scholarly journals Loss of H3K27 Methylation Identifies Poor Outcome in Adult-Onset Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-24
Author(s):  
Anneke D. van Dijk ◽  
Fieke W Hoff ◽  
Yihua Qiu ◽  
Eveline S. de Bont ◽  
Sophia W.M. Bruggeman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Functional Enrichment ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
H3k27 Methylation ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus of H3K27 methylation in relation to mutations in chromatin, splicing and transcriptional regulators. Material and methods: Histone methylation mark expressions were evaluated in a cohort of 241 AML bone marrow (BM) and peripheral blood (PB) samples from patients admitted at the MD Anderson Cancer Center relative to their expression in CD34+ BM derived samples from healthy donors. Simultaneous analysis of 230 proteins was performed using the reverse phase protein array - a high-throughput, quantitative proteomic platform that enables identification of aberrant expressed proteins and the pathways they act in. Additional mutational analysis was performed on 65 BM samples. Results:H3K27Me3 was significantly lower in both BM and PB leukemic-derived samples compared to their expression in normal BM (figure 1A). A greater loss of H3K27Me3 associated with increased proliferative potential and shorter overall survival (OS) in the whole patient population (n=241, HR=0.64, 95% CI=0.47-0.87, p<0.01), as well as in subsets, e.g. cytogenetically normal AML (n=110, HR=0.62, 95% CI=0.40-0.97, p=0.03). To study the prognostic impact of H3K27Me3 in the context of cytogenetic aberrations and mutations, multivariate cox regression analysis was performed which identified H3K27Me3 level as an independent favorable prognostic factor in all (HR=0.74, 95%CI=0.57-0.95, p=0.02) as well as in P53 mutated AML (n=54, HR=0.48, 95%CI=0.26-0.87, p=0.02). A total of 78 AML patients had molecular data available for the major methylation affecting genes, i.e. IDH1, IDH2, DNMT3A and TET2. The level of H3K27Me3 was not prognostic in patients without any DNA methylation affecting mutation present, but patients with at least one mutation in any of these had better outcome when H3K27Me3 levels were high (highest tertile, figure 1A) compared to those with lower levels (median OS 7.1 vs. 24.1 months, HR=0.42, 95% CI=0.21-0.83, p=0.01, figure 1B). Mutations in U2AF1 and SRSF2 affect the spliceosome and are frequently found in antecedent hematological disorders (AHD), as well as are mutations in chromatin regulating genes ASXL1 and BCOR. We observed significant decreased H3K27Me3 in patients with these mutations corresponding with observed lower levels of H3K27Me3 in patients with AHD than those without (p=0.035). BCOR, SRSF2, U2AF1 and ASXL1 mutations confer poor prognosis in myeloid malignancies, however, in our cohort of 65 sequenced AML patients; not individual or a combination of these mutations were independent prognostic factors, but the degree of H3K27Me3 in these patients (HR= 0.49, 95% CI=0.25-0.95, p=0.03). To recognize dysregulated pathways in AML patients with the identified loss of H3K27Me3, we examined correlations of H3K27Me3 with the other 229 proteins on the array. H3K27Me3 is catalyzed by the polycomb group protein EZH2 and is linked to transcriptional repression via the formation of heterochromatin regions. To identify upregulated proteins and pathways upon the loss of H3K27Me3, we focused on significant negatively correlated proteins with H3K27Me3 leading us to the identification of 20 total and 6 phospho-proteins that showed increased expression upon decreased H3K27Me3. Functional enrichment analysis of this protein set revealed an upregulated anti-apoptotic phenotype. Conclusion:This study shows that proteomic profiling of epigenetic modifications on the histone level have clinical implications in AML and support the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state complementing cytogenetic and molecular genetic subgrouping. Figure 1. A) Lower H3K27Me3 in BM and PB derived AML samples compared to normal CD34+. **** represents p<0.0001, ns = not significant. B) Overall survival probability in AML patients with any DNA methylation affecting mutation (i.e. IDH1/2, DNMT3A, TET2, n=53) according to H3K27Me3 low (blue) and high (orange) status. Figure 1 Disclosures No relevant conflicts of interest to declare.

Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4505-4511 ◽  
Author(s):  
Verena Ingeborg Gaidzik ◽  
Richard Friedrich Schlenk ◽  
Simone Moschny ◽  
Annegret Becker ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Serum Lactate Dehydrogenase ◽  
Study Group ◽  
Prognostic Impact ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Acute Myeloid

AbstractTo evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically normal acute myeloid leukemia (CN-AML), sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols. WT1 mutations were identified in 78 (12.6%) of the 617 patients; mutations clustered in exon 7 (54 of 78) and exon 9 (13 of 78), but also occurred in exons 1, 2, 3, and 8. WT1 mutations were significantly associated with younger age, higher serum lactate dehydrogenase levels, higher blood blast counts, and the additional presence of FLT3-ITD (P < .001) and CEBPA mutations (P = .004). There was no difference in relapse-free survival and overall survival between patients with (WT1mut) or without WT1 mutations. Subset analysis showed that patients with the genotype WT1mut/FLT3-ITDpos had a lower complete remission rate (P = .003) and an inferior relapse-free survival (P = .006) and overall survival (P < .001) compared with those with the genotype WT1mut/FLT3-ITDneg. In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1mut/FLT3-ITDpos.

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2518-2518
Author(s):  
Ulrike Bacher ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Tamara Weiss ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Biological Entity ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Cox Regression Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

Prognostic Impact of 3q21 and 3q26 Cytogenetic Abnormalities in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2594-2594
Author(s):  
Mario Annunziata ◽  
Piera Angelillo ◽  
Laura Vicari ◽  
Clelia Criscuolo ◽  
Felicetto Ferrara
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Platelet Count ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Chromosome 3 ◽  
Prognostic Impact ◽  
Acute Myeloid

Abstract Abstract 2594 Background: Abnormalities affecting long arm of chromosome 3 are rare but recurrent in Acute Myeloid Leukemia (AML) and are detected in a variable percentage of AML patients according to different series. The 2008 World Health Organization classification recognizes AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) as a distinct subtype characterized by a poor prognosis. Allogeneic stem cell transplantation seems to improve outcome in eligible patients with these aberrations. Inappropriate expression of the ecotropic viral integration site 1 (EVI1) was demonstrated in virtually all patients with t(3;3)(q21;q26.2) and inv(3)(q21q26.2); as well as in a majority of patients with other 3q26 rearrangements. Other chromosome 3 abnormalities are rarely recognized in AML patients; clinical and prognostic relevance of these alterations is not yet defined. The aim of this study is to assess the prognostic impact of chromosome 3 abnormalities on disease characteristics and treatment outcome in AML. Patients and methods: A total of 580 consecutive adult patients were diagnosed with AML at our institution between February 2002 and July 2012. Conventional cytogenetic analysis performed on diagnostic bone marrow samples detected the presence of 3q abnormalities in 16 patients (2.7%). Two patients were lost to follow-up and were not evaluated for survival analysis. Molecular status of FLT3 and NPM1 was also performed and results are available for 10 patients. Median follow-up time for patients in this series was 47 months ( range 6–125). Results: There were 10 male and 6 female patients, the median age being 64.5 years (range 33–81), 10 patients had de novo AML while 6 evolved from a previously diagnosed myelodysplastic syndrome (MDS). Karyotype from MDS phase was available in 2 patients; both acquired 3q rearrangement at time of progression to AML. At time of diagnosis median haemoglobin value was 9.0 g/dL (range 4–11); median leucocyte count was 10.5 × 103̂/L (range 2.3 – 431). Median platelet count was 116 × 109̂/L (range 28 – 529), consistently with previous studies, which have shown that these patients present with higher platelet count at diagnosis when compared with no 3q rearranged ones. Regarding cytogenetic features 3 patients had t(3;3)(q21;q26), 3 patients had inv(3) (q21; q26), 3 patients showed a balanced rearrangement involving 3q26, while 6 patients harbored a del3q. One patient showed monosomy 3. Additional chromosomal changes were demonstrated in 5 patients, two of them had a complex karyotype (see Table 1), 3 had a monosomy 7. Thirteen patients out of 14 received intensive induction chemotherapy; complete remission (CR) was achieved in 5 patients (CR rate: 35.7%), the remaining 7 patients were resistant to induction as well as to salvage chemotherapy. Four patients underwent autologous stem cell transplantation. Median overall survival in this series is 5.5 months (range 0 – 20). At present only one patient is still alive and in CR, 20 months after diagnosis. Median disease free survival (DFS) for patients achieving a CR was 9 months (range 6–20). Median overall survival for patients resistant to first-line therapy was 3 months (range 0–6). Clinical features and treatment outcome of the patients are summarized in Table 1. Conclusions: The incidence of 3q abnormalities in our single institution series is 2.4%, in keeping with previous studies. Our findings confirm the association between these alterations and thrombocytosis at diagnosis, preceding MDS or multilineage dysplasia, presence in all FAB subtypes (except M3), association with additional chromosomal abnormalities as well as the poor response to conventional chemotherapy (CR rate 35.7%), and very short DFS in spite of obtaining CR. Disclosures: No relevant conflicts of interest to declare.

