scholarly journals Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia

Leukemia ◽  
2013 ◽  
Vol 28 (1) ◽  
pp. 50-58 ◽  
Author(s):  
H-A Hou ◽  
C-C Lin ◽  
W-C Chou ◽  
C-Y Liu ◽  
C-Y Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Molecular Alterations ◽  
Acute Myeloid

FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1574-1574
Author(s):  
Shuhong Shen ◽  
Yin Liu ◽  
JingYan Tang ◽  
Long-Jun Gu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1574 Poster Board I-600 Introduction Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ? Patients and Methods 155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis. Results Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children. Disclosures No relevant conflicts of interest to declare.

The Prognostic Impact of the Revised IPSS Cytogenetic Scoring System for Patients with MDS Allows a Risk-Stratification for Patients with MDS-Derived Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1715-1715
Author(s):  
Friedrich Stölzel ◽  
Michael Kramer ◽  
Brigitte Mohr ◽  
Martin Wermke ◽  
Martin Bornhäuser ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Scoring System ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Poor Risk ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 1715 Besides cytopenias and the medullary blast count, cytogenetic risk groups (good vs. intermediate vs. poor) according to IPSS are of main prognostic relevance for overall survival (OS) in patients with myelodysplastic syndrome (MDS). Recently, the revised IPSS (rIPSS) was introduced involving 5 (very good vs. good vs. intermediate vs. poor vs. very poor) instead of 3 cytogenetic risk groups, which better predict disease progression to MDS-derived acute myeloid leukemia (mdsAML) and OS of MDS patients receiving supportive care only. We analyzed the impact of the rIPSS-based cytogenetic scoring systems on the outcome of patients with AML undergoing intensive chemotherapy within the AML96, AML2003, and AML60+ trials of the Study Alliance Leukemia (SAL). This was done in an intention to compare its general prognostic influence as well as between patients with mdsAML and those with a de novo disease (dnAML). A total of 258 patients (median age 63 years, range 24 – 82) with mdsAML were identified and 258 patients with dnAML were matched with regards to age, gender, clinical trial, induction and consolidation therapy, respectively. Distributions of the cytogenetics in both groups according to MRC, IPSS and rIPSS score are shown in Table 1. Expectedly, the MRC cytogenetic scoring system revealed a stratification into two risk groups for patients with mdsAML with intermediate (3-year OS 27%) and adverse (3-year OS 10%), p=.004, and stratification into three groups for dnAML with favorable (3-year OS 50%), intermediate (3-year OS 32%) and adverse (3-year OS 10%), p=.001. When using the new rIPSS, this allowed a stratification of mdsAML patients with a 3-year OS of 28% for good+intermediate, 12% for poor, and 2% for very poor, p<.001, compared to 28% for good, 22% for intermediate, and 7% for poor risk cytogenetics according to the IPSS, p=.002. Importantly, the rIPSS allowed for a refined subdivision of patients within the poor and very poor group. By applying the rIPSS in dnAML patients we observed a 3-year OS of 34% for good+intermediate, 22% for poor, and 11% for very poor, p<.001, compared to 37% for good, 23% for intermediate, and 19% for poor risk cytogenetics according to the IPSS, p=.028. In conclusion, the rIPSS and IPSS-based classifications are feasible for prognostic risk stratification of patients with both dnAML and mdsAML. Interestingly, the rIPSS-based good and intermediate risk groups do not separate patients in both groups sufficiently. Furthermore, the rIPSS as compared to the current MRC-based cytogenetic scoring system allowed for a more concise distribution of mdsAML patients with the detection of a very poor (rIPSS) risk group with a dismal outcome. Table 1. dnAML, n=258 (%) mdsAML, n=258 (%) Cytogenetics MRC AML Good 16 (7) 0 Intermediate 210 (81) 179 (69) Poor 32 (12) 79 (31) Cytogenetics IPSS Good 158 (61) 121 (47) Intermediate 59 (23) 79 (31) Poor 41 (16) 58 (22) Cytogenetics rIPSS Very good 0 0 Good 167 (65) 131 (51) Intermediate 47 (18) 53 (20) Poor 18 (7) 34 (13) Very poor 26 (10) 40 (15) Disclosures: Platzbecker: Novartis: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy.

scholarly journals Complete Molecular Risk Stratification of De Novo Acute Myeloid Leukemia with Intermediate Cytogenetics Using an Eight-Gene Panel

