EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2544-2544
Author(s):  
Xiuli Wang ◽  
Haiping Dai ◽  
Qian WANG ◽  
Qinrong Wang ◽  
Yang Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Coding Region ◽  
Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1003-1003 ◽  
Author(s):  
Isabel Granada ◽  
Salut Brunet ◽  
Montserrat Hoyos ◽  
Dolors Costa ◽  
Anna Aventín ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective: To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods: Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were calculated. Results: The karyotype was assessable in 904 (79%) of the 1149 cases. In 145 of the 904 cases (16%), abnormalities involving CBF gene were detected and in 437 (48%) the karyotype was normal (NK). In 253 (28%) additional patients the karyotype was not monosomal; of them, 61 (24%) belonged to the unfavorable MRC with 17 cases harboring a complex karyotype ≥ 5 abnormalities, 7 cases with rearrangements 3q, 13 cases with -7, 9 cases with 5q abnormalities and 16 cases with t(6;9)). The remaining 69 (7.7%) patients had a MK; of them, 59 (85.5%) were from the unfavorable MRC category and included 43 cases with complex karyotype ≥ 5 abnormalities, 6 cases with rearrangements 3q, 5 cases with -7, 5 cases with alterations of 5q). The following table summarizes the results in terms of CR rate, DFS and OS: Conclusions: The addition of MK to the MRC cytogenetic classification refines the prognostic prediction. In our series, the dismal outcome of patients with MK is confirmed; these patients had worse prognosis than those with adverse cytogenetics without MK. Alternative treatment strategies are mandatory for MK+ patients. Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures: No relevant conflicts of interest to declare.

Clinical Implications of Reticulin Fibrosis of Bone Marrow in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2585-2585
Author(s):  
Tzung-Chih Tang ◽  
Hung Chang ◽  
Chien-Feng Sun ◽  
Lee-Yung Shih ◽  
Po Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Recovery Duration ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 2585 Background: Microenvironment of bone marrow (BM) plays an important role to support proliferation, renewal and differentiation of hematopoietic stem cells. Whether the stroma of BM affects leukemic cells with the same manner, or impacts on the prognosis in leukemia patients, has not been fully investigated. Previous studies have described that increased reticulin content in the BM is associated with poor outcome in patients with acute lymphoblastic leukemia, chronic myeloid leukemia and primary myelofibrosis, but there is no cohort study to determine the clinical correlation between degree of reticulin fibrosis of BM and acute myeloid leukemia (AML). To investigate prognostic impact of reticulin fibrosis on de novo AML, 881 patients diagnosed between Jun 1999 to Dec 2011 in Chang Gung Memorial Hospital and treated with anthracycline-containing induction chemotherapy were retrospectively reviewed. Patients and methods: According to the grading of reticulin content in the bone marrow, we categorized the 881 patients into four groups: A. BM easily aspirated without biopsy, n = 698; B. Reticulin grade 0, n = 99; C. Reticulin grade 1–2, n = 51; D. Reticulin grade 3–4, n = 33. The induction failure (IF) rate after treatment with induction chemotherapy, the recovery duration of absolute neutrophil count (ANC) greater than 0.5 × 109/L in patients who achieved the first complete remission, the overall survival (OS) and relapse-free survival (RFS) in four groups were analyzed. Based on the cytogenetic or molecular features, 648 of the patients were stratified into unfavorable, intermediate and favorable risk groups, and the clinical significance of reticulin fibrosis of BM were also examined for various risk groups. Results: Of the 881 patients, the patients in group D had a statistically higher IF rate (P = 0.0108) and longer ANC recovery duration (P = 0.0008). But the OS and RFS between four groups were not significantly different (P = 0.5146 and 0.3853, respectively). After risk stratified by cytogenetic and molecular analysis, increased reticulin content of BM (group C or D) had an adverse impact on OS in the intermediate and favorable risk groups (P = 0.006 and 0.0215, respectively). Conclusion: Reticulin content of BM influences the IF rate and myeloid recovery for the patients of de novo AML, and affects OS in patients with intermediate or favorable risk factors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1603-1611 ◽  
Author(s):  
A Neubauer ◽  
RK Dodge ◽  
SL George ◽  
FR Davey ◽  
RT Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Bone Marrow Blast ◽  
Ras Mutations ◽  
Ras Genes ◽  
Oligonucleotide Hybridization ◽  
Acute Myeloid

Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras- positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

Acquisition or Loss of Gene Mutations Occurs in Relapsed Pediatric Acute Myeloid Leukemia: A Comparative Analysis of Paired Matched Diagnosis and Relapse Bone Marrow Samples

