scholarly journals Genomic Landscape and Prognosis in Pediatric Acute Myeloid Leukemia: A Study on the French ELAM02 Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1676-1676
Author(s):  
Alice Marceau-Renaut ◽  
Nicolas Duployez ◽  
Christine Ragu ◽  
Arnaud Petit ◽  
Odile Fenneteau ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Driver Mutations ◽  
Mutational Profiling ◽  
Genomic Landscape ◽  
Diagnostic Samples ◽  
Pediatric Aml ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Background. Acute Myeloid Leukemia (AML) is a rare and genetically heterogeneous disease that constitutes 15 to 20% of childhood leukemia. Despite major treatment improvement over the past decades pediatric AML remains a challenging disease with poor outcome compared to acute lymphoid leukemia (ALL). About 50% of these patients relapse after standard intensive chemotherapy. Molecular analysis pointed out the prognostic impact of gene mutation such as FLT3-ITD, NPM1 or CEBPA; and new categories of regulators like epigenetic modifiers. More recently mutational profiling studies revealed distinct molecular subgroups with prognostic significant and stratification in adult AML. Nevertheless cytogenetic and mutational profiles are quite different between adult and pediatric AML. Extensive genomic studies have not been reported to date in pediatric AML. In this context it is of importance to identify additional genetic or molecular abnormalities to better understand leukemogenesis and also to predict outcome and serve as novel therapeutic targets. Methods. We performed a mutational analysis on diagnostic samples from patients enrolled in the French National Multicenter ELAM02 trial. 438 patients with de novo AML (except AML3) were enrolled between march 2005 and December 2011 (median age: 8,22yrs [0-18.61]; median WBC: 15.4G/l [0.4-575]; cytogenetic subgroups: CBF-AML[n=97], NK-AML [n=109], MLL-AML[n=95], MRC2 other[n=77], MRC3 [n=55], failure [n=5]). Diagnostic samples were prospectively collected and 386 of the 438 patients (88%) were studied by next-generation sequencing (Miseq, Illumina with haloplex librairy and ion Proton, thermofischer with ampliseq librairy) including 36 genes frequently reported in myeloid malignancy. Two different technologies of next generation sequencing (NGS) were used, allowing direct validation. FLT3-ITD was detected and quantified by Genescan analysis. Results. We identified 579 driver mutations involving 36 genes or regions in 386 patients (mean 1.5 per case), with at least 1 driver mutation in 291 patients (75%) and 2 or more driver mutations in 44% of samples. The number of mutation identified at diagnosis in cytogenetic subgroup is significantly lower in MLL-AML (0.44 mutation/patient; p<10-4). Mutations involving genes from the tyrosine kinase pathways (i.e RAS, FLT3, KIT, PTPN11, JAK2, MPL, CBL) were the most frequent and represent 56.3% of all aberrations. Among them N-RAS was detected in 26.4% of all cases, followed by FLT3-ITD, KIT and K-RAS in 14.8%, 12.4% and 12.2% respectively. We identified 64 driver mutations in the group of transcription factors (CEBPA, RUNX1, GATA, ETV6), 60 in the combined group of chromatin modifier (ASXL1, EZH2, BCOR) and DNA methylation (DNMT3A, IDH, TET2), 59 in the group of tumor suppressor genes (WT1, PHF6, TP53) 36 mutations in NPM1 gene, and few mutations in cohesion and spliceosome sub-groups. Identified mutations are indicated in the figure according cytogenetic subgroups. Among the 438 patients, 398 (91%) were in complete remission (CR) after two courses (induction and first consolidation), the 5-year overall survival (OS) is 71.5% [65-78] and the 5-year leukemia free survival (LFS) is 56.6% [49.7-63.5]. In univariate analysis, we found that FLT3-ITD, mutations in RUNX1, WT1 and PHF6 were associated with reduced LFS (p=0.0003 for FLT3-ITD, p=0.01 for RUNX1, p=0.02 for WT1 and p=0.025 for PHF6) and reduced OS (p=0.0003 for FLT3-ITD, p=0.0003 for RUNX1, p=0.015 for WT1 and p=0.04 for PHF6). Mutations in NPM1 is associated with an improved 5-yr LFS (p=0.014) and 5-yr OS (p=0.005). Multivariate analysis revealed that FLT3-ITD, RUNX1 and PHF6 were independently associated with an adverse outcome and NPM1 with an improved outcome. Conclusions. We performed an extensive mutational study in de novo pediatric AML enrolled in the ELAM02 trial. We described the genomic landscape of 386 patients and showed the frequency of different mutations according cytogenetics. Interestingly we found mutations in genes involved in constitutional or pre-leukemic disease such as PTPN11, RUNX1, MPL or ETV6. We found that FLT3-ITD, RUNX1 and PHF6 mutations predict poor outcome although NPM1 mutations predict a better outcome. Mutational profiling reveals useful information for risk stratification and therapeutic decisions. Figure Figure. Disclosures Baruchel: Amgen: Consultancy.

