Characterization of Acute Myeloid Leukemia with PTPN11 Mutation - The Mutation Is Closely Associated with NPM1 Mutation but Inversely Related to FLT3/ITD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3490-3490 ◽  
Author(s):  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Yuan Chen ◽  
Liang-In Lin ◽  
Jih-Luh Tang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Tyrosine Phosphatase ◽  
Normal Karyotype ◽  
Receptor Protein ◽  
Missense Mutations ◽  
Npm1 Mutation ◽  
Ptpn11 Mutation ◽  
Acute Myeloid

Abstract The development of acute myeloid leukemia (AML) is a multistep process. Recently, somatic mutations of PTPN11, the gene encoding non-receptor protein tyrosine phosphatase SHP-2, were observed in some hematological malignancies. However, the characteristics of adult AML with PTPN11 mutations have not been comprehensively studied, and the specific genetic alteration cooperative with a PTPN11 mutation in the leukemogenesis remains largely unknown. In this study, PTPN11 mutation and its association with other gene aberrations were analysed for 272 adult patients with de novo AML. Missense mutations were identified in 14 individuals (5.1%). The PTPN11 mutation was closely associated with old age (P=0.036), FAB M4/M5 subtypes (P=0.049), CD14 expression (P=0.026), a normal karyotype (P=0.044) and NPM1 mutation (P=0.037), but negatively associated with FLT3/ITD (P = 0.025). In addition, four patients revealed simultaneous mutations of PTPN11 and AML1 (n=3) or MLL (n=1). We observed a shorter overall survival for patients with PTPN11 mutation than those without amongst NPM1-wild patients (P=0.001), but not amongst NPM1-mutated patients (P=0.738). Our findings provide evidence that AML patients with PTPN11 mutations had some distinct biological and clinical characteristics, and the mutation may cooperate with other gene alterations to lead to AML in a subset of patients.

Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
B. C. Medeiros ◽  
J. R. Gotlib ◽  
S. E. Coutre ◽  
C. Jones ◽  
S. A. Khan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Low Doses ◽  
Npm1 Mutation ◽  
Acute Myeloid

