Prognostic Significance of Partial Tandem Duplications of the MLL Gene in Adult Patients 16 to 60 Years Old With Acute Myeloid Leukemia and Normal Cytogenetics: A Study of the Acute Myeloid Leukemia Study Group Ulm

2002 ◽  
Vol 20 (15) ◽  
pp. 3254-3261 ◽  
Author(s):  
Konstanze Döhner ◽  
Karen Tobis ◽  
Regina Ulrich ◽  
Stefan Fröhling ◽  
Axel Benner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Mll Gene ◽  
Remission Duration ◽  
Normal Cytogenetics ◽  
Tandem Duplications ◽  
Acute Myeloid

PURPOSE: To evaluate the incidence and clinical significance of partial tandem duplications (PTDs) of the mixed lineage leukemia (MLL) gene in a large series of newly diagnosed adult patients (16 to 60 years old) with acute myeloid leukemia (AML) intensively treated within the multicenter treatment trials AML-HD93 and AML-HD98A. PATIENTS AND METHODS: Identification of MLL PTD was performed centrally using Southern blot analysis in pretreatment samples from 525 of 683 assessable patients. PTD was confirmed by polymerase chain reaction (PCR) and sequencing of the PCR products. RESULTS: MLL PTD was identified in none of the 129 patients with t(8;21), inv(16), and t(15;17); in 19 (7.7%) of 247 patients with normal karyotype; and in 10 (8.5%) of 119 patients with all other abnormalities, with 30 cases of t(11q23) excluded. In the group of patients with a normal karyotype, there was no difference in the presenting clinical features between the PTD-positive and the PTD-negative cases. Sixteen (89%) of the 18 assessable PTD-positive patients and 158 (78%) of the 203 PTD-negative patients achieved a complete remission. After a median follow-up time of 19 months, 11 of the 16 PTD-positive patients relapsed compared with 54 of the 158 PTD-negative patients; the median remission durations of the PTD-positive and the PTD-negative groups were 7.75 months and 19 months, respectively (P < .001). Multivariate analysis identified the MLL PTD status as the single prognostic factor for remission duration. CONCLUSION: Within the subgroup of young adult AML patients with normal karyotype, MLL PTD is associated with short remission duration.

scholarly journals The Prognostic Significance of IRF8 Transcripts in Adult Patients with Acute Myeloid Leukemia

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70812 ◽  
Author(s):  
Era L. Pogosova-Agadjanyan ◽  
Kenneth J. Kopecky ◽  
Fabiana Ostronoff ◽  
Frederick R. Appelbaum ◽  
John Godwin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Acute Myeloid

NPM1, IDH1/2 and DNAH11 Gene Mutations Can Improve a Prognostic Stratification of Acute Myeloid Leukemia Patients with Normal Karyotype but Not Harboring FLT3/ITD Mutation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2534-2534
Author(s):  
Yeo-Kyeoung Kim ◽  
Il-Kwon Lee ◽  
Dennis Dong Hwan Kim ◽  
Chul Won Jung ◽  
Jun-Ho Jang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Npm1 Mutation ◽  
Group 3 ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