scholarly journals Marked Differences in the Genomic Landscape of Pediatric Compared to Adult Acute Myeloid Leukemia: A Report from the Children's Oncology Group and NCI/COG Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 595-595
Author(s):  
Jason E Farrar ◽  
Hamid Bolouri ◽  
Rhonda E. Ries ◽  
Timothy Junius Triche ◽  
Emilia L. Lim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Silencing ◽  
Mirna Expression ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Transcriptional Regulator ◽  
Oncology Group ◽  
Diagnostic Samples ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract The age distribution of acute myeloid leukemia is unusual among malignancies, with onset spanning from early infancy until past the 9th decade. Despite similar histology, cytogenetic abnormalities and recent identification of somatic mutations (e.g., DNMT3A mutations) have highlighted differences in the events driving adult compared to childhood de novo AML. However, the full extent of these differences remains unknown and is likely to have relevance to treatment approaches. The TARGET AML initiative is an effort of the Children's Oncology Group (COG) and the National Cancer Institute to comprehensively characterize the molecular abnormalities of pediatric AML. The dataset comprises 1) whole genome sequencing (WGS) of AML and matched remission bone marrow in 197 cases, 2) mRNA transcriptome sequencing of 284 cases, 3) miRNA sequencing of 692 cases, 4) methylation array data on 289 cases, and 5) targeted capture sequencing of 174 candidate genes identified from WGS in 800 diagnostic samples, including 182 with WGS (Figure 1). The majority of patients (93%) studied were uniformly treated on COG study AAML0531 or its pilot safety precursor study, AAML03P1. Relapsed specimen data (not shown) are available for a subset of these cases. All patient samples were obtained by written consent upon enrollment in the clinical trial. Consistent with adult studies, we identified a relatively low mutational burden, with 2206 somatic tier 1 mutations resulting in a coding change in 1682 genes (median 6 per patient) from the WGS discovery data. We successfully verified 70-90% of variant calls by secondary methods. Also as with adult data, there were relatively few recurrently mutated genes, with fewer than 40 genes altered in >2% of samples. However, there were marked differences in somatic mutation frequencies in comparison to adult TCGA data, both by raw frequency and after adjustment for cytogenetic subtypes present among the two cohorts (Figure 2). Mutations in TP53, NPM1, IDH1, IDH2, TET2 and DNMT3A are more frequent in adult compared to pediatric disease; in contrast, mutations in NRAS, KRAS, WT1, FLT3, PTPN11, GATA2, ASXL2, MYC, SETD2, EZH2 and IKZF1 appear more common in pediatric AML. Mutations of several genes, including CEBPA, ASXL2 and KRAS are not only more common in pediatric AML, they show peak prevalence within specific pediatric age groups. In addition, several genes, including FLT3, WT1, and KIT show significant differences in mutational hotspots compared to adults. Pediatric-adult differences in AML were not limited to somatic gene mutations, but extended to focal and chromosomal copy number alterations (CNA), translocations, miRNA expression, and methylation-induced gene silencing. We identified recurrent focal CNAs in multiple regions not reported in adult AML including 15 heterozygous focal deletions impacting ELF1, an ETS-family transcriptional regulator of hematopoiesis and leukemia driver as well as deletions of the splicing regulator MBNL1 in 10 cases, 8 of which co-occurred with focal deletions of the hematopoietic transcriptional regulator, ZEB2. De novo assembly of mRNA sequencing data identified fusion transcripts in 63% of cases compared to 45% of TCGA LAML. In addition to cytogenetically evident fusions with well-described enrichment for MLL translocations in pediatrics, we identified 29 diagnostic samples (10%) with nucleoporin family fusions (NUP98 with NSD1, KDM5A, PHF23, HOXD13, HMGB3, BRWD3, and CLINT; NUP214 with DEK and SET), CBFA2T3-GLIS2 fusions in 5, and rare fusions of ETS transcription factor genes (FUS-FEV, ETV6-INO8D). Comparison of miRNA expression patterns between adult and pediatric specimens similarly showed marked differences in expression of key regulatory miRNAs including let-7 family members. Finally, analysis of mRNA expression and DNA methylation for the identification of epigenetically silenced genes suggested that, although specific events favor silencing in adults or children, an overall pattern of gene silencing was more prevalent in pediatric compared to adult cases. This work extends our understanding of the heterogeneity of AML, demonstrates fundamental differences in the biology of pediatric- and adult-onset disease, and suggests important age-related differences within "pediatric" AML. This rich dataset should provide a foundation for the establishment of biologically-guided treatment in children with AML. Disclosures No relevant conflicts of interest to declare.

