showed that CHFR hypermethylation was a frequent event in acute myeloid leukemia (AML) and correlated with adverse clinical outcome, herein, we found that CHFR methylation was a rare event in patients with myeloid malignancies (including AML, chronic myeloid leukemia, and myelodysplastic syndromes), but its expression may serve as an independent prognostic biomarker in AML. CHFR expression was assessed by real-time quantitative PCR, whereas CHFR methylation was detected by methylation-specific PCR and bisulfite sequencing PCR. In AML patients, lower CHFR expression was associated with lower complete remission (CR) rate, and CHFR expression was significantly increased in CR after chemotherapy. Moreover, patients with lower CHFR expression showed shorter overall survival and leukemia-free survival, and multivariate analysis confirmed that lower CHFR expression was an independent risk factor in AML. Importantly, the prognostic value of CHFR expression was validated using the published Gene Expression Omnibus datasets. Notably, CHFR promoter was nearly unmethylated in patients with myeloid malignancies. Our findings revealed that lower CHFR expression was independently associated with unfavorable prognosis in AML. Moreover, aberrant CHFR promoter methylation was a rare event in myeloid malignances.

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia.

Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ⩾1 mutation during remission at a variant allele frequency of ⩾2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (P<0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; P=0039) and overall survival (hazard ratio, 2.14; P=036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.350.

Associations of NQO1 C609T and NQO1 C465T polymorphisms with acute leukemia risk: a PRISMA-compliant meta-analysis.

ObjectiveThe NAD(P)H:quinone oxidoreductase (NQO1) C609T and C465T polymorphisms have been widely thought to be associated with the risk of acute leukemia (AL) in recent years, but the correlations are still unclear. A meta-analysis is generally acknowledged as one of the best methods for secondary research, and so it was applied in this study with the aim of elucidating how the NQO1 C609T and C465T polymorphisms are related to the risk of AL.MethodsRelevant studies were searched in the PubMed, EMBASE, CNKI, and Wanfang databases, and the obtained data were analyzed using Stata (version 12.1). The allele-contrast model was applied, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationship strengths. Meta-regression was used to identify sources of heterogeneity, and subgroup analyses were conducted. Publication bias was analyzed using funnel plots, with the trim-and-fill method used to analyze the effect of publication bias on pooled results. In addition, sensitivity analysis, the fail-safe number method, and cumulative analysis by publication year were performed to measure the stability of the obtained results.ResultsThis meta-analysis included 28 relevant studies involving 5,953 patients and 8,667 controls. Overall, the C609T polymorphism was associated with the risk of acute lymphoblastic leukemia (ALL; OR =1.18, 95% CI =1.00–1.39, P=0.05). Meanwhile, race was found to be a potential source of heterogeneity for the relationship between the C609T polymorphism and acute myeloid leukemia (AML) risk, and the subgroup analysis identified the C609T polymorphism as a risk factor for AML in Asians (OR =1.34, 95% CI =1.03–1.74, P=0.03). The number of studies about C465T polymorphism was too small to pool the data.ConclusionThere are increased risks of ALL in all subjects and of AML in Asians for carriers of the NQO1 C609T polymorphism. Further studies are needed to verify the associations of the C465T polymorphism with the risk of AL.

Acute myeloid leukemia: a retrospective claims analysis of resource utilization and expenditures for newly diagnosed patients from first-line induction to remission and relapse

Objective: The objective of this study was to estimate resource utilization and expenditures for patients with acute myeloid leukemia (AML) in a real-world claims database.Research design and methods: AML patients were identified in MarketScan claims databases between 1 January 2009 and 31 January 2015. Patients had a minimum of two AML diagnosis codes, hospitalization within 14 days after initial diagnosis, and ≥6 months of enrollment before initial diagnosis. Patients were monitored from first-line induction to a record of remission. A subset had a record of a second treatment period, defined as time from relapse to remission. Patient demographics, AML risk factors, and comorbidities were recorded. Descriptive analysis of utilization and expenditures (in 2014 $US) were reported for each cohort.Results: The inclusion criteria were met in 1597 patients (mean age, 58.4 years; 51.0% male). Ninety percent of patients had ≥1 risk factor for AML. Mean (SD) healthcare expenditures for patients from first-line induction to remission (n = 681) were $208,857 ($152,090). Of the 157 who had a record of relapse, 70 had a record of a second remission. Expenditures for these patients (n = 70) from relapse to remission were $142,569 ($208,307); 60% were admitted to a hospital for a mean of 18.5 hospital days, and 20% had ≥1 emergency room visit.Conclusions: Although this claims-based analysis is limited by a lack of generalizability to noninsured populations and potential underreporting of certain events and diagnoses, we found that treating AML patients poses a significant healthcare burden, during both first-line induction and relapse. With people living longer, the number of cases of AML is expected to increase in the future.