Abstract Abstract 2534 Background: Acute myeloid leukemia with normal karyotype (AML-NK) is known to be heterogeneous in the molecular level. Accordingly, it has become more critical to dissect this group of patients according to their prognosis using a molecular genetic technology. We attempted to analyze the incidence and prognostic implication of genetic abnormalities on survival in 426 adult patients with AML-NK. Methods: A total of 67 AML-NK patients achieved complete remission (CR), candidate mutations in 21 genes were identified by whole exome sequencing which has 41–89× coverage and by single-nucleotide polymorphism array analysis using marrow mononuclear cells at diagnosis of AML-NK. Subsequently, mutation analysis of 11 genes (i.e. FLT3/ITD, NPM1, DNMT3a, IDH1, IDH2, TET2, NRAS, WT1, DNAH11, SF3B1, and PHF6) which are known to be involved in the pathogenesis of hematologic diseases, were performed using Sanger sequencing in another subset of 359 AML-NK patients as a validation cohort. Results: Of 426 patients in total (median age: 51, ranges: 15–85), FLT3/ITD, NPM1, and DNMT3a mutations were associated with higher leukocytes counts at presentation of AML-NK. In 284 patients who received standard remission induction (RI) chemotherapy (excluding 119 patients with conservative treatment and 22 early death/1 follow-up loss after RI chemotherapy), those with FLT3/ITD mutation were significantly associated with a higher risk of relapse (p=0.02), a shorter leukemic-free survival duration (LFS)(p<0.01) or overall survival (OS) (p=0.01). Accordingly, we divided the patients into FLT3/ITD+ and FLT3/ITD− population, and analyzed their treatment outcomes according to the other mutations. In the FLT3/ITD− group (n=200), those with NPM1 mutation showed a higher CR rates after one or two cycles of RI chemotherapy (p<0.01) and a longer OS duration (p<0.01), hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.25–0.73, adjusted by other clinical variables including age, leukocyte counts at diagnosis, and transplantation (Figure 1). In the FLT3/ITD+ patients (n=84), NPM1 mutation was found to be a favorable prognostic factor showing a lower relapse rate (p=0.00), a longer LFS duration (p<0.01, HR 0.35, 95% CI 0.18–0.70), and OS duration (p=0.04, HR 0.55, 95% CI 0.31–0.98) in NPM1 mutated patients. In addition, OS was significantly different in favor of those with IDH2, especially R140Q IDH2 mutation, (p=0.04, HR 0.30, 95% CI 0.09–0.99), whereas DNAH11 mutation was associated with inferior OS (p<0.01, HR 5.78, 95% CI 1.65–20.25). Accordingly, we stratified the FLT3/ITD+ patients into three subgroups according to the NPM1, IDH1/2 and DNAH11 mutation status, Group 1: NPM1 mutation and IDH1 or 2 mutations (n=16), Group 2: isolated DNAH11 mutation (n=4) and Group 3: all mutations were negative (n=64). The group 1 showed significantly better OS than group 2 (p<0.01, HR 16.90, 95% CI 3.48–82.15) or group 3 (p<0.01, HR 3.40, 95% CI 1.20–9.55) (Figure 2). In a subgroup analysis of younger patients less than 60 years of age, similar outcomes were also observed in favor of group 1 in terms of OS (data not shown). Conclusion: Our study confirmed that NPM1 mutation is an independent prognostic factor in adult patients with AML-NK not harboring FLT3/ITD mutation. In addition, several other genetic markers were identified as prognostic including IDH1/2 or DNAH11 mutations as well as NPM1 mutation in a subgroup of AML-NK patients with FLT3/ITD mutation. Disclosures: No relevant conflicts of interest to declare.

