Risk Acute Myeloid Leukemia Research Articles

10-year real-world data on acute myeloid leukemia: The paradigm of a public health center in Brazil.

e19022 Background: Acute myeloid leukemia (AML) is a heterogeneous disease with different predominant molecular pathways. The last few years have witnessed great advances in targeted therapy. There are several trials in developed countries evaluating clinical outcomes. Nevertheless, data from low and middle-income (LMIC) countries frequently describe inferior results. Methods: This was a retrospective single-center cohort conducted in a university hospital in Northeast Brazil. We have analyzed the outcomes of all 62 patients diagnosed with AML between 2007 and 2017. Patients were classified using the European LeukemiaNet 2017 model into favorable (n=8), intermediate (n=18), and adverse risk (n= 7). 29 were not otherwise classified because of the absence of cytogenetic and/or molecular tests. We used logistic regression for data analysis assessing death as the outcome. Survival measures were estimated using the Kaplan-Meier method. The impact of bone marrow transplant (BMT) on patients eligible for intensive treatment on overall survival (OS) was assessed using a Cox proportional hazards model. Results: The median OS (mOS) of the entire cohort was 7 months (CI: 3.14-10.85). Stratifying by the risk, the mOS was shorter in patients with unknown and adverse risk (3 and 5 months, respectively) than in favorable and intermediate risk (22 and 11 months, respectively, P = 0.05). 16 (38%) patients were submitted to allogeneic BMT. We found a survival advantage (hazard ratio, HR: 0.32, 95% CI: 0.15-0.71) – p=0.005) in transplant patients, with superior median overall survival (mOS) (49 months) when compared with the chemotherapy group (6 months) ( P = 0.003). A total of 48 (77%) patients died during the follow-up and most deaths (n=39, 81%) occurred during the first year of diagnosis. Univariate analysis of clinical and laboratory characteristics found no association with death. A multivariate model including AML origin, risk stratification, and alloBMT as predictor variables demonstrated the protective power of alloBMT (table). Conclusions: Inferior outcomes found in LMIC are the result of a multifactorial scenario that reflects the absence of proper diagnostic tools, hospital infrastructure, and the lack of more effective and less toxic therapies. We suggest that patients with inadequate risk assessment should undergo consolidation with alloBMT as this remains the primary curative intervention in the real-world setting of LMIC. [Table: see text]

Defining risk of central nervous system relapse in acute myeloid leukemia following allogeneic stem cell transplantation.

e19009 Background: Relapse following allogeneic stem cell transplant (AlloSCT) for acute myeloid leukemia (AML) remains the commonest cause of death post-transplant. Central nervous system (CNS) relapse is a devastating complication. With an estimated incidence of 2-8%, defining those patients at high risk and the management following CNS relapse remains controversial. We sought to identify demographic, clinical, molecular, and laboratory risk factors that would predispose AML patients to CNS relapse. Methods: This was a single institution retrospective study at Loyola University Medical Center. Inclusion criteria were adult patients with AML undergoing first AlloSCT from January 2012 to June 2021. Diagnosis of CNS relapse following AlloSCT was defined as leukemic blasts detected in spinal fluid analysis in accordance with established criteria. Chi-square tests were used to test the association between the experiencing of relapse and the categorical variables recorded. Wilcoxon Rank Sum test were used to assess the relationship between relapse experience and each of the demographic variables. Due to the low count of patients with CNS relapse and in order to avoid a poor estimation of confidence limits of any effect size, we limited our analyses to descriptive statistics and univariable analyses. Results: 198 patients met inclusion criteria with 8 cases (4.0% total) identified with CNS relapse following AlloSCT. Our analysis initially characterized 44 variables including age, race, HCT-CI risk, and day 100 chimerism. Univariate analysis is shown in the table below. Of note, it revealed that 62.50% of patients with CNS relapse had a chimerism value ≤98% at day 100 post-transplant as compared to 22.58% of patients without CNS relapse (p-value 0.02). Additionally, 87.50% of the CNS relapse group versus 51.38% of the group without relapse had favorable to intermediate AML risk scores (p-value 0.07). Conclusions: We observed a 4.0% rate of CNS relapse, which is consistent with what has been repored in the literature. Our results suggest that day 100 chimerism and disease risk index may be predictive of CNS relapse. Since there is a 10.6% incidence (5/47) of eventual CNS relapse amongst those with ≤98% chimerism at day 100, these patients could be considered for a lumbar puncture and bone marrow biopsy to prevent full relapse. Further research in this topic would be valuable to provide additional AML guidance in managing this uncommon complication, such as which patients may benefit from prophylactic strategies. [Table: see text]