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2333-2333
Author(s):  
Maya Thangavelu ◽  
Ryan Olson ◽  
Li Li ◽  
Wanlong Ma ◽  
Steve Brodie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Direct Sequencing ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Molecular Abnormality ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Refining risk stratification of acute myeloid leukemia (AML) using molecular profiling, especially those with intermediate cytogentic risk, is becoming standard of care. However, current WHO and ELN classifications are focused on few markers, mainly FLT3, NPM1, and CEBPA. While these abnormalities are relatively common, not all patients with AML and intermediate or normal cytogenetics will have abnormalities in these genes leaving large percentage of patients without refined risk stratification. We demonstrate that using 8 different AML-related genes are adequate to provide one or more molecular markers to further risk stratify patients with de novo AML. Method: Using direct sequencing we analyzed 211 samples referred from community practice with the diagnosis AML for molecular analysis. All samples were evaluated prospectively for mutations in FLT3, NPM1, IDH1, IDH2, CEBPA, WT1, RUNX1, and TP53 using direct sequencing. Fragment length analysis was used in addition to sequencing for FLT3 and NPM1. Available morphology, cytogenetics, and clinical data along with history were reviewed. Results: Of the 211 samples tested 103 (49%) had at least one or more molecular abnormality adequate for refining the risk classification. The mutations detected in these 103 patients were as follows: 27 (26%) FLT-ITD, 10 (10%) FLT3-TKD, 30 (29%) NPM1, 7 (7%) CEBPA, 14 (14%) IDH1, 13 (13%) IDH2, 10 (10%) WT1, 38 (37%) RUNX1, and 2 (2%) TP53. There was significant overlap and most patients had more than one mutation as illustrated in the graph below. However, if the testing was restricted to FLT3, NPM1, CEBPA and DNMT3A, only 56 (54%) would have had refined risk classification and 46% of patients would have remained without subclassification. The most striking finding was that all the remaining patients, who had no molecular abnormality detected in any of these 8 genes, had either history of MDS evolved to AML, therapy-related AML, or cytogenetic abnormalities other than intermediate (multiplex cytogenetic abnormalities or core-binding factor abnormality). Conclusion: Using FLT3, NPM1, CEBPA, and DNMT3A is inadequate for the molecular characterization of patients with AML. Patients with de novo AML and intermediate risk cytogenetics can be adequately prognostically subclassified and molecularly studied by testing only 8 genes. More importantly, this data confirms that the molecular biology driving de novo AML is significantly different from that driving MDS, AML with myelodysplasia-related changes, therapy-related AML, or AML with core binding factor or multiplex cytogenetics. Unlike de novo AML, these entities should be molecularly studied using MDS-specific driver genes. Furthermore, this data suggests that different therapeutic approaches should be developed for MDS and MDS-related AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

ERG, EVI1 and PRAME Are Relevant Markers of Treatment Response and Survival, and They Could Be Useful for Improving the Risk-Stratification in Citogenetically Normal Acute Myeloid Leukemia (CN-AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4844-4844
Author(s):  
Carlos Santamaría ◽  
Carmen Chillón ◽  
Ramon García-Sanz ◽  
Cristina Pérez ◽  
Fernando Ramos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Value ◽  
Aberrant Gene Expression ◽  
Risk Patients ◽  
Aberrant Gene ◽  
Acute Myeloid ◽  
Rna Levels

Abstract Several mutations and aberrant gene expression have been proposed as prognostic factors in cytogenetically normal acute myeloid leukemia (CN-AML), but few studies have analyzed the clinical value of several genes in a large group of CN-AML patients. In 121 de novo CN-AML included into the Spanish PETHEMA therapeutic protocols, we evaluated FLT3 and NPM1 mutations and BAALC, ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM and WT1 RNA levels. Ninety-one patients achieved CR with standard induction therapy while 20/111 (16.5%) were refractory to treatment. This latter subgroup showed higher ERG (media 1.0±0.8 vs. 0.6±0.6;p=0.012) and lower PRAME (media 28.8±52.9 vs. 1640.6±6102.0;p=0.014) levels than no-refractory patients. Moreover, high ERG expression (defined by median value) was associated with shorter OS at 2-years (38% vs. 61%;p=0.012) and RFS at 2-years (38% vs. 60%;p=0.005). By contrast, high PRAME levels (defined by 75th percentile) was related to longer OS (61% vs. 48%;p=0.029) and RFS (74% vs. 43%;p=0.016). Additionally, high EVI expression (defined by 75th percentile) was associated with a poorer OS (37% vs. 56%;p=0.049). The same results in OS were observed in patients with high BAALC RNA levels (median value; 41% vs. 62%; p=0.049). Interestingly, ERG, EVI1 and PRAME markers improved the current prognostic classification of CN-AML based on FLT3 and NPM1 status. Therefore, intermediate risk patients (FLT3-ITD/NPM1mut and FLT3wt/NMP1wt) with low ERG, low EVI1 or high PRAME achieved long OS and RFS, similar to the favorable FLT3wt/NPM1mut subgroup. By contrast, the opposite expression subgroup (high ERG, high EVI1 or low PRAME) showed OS and RFS similar to the adverse FLT3-ITD/NPM1wt subset. These results allowed identify clearly two risk-subgroups for OS and RFS, based on three molecular markers (FLT3, NPM and one of the 3 proposed genes). In conclusion, we demonstrated that ERG, EVI1 and PRAME are relevant prognostics markers in CN-AML and they could improve their risk-stratification.