Mutational profiling of acute myeloid leukemia with normal cytogenetics in Brazilian patients: the value of next-generation sequencing for genomic classification

2017 ◽  
Vol 65 (8) ◽  
pp. 1155-1158 ◽  
Author(s):  
Thiago Rodrigo de Noronha ◽  
Miguel Mitne-Neto ◽  
Maria de Lourdes Chauffaille
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Regulation Of Gene Expression ◽  
Uniparental Disomy ◽  
Driver Mutations ◽  
Next Generation ◽  
Normal Cytogenetics ◽  
Generation Sequencing ◽  
Acute Myeloid

Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients’ risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation:DNMT3Ain nine patients;IDH2in six;IDH1in three;NRASandNPM1in two; andTET2,ASXL1,PTPN11, andRUNX1in one patient. No mutations were found inFLT3,KIT,JAK2,CEBPA,GATA2,TP53,BRAF,CBL,KRAS,andWT1genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation (DNMT3A,IDH1,IDH2,andTET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.

Next-generation sequencing panel in de novo acute myeloid leukemia

2019 ◽  
Vol 85 ◽  
pp. S69-S70
Author(s):  
A. Bolaman ◽  
İ. Erdoğdu ◽  
A. Turgutkaya ◽  
C. Selim ◽  
A. Eroglu Kucukerdiler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Next Generation ◽  
Generation Sequencing ◽  
Acute Myeloid