DHX9-mediated pathway contributes to the malignant phenotype of myelodysplastic syndromes

DHX9 is a member of the DEAH (Asp-Glu-Ala-His) helicase family and regulates DNA replication and RNA processing. DHX9 dysfunction promotes tumorigenesis in several solid cancers. However, the role of DHX9 in MDS is still unknown. Here, we analyzed the expression of DHX9 and its clinical significance in 120 MDS patients and 42 non-MDS controls. Lentivirus-mediated DHX9-knockdown experiments were performed to investigate its biological function. We also performed cell functional assays, gene microarray, and pharmacological intervention to investigate the mechanistic involvement of DHX9. We found that overexpression of DHX9 is frequent in MDS and associated with poor survival and high risk of acute myeloid leukemia (AML) transformation. DHX9 is essential for the maintenance of malignant proliferation of leukemia cells, and DHX9 suppression increases cell apoptosis and causes hypersensitivity to chemotherapeutic agents. Besides, knockdown of DHX9 inactivates the PI3K-AKT and ATR-Chk1 signaling, promotes R-loop accumulation, and R-loop-mediated DNA damage.

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia.

Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.

Contribution of the Oral and Gastrointestinal Microbiomes to Bloodstream Infections in Leukemia Patients.

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (blaCTX-M-15, blaCTX-M-14, cfrA, and vanA) were confirmed via digital droplet PCR (ddPCR). Individuals with Escherichia coli (stool P < 0.001), Pseudomonas aeruginosa (oral P = 0.004, stool P < 0.001), and viridans group streptococci (VGS) (oral P = 0.001) bacteremia had a significantly higher relative abundance of those respective genera than other BSI patients, which appeared to be site specific. Although 78% of patients showed presence of the infectious genera in the stool and/or saliva, only 7 exhibited microbiome domination. ddPCR confirmed species specificity of the 16S data and detected the antibiotic resistance determinants found in the BSI isolates within concurrent stools. Although gastrointestinal (GI) domination by an infecting organism was not present at the time of most BSIs in AML, the pathogens, along with AMR elements, were detectable in the majority of patients. Thus, rapid genetic assessment of oral and stool samples for the presence of potential pathogens and AMR determinants might inform personalized therapeutic approaches in immunocompromised patients with suspected infection. IMPORTANCE A major cause of mortality in hematologic malignancy patients is BSI. Previous studies have demonstrated that bacterial translocation from the GI microbiome is a major source of BSIs and is often preceded by increased levels of the infectious taxa in the GI (>30% abundance by 16S rRNA sequencing). In this study, we sought to better understand how domination and abundance levels of the oral and gut microbiome relate to bacteremia occurrence in acute myeloid leukemia patients. We conclude that analyses of both oral and stool samples can help identify BSI and antimicrobial resistance determinants, thus potentially improving the timing and tailoring of antibiotic treatment strategies for high-risk patients.

Somatic exonic deletions in RUNX1 constitutes a novel recurrent genomic abnormality in acute myeloid leukemia.

In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML. Sixty well-characterized AML patients were analyzed with Multiplex Ligation-dependent Probe Amplification (MLPA, n=60), micro-array (n=11) and/or whole genome sequencing (WGS, n=8). In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs 38.8 months respectively, p=0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were re-assigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate and high-risk group (18.9 vs 9.6 months, p=0.09). Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk-stratification and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.

Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group.

A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

An Updated Overview of the Role of CYP450 during Xenobiotic Metabolization in Regulating the Acute Myeloid Leukemia Microenvironment.