Low Frequency and Poor Prognosis Of MLL-Partial Tandem Duplications In Pediatric Acute Myeloid Leukemia Using MLPA Method: The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1374-1374
Author(s):  
Kentaro Ohki ◽  
Myoung-ja Park ◽  
Hitoshi Sano ◽  
Yusuke Hara ◽  
Norio Shiba ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Pediatric Patients ◽  
Low Frequency ◽  
Rt Pcr ◽  
Mll Gene ◽  
Pediatric Aml ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Background Mixed-lineage leukemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukemia (AML), and are associated with poor prognosis. Report of the incidence and prognostic relevance of MLL-PTD in pediatric AML is limited and large differences in the frequency have been reported. In pediatric AML cases, a frequency of 10-13% for MLL-PTD was detected using mRNA RT-PCR, whereas a frequency of only 2.5% was detected using multiplex ligation-dependent probe amplification (MLPA). We studied the frequency and prognostic effect of MLL-PTD in pediatric patients with AML treated with JPLSG AML-05 trial (between 2006-2010). Methods MLL-PTD of 331 pediatric de novo AML in the AML-05 trial was analyzed from genomic DNA extracted from their diagnostic bone marrow samples using MLPA analysis. We designed a probe mix for MLPA analysis containing adjacent probes within exon 2-5 and exon 7-13 of the MLL gene for the detection of common and rare type MLL-PTD. Exon 17 of the MLL gene was used as an internal control. We also performed RT-PCR to detect MLL-PTD transcripts to allow comparison with the MLPA results. To assess whether MLL-PTD overlap with known gene abnormalities, such as FLT3, KIT, and NPM1 mutations, mutational analyses of these genes were also performed in patients in the AML-05 trial. Results MLL-PTD was detected in 9 (2.7%) of 331 patients by MLPA analysis. In 303/331 samples mRNA RT-PCR screening for MLL-PTD was performed, and MLL-PTD was detected in 38 (12.5%). In 9 cases, both MLPA and mRNA-RT-PCR were positive for MLL-PTD. The characteristics of the 9 patients with MLL-PTD using MLPA analysis were below. None of the patients harbouring an MLL-rearrangement, t(8;21) or inv(16) revealed a MLL-PTD. All MLL-PTD cases were found in patients with normal cytogenetics. FLT3-ITD was present in 4 of 9 patients with MLL-PTD, while none of KIT and NPM1 mutation was detected in MLL-PTD cases. There was a significantly higher frequency of FLT3-ITD in patients with an MLL-PTD than in those without MLL-PTD (p=0.016). Among these 9 patients, 5 patients were classified as FAB-M5a (p=0.0068), and other 4 patients were classified as FAB-M1, M2, M4 and M6a. The age of patients with MLL-PTD was higher than that of patients without MLL-PTD (median 11.8 years (range; 9-15) and 7.4 years (range; 0-17), respectively; p=0.004). Patients with MLL-PTD tend to have higher white blood cell counts (WBC) at initial diagnosis than those without MLL-PTD (median WBC 6.0×10*9/l (range; 1500-151000) versus 2.2×10*9/l (range; 617-985000a) respectively; p=0.18). All 9 patients with MLL-PTD had events. There was a significantly higher frequency of event including refractory disease, relapse and death in patients with an MLL-PTD than in those without MLL-PTD (p=0.001). Only one of 9 patients was achieved complete remission (CR) after induction therapy (p= 1.1×10-11). Six of 9 patients relapsed, and 5 patients died. Conclusion Using DNA-MLPA as a novel screenings technique, low frequency of MLL-PTD in pediatric AML was found. However, MLL-PTD is highly associated with a poor prognosis in pediatric AML. These data suggest that screening for MLL-PTD in pediatric patients with AML is critical not only for outcome prediction but also for risk-adapted therapy. Disclosures: No relevant conflicts of interest to declare.

BCRPmRNA andFLT3-ITD are independent poor risk factors in adult patients with acute myeloid leukemia and intermediate or normal karyotype

2017 ◽  
Vol 99 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Barbara Nasiłowska-Adamska ◽  
Krzysztof Warzocha ◽  
Iwona Solarska ◽  
Katarzyna Borg ◽  
Barbara Pieńkowska-Grela ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Poor Risk ◽  
Acute Myeloid

Low SOX17 expression: prognostic significance in de novo acute myeloid leukemia with normal cytogenetics

2014 ◽  
Vol 52 (12) ◽  
Author(s):  
Chun-yan Tang ◽  
Jiang Lin ◽  
Wei Qian ◽  
Jing Yang ◽  
Ji-chun Ma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Quantitative Pcr ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Aberrant Expression ◽  
Real Time Quantitative Pcr ◽  
The Status ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract: Aberrant expression of SRY-box containing gene 17 (: Real-time quantitative PCR (RQ-PCR) was performed to analyze the status of:Our findings indicated that low

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