Cytogenetic Diagnostics and Outcome in a Series of Thirty Three Greek Pediatric Acute Myeloid Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4889-4889
Author(s):  
Kalliopi N Manola ◽  
Agapi Parcharidou ◽  
Vassilios Papadakis ◽  
Maria Kalntremtziou ◽  
Chryssa Stavropoulou ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Normal Karyotype ◽  
Acute Leukemias ◽  
Early Treatment Response ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) accounting for approximately 17% of all childhood acute leukemias, arises either de novo or from a backround of myelodysplasia or previous chemotherapy. Cytogenetics is considered one of the most valuable prognostic determinants in AML while current risk–group classification in the limited cases of pediatric AML, is mainly based on cytogenetics and early treatment response. We reviewed the clinical and cytogenetic characteristics and the outcomes of 33 cases of childhood AML between 1997 and 2007 in order to investigate the incidence of the main FAB subtypes, the incidence of primary AML compared to secondary AML (s-AML) and the correlation between specific chromosome abnormalities and outcome in greek pediatric AML patients. Chromosome studies were performed on unstimulated bone marrow cells, derived from 33 pediatric AML patients, who were &lt;18 years of age at the time of diagnosis. Eighteen patients were male and 15 were female. According to FAB classification one patient was classified as M0 (3%), 13 patients as M2 (39.4%), 4 as M3 (12.12%), 4 as M5 (12.12%), 2 as M6 (6.1%) and 4 as M7 (12.12%). No patient was classified as M4 while 5 patients with s-AML (15.15%) could not be classified. The median follow-up of all patients was 57.95 months (0.03–132.47). Overal survival and event free survival were 66,7% and 75,8% respectively. Eight patients with s-AML and 25 patients with primary AML were identified. The median age of patients with s-AML at diagnosis was 9.15 years while the median age of patients with primary AML was 7.2 years. Six out of 8 patients with s-AML died at a median follow up of 11.03 months. Nineteen out of 25 patients with primary AML are alive in complete remission (CR). Cytogenetic analysis was performed at diagnosis in 32 patients and results were obtained in 30 of them. The karyotype was abnormal in 21 out of 30 patients (70%). Normal karyotype was found in 9 patients, t(8;21)(q22;q22) in 5, t(15;17)(q22;q21) in 3, t(9;11)(p22;q23) in 3, −7/del(7q) in 5, del(9q) in 3, and complex karyotype in 4 patients. Three out of 4 patients with M3 are alive in CR with a median follow-up of 98.6 months while one with s-AML-M3 died 13 days post diagnosis. Three out of five patients with M2 and t(8;21), including 1 patient with s-AML, died at a median follow-up of 4.35 months. Three out of 5 patients with −7/del(7q) had s-AML and died in less than 4 years, while the two others are alive for more than 5 years, in CR. Although all patients with M7 had complex karyotypes, they are alive after a median follow-up of 96.73 months, 3 of them in CR and 1 in relapse. These results indicate that in greek patients, the main FAB subtypes show a distribution similar to that reported in the literature with the exception of M4 which is absent in our study but with a reported incidence of 20%. Pediatric patients with s-AML are older and their outcome is poor and is related to a higher probability of poor cytogenetic features compared to primary AML patients. Interestingly all patients with M7 had a good clinical course although they exhibited complex karyotypes.

Predicting prognosis in patients with acute myeloid leukemia: The role of next-generation sequencing and mutational profiling.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 7068-7068
Author(s):  
Caroline E Sloan ◽  
Phyllis A. Gimotty ◽  
Anne M Boccuti ◽  
Alison Sehgal ◽  
Jianhua Zhao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Next Generation ◽  
Mutational Profiling ◽  
Generation Sequencing ◽  
Acute Myeloid