Oxidative stress is associated with several acute and chronic disorders, including hematological malignancies such as acute myeloid leukemia, the most prevalent acute leukemia in adults. Xenobiotics are usually harmless compounds that may be detrimental, such as pharmaceuticals, environmental pollutants, cosmetics, and even food additives. The storage of xenobiotics can serve as a defense mechanism or a means of bioaccumulation, leading to adverse effects. During the absorption, metabolism, and cellular excretion of xenobiotics, three steps may be distinguished: (i) inflow by transporter enzymes, (ii) phases I and II, and (iii) phase III. Phase I enzymes, such as those in the cytochrome P450 superfamily, catalyze the conversion of xenobiotics into more polar compounds, contributing to an elevated acute myeloid leukemia risk. Furthermore, genetic polymorphism influences the variability and susceptibility of related myeloid neoplasms, infant leukemias associated with mixed-lineage leukemia (MLL) gene rearrangements, and a subset of de novo acute myeloid leukemia. Recent research has shown a sustained interest in determining the regulators of cytochrome P450, family 2, subfamily E, member 1 (CYP2E1) expression and activity as an emerging field that requires further investigation in acute myeloid leukemia evolution. Therefore, this review suggests that CYP2E1 and its mutations can be a therapeutic or diagnostic target in acute myeloid leukemia.

Clinicopathologic Features of IDH2 R172-Mutated Myeloid Neoplasms.

IDH1 and IDH2 are among the most commonly mutated genes in myeloid neoplasms (MNs). It has been proposed that IDH2 R172 mutations (mR172) define a molecular subtype of acute myeloid leukemia (AML), but the clinicopathologic features of AML with mR172 have not been fully described. We retrospectively identified and characterized all mR172 MNs with increased blasts in our archive for comparison to a similar number of MNs with IDH2 R140 (mR140) and IDH1 R132 (mR132) mutations (n = 39). mR172 cases had lower leukocyte counts and bone marrow cellularity than did non-mR172 cases. mR172 MNs often displayed blasts with highly invaginated, cleaved nuclei and typically expressed CD34, HLA-DR, CD117, and CD13 but often with diminished CD33. mR172 cases often had co-occurring mutations in myelodysplasia-associated genes and/or an adverse karyotype. Despite frequent adverse-risk genetic changes, in our cohort mR172 cases had significantly improved overall survival vs non-mR172 cases (P = .01), and we validated that mR172 was associated with improved survival in an independent large data set. We show that MNs with mR172 represent a morphologically and phenotypically distinct subtype, which in our cohort exhibited relatively favorable survival that is not captured in current AML risk assignment.

RNA demethylase ALKBH5 promotes tumorigenesis of t (8;21) acute myeloid leukemia via ITPA m6A modification

BackgroundAlthough t (8;21) is in fact considered a good risk acute myeloid leukemia (AML), only 60% of the patients live beyond 5 years after diagnosis. Studies have shown that RNA demethylase ALKBH5 promotes leukemogenesis. However, the molecular mechanism and clinical significance of ALKBH5 in t (8;21) AML have not been elucidated.MethodsThe expression of ALKBH5 was assessed in t (8;21) AML patients via qRT-PCR and western blot. The proliferative activity of these cells was examined through CCK-8 or colony-forming assays, while flow cytometry approaches were used to examine apoptotic cell rates. The in vivo role of ALKBH5 promoting leukemogenesis was assessed using t (8;21) murine model, CDX, and PDX models. RNA sequencing, m6A RNA methylation assay, RNA immunoprecipitation, and luciferase reporter assay were used to explore the molecular mechanism of ALKBH5 in t (8;21) AML.ResultsALKBH5 is highly expressed in t (8;21) AML patients. Silencing ALKBH5 suppresses the proliferation and promotes the apoptosis of patient-derived AML cells and Kasumi-1 cells. With integrated transcriptome analysis and wet-lab confirmation, we found that ITPA is a functionally important target of ALKBH5. Mechanistically, ALKBH5 demethylates ITPA mRNA and increases its mRNA stability, leading to enhanced ITPA expression. Furthermore, transcription factor TCF15, specifically expressed in leukemia stem/initiating cells (LSCs/LICs), is responsible for the dysregulated expression of ALKBH5 in t (8;21) AML.ConclusionOur work uncovers a critical function for the TCF15/ALKBH5/ITPA axis and provides insights into the vital roles of m6A methylation in t (8;21) AML.

