scholarly journals Presence of TP53 Mutation and Monosomal Karyotype Predict the Outcome of Patients with Acute Myeloid Leukemia in Non-Remission at Allogeneic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2168-2168
Author(s):  
Yuho Najima ◽  
Daichi Sadato ◽  
Yuka Harada ◽  
Chizuko Hirama ◽  
Keisuke Oboki ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
De Novo Aml ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Background Although the outcome after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for the patients with acute myeloid leukemia (AML) in complete remission has been improved, the prognosis of patients with active disease is still dismal, generally with 20 - 30% of overall survival (OS) at 2 years. Prognostic value of gene mutations detected by the next generation sequencing (NGS) for this extremely poor group remains to be evaluated. Methods A total of 120 patients with AML not in hematological remission who received the first allo-HSCT at our institute between April 2005 and December 2017 were enrolled. For each patient, genomic DNA was extracted from the frozen bone marrow sample harboring leukemic blasts which was preserved at the nearest available date before the initiation of conditioning regimen. Sequencing was performed using TruSight Myeloid Sequencing Panel® on the MiniSeq system (Illumina). Gene variants were detected by in-house analysis pipeline. Charts were retrospectively reviewed on survival, relapse, and non-relapse mortality (NRM). The Kaplan-Meier method was used to assess OS using the log-rank test. Univariate and multivariate analysis were performed to identify potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS. Gray's test and the Fine-Gray test were used to assess the cumulative incidence of relapse (CIR). Competing risks were relapse and NRM. Results Median follow-up of survivors was 1345 days (235 - 4888 days). Median age at transplant was 51 (range 21 - 71). Grafts were from bone marrow (n = 67, 55.8%), peripheral blood (n=42, 35.0%) and cord blood (n=11, 9.2%). Refined disease risk index (Blood. 2014;123:3664-71) scored high (n=61, 51.3%) and very high (n=58, 48.7%). OS at 2 years of the whole cohort was 27.3% (95% confidence interval [CI], 19.4% - 35.7%). There was no significant difference in OS between patients in primary induction failure and in relapse (OS at 2 years: 26.5% [n=50] vs 28.7% [n=70], p= 0.293). NGS analysis revealed TP53 loss-of-function mutation in 23 (19.2%) patients. Among all detected gene mutations, TP53 mutation was the most powerful predictor of poor OS after allo-HSCT (OS at 2 years: 13.5% vs 30.5% for TP53+ [n=23] vs TP53- [n=97], p= 0.0184). Consistent with previous reports, monosomal karyotype (MK, J Clin Ocnol 2010:26;4791-7) was significantly associated with positive TP53 mutation (13.3% of non-MK vs 37.9% of MK, p=0.006). Of note, all the patients (n=11) positive for both prognostic factors died within 1 year after allo-HSCT, whereas OS of the patients without either factor (n=78) was 33.6% at 2 years. Multivariate analysis on OS revealed MK, TP53 mutation, de novo AML (no prior history of MDS), ECOG performance status score 2 or more, C reactive protein 1.0 mg/dL or more, peripheral blood blast frequency of 1% or more at the initiation of conditioning regimen were independent prognostic factors for poor OS. Among them, to determine the prognostic factors critical for deciding the indication of allo-HSCT, we chose pre-transplant factors which were available around one months before transplant. From this point of view, multivariate analysis revealed independent prognostic factors for poor OS after allo-HSCT including MK (Hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.30 - 3.25, p=0.00217), TP53 mutation (HR 1.72; 95% CI 1.04 - 2.86, p=0.035), and de novo AML (HR 1.67; 95% CI 1.04 - 2.86, p=0.036). Because the HR of these three factors were comparable, a score of 1 was assigned to each factor. OS at 2 years was 49.7%, 26.5% and 13.1% for patients with low (score 0, n=23), intermediate (score 1, n=63) and high (score 2 or 3, n=34) risk, respectively (p<0.001, Figure 1A). CIR was significantly lower in low risk group compared to intermediate and high risk groups (9.0%, 49.7% and 48.0% at 2 years, p=0.0128, Figure 1B), whereas NRM was comparable (41.3%, 32.5% and 41.7% at 2 years, p =0.515). Conclusions NGS-analysis revealed the importance of TP53 mutation on transplant outcome of AML in non-remission. The combined score with the information on MK, de novo AML, and TP53 mutation stratified the patients into three groups, including low risk with 50% survival rate, and high risk with shorter survival after allo-HSCT for whom the other strategy might be optimal. Our results would require further validation in larger cohorts. Disclosures Harada: Celgene: Research Funding.