Acute Myeloid Leukemia (AML) with t(6;9)(p23;q34) Defines a Very Poor Risk Leukemia Subgroup with Distinguishing Clinicopathological Features: A United States (US) Cytogenetics Intergroup Study of 62 AML and MDS Cases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 567-567
Author(s):  
Marilyn L. Slovak ◽  
Clara D. Bloomfield ◽  
Holly Gundacker ◽  
Gordon Dewald ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
Young Patients ◽  
Disease Free Survival ◽  
Clinicopathological Features ◽  
Published Data ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract The t(6;9)(p23;q34) translocation, which results in the formation of a chimeric fusion gene DEK/CAN on the der(6) chromosome, is a rare recurring cytogenetic aberration reported in patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Because the abnormality is an infrequent finding in AML with most reports describing 2 to 8 cases, the US Intergroup Cytogenetics Consortium investigated the frequency and clinical, pathologic and cytogenetic characteristics of t(6;9) leukemia among pts registered to 19 different treatment protocols. Among 6567 pts with evaluable karyotypes, 62 (0.9%) had t(6;9): 30 on pediatric trials (mean 12 yrs; 15/15 male/female) and 32 on adult trials (mean 38 yrs; 21/11 male/female), compared to the mean age of 8 yrs for pts on pediatric AML/MDS trials and 54 yrs for pts on adult AML/MDS trials. Three cases (5%) showed a complex (3- or 4-way) variant translocation and only 7 (11%) of the 62 pts showed secondary aberrations: 3 (10%) of 30 pediatric cases and 4 (13%) of 32 of the adult cases. The majority of t(6;9) cases were classified as FAB-M2 (34%), M4 (31%) or M1 (19%). Although the immunophenotyping (N=7) and morphology data (N=17) were limited, increased basophilia and Auer rods were observed and the blasts showed CD13, CD15, and CD33 expression, in agreement with a previously reported preliminary study (Am J Clin Pathol107:430–437,1997). Four pts (1 pediatric and 3 adults) had MDS. Among the remaining 58 pts, 25 (78%) adults had previously untreated AML (16 de novo, 2 secondary, and 7 unknown secondary/de novo status) while all 29 pediatric AML patients had de novo AML. For the 54 patients with previously untreated AML, complete remission rates were slightly higher, but not statistically significantly (p=.20) in children (69%), when compared to adults (52%). Disease-free survival (DFS) (combined median 8.8 mo, 95% CI, 5.1–13.7) and overall survival (OS) (combined median 11.9 mo, 95% CI, 10.0–14.3) were poor regardless of age, a finding in distinct contrast to the t(8:21) favorable risk group also commonly observed in M2/M4 AML. Kaplan-Meier estimates of 3-yr survival were 25% for pediatric cases and 9% for adults. Analysis of stem cell transplantation (SCT) was inconclusive due to the small number of transplanted patients (N=15), but suggested that allogeneic SCT might be associated with better OS than no SCT (hazard ratio [HR] 0.39 after SCT, 95% CI 0.14 – 1.11), while autologous SCT might not (HR 1.49, 95% CI 0.57–3.85). Based on this study of t(6;9), largest to date and previously published data, AML with t(6;9) leukemia is a distinct AML subgroup with distinguishing clinicopathological features including poor outcome in relatively young patients, not explained by other known poor prognostic factors that warrants novel therapeutic strategies. Similar to other recurring cytogenetic abnormality subtypes of de novo acute myeloid leukemia of the WHO classification, t(6;9) may warrant a specific leukemia disease subtype.

Treatment of Children with Relapsed Acute Myeloid Leukemia with Gemtuzumab in Combination with Mitoxantrone and Cytarabine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4641-4641
Author(s):  
Richard Aplenc ◽  
Todd A. Alonzo ◽  
Robert Gerbing ◽  
Franklin O. Smith ◽  
Sievers Eric ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Infectious Complications ◽  
Dose Finding ◽  
Cell Transplant ◽  
Entire Cohort ◽  
Pediatric Aml ◽  
Grade Iii ◽  
Acute Myeloid

Abstract Despite improvements in the treatment of children with de novo acute myeloid leukemia (AML), a substantial fraction of patients experience relapse. The Children’s Oncology Group Phase I trial, AAML00P2, sought to test the safety and feasibility of combining Gemtuzumab (GMTZ) with a standard AML reinduction regimen of mitoxantrone and cytarabine in a dose de-escalation design. Patients received cytarabine 1000 mg/m2/dose every 12 hours on days 1–4 with mitoxantrone 12 mg/m2/dose daily on days 3–6. The starting dose of GMTZ for dose finding was 3 mg/m2 once on day 7. Doses for patients under 3 years of age were as follows: cytarabine 33 mg/kg/dose, mitoxantrone 0.4 mg/kg/dose, and GMTZ 0.1 mg/kg/dose. Three patients were enrolled in the dose finding strata and an additional 18 patients were subsequently enrolled to acquire further toxicity data. Of these, 15 were male and 6 female. The median patient age was 11.3 years, range 1.2 to 19.2 years. No patients in the initial dose finding cohort experienced a dose limiting toxicity. Toxicities observed in the entire cohort of 21 patients included hematologic and infectious complications typical of AML therapy. One patient had grade III bilirubin elevation. No patients had grade III or IV hepatic toxicity or grade III or IV veno-occlusive disease (VOD). Data on toxicity in stem cell transplant post GMTZ exposure is limited. However, no episodes of VOD have been reported. In summary, GMTZ combined with cytarabine and mitoxantrone is reasonably well tolerated in pediatric AML patients.