The impact of the ERCC2 Lys751Gln polymorphism on the risk of acute myeloid leukemia in an Iraqi patients

Objectives: AML is the only type of acute leukemia diagnosed in adults and is less common in children. It has the lowest survival rate. This study aimed to investigate the epidemiological risk factors for AML expansion comprise environmental factors, for instance, smoking , and therapy-related factors. Methods :The study was conducted on 70 acute myeloid leukemia patients—37 females and 33 males and on 30 healthy people—12 females and 18 males—as a control group. DNA was extracted from the study groups' whole blood samples using the gSYNCTM DNA Extraction Kit. The T751G polymorphism of the ERCC2 gene was determined by the PCR-RFLP technique. Results: In genetic analysis, it was shown that the carriers of allele Lys and genotype Lys/Lys have a lower risk of developing AML, while allele carriers Gln have an increased risk. The results showed the ERCC2 gene, Lys 751 Gln (T/G) heterozygous TG genotypes, and the G allele were significantly higher (P&lt;0.05) in AML patients compared to the control group. In the sequencing of the region we studied, it was found that there is a site of diversity that is located between the CTTCAG and CTGCAG, where a change in nucleotides (T to G) represents the restriction site of the restriction enzyme. Conclusion : The polymorphic marker 751 Gln&gt; Lys of the ERCC2 gene was associated with the development of AML in Iraqi patients. It was discovered that allele Lys genotype Lys/Lys carriers have a lower risk of developing AML, whereas allele Gln carriers have an increased risk.

Solute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines.

Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance. AML cell lines were exposed to increasing concentrations of AZA to create resistant clones. 14C-AZA IUR was significantly lower in MOLM-13- (1.65 ± 0.08 ng vs. 5.79 ± 0.18 ng; p < 0.0001) and SKM-1- (1.10 ± 0.08 vs. 5.08 ± 0.26 ng; p < 0.0001) resistant cells compared to respective parental cells. Importantly, 14C-AZA IUR progressively reduced with downregulation of SLC29A1 expression in MOLM-13- and SKM-1-resistant cells. Furthermore, nitrobenzyl mercaptopurine riboside, an SLC29A inhibitor, reduced 14C-AZA IUR in MOLM-13 (5.79 ± 0.18 vs. 2.07 ± 0.23, p < 0.0001) and SKM-1-naive cells (5.08 ± 2.59 vs. 1.39 ± 0.19, p = 0.0002) and reduced efficacy of AZA. As the expression of cellular efflux pumps such as ABCB1 and ABCG2 did not change in AZA-resistant cells, they are unlikely contribute to AZA resistance. Therefore, the current study provides a causal link between in vitro AZA resistance and downregulation of cellular influx transporter SLC29A1.

Safety and efficacy of a modified busulfan/cyclophosphamide conditioning regimen incorporating cladribine for autologous hematopoietic stem cell transplantation in acute myeloid leukemia.

This is a small phase I study examining the safety and efficacy of a cladribine (CLAD)-containing conditioning regimen prior to autologous hematopoietic stem cell transplantion (auto-HSCT) for patients with acute myeloid leukemia (AML). All patients, aged 15-54years (median 32years), had favorable/intermediate risk AML (n = 20) or acute promyelocytic leukemia (APL; n = 2) and no evidence of minimal residual disease (MRD) prior to transplantation. Fourteen of the 22 patients received the conditioning regimen as follows: busulfan (Bu) + cyclophosphamide (Cy) + CLAD + cytarabine (Ara-c) or idarubicin. The conditioning regimen of 8 patients was without Cy nor idarubicin to reducing adverse cardiac reaction: the regimen of Bu + CLAD+ Ara-c for 6 patients; and the regimen of Bu + melphalan + CLAD + Ara-c for the other 2 patients. All 22 AML patients received peripheral blood stem cell transplantation. The number of infused mononuclear cells and CD34+ cells was 10.00 (2.88-20.97) × 108/kg and 1.89 (1.52-10.44) × 106/kg, respectively. Hematopoietic reconstitution was achieved in all patients, with a median time of 13 (10-34) days for neutrophils and 28 (14-113) days for platelets. Two patients suffered from pulmonary infection, 4 patients suffered from septicemia during the neutropenic stage, and the others suffered from infection or gastrointestinal reaction without exceeding grade 3 after conditioning, which were all alleviated by anti-infection and other supportive treatment. None of the patients died of transplantation-related complications. At a median follow-up of 29.5 (ranging from 4.0 to 60.0) months, three patients relapsed after auto-HSCT at a median time of 6 (ranging from 0.5 to 10.0) months. One patient died due to relapse at 18months after auto-HSCT. The remaining 21 patients were all alive, including 19 patients with negative MRD. The other 2 patients achieved negative MRD after allogeneic HSCT or chemotherapy. The estimated 2-year survival, relapse, and Leukemia-free survival rates were 94.1 ± 5.7%, 14.7 ± 7.9% and 85.3 ± 7.9%, respectively. A CLAD-combination conditioning regimen is efficient and safe for auto-HSCT, indicating an effective approach for AML treatment.

