scholarly journals Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia

2022 ◽  
Author(s):  
Garrett M. Dancik ◽  
Ioannis F. Voutsas ◽  
Spiros Vlahopoulos
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Rna Expression ◽  
Acute Myeloid

scholarly journals Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia

2021 ◽  
Author(s):  
Garrett M. Dancik ◽  
Ioannis F. Voutsas ◽  
Spiros A. Vlahopoulos
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Rna Expression ◽  
Poor Overall Survival ◽  
Activity Of Enzymes ◽  
Acute Myeloid

The expression and activity of enzymes that belong to the aldehyde dehydrogenases is a characteristic of both normal and malignant stem cells. ALDH1A1 is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, which include inhibitors of protein tyrosine kinases. Furthermore, ALDH1A1 proves vital for the establishment of human AML xenografts in mice. We review here important studies characterizing the role of ALDH1A1 in AML and its potential as a therapeutic target. We also analyze datasets from leading studies, and show that decreased ALDH1A1 RNA expression consistently characterizes the AML patient risk group with a favorable prognosis, while there is a consistent association of high ALDH1A1 RNA expression with high risk and poor overall survival. Our review and analysis reinforces the notion to employ both novel as well as existing inhibitors of the ALDH1A1 protein against AML.

scholarly journals Functional implications of microRNAs in acute myeloid leukemia by integrating microRNA and messenger RNA expression profiling

Cancer ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 4696-4706 ◽  
Author(s):  
Violaine Havelange ◽  
Nicole Stauffer ◽  
Catherine C. E. Heaphy ◽  
Stefano Volinia ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Expression Profiling ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Rna Expression ◽  
Functional Implications ◽  
Rna Expression Profiling ◽  
Acute Myeloid

scholarly journals The Clinical Features and Prognostic Impact of PRDM16 gene Expression in Adult Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5228-5228
Author(s):  
Genki Yamato ◽  
Hiroki Yamaguchi ◽  
Hiroshi Handa ◽  
Norio Shiba ◽  
Satoshi Wakita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Pediatric Aml ◽  
Prdm16 Gene ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a complex disease caused by various genetic alterations. Some prognosis-associated cytogenetic aberrations or gene mutations such as FLT3-internal tandem duplication (ITD), t(8;21)(q22;q22)/RUNX1-RUNX1T1, and inv(16)(p13q22)/CBFB-MYH11 have been found and used to stratify the risk. Numerous gene mutations have been implicated in the pathogenesis of AML, including mutations of DNMT3A, IDH1/2, TET2 and EZH2 in addition to RAS, KIT, NPM1, CEBPA and FLT3in the recent development of massively parallel sequencing technologies. However, even after incorporating these molecular markers, the prognosis is unclear in a subset of AML patients. Recently, NUP98-NSD1 fusion gene was identified as a poor prognostic factor for AML. We have reported that all pediatric AML patients with NUP98-NSD1 fusion showed high expression of the PR domain containing 16 (PRDM16; also known as MEL1) gene, which is a zinc finger transcription factor located near the breakpoint at 1p36. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of EVI1. Furthermore, PRDM16 is essential for hematopoietic stem cell maintenance and remarkable as a candidate gene to induce leukemogenesis. Recent reports revealed that high PRDM16 expression was a significant marker to predict poor prognosis in pediatric AML. However, the significance of PRDM16 expression is unclear in adult AML patients. Methods A total of 151 adult AML patients (136 patients with de novo AML and 15 patients with relapsed AML) were analyzed. They were referred to our institution between 2004 and 2015 and our collaborating center between 1996 and 2013. The median length of follow-up for censored patients was 30.6 months. Quantitative RT-PCR analysis was performed using the 7900HT Fast Real Time PCR System with TaqMan Gene Expression Master Mix and TaqMan Gene Expression Assay. In addition to PRDM16, ABL1 was also evaluated as a control gene. We investigated the correlations between PRDM16 gene expression and other genetic alterations, such as FLT3-ITD, NPM1, and DNMT3A, and clarified the prognostic impact of PRDM16 expression in adult AML patients. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, and the next-generation sequencer Ion PGM. Results PRDM16 overexpression was identified in 29% (44/151) of adult AML patients. High PRDM16 expression correlated with higher white blood cell counts in peripheral blood and higher blast ratio in bone marrow at diagnosis; higher coincidence of mutation in NPM1 (P = 0.003) and DNMT3A (P = 0.009); and lower coincidence of t(8;21) (P = 0.010), low-risk group (P = 0.008), and mutation in BCOR (P = 0.049). Conversely, there were no significant differences in age at diagnosis and sex distribution. Patients with high PRDM16 expression tended to be low frequency in M2 (P = 0.081) subtype, and the remaining subtype had no significant differences between high and low PRDM16 expression. Remarkably, PRDM16 overexpression patients were frequently observed in non-complete remission (55.8% vs. 26.3%, P = 0.001). Patients with high PRDM16 expression tended to have a cumulative incidence of FLT3-ITD (37% vs. 21%, P = 0.089) and MLL-PTD (15% vs. 5%, P = 0.121). We analyzed the prognosis of 139 patients who were traceable. The overall survival (OS) and median survival time (MST) of patients with high PRDM16 expression were significantly worse than those of patients with low expression (5-year OS, 17% vs. 32%; MST, 287 days vs. 673 days; P = 0.004). This trend was also significant among patients aged <65 years (5-year OS, 25% vs. 48%; MST, 361 days vs. 1565 days, P = 0.013). Moreover, high PRDM16 expression was a significant prognostic factor for FLT3-ITD negative patients aged < 65 years in the intermediate cytogenetic risk group (5-year OS, 29% vs. 58%; MST, 215 days vs. undefined; P = 0.032). Conclusions We investigated the correlations among PRDM16 expression, clinical features, and other genetic alterations to reveal clinical and prognostic significance. High PRDM16 expression was independently associated with non-CR and adverse outcomes in adult AML patients, as well as pediatric AML patients. Our finding indicated that the same pathogenesis may exist in both adult and pediatric AML patients with respect to PRDM16 expression, and measuring PRDM16 expression was a powerful tool to predict the prognosis of adult AML patients. Disclosures Inokuchi: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