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1389-1389
Author(s):  
Der-Cherng Liang ◽  
Hsi-Che Lui ◽  
Chao-Ping Yang ◽  
Tang-Her Jaing ◽  
Iou-Jih Hung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Comparative Analysis ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Clonal Selection ◽  
Gene Mutations ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1389 Background and purpose: Relapse is the major cause of treatment failure in patients with acute myeloid leukemia (AML). The molecular pathogenesis in the relapse of AML is not well understood. A better understanding of molecular aberrations of relapsed AML will further improve the treatment outcome. In the present study, we aimed to determine the role of gene mutations in the relapse of de novo pediatric AML by comparative analysis of the paired matched diagnosis and relapse samples for the mutational status of 18 known mutated genes involved in myeloid neoplasms. Patients and Methods: Two hundred and six children aged below 18 with de novo AML were diagnosed at Chang Gung Children's Hospital, Taoyuan, Taiwan and MacKay Memorial Hospital, Taipei, Taiwan, between 1996 and 2011. They were treated with Taiwan Pediatric Oncology Group AML-97 Protocol (Leukemia 2006). Sixty patients had relapses of leukemia, 46 of them had paired diagnosis and relapse bone marrow samples available for examination on the 18 mutated genes, including FLT3-ITD, FLT3-TKD, C-KIT, C-FMS, NRAS, KRAS, PTPN11, JAK2V617F, RUNX1, CEBPα, NPM1, MLL-PTD, WT1, P53, DNMT3A, IDH1, IDH2 and ASXL1. Mutational analysis was performed with PCR-based assay followed by direct sequencing. Results: The results are summarized in Table 1. Fifteen patients with one mutated gene and 4 with two mutated genes at diagnosis remained unchanged at relapse, all the mutations detected were not present in the complete remission samples. Twenty-five patients without gene mutations at diagnosis did not acquire mutations at relapse. Six patients acquired gene mutations, 5 WT1 and one P53 mutations, indicating clonal evolution during leukemia relapse. Another 7 patients lost gene mutations including 2 FLT3-ITD, 2 FLT3-TKD, one NRAS, one JAK2V617F and one IDH1genes; notably, 4 of them harboring other mutated genes at relapse, suggesting outgrowth or clonal selection of these mutated clone(s) in relapse. Conclusion: Our study showed that gene mutation status in the majority of pediatric AML patients remained unchanged at both diagnosis and relapse, but acquisition or loss of gene mutations may occur at relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1603-1611 ◽  
Author(s):  
A Neubauer ◽  
RK Dodge ◽  
SL George ◽  
FR Davey ◽  
RT Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Bone Marrow Blast ◽  
Ras Mutations ◽  
Ras Genes ◽  
Oligonucleotide Hybridization ◽  
Acute Myeloid

Abstract Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras- positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

Prevalence and Prognostic Impact of RUNX1 Mutations In Patients with Acute Myeloid Leukemia (AML): A Study In 1649 Patients Registered In the AML96 Protocol of the DSIL/SAL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 754-754
Author(s):  
Katharina Gerstenberger ◽  
Christoph Röllig ◽  
Markus Schaich ◽  
Thomas Illmer ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Significant Proportion ◽  
Normal Karyotype ◽  
Trisomy 13 ◽  
Prognostic Impact ◽  
Coding Region ◽  
Acute Myeloid