High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9–positive patients

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5613-5621 ◽  
Author(s):  
Sylvie M. Noordermeer ◽  
Mathijs A. Sanders ◽  
Christian Gilissen ◽  
Evelyn Tönnissen ◽  
Adrian van der Heijden ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Poor Survival ◽  
Favorable Prognosis ◽  
Protein Ubiquitination ◽  
Idh1 And Idh2 Mutations ◽  
Acute Myeloid ◽  
Independent Cohort

Abstract Aberrations in protein ubiquitination have recently been identified in the pathogenesis of acute myeloid leukemia (AML). We studied whether expression changes of more than 1600 ubiquitination related genes correlated with clinical outcome in 525 adult AML patients. High expression of one of these genes, BRE, was observed in 3% of the cases and predicted favorable prognosis independently of known prognostic factors (5-year overall survival: 57%). Remarkably, unsupervised expression profiling showed that 86% of high BRE-expressing patients were confined to a previously unrecognized cluster. High BRE expression was mutually exclusive with FLT3 ITD, CEBPA, IDH1, and IDH2 mutations, EVI1 overexpression, and favorable karyotypes. In contrast, high BRE expression co-occurred strongly with FAB M5 morphology and MLL-AF9 fusions. Within the group of MLL-AF9–positive patients, high BRE expression predicted superior survival, while normal BRE expression predicted extremely poor survival (5-year overall survival of 80% vs 0%, respectively, P = .0002). Both the co-occurrence of high BRE expression with MLL-AF9 and its prognostic impact were confirmed in an independent cohort of 436 AML patients. Thus, high BRE expression defines a novel subtype of adult AML characterized by a favorable prognosis. This work contributes to improved risk stratification in AML, especially among MLL-AF9–positive patients.

scholarly journals Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

2020 ◽  
pp. JCO.20.02308
Author(s):  
Charles Craddock ◽  
Aimee Jackson ◽  
Justin Loke ◽  
Shamyla Siddique ◽  
Andrea Hodgkinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Reduced Intensity ◽  
Acute Myeloid

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 551-558 ◽  
Author(s):  
Sabine Kayser ◽  
Manuela Zucknick ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
World Health ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Allogeneic Hsct ◽  
Monosomal Karyotype ◽  
Acute Myeloid

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of −5/5q−, −7, 7q−, abnl(12p), abnl(17p), −18/18q−, −20/20q−, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

scholarly journals Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3578-3584 ◽  
Author(s):  
Felicitas Thol ◽  
Sofia Kade ◽  
Carola Schlarmann ◽  
Patrick Löffeld ◽  
Michael Morgan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Confidence Interval ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Wild Type ◽  
Acute Myeloid