High expression of LOC541471, GDAP1, SOD1, and STK25 is associated with poor overall survival of patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive heterogeneous hematological malignancy with remarkably heterogeneous outcomes. This study aimed to identify potential biomarkers for AML risk stratification via analysis of gene expression profiles. RNA sequencing data from 167 adult AML patients in the Cancer Genome Atlas (TCGA) database were obtained for overall survival (OS) analysis, and 52 bone marrow (BM) samples from our clinical center were used for validation. Additionally, siRNA was used to investigate the role of prognostic genes in the apoptosis and proliferation of AML cells. Co-expression of 103 long non-coding RNAs (lncRNAs) and mRNAs in the red module that were positively correlated with European Leukemia Network (ELN) risk stratification and age was identified by weighted gene co-expression network analysis (WGCNA). After screening by uni- and multivariate Cox regression, Kaplan-Meier survival, and protein-protein interaction analysis, four genes including the lncRNA LOC541471, GDAP1, SOD1, and STK25 were incorporated into calculating a risk score from coefficients of the multivariate Cox regression model. Notably, GDAP1 expression was the greatest contributor to OS among the four genes. Interestingly, the risk score, ELN risk stratification, and age were independent prognostic factors for AML patients, and a nomogram model constructed with these factors could illustrate and personalize the 1-, 3-, and 5-year OS rates of AML patients. The calibration and time-dependent receiver operating characteristic curves (ROCs) suggested that the nomogram had a good predictive performance. Furthermore, new risk stratification was developed for AML patients based on the nomogram model. Importantly, knockdown of LOC541471, GDPA1, SOD1, or STK25 promoted apoptosis and inhibited the proliferation of THP-1 cells compared to controls. High expression of LOC541471, GDAP1, SOD1, and STK25 may be biomarkers for risk stratification of AML patients, which may provide novel insight into evaluating prognosis, monitoring progression, and designing combinational targeted therapies.

Comparison of the effect of DLI according to cell sources in relapsed AML after allogeneic stem cell transplantation

For relapsed acute myeloid leukemia (AML) patients who received allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion (DLI) is an effective therapy. However, the cell source of DLI remains a topic of debate. In this study, we aimed to compare the efficacy and safety of G-CSF mobilized cells (G-DLI) with conventionally collected DLI (C-DLI). A total of 81 patients (50 C-DLI vs. 31 G-DLI) were assessed for clinical outcomes. There were no statistically significant differences in the baseline characteristics between the two groups including AML risk, donor types, interval from relapse to DLI, and infused CD3+ cell count. Although not statistically significant, complete remission (CR) and chimerism conversion rates were higher in G-DLI than in C-DLI: 51.6% vs. 28.0%, P = 0.057 and 42.3% vs. 28.2%, P = 0.363, respectively. There was no difference in acute graft-versus-host disease (GVHD) incidence and severity of acute GVHD between the two groups. The median overall survival (OS) of the G-DLI and C-DLI groups was 139 days and 106 days, respectively (P = 0.58). In conclusion, G-DLI appears to be a safe and an equally efficacious substitute for C-DLI, which is more readily available.

Novel high–risk acute myeloid leukemia subgroup with ERG amplification and Biallelic loss of TP53

ETS-related gene (ERG) amplification, observed in 4–6% of acute myeloid leukemia (AML), is associated with unfavorable prognosis. To determine coincident effects of additional genomic abnormalities in AML with ERG amplification (ERGamp), we examined 11 ERGamp cases of 205 newly diagnosed AML using chromosomal microarray analysis and next generation sequencing. ERGamp cases demonstrated a distinct pattern of high genetic complexity: loss of 5q, chromothripsis and TP53 loss of function variants. Remarkably, allelic TP53 loss or loss of heterozygosity (LOH) co-occurring with TP53 inactivating mutation dramatically effected ERGamp tumor patient outcome. In the presence of homozygous TP53 loss of function, ERGamp patients demonstrated no response to induction chemotherapy with median overall survival (OS) of 3.8 months (N = 9). Two patients with heterozygous loss of TP53 function underwent alloSCT without evidence of relapse at one year. Similarly, a validation TCGA cohort, 6 of the 8 ERGamp cases with TP53 loss of function demonstrated median OS of 2.5 months. This suggests that with TP53 mutant ERGamp AML, successive loss of the second TP53 allele, typically by 17p deletion or LOH identifies a specific high-risk subtype of AML patients who are resistant to standard induction chemotherapy and need novel approaches to avert the very poor prognosis.