Clinico-Biological Characteristics and Prognosis of Non-M3 Acute Myeloid Leukemia with High Percentage of Myeloperoxisase Positive Blasts. Single Center Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4462-4462
Author(s):  
Pau Montesinos ◽  
Lorenzo Algarra ◽  
Jaime Sanz ◽  
Mari Luz Perez ◽  
Leonor Senent ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Favourable Outcome ◽  
Biological Characteristics ◽  
Prognostic Impact ◽  
Acute Myeloid

Abstract Introduction: It has been suggested that acute myeloid leukemia (AML) showing mature phenotype is associated with favourable outcome. In a study recently published by JALSG, myeloperoxidase (MPO) positivity in over 50% of blasts had favourable prognostic impact, independent from karyotype, on achieving complete remission (CR), overall survival (OS) and disease free survival (DFS). No other studies have established the independent prognostic value of MPO expression. Objectives: Analyze the clinico-biological characteristics of AML with high percentage of MPO+ blasts and its impact on CR, OS and DFS. Material and methods: Between 1986 and 2005, 418 adult patients (median 53 years, range 15–80) were diagnosed with de novo non-APL AML and evaluated for percentage of MPO+ blasts. All patients received intensive chemotherapy. Diagnosis was made by optic microscopy of bone marrow (BM) aspirates stained with May-Grumwald giemsa, MPO, butyrate esterase and or non specific esterase. Cytogenetic and immunophenotype analysis was evaluated in 66% and in 76% of the cases respectively. Results: 118 patients (28%) showed a percentage of MPO+ blasts >75%. AML with MPO+ blasts >75% was associated with M1-M2-M4 subtypes, leucocytes >50×109/L, blasts in BM >70% and HLA-DR negativity (p<0.01). It was also significantly associated with favourable karyotype (11% vs 3% favourable, 52% vs 48% intermediate and 3% vs 15% unfavourable). Patients with AML and MPO+ blasts >75% obtained higher CR rate (71% vs 55%), due to less resistant disease (9% vs 22%, p<0.01). In multivariate analysis favourable karyotype, leukocytes <50×109/L and age <60 were favourable prognostic factors for CR. Median OS and DFS was higher in patients with AML and MPO+ blasts >75% (15 vs 7 months, p<0.001, y 41 vs 12 months, p<0.001, respectively). ). In multivariate analysis, favourable karyotype, leukocytes <50×109/L, age <60 years and MPO+ >50% were favourable prognostic factors for OS; and age <60 and MPO+ >75% were the only independent factors for DFS. Median DFS was higher in patients with AML and MPO+ blasts >75% in the intermediate cytogenetic risk group (59 vs 13 months, p=0.015), age <60 (109 vs 15 months, p=0.003), age >60 (13 vs 7 months, p=0.03), autologous stem cell transplantation (100 vs 9 months, p=0.04) and chemotherapy alone (16 vs 8 months, p=0.003). Conclusion: In our series, patients with AML and MPO+ blasts >75% show less chemoresistant disease and a longer remission duration, the latter independently from the karyotype. This biological characteristic could be useful in designing therapeutic strategies in patients that lack other prognostic markers.

Addition of Lomustine to Idarubicin and Cytarabine Improves the Outcome of Elderly Patients With De Novo Acute Myeloid Leukemia: A Report From the GOELAMS

2010 ◽  
Vol 28 (18) ◽  
pp. 3028-3034 ◽  
Author(s):  
Arnaud Pigneux ◽  
Jean-Luc Harousseau ◽  
Francis Witz ◽  
Mathieu Sauvezie ◽  
Marie-Christine Bene ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Elderly Patients ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Group I ◽  
Acute Myeloid

Purpose No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML. Patients and Methods The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m2, days 1 through 5) and cytarabine (100 mg/m2, days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m2 orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine. Results The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 ± 2.2 months v 8.7 ± 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age ≤ 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001). Conclusion Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.