Abstract Abstract 754 Background: The key hematopoietic transcription factor RUNX1 is inactivated by several mechanisms in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), including translocations and mutations. Mutations have been reported in 10–20% of patients with AML, and appear to be associated with an inferior outcome. However, the analyzed patient populations were either small, contained highly selected patients or the spectrum of mutations investigated was limited. Thus, the information on the prevalence and the prognostic relevance of RUNX1 mutations is still incomplete. Methods: In order to study this abnormality in an unselected cohort including older patients and all karyotype abnormalities, we retrospectively analyzed DNA from 1649 newly diagnosed AML patients. The prognostic impact was studied in those 1303 patients treated within the AML96 protocol of the DSIL/SAL. Screening was performed for exons 3–8 using denaturing HPLC (dHPLC). All patients with aberrant dHPLC-profile were sequenced. Results: Overall 217 mutations were identified in 186/1649 patients (11.3%); 31 patients had two different mutations. The mutations affected the entire coding region, with a cluster in exons 3–5 coding for the RUNT-homology-Domain (RhD). The alterations consisted predominantly of point mutations, but small insertions or deletions were also found, especially in exons 7 and 8. In addition, several patients showed mutations affecting splice donor or acceptor sites. Correlation with clinical data revealed that patients with RUNX1 mutations had a higher median age than patients with wild-type RUNX1 (64 vs. 59 years; P<.001). No significant differences were found regarding other parameters, including the percentage of BM-blasts, gender, platelet or WBC counts. Mutations were observed in almost all FAB-subtypes besides M3 and M7, but as reported, they clustered in FAB M0 and M1. Consistent with the reported role of RUNX1 mutations in MDS, patients with a history of prior MDS had a rate of 20.1% compared to 9.4% in de novo AML and 12.2% in tAML (P<.001). A similar prevalence of mutations was found in patients with cytogenetic abnormalities (86/765; 11.2%) and patients with normal karyotype (84/766; 11%). A high prevalence of RUNX1-mutations was found in patients with trisomy 13, trisomy 21 and also in patients with t(9;22), whereas significantly fewer mutations were observed in good risk cytogenetics t(8;21) and inv(16). Patients with RUNX1-mutations displayed a similar prevalence of FLT3-ITD mutations but significantly less NPM1-mutations (2.2%; P<.001) and a trend for less CEBPA mutations (2.8%; P=.064). When treatment response was investigated, RUNX1-mutant patients had a significantly lower rate of complete remission after double induction, even if restricted to patients <60 yrs (67.5% vs. 49.2%; P=.006). RUNX1 mutations were also associated with inferior overall survival (OS) in all age groups analyzed, e.g. in patients age 60 and younger with normal karyotype, the median OS was 0.96 years in RUNX1 mutant compared to 1.78 years in wt patients (P=.009). In patients achieving CR, treatment failure was due to a significantly increased relapse rate. Conclusions: RUNX1 mutations can be found in a significant proportion of patients with AML. They are associated with prior MDS and older age and appear to characterize a patient group with an increased rate of treatment failure. Disclosures: Thiede: AgenDix GmbH: Equity Ownership.

scholarly journals Pretreatment platelet count predicts survival outcome of patients with de novo non-M3 acute myeloid leukemia

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4139 ◽  
Author(s):  
Qianying Zhang ◽  
Kanchun Dai ◽  
Laixi Bi ◽  
Songfu Jiang ◽  
Yixiang Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Survival Outcome ◽  
Cox Regression Analysis ◽  
High Platelet Count ◽  
Acute Myeloid

Background Pretreatment platelet count has been reported as a potential tool to predict survival outcome in several solid tumors. However, the predictive value of pretreatment platelet count remains obscure in de novo acute myeloid leukemia (AML) excluding acute promyelocytic leukemia (M3). Methods We conducted a retrospective review of 209 patients with de novo non-M3 AML in our institute over a period of 8 years (2007–2015). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal platelet (PLT) cutoff in patients. We analyzed the overall survival (OS) and disease free survival (DFS) using the log-rank test and Cox regression analysis. Results By defining the platelet count 50 × 109/L and 120 × 109/L as two cut-off points, we categorized the patients into three groups: low (<50 × 109/L), medium (50–120 × 109/L) and high (>120 × 109/L). On univariate analysis, patients with medium platelet count had longer OS and DFS than those with low or high platelet count. However, the multivariate analysis showed that only longer DFS was observed in patients with medium platelet count than those with low or high platelet count. Conclusion Our findings indicate that pretreatment platelet count has a predictive value for the prognosis of patients with non-M3 AML.

scholarly journals HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3197-3203 ◽  
Author(s):  
SP Hunger ◽  
DC Tkachuk ◽  
MD Amylon ◽  
MP Link ◽  
AJ Carroll ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Chromosome Band ◽  
11Q23 Abnormalities ◽  
Acute Myeloid ◽  
Secondary Leukemias

Abstract Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.

Mesenchimal Stroma Cells From Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia Show Distinct Cytogenetic and DNA-Mutation Data as Compared with Bone Marrow Leukemic Blasts.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4697-4697
Author(s):  
Olga Blau ◽  
Wolf-Karsten Hofmann ◽  
Claudia D Baldus ◽  
Gundula Thiel ◽  
Florian Nolte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Control Analysis ◽  
Npm1 Mutation ◽  
Dna Mutation ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Abstract 4697 Bone marrow mesenchymal stroma cells (BMSC) are key components of the hematopoietic microenvironment. BMSC from patients with acute myeloid leukemia (AML) and myelodisplasic syndrome (MDS) display functional and quantitative alterations. To gain insight into these questions, we carried out cytogenetic analyses, FISH, FLT3 and NPM1 mutation examinations of both hematopoietic (HC) and BMSC derived from 53 AML and 54 MDS patients and 35 healthy donors after in vitro culture expansion. Clonal chromosomal aberrations were detectable in BMSC of 12% of patients. Using FISH we have assume that cytogenetic markers in BMSC were always distinct as the aberrations in HC from the same individual. 17% and 12% of AML patients showed FLT3 and NPM1 mutations in HC, respectively. In BMSC, we could not detect mutations of NPM1 and FLT3, independent from the mutation status of HC. For control analysis, BMSC cultures from 35 healthy donors were prepared under the same conditions. BMSC from healthy donors did show normal diploid karyotypes and absence of specific DNA-mutations of NPM1 and FLT3. Our data indicate that BMSC from MDS and AML patients are not a part of malignant clone and characterized by genetic aberrations. Lack of aberrations as detected in HC and appearance of novel clonal rearrangements in BMSC may suggest enhanced genetic susceptibility and potential involvement of BMSC in the pathogenesis of MDS and AML. Disclosures: No relevant conflicts of interest to declare.