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.

scholarly journals Clinical Features of Patients with ASXL1 and ASXL2 Mutations in Pediatric Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1024-1024
Author(s):  
Genki Yamato ◽  
Norio Shiba ◽  
Kenichi Yoshida ◽  
Kentaro Ohki ◽  
Myoung-ja Park ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
The Other ◽  
Prognostic Impact ◽  
Other Hand ◽  
Recurrent Mutations ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background; Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Currently, a number of gene mutations have been implicated in the pathogenesis of both adult and pediatric AML, including mutations of CEBPA,NPM1, DNMT3A, IDH1/2, TET2 and EZH2 in addition to RAS, KIT and FLT3, because the recent development of massively parallel sequencing technologies. We have performed whole-exome sequencing of paired tumor-normal DNA from 19 patients, and identified 80 somatic mutations or 4.2 mutations per sample. Many of the recurrent mutations identified in this study involved previously reported targets in adult AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1, BCORL1, EZH2, and major cohesin components including SMC3 and RAD21. In addition to these mutations, we also identified disease-associated candidate genes of ASXL2, PAX5 and others. Recently, recurrent somatic mutations in ASXL1 have been reported to occur in patients with adult AML, and to be associated with adverse outcome. Another study suggested that ASXL1 or ASXL2 mutations were associated with a high incidence of relapse. To reveal the significance of these mutations, we performed mutational analysis of ASXL1 and ASXL2 in 184 pediatric AML patients. Methods; Between 2006 and 2010, 485 de novo pediatric AML patients aged <18 years old participated in the Japanese AML-05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Among them, 369 samples were available. We analyzed the first half of these samples which were registered in the order (184 samples). To estimate the frequency and prognostic impact of the ASXL1 and ASXL2 mutations in pediatric AML, we performed targeted sequencing of ASXL1 (exon 12) and ASXL2 (exon 12) genes using next-generation sequencer in 184 de novo AML patients including 51 patients with t(8;21). We validated the mutations in ASXL1 and ASXL2 by Sanger sequencing. Furthermore, we investigated the correlation among these mutations, other cytogenetic alterations and clinical characteristics. Results and Discussion; ASXL1 mutations were identified in 4 of 184 de novo pediatric AML patients (2.2 %) and all 4 ASXL1 mutation positive patients harbored t(8;21). Two of them relapsed, and one died after relapsed. On the other hand, ASXL2 mutations were identified in 10 of 184 de novo pediatric AML patients (5.4%) and 6 of them harbored t(8;21). Five of these 10 patients relapsed, and 2 of them died after relapsed. Especially, all of 4 patients without t(8;21) relapsed (2 in M5a and 2 with CBFA2T3-GLIS2 in M7), and 2 died after relapsed. Although only one ASXL2 patients with t(8;21) relapsed (1/6 or 17%), no ASXL2 positive patients with t(8;21) died. ASXL2 mutations were more observed in AML patients with t(8;21) (11.8%, 6/51), but not in 13 patients with inv(16). Overall survival of the patients with or without ASXL2 mutations were 80% and 66.7% (p=0.54), respectively. ASXL1 and ASXL2 mutations were mutually exclusive in this study. Conclusion; Ten of 184 patients (5.4%) had mutations of ASXL2 in pediatric AML, and the outcome of ASXL2 mutant patients with t(8;21) was favorable. Among the 51 pediatric AML patients with t(8;21), ASXL2 mutations were detected in 6 (11.8%) patients. All of them have been survived, suggesting that ASXL2 mutations in patients with t(8;21) may be associated with favorable prognosis in pediatric AML in contrast to adult AML. On the other hand, 4 (2.2%) of 184 patients had ASXL1 mutations, and all of them were t(8;21). In these 4 patients, 2 of them relapsed, and one died after relapsed. Although the number of patients is too small, ASXL1 mutations were not considered to be associated with favorable outcome. Both ASXL1 and ASXL2 mutations were detected at high frequency among pediatric AML patients with t(8;21) and mutual exclusive. As we consider that further study will be needed to clarify the significance of these mutations, we are now analyzing mutations in other exons of ASXL2, and would like to report these data in the annual meeting. Disclosures No relevant conflicts of interest to declare.

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