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

Association of TET2 Alterations with NPM1 Mutations and Prognostic Value in De Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 163-163 ◽  
Author(s):  
Olivier Nibourel ◽  
Olivier Kosmider ◽  
Meyling Cheok ◽  
Nicolas Boissel ◽  
Aline Renneville ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Prognostic Value ◽  
De Novo ◽  
Missense Mutations ◽  
Npm1 Mutation ◽  
Tet2 Mutation ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 163 In acute myeloid leukemia (AML), both cytogenetic and molecular abnormalities are strongly associated with prognosis. In particular, in cytogenetically normal AML (CN-AML), FLT3-ITD (internal tandem duplication) carries adverse prognostic factor whereas NPM1 or CEBPA mutations are associated with favorable outcome. Recently, mutations of the ten eleven translocation 2 gene (TET2) have been reported myeloid neoplasms. We evaluated the frequency and prognostic value of TET2 alterations, in a cohort of 111 de novo AML patients. We studied 111 patients aged between 15 years and 69 years with previously untreated de novo AML who had reached complete remission (CR) using intensive chemotherapy. 28 of them also received an allogenic bone marrow transplantation in first CR. Analysis of TET2 sequence variation was performed by direct sequencing of PCR products from 111 genomic DNA samples obtained at diagnosis. Frameshift and nonsense variations were all scored as mutation whereas missense mutations were retained when observed at diagnostic but absent in the CR paired sample obtained. Previously identified single nucleotide polymorphisms (SNP) were not considered. TET2 anomalies were numbered according to Genebank reference FM992369. Paired diagnosis and CR genomic DNAs were analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Data were analyzed using Gene Chip Genotyping Console 3.0.2 and Partek Genomics Suite (www.partek.com/). Comparisons were made by Fisher's exact test for binary variables and the Mann-Whitney‘s test for continuous variables. Disease Free Survival (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Comparisons regarding DFS and OS were performed with the log-rank test. 24 acquired TET2 mutations were observed in 19 of the 111 (17%) de novo AML patients, suggesting the alteration of the two TET2 alleles in 5 patients. They included 21 different events: 6 frameshift, 7 non-sense and 11 missense mutations. Four of the missense mutations were located in conserved regions and 7 outside. All of them were detected in the diagnostic sample but were absent in the paired remission sample. Except for two missense mutations (S282F, T492S) both detected in two patients, no recurrent TET2 mutation was observed. Acquired mutations were spread over all exons. No case of uniparental disomy (UPD) was observed and only one patient presented a small deletion of 60Kb in the TET2 gene locus without TET2 mutation. No significant difference was observed between patients with or without TET2 alterations for gender, age, hemoglobin level, platelet count, FAB subtypes distribution and cytogenetics according to MRC classification, but there was a trend for higher WBC count in patients with TET2 alteration. No significant association was observed between TET2 mutations and FLT3 or CEBPA alterations. However, TET2 alterations were significantly associated with NPM1 mutations (p=0.032). In the entire patient cohort, no difference in DFS or OS was seen between patients with and without TET2 alteration. However, a significantly worse DFS was observed for patients presenting TET2 mutations within the subgroup of patients with NPM1 mutations (3y-DFS: 0% vs 66.4%, 95% CI [45.6–87.2], p=0.008) Considering both the favorable prognosis of NPM1 mutations without FLT3-ITD in CN-AML and the absence of clear association between FLT3-ITD and TET2 alterations in this study, prognostic value of the genotype characterized by NPM1 mutation without FLT3-ITD or TET2 alteration (NPM1+FLT3-ITD-TET2-) was compared to other patients within CN-AML group (N=54). NPM1+FLT3-ITD-TET2- patients showed a significantly better DFS and OS compared to other patients in CN-AML group (3y-DFS: 82.1%, 95% CI [59.1–100] vs 37.3%, 95% CI [20.2–54.3], p=0.01; 3y-OS: 80.8%, 95% CI [56.1–100] vs 42.3%, 95% CI [23.3–61.3], p=0.04). In conclusion, we observed point mutations of TET2 in 17% of patients, whereas TET2 deletion or UPD are very rare. In our study, TET2 mutations were clearly associated with NPM1 mutations and carried a negative prognostic impact in this subgroup. Screening for TET2 mutations may improve the characterization of CN-AML and help to identify within the low-risk subgroup with NPM1 mutation and without FLT3-ITD, patients at high risk of relapse. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Incidence and Prognostic Value of FLT-3 and NPM1 Genes Abnormalities in Acute Myeloid Leukemia in the Côte D’or Population, France

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4873-4873
Author(s):  
Marc Maynadié ◽  
Martine Courtois ◽  
Morgane Mounier ◽  
Ines Janoray-Manivet ◽  
Ingrid Lafon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
De Novo ◽  
Relative Survival ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Clinical Series ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Context: In acute myeloid leukemia (AML), the recently described FLT-3 and NPM1 genes abnormalities were found to have a prognostic value in AML with normal karyotype and a specific therapeutic strategy was proposed according to these abnormalities. We look for the incidence and prognostic value of these abnormalities in cases diagnosed on a well defined population. Material and Methods: AML diagnosed according to WHO classification between 01/01/2001 and 31/12/2006 in the population of the Côte d’Or department, were included. Karyotype analyses were performed in 81% of the cases. The FLT3 D835 mutation, the FLT3 internal duplication (ITD) and the NPM1 mutation were systematically studied on the biological material of the diagnosis cryopreserved in the Ferdinand Cabanne Biobank of Burgundy, by PCR and DNA sequencing techniques. The vital status of the patients was update on 31/10/2007. The relative survival was calculated with the STATA (V9) software. Results: 100 de novo AML and 47 secondary AML (sAML) were registered (72 females and 75 males). The world standardized incidence rate was 2.4 in men and 1.5 in women for de novo AML instead of what it was respectively of 1.1 and 0.6 in sAML. The urban predominance was present in both type of AML. The karyotype was normal in 38% (45/119) of cases (35% of de novo AML and 21% of sAML). It was abnormal in 62% of cases (74/119)(51% of de novo AML and 49% of sAML). Molecular analyses were performed in 78 de novo AML and in 24 sAML. FLT3 ITD was present in 19% (15/78) de novo AMl and in any sAML. The FLT3 D835 mutation was present in 6.5% of de novo AML and in 8% of sAML. NPM1 was mutated respectively in 26% and 4% of the cases. There was a significantly higher WBC count and proportion of blast cells in peripheral blood in FLT3 ITD cases. Overall and relative survivals of FLT3 ITD cases were decreased compared to FLT3 wild type cases. No difference according to NPM1 status was found. Conclusions: These data confirm the bad prognostic value of FLT3 ITD status in AML observed in clinical series. Furthermore their particular interest lies in the fact that they are the first molecular data in AML produced on a population-based series indicating the feasibility of such epidemiological studies.

Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Abstract Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

scholarly journals Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings [see comments]

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3688-3694 ◽  
Author(s):  
A Cuneo ◽  
A Ferrant ◽  
JL Michaux ◽  
M Boogaerts ◽  
H Demuynck ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical Findings ◽  
Trisomy 13 ◽  
Professional Exposure ◽  
Cytogenetic Profile ◽  
Acute Myeloid ◽  
Clonal Abnormalities

Cytogenetic data were studied in 26 patients with de novo acute myeloid leukemia (AML) with minimal myeloid differentiation, corresponding to the M0 subtype of the French-American-British classification, in correlation with cytoimmunologic and clinical findings. Clonal abnormalities were detected in 21 cases (80.7%), 12 of which had a complex karyotype. Partial or total monosomy 5q and/or 7q was found, either as the sole aberration or in all abnormal metaphases, in 11 patients; in 8 cases, additional chromosome changes were present, including rearrangements involving 12p12–13 and 2p12–15 seen in 3 cases each. Five patients had trisomy 13 as a possible primary chromosome change; in 5 cases, nonrecurrent chromsome abnormalities were observed. Comparison of these findings with chromosome data from 42 patients with AML-M1 shows that abnormal karyotypes, complex karyotypes, unbalanced chromosome changes (-5/5q- and/or -7/7q- and +13) were observed much more frequently in AML-M0 than in AML-M1. Patients with abnormalities of chromosome 5 and/or 7 frequently showed trilineage myelodysplasia and low white blood cell count. Despite their relatively young age, complete remission was achieved in 4 of 11 patients only. Patients with +13 were elderly males with frequent professional exposure to myelotoxic agents. Unlike patients with clonal abnormalities, most AML-M0 patients with normal karyotype showed 1% to 2% peroxidase-positive blast cells at light microscopy and frequently achieved CR. It is concluded that (1) AML-M0 shows a distinct cytogenetic profile, partially recalling that of therapy-related AML, (2) different cytogenetic groups of AML-M0 can be identified showing characteristic clinicobiologic features, and (3) chromosome rearrangements may partially account for the unfavorable outcome frequently observed in these patients.

Clinical Characteristics and Prognostic Implications of NPM1 Mutations in Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2368-2368
Author(s):  
Tatsuya Suzuki ◽  
Hitoshi Kiyoi ◽  
Kazutaka Ozeki ◽  
Akihiro Tomita ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Sequential Analysis ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Distinct Subgroup ◽  
Paired Samples ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Nucleophosmin (NPM) is a nucleolar protein with multi-functions including centromere duplication, nuclear-cytoplasmic shuttling, ribosomal biogenesis, p53 stability. NPM1 mutations were found in a large number of patients with acute myeloid leukemia (AML) especially with normal karyotype. The mutations lead to the aberrant subcellular localization of NPM protein. However, their impacts on clinical outcome remain controversial. We screened the mutations of NPM1 in 257 AML patients and analyzed the clinical significance. NPM1 mutations were found in 64 of 257 patients (24.9%). Seven types of mutations, including four novel mutations, were identified. NPM1 mutations were associated with normal karyotype, FLT3 mutations (both FLT3-ITD and D835 mutation) but not with other gene alterations such as N-RAS, p53 mutations and partial tandem duplication of the MLL gene. In 190 patients except the M3 subgroup, who were treated according to the protocol of Japan Adult Leukemia Study Group, the multivariate analysis revealed that NPM1 mutation was a favorable factor for achieving complete remission, but significantly associated with relapse. A sequential analysis, using paired samples obtained at diagnosis and relapse in 39 patients, revealed that NPM1 mutations were lost at relapse in 2 of the seventeen patients who had NPM1 mutations at diagnosis and none of the patients, who did not have NPM1 mutations at diagnosis, gained NPM1 mutations at relapse. Our results suggest that NPM-mutated AML should be a distinct subgroup with specific clinical characteristics and outcome. Loss of NPM mutations at relapse implies that NPM mutation is not necessarily a primary genetic alteration and that these leukemic clones could be sensitive to chemotherapy.