Rare cytogenetic abnormalities in MDS evolving from fanconi anemia-A case report

Fanconi anemia (FA) is a genetically heterogenous rare autosomal recessive disorder. Mutations in FANCA gene are the most frequent among FA patients accounting for 60-65%. FA is characterised by congenital malformations, progressive bone marrow failure (BMF) and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The risk of developing hematological abnormalities in FA patients is around 98% by 40 years of age. The risk of clonal cytogenetic abnormalities during BMF is around 67% by 30 years of age and risk of developing MDS or AML is 52% by 40 years of age. The frequent chromosomal abnormalities are 1q+, monosomy 7 and gains of 3q. Partial duplications/triplications of chromosome 1q are known to represent a nonrandom chromosomal anomaly in myeloid disorders.

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry.

Next-Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross-validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS-AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co-occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia-related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

SETD2 detection may reveal response to induction therapy and survival profile in acute myeloid leukemia patients

ABSTRACTObjective:SET domain containing protein 2 (SETD2) involves in the progression and development of chemotherapy resistance in acute myeloid leukemia (AML). Hence, this study aimed to investigate the relationship of SETD2 expression with disease risk, features, treatment response, and survival profile in AML.Methods:One-hundred and sixty primary AML patients were retrospectively analyzed. Their bone marrow (BM) samples before and after induction therapy were retrieved for SETD2 detection by RT-qPCR. Moreover, SETD2 expression in BM samples of 20 disease controls (DCs) were also determined.Results:SETD2 expression was downregulated in AML patients compared to DCs (P < 0.001). Higher SETD2 expression related to white blood cells ≤10 × 109/L despite not reaching statistical significance (P = 0.062). One-hundred and nineteen (74.4%) AML patients achieved complete response (CR), while the remaining 41 (25.6%) did not achieve that. Furthermore, increased SETD2 expression was associated with CR achievement (P = 0.015). Survival analyses displayed that SETD2 high (vs. low) was related to prolonged event-free survival (EFS) (P = 0.001) and overall survival (OS) (P = 0.021). Moreover, increased SETD2 quartile was correlated with favorable EFS (P = 0.004) and OS (P = 0.042). After adjustment using multivariate Cox’s regression analysis, higher SETD2 quartile was independently related to prolonged EFS [hazard ratio (HR): 0.766, P = 0.013] and OS (HR: 0.669, P = 0.013). It was also noticed that SETD2 expression was elevated during the induction therapy (P < 0.001).Conclusion:Detection of SETD2 may assist in estimating treatment response and survival profile in AML patients.

Cancer risk and mortality in multiple sclerosis: The need for vigilance

Several investigators have addressed the possibility of a link between cancer and multiple sclerosis (MS). The consensus view favours an increased risk, but analysis is compromised by multiple confounders, including small sample sizes, age and socio-economic group of the population in question, level of education and whether a cancer diagnosis was based on the less reliable death certificates compared to cancer registries. Coupled with this is the problem of subsequent cancer-related mortality in those with MS compared to those without MS. Until 1996 patients were treated chiefly with steroids, azathioprine, cyclophosphamide and occasionally mitoxantrone. Each of these has its own potential long-term risk of cancer probably least of all with steroids. Mitoxantrone has a small but definite risk of acute myeloid leukaemia particularly if patients are exposed to more than 60mg/M2 ( Lebrun and Rocher, 2018 Lebrun C Rocher F. Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS drugs. 2018; 32 (Oct): 939-949 Google Scholar ). Azathioprine is connected with a particularly high rate of non-Hodgkin lymphoma in renal transplant cases ( Kinlen, 1992 Kinlen L. Immunosuppressive therapy and acquired immunological disorders. Cancer research. 1992; 52 (Oct 1): 5474s-5476s Google Scholar ) but this has not been found for large studies in MS that had a follow-up range of <10 years and a total dose exposure of no more than 600g ( Casetta et al., 2007 Casetta I Iuliano G Filippini G. Azathioprine for multiple sclerosis. Cochrane Database of Systematic Reviews. 2007; Google Scholar ).