Secondary Acute Myeloid Leukemia Is an Heterogeneous Subgroup of Elderly AML Where Patient’s Fitness Criteria and ELN Prognostic Stratification Can be Applied to Guide Treatment Decisions: An Analysis of 127 Patients By the Network Rete Ematologica Lombarda (REL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 953-953
Author(s):  
Erika Borlenghi ◽  
Chiara Pagani ◽  
Claudia Basilico ◽  
Massimo Bernardi ◽  
Matteo Carrabba ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Treatment Modalities ◽  
Secondary Acute Myeloid Leukemia ◽  
Elderly Aml ◽  
Prognostic Stratification ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: According to the WHO classification, secondary acute myeloid leukemia (s-AML) includes cases occurring in patients (pts) receiving prior antineoplastic treatments as well as cases developing in pts with a history of previous hematology disorders, such as a myelodysplastic syndrome (MDS) or a chronic myeloproliferative disease (MPD). Outcomes for this large group of pts, which has a high median age and a high frequency of unfavourable cytogenetics, has been traditionally considered very poor, compared to AML developing “de novo”, and treatment with intensive chemotherapy (iCT) is not standardized in elderly pts. Indeed pts with s-AML have been excluded from molecular and cytogenetic prognostic stratification defined by the ELN criteria. Aim: Since patients with s-AML actually represent an heterogeneous subgroup of pts a multicenter retrospective study was performed to analyse their outcome in relationship to age, fitness and ELN risk stratification, in order to potentially identify subgroups at different prognosis. Patients and Methods: We evaluated 127 pts, representing 35% of a population-based series of elderly AML, aged > 65 years (y), diagnosed at five Hematology Centers of the Hematological Network of Lombardy in Northern Italy from January 2008 to May 2014. Thirteen pts (10%) had t-AML and 114 (90%) had AML secondary to previous hematological disorders (89 MDS and 25 MPD). Median age was 74 y (range 65-94 y). Performance status (PS) was evaluable in 122 pts (96%) and PS ECOG was >3 in 32 pts (26%). According to “fitness criteria”, (Ferrara et al, Leukemia, 2013), 126 pts (99%) were evaluable: 54 pts (42.5%) were fit to i-CT (FIT), 55 (43.3%) unfit to i-CT (UNFIT), 17 (13.4%) unfit to ni-CT (FRAIL). Intensive CT was given to 34 (27%), ni-CT (low-dose arac, azacytidine or experimental non-myelotoxic drugs) to 26 (20%) and best supportive care (BSC) to 67 pts (53%). Overall concordance between the fitness and the treatment actually received was 78%.The ELN prognostic criteria were applicable in 69 pts (54%), because of lack of complete molecular and cytogenetic data in the others. Six pts (8.5%, all NPM1+) were at low, 14 (20%) at intermediate-1, 11 (16%) at intermediate-2 and 38 (55%) at high risk. Results: The median OS according to fitness was 9,6, 4 and 3 months (ms), in FIT, UNFIT and FRAIL pts, respectively (p=0.0021) (Figure 1). Both the treatment received (i-CT or ni-CT vs BSC) and the risk ELN classification were related to OS (p< 0.0001 and p=0.0089, respectively). In FIT pts the median OS was 8 ms in pts treated with i-CT, 11 ms with ni-CT, and 3 ms with BSC (p<0.0001) (i-CT vs ni-CT : p=0.6) (Figure2). The achievement of CR was related to outcome (median OS 12.7 ms vs 5 ms) (p= 0.0035). AML with antecedent hematological disorder (53.8%) or with t-AML (50%) had similar CR rate (53,8% vs 50%) as well as OS (median OS 11 ms vs 7 ms) (p =0.5). According to ELN risk, OS was better in LR/Int-1/int2 vs HR (median OS 11,4 vs 5 ms, p=0.0035) (Figure 2). Moreover, also the achievement of CR was related to ELN risk: 100% in LR, 57% in Int1/Int2, 14% in HR (p= 0.012), and percentages differed from de novo AML only in HR pts. Prognosis of the subgroup of 34 ELN low/Int1 risk pts treated with i-CT was fair with CR rate of 53%, and 2 y OS 40% compared to 10% in similarly treated Int2/HR pts (p=0.07). Conclusion: Elderly pts with s-AML are an heterogeneous subgroup both according to fitness and to ELN risk stratification and these parameters are significantly related to clinical outcome. Overall prognosis of elderly patients with s-AML is not exceedingly worse than in elderly with de novo AML. Outcome was better using i-CT or ni-CT compared to BSC, with no differences between the two treatment modalities. ELN risk stratification merits to be applied also to patients with s-AML and its integration with fitness criteria can identify a subgroup of patients which may benefit from intensive CT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

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