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.

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.

Rapid Detection of Nucleophosmin (NPM1) Mutations to Determine Prognostic Implications in Acute Myeloid Leukemia Patients with a Normal Karyotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4676-4676
Author(s):  
Seo-Jin Park ◽  
Hyun-Sook Chi ◽  
Kyung Ran Jun ◽  
Sook Kyoung Min ◽  
Seongsoo Jang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Direct Sequencing ◽  
Screening Method ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract Abstract 4676 INTRODUCTION Mutations of the nucleophosmin gene (NPM1) occur in up to 40-50% of adult acute myeloid leukemia (AML) with a normal karyotype and are associated with a higher frequency of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) and responsiveness to induction chemotherapy. The incidence of NPM1 mutations in Caucasians have been previously reported in several studies whereas there have been few reports from Asian countries including Japan, China, and Taiwan. The objectives of our study was to determine the prevalence of NPM1 mutations and distribution of AML subtypes in the normal karyotype AML Korean population in addition to establishing an easily applicable yet reliable method to indentify these mutations. We also examined treatment outcomes and survival (relapse-free survival (RFS) and overall survival (OS)) by stratifying them into groups according to NPM1 and FLT3-ITD mutation status. METHODS We retrospectively analyzed the prevalence of NPM1 mutations in 185 patients with normal karyotype AML diagnosed between 2002 and 2009. Genomic DNA extracted from bone marrow aspirate specimens obtained at diagnosis was amplified by PCR, followed by analysis on an ABI 3130 Genetic Analyzer (Applied Biosystems) by capillary electrophoresis. Cases found to have mutation peaks at 174bp by Gene Mapper ID v3.2 software (Applied Biosystems) were further analyzed by direct sequencing of exon 12 of NPM1 gene. Follow-up data was reviewed by retrospective chart review for treatment outcome and survival analyses. Among the 185 AML patients, 18 with less than a 1-month follow-up period were excluded since they could not be sufficiently evaluated. RESULTS Mutations in exon 12 of NPM1 were found in 37 of 185 (20.0%) normal karyotype AML patients and were composed of TCTG duplications (Type A, 32/37, 86.5%), 3 previously reported variants, and 2 new variants previously not reported. Mutations were most frequently seen in AML M1 patients (12/37, 32.4%) and other subtypes such as M2, and M4 were often observed. NPM1 mutations were particularly associated with CD34-negativity (<0.0001) and higher bone marrow blast (%) at diagnosis (p=0.0067). There was a mild trend towards frequent FLT3-ITD mutations in NPM1+ patients in comparison to the NPM1- group (35.1% and 19.6%, p=0.0787). After exclusion of the 18 patients lost during follow-up, no significant differences in RFS (8.5 and 10.8 months, p=0.7922) and OS (11.5 and 13.6 months, p=0.6147) were observed between the NPM1+ and NPM1- groups. Stratification into good (NPM1+/FLT3-ITD-), intermediate (NPM1-/FLT3-ITD- & NPM1+/FLT3-ITD+), and poor (NPM1-/FLT3-ITD+) prognostic groups did not reveal significant differences in median values of RFS and OS (in months; RFS, 16.0 and 13.8 and 7.3, p=0.1872; OS, 16.0 and 10.8 and 7.3, p=0.3661). However, the Kaplan-Meier survival analysis of these stratified prognostic groups showed a trend toward a difference in RFS (p=0.084) and a significantly longer OS in the NPM1+/FLT3-ITD- (good prognostic) group (p=0.031). CONCLUSIONS The prevalence of NPM1 mutations in normal karyotype AML patients in Koreans was lower than those reported in Western studies. In areas with low prevalence, a screening method to detect mutations enables rapid reporting with only selective cases requiring the labor-intensive direct sequencing step. In accordance with previous studies, a significantly longer OS in the NPM1+/FLT3-ITD- group suggests that NPM1+ may be associated with a favorable outcome. However, discordant parameters such as prevalence and RFS may signify that elucidation of the prognostic significance of NPM1 mutations in different ethnic groups may be necessary. Thus, NPM1 mutation studies should be considered in the diagnostic work-up of all AML patients with a normal karyotype given its role as a prognostic marker. Disclosures: No relevant conflicts of interest to declare.

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