Trisomy 8 in the Light of Recent Cytogenetic Classification Advances. A Study From the French Acute Myeloid Leukemia Intergroup.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2594-2594 ◽  
Author(s):  
Nicolas Boissel ◽  
Christine Terré ◽  
Pascale Cornillet-Lefebvre ◽  
Odile Maarek ◽  
Eric Lippert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Prognostic Impact ◽  
Trisomy 8 ◽  
Factors Associated ◽  
Acute Myeloid ◽  
Similar Incidence

Abstract Abstract 2594 Poster Board II-570 Background: Trisomy 8 (+8) is one of the most common cytogenetical abnormality observed in acute myeloid leukemia (AML). The prognostic impact of +8 as sole aberration remains unclear and +8 may be classified either within intermediate- or high-risk subgroups. Recently, the prognostic impact of cytogenetic in AML has been refined by the identification of: 1) favorable genotypes in cytogenetically normal (CN) AML defined by the presence of either NPM1 gene mutation (NPM1m) or CEBPA gene mutation (CEBPAm) and the absence of FLT3 duplication (FLT3/ITD); 2) highly unfavorable AML with monosomal karyotype (MK). The aim of this study was to precise the prognostic impact of: 1) additional +8 in various cytogenetic risk subgroups; and 2) +8 as sole aberration when compared to different CN-AML genotypes. Patients: A total of 2087 patients with AML (AML-M3 excluded) were treated in the LAM-2001, LAM-SA-2002, ALFA-9802 and ALFA-9801 studies from the French AML Intergroup. After central review, cytogenetic analysis was considered successful in 1796 patients. Abnormalities were categorized according to the French AML Intergroup classification. All analysis (complete remission, CR; overall survival, OS; probability of continuous complete remission, %CCR) were stratified on studies. Results: +8 was present in 171/1796 (9.5%) with a similar incidence among the different cytogenetic subgroups: 22/243 fav-risk (9.1%), 99/1121 int-risk (8.8%), and 50/432 unfav-risk (11.6%). The incidence of +8 was significantly higher in MK-AML versus non MK-AML (30/223, 13.5%, p=.04). In none of these subgroups (fav, int, unfav, and MK), the presence of +8 was associated with a significantly different outcome (CR, OS, %CCR). When compared to patients with CN-AML, the 78 patients with +8 as sole anomaly had a similar age, a lower WBC (median WBC: 5 G/L vs 11.5 G/L, p=.004), a similar incidence of FLT3/ITD (22.2% vs 23.7%, 6/27 vs 101/426, p=.99), and a lower incidence of NPM1m (23.8% vs 46.5%, 5/21 vs 187/402, p=.05). In patients with +8 as sole anomaly, prognostic factors associated with a shorter OS were age (p=.01), high WBC (p=.01), and presence of +8 in all analyzed metaphases which was found in 1/3 of patients (p=.05). In those patients, when compared to CN-AML in general, CR rate was similar (88% vs 87%, p=.99), but %CCR and OS were shorter without, however, reaching significance (5y-%CCR: 31.8% vs 45.7%, p=.18). When compared to CN-AML patients with favorable genotypes (NPM1m or CEBPAm w/o FLT3/ITD), patients with +8 as sole anomaly had now a lower CR rate (87% vs 93%, p=.13) and significantly shorter %CCR and OS (5y-%CCR: 37.4% vs 57.8%, p=.05; 5y-OS 35.6% vs 59.0%, p=.05). Conversely, the prognosis of patients with +8 as sole anomaly appeared similar to that of patients with CN-AML w/o favorable genotypes (5y-OS: 32.6%). Conclusion: We report here the largest cohort of patients with +8. Additional +8 is equally distributed among cytogenetic risk subgroups and does not impact prognosis in each of these subgroups. Patients with AML with +8 as sole anomaly have an outcome comparable to that of CN-AML without favorable genotypes, suggesting that these patients should be managed similarly. Disclosures: No relevant conflicts of interest to declare.

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