scholarly journals Survival Improvement Of Secondary Acute Myeloid Leukemia Over Time: Experience From 962 Patients Included In 13 EORTC-Gimema-HOVON Leukemia Group Trials

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 829-829 ◽  
Author(s):  
Safaa M. Ramadan ◽  
Stefan Suciu ◽  
Marian J.P.L. Stevens-Kroef ◽  
Roelof Willemze ◽  
Sergio Amadori ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Malignant Disease ◽  
Risk Group ◽  
Toxic Exposure ◽  
Secondary Acute Myeloid Leukemia ◽  
History Of ◽  
Over Time ◽  
Acute Myeloid

Abstract Background Secondary acute myeloid leukemia (sAML) describes patients (pts) with a history of malignant or non-malignant disease or AML secondary to environmental, occupational or therapeutic exposures. They are generally associated with poor outcome despite the use of intensive treatments. The impact of clinical features and type of treatment on pts' outcome is still not well established. In the current analysis we evaluated sAML pts who were treated in 13 EORTC collaborative trials conducted between May 1986 and January 2008. sAML pts in the database were pooled to characterize clinical features of the disease and evaluate changes in survival over these years (yrs). Method Main selection criteria were AML with bone marrows blasts ≥20% and documented history of prior malignancy, non-malignant disease and/or toxic exposure. AML-M3 and MDS without confirmed diagnosis ≥2 months before AML were excluded. All pts were eligible for standard treatment. Induction regimens were anthracycline and AraC based: 7+3, including etoposide, intensified with high dose (HD)-AraC randomized to standard doses (SD) in younger (AML12) or gemtuzumab ozogamicin in elderly pts. Consolidation regimens were age adapted. In mid-1980s, autologous transplant was tested vs a 2nd consolidation cycle (AML8A) in pts ≤45 yrs and thereafter used systematically in pts ≤60 yrs without available donor. Allogeneic transplant (Allo-SCT) was offered to pts ≤46 yrs with HLA-compatible sibling since mid-1980s and expanded in the last decade to pts up to 59 yrs. Selected pts were divided into 3 sAML cohorts, cohort A after MDS, cohort B after other malignant diseases and cohort C after non-malignant conditions and/or toxic exposure. Results Of 8858 pts enrolled in the 13 evaluated studies, 962 were sAML. Median age was 63 yrs (range 16-85), 413 were young (≤60 yrs) and 549 were elderly (≥61 yrs); 54% were males. Cohort A consisted of 509 pts (median age 64 yrs), cohort B of 362 pts (median age 59 yrs) and cohort C of 91 pts (median age 61 yrs). In cohort B, breast cancer (24%) and lymphoma (14%) were the most frequent primary tumors. Autoimmune diseases represented 22% of non-malignant conditions. In young pts, complete remissions (CR/CRi) rate was 59%; 55% in SD-AraC vs 89% in HD-AraC treated pts. Allo-SCT in CR1 was performed in 21% of all pts. The Allo-SCT rate increased from 5% before 1990, 20% in 1990-1999 to 25% from 2000 (20% in SD-AraC vs 31% of HD-AraC treated pts). CR/CRi was achieved in 45% of elderly pts. Median follow-up was 6 yrs. Median overall-survival (OS) was 14.5 months in young and 9 months in elderly pts. The 5-yr OS was 28% and 7% respectively. Five-yr OS was 11% in cohort A and 22% in both cohort B and C. Treatment outcome of younger pts according to disease features and treatment type over time in cohort A and B are detailed in table 1 & 2. Using Cox model stratified by cohort age, gender, WBC, risk group, year of treatment and HD-AraC were independent prognostic factors for OS. In the AML12 study, compared to denovo pts, sAML pts ≤45 yrs had worse outcome if treated with SD-AraC whereas a better OS was seen if treated with HD-AraC. In elderly pts only the good/intermediate risk group of cohort B had a relatively better 5-yr OS (15%). Conclusions The outcome of sAML in younger pts has improved over the yrs in parallel with HD-AraC introduction in induction of remission. HD-AraC should be considered for younger pts with sAML. Disclosures: Ramadan: Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Suciu:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Meert:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. de Schaetzen:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other Other.

Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia

2012 ◽  
Vol 13 (3) ◽  
pp. 269-282 ◽  
Author(s):  
Ajay Abraham ◽  
Savitha Varatharajan ◽  
Salar Abbas ◽  
Wei Zhang ◽  
Ramachandran V Shaji ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Cytidine Deaminase ◽  
Rna Expression ◽  
Acute Myeloid

Clinical Useful Prognostic Index for Adult Patients with Acute Myeloid Leukemia in First Relapse.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2011-2011
Author(s):  
Dimitri A. Breems ◽  
Wim L.J. Van Putten ◽  
Bob Lowenberg
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Prognostic Index ◽  
Free Interval ◽  
First Relapse ◽  
One Year ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that are usually short lived. Previously proposed prognostic classification methods serving therapeutic decisions and evaluation of investigational treatment strategies at relapse of AML have been based on the duration of the relapse free interval and have largely neglected the influence of other known prognostic factors. Here we present an improved clinically useful prognostic index. This index has been developed from a multivariate analysis of 667 AML patients in first relapse among 1540 newly diagnosed non-M3 AML patients of age 15 to 60 years entered into three successive HOVON/SAKK Collaborative Group trials. The score, which has a range of 0 to 14 points, uses four relevant parameters. The parameters are: length of relapse free interval after first complete remission (more than 18 months: 0 points; 7 to 18 months: 3 points; 6 months or less: 5 points), cytogenetics at diagnosis (t(16;16) or inv(16): 0 points; t(8;21): 3 points; other cytogenetics: 5 points), age at relapse (35 years or younger: 0 points; 36 to 45 years: 1 point; older than 45 years: 2 points) and whether or not a previous stem cell transplantation (SCT) has been undertaken in first complete remission (no SCT: 0 points; previous SCT: 2 points). These points were assigned following estimations of the relative values of each of these factors contributing to outcome. Ultimately, three risk groups were defined: a favorable prognostic group A (0 to 6 points; overall survival of 70% at one year and 46% at five years), an intermediate risk group B (7 to 9 points; overall survival of 49% at one year and 18% at five years), and an unfavorable risk group C (10 to 14 points; overall survival of 16% at one year and 4% at five years). Thus, four commonly applied clinical parameters may identify among patients with AML in first relapse those for salvage or investigational therapy.

Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 803-803 ◽  
Author(s):  
Corine J. Hess ◽  
Johannes Berkhof ◽  
Fedor Denkers ◽  
Gert J. Ossenkoppele ◽  
Gerrit Jan Schuurhuis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
Total Population ◽  
Risk Group ◽  
Methylation Status ◽  
Methylation Index ◽  
Group B ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15, and IGSF4 (28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1 methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1 methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1 methylated (ESR1+) and ESR1 unmethylated (ESR1−) subgroups. Combining ESR1 methylation status with the absence or presence of promoter methylation of other TSGs (TSG+ or TSG−); yielded 4 patient subgroups with large differences in OS in univariate analysis (p=.0001, figure 1A). In multivariate analysis that included, FLT3-status, age at diagnosis, cytogenetics and achievement of CR, the predictive impact of the 4-group division on OS was maintained, HR 2.12 (95%CI 1.04–4.29; p=.037). Moreover, the combination identified a good prognostic patient subgroup (n=15, median OS 39 month) within the intermediate cytogenetic risk group (n=54, median OS 8.3 month), figure 1B. In conclusion, concurrent methylation occurs frequent in AML and is best predicted by ESR1 methylation. Methylation of ESR1 and methylation of other TSGs represent processes with independent predictivity. When combined, they constitute a unique and powerful factor for predicting overall survival, both in the total AML population as well as within the intermediate cytogenetic risk group. Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B) Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B)

Immunogenicity and Antileukemic Activity of Dendritic Cells Electroporated with Wilms’ Tumor WT1 mRNA: A Phase I/II Trial in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 830-830 ◽  
Author(s):  
Zwi N. Berneman ◽  
Ann Van de Velde ◽  
Ann Van Driessche ◽  
Nathalie Cools ◽  
Barbara Stein ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Rna Expression ◽  
Antileukemic Activity ◽  
Dc Vaccines ◽  
Acute Myeloid

Abstract The Wilms’ tumor protein WT1 is a target for immunotherapy in malignancies, such as acute myeloid leukemia (AML). Following our demonstration that dendritic cells (DC) can be efficiently transfected by messenger (m)RNA electroporation (Van Tendeloo VF et al. Blood2001;98:49–56) and that WT1 mRNA-electroporated DC stimulate WT1-specific T cells in vitro (Van Driessche A et al. Leukemia2005;19:1863–1871), we performed a phase I/II dose-escalation trial, in which patients with AML in remission but at high risk of relapse and without a direct sib allo-transplant option (9 patients) or with slowly progressive AML (1 patient) received intradermal injections of WT1 RNA-loaded DC. Following apheresis and CD14 immunomagnetic monocyte separation, DC were generated in 6-day cultures in clinical-grade medium supplemented with serum, granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, matured with prostaglandin (PG)E2 and tumor necrosis factor (TNF)-alpha, harvested, electroporated with WT1 mRNA and used as vaccines. The patients received four biweekly DC vaccines and a delayed-type hypersensitivity (DTH) test was performed 2 weeks following the last vaccination. Patients were monitored for minimal residual disease (MRD) by analyzing WT1 RNA expression in peripheral blood by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (Cilloni D et al. Leukemia2002;16:2115–2121 & Cilloni D et al. Haematologica2008;93:921–924). Before and after vaccination, peripheral blood was collected for immunomonitoring purposes. Feasibility, safety, immunogenicity and effect on MRD were investigated. There was successful DC generation and vaccine production in all 10 patients. No serious adverse events or toxicity were observed and vaccinations were well tolerated. A decrease in WT1 RNA expression was observed during the course of the vaccination in 4/7 patients who had an increased WT1 mRNA level in peripheral blood. Three of those patients are still in complete hematological remission. An in vivo vaccine-specific immune response was demonstrated in 10/10 patients by DTH. Ex vivo immunomonitoring analysis showed a significant increase in circulating activated HLA-DR+ CD4+ T cells and in IL-2 plasma levels following vaccination. Importantly, in vitro restimulation assays of peripheral blood mononuclear cells revealed a significant postvaccination increase in interferon (IFN)-gamma-producing WT1-specific CD8+ T cells (n= 8 evaluable patients), but not in cytokine-producing WT1-specific CD4+ T cells. There was no significant change in WT1-specific antibodies following vaccination. We conclude that vaccination of AML patients with WT1 RNA-loaded DC is feasible and safe. Furthermore, the DC elicit vaccine-specific and WT1-specific CD8+ T-cell responses. The correlation between reduction of circulating WT1 mRNA and the administration of the DC vaccines strongly suggests that this DC vaccine elicits an antileukemic activity.

Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 922-922
Author(s):  
Olga K Weinberg ◽  
Mahesh Seetharam ◽  
Li Ren ◽  
Lisa Ma ◽  
Katie Seo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Risk Group ◽  
Who Criteria ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup. Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65). Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. Figure Figure

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