Abstract Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.

scholarly journals Methscore As a New Prognostic Tool for Complex DNA Methylation Changes Assessment in Patients with Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Sarka Sestakova ◽  
Cyril Šálek ◽  
Dávid Kundrát ◽  
Ivana Ježíšková ◽  
Jiří Mayer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Methylation Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cox Regression ◽  
Validation Cohort ◽  
Prognostic Impact ◽  
Logrank Test ◽  
Acute Myeloid

Changes in DNA methylation are characteristic for patients with acute myeloid leukemia (AML) and many studies have reported the prognostic significance of these epigenetic aberrations. We aimed for a complex evaluation of DNA methylation changes in AML patients at diagnosis. Therefore, we designed a sequencing panel targeting 239 regions annotated to 186 genes previously described in literature as having a prognostic impact or being commonly associated with AML pathogenesis (e.g. WT1, HOX genes). We used diagnostic whole-blood DNA samples of adult AML patients who were treated with curative intent starting with 3+7 induction regimen. In the testing cohort, we sequenced 128 AML patients and 11 samples from healthy donors. We analyzed another 50 AML patients from partner institution University Hospital Brno as an independent validation cohort. The libraries were prepared using SeqCap Epi Enrichments System (Roche) and sequenced on MiSeq instrument (Illumina). Data were processed in Linux opensource software and further analyzed in R. For each sample, we measured the methylation level of nearly 50 000 CpGs. In the testing cohort, we used the Cox regression to evaluate the effect of each CpG's methylation level on overall survival (OS). As a result, we found 1961 CpGs significantly effecting the OS (p&lt;0.05) annotated to 141 genes. In gene ontology analysis, these loci were mainly connected to transcription and RNA regulation, DNA binding, and embryonic development. In 1097 CpGs, higher methylation indicated better outcome and, on the contrary, a poorer prognosis in the remaining 864 CpGs. Next, we used linear combination of the methylation levels and Cox's beta regression coefficients for each CpG to count a summarizing value that we called MethScore. Patients with lower MethScore (n=64) had markedly longer OS and event-free survival (EFS) than patients with higher MethScore (n=64, Logrank test for OS: p&lt;2e-16, for EFS: p&lt;2e-12). To further specify the prognostically most influential CpGs out of the selected 1961 loci, we subjected them individually to Cox multivariate regression analysis together with age, leukocytes count, cytogenetics, FLT3-ITD mutation, and transplantation in the 1st complete remission. Only 625 CpGs remained significant (p&lt;0.05) and from these, we calculated MethScore-MVA via the same procedure as MethScore. MethScore-MVA was also very well predictive of patients' survival (Logrank test comparing patients with higher and lower MethScore-MVA for OS: p&lt;7e-14, for EFS: p&lt;2e-10). MethScore and MethScore-MVA proved to be the most significant variables in multivariate Cox regression for both OS (p=2e-12 and p=2e-13) and EFS (p=2e-12 and p=3e-12, respectively). To validate these results, we counted MethScore and MethScore-MVA for 50 patients from the validation cohort and performed the same Cox multivariate analysis. MethScore remained highly significant for both OS and EFS (p=0.002 and p=0.004, respectively). MethScore-MVA was significant for OS (p=0.02) but not for EFS (p=0.09). Here, we present the MethScore as a novel complex characterization of predictive DNA methylation changes in patients with AML. MethScore might be used as a new surrogate marker that could enrich the currently used cytogenetic and genetic markers to refine the prognostication of newly diagnosed AML patients. This study was supported by the Ministry of Health of the Czech Republic, project for conceptual development of research organizations (00023736, IHBT). Disclosures Šálek: Amgen: Consultancy, Honoraria, Research Funding. Mayer:Celgene: Research Funding.

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