Gene Mutations in Paired Initial Presentation and Relapse Samples From Acute Myeloid Leukemia Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3592-3592
Author(s):  
Satoshi Wakita ◽  
Hiroki Yamaguchi ◽  
Yoshio Mitamura ◽  
Fumiko Kosaka ◽  
Takashi Shimada ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
Gene Mutations ◽  
Initial Presentation ◽  
Paired Samples ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3592 Introductions: Gene mutationswere found in acute myeloid leukemia (AML) and their importance has been noted. Flt3, NPM1 and CEBPA were detected in “intermediate cytogenetic risk” group, and are becoming possible to distinguish subsets of patients with different outcomes. Moreover, several groups have reported that these mutations would be useful for not only predictive markers, but also minimal residual disease (MRD) markers in AML. Several recent studiesprovided compelling evidence that mutations in epigenetics modifying genes contribute to AML pathogenesis. DNMT3a mutations were common (about 20% frequency) in de novo AML and associated with poor prognosis. Furthermore, mutations of IDH1/2 and TET2 that also seem to be collaborating on DNA methylation modifying are detected, too. To clarify the importance and dynamics of these mutations in clinical course, we examined Flt3, NPM1, CEBPA, DNMT3a and IDH1/2 gene mutations in paired samples at initial presentation and relapse of AML patients. Materials and Methods: We analyzed the samples from adultpatients with de novo AML diagnosed at Nippon Medical School Hospital from 2000 to 2010. Mutation analyses were performed for Flt3 ITD by PCR amplification, Flt3 TKD by PCR-RFLP, and NPM1, CEBPA, IDH1/2 and DNMT3a mutations by direct sequence. Results: The 31 AML patients were enrolled. In chromosomal analysis at initial presentation, 19 with normal karyotype (NK-) AML, 2 with trisomy8, 4 with 11q23 associated, 1 with monosomy7, 2 with complex karyotypes and 3 with non-specific aberrations were observed. 15 cases were comparable for paired samples at diagnosis and relapse. 13 of them (86.7%) showed additional chromosomal aberrations at relapse. Gene mutations were detected more frequently in cytogenetic intermediate risk group (83.3%) than poor risk group (0%). There were 11 patients with Flt3 ITD at initial presentation, but 3 of them had no detectable mutation at relapse. Flt3 TKD were found in 3 patients at initial presentation, but all of them were lost at relapse. Among 12 patients with NPM1 mutation at initial presentation, 3 of them lost their mutation at relapse. CEBPA mutation was detected in only one paired sample at diagnosis and relapse. DNMT3a mutations were detected in 8 patients both at initial presentation and relapse. IDH2 mutations were detected in two patients at initial presentation, but 1 of them was lost at relapse. In summary, of the 37 gene mutations at initial presentation, 10 gene mutations were lost at relapse, and only 1 acquired gene mutation was detected at relapse. Flt3 ITD, NPM1, DNMT3a and IDH2 mutations frequently coexisted with another mutation. Discussion: This study is the first report of consecutive analyses on the major gene mutations in AML. Newly acquired gene mutations at relapse are rare compared to frequent additional chromosomal aberrations at relapse. Flt3 ITD mutations at initial presentation were detected also at relapse. This finding indicates that Flt3 ITD are responsible for relapse and refractoriness. On the other hand, all 3 cases with Flt3 TKD lost the mutation at relapse, suggesting that Flt3 TKD mutation does not contribute to their relapse. Some of Flt3 ITD, Flt3 TKD and NPM1 mutations could not be detected at relapse, indicating that these mutations should be used carefully for MRD marker. DNMT3a mutations were detected both at diagnosis and relapse in all 8 cases. This finding suggests that DNMT3a mutations might be a useful MRD marker. Disclosures: No relevant conflicts of interest to declare.

Analysis Of Micro-RNA-142 Mutations In a Cohort Of 944 Patients With MDS and AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2804-2804
Author(s):  
Felicitas Thol ◽  
Aylin Kirchner ◽  
Rabia Shahswar ◽  
Sofia Kade ◽  
Christian Koenecke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Gene Mutations ◽  
Seed Region ◽  
Target Specificity ◽  
Related Gene ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background MicroRNAs are short (20-40 nucleotides) non-coding RNA molecules that are responsible for the post-transcriptional regulation of gene expression. Aberrant expression of MicroRNAs has been associated with various malignancies. Specifically, downregulation of MicroRNA-142 (miR-142) has been shown to occur in acute myeloid leukemia (AML). Interestingly, also gene mutations in miR-142 have been recently described in de novo AML. So far, little is known about mutations in miR-142 in myeloid malignancies. The aim of this study was to analyze mutations in the miR-142 in a large cohort of 944 patients with AML and myelodysplastic syndrome (MDS). Patients and Methods The patient group consisted of 425 de novo AML patients (excluding AML M3) who entered the multicenter treatment trials AML SHG 0199 or AML SHG 0295, 326 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for secondary acute myeloid leukemia after a prior diagnosis of MDS (sAML) (n=170) or primary MDS (n=156), and 193 primary MDS patients not undergoing intensive therapy or allogeneic HSCT. The genomic region of the miR-142 gene, containing miR-142-5p and miR-142-3p, was sequenced by Sanger sequencing. Patient samples were also assessed for other frequently mutated genes in AML and MDS. Results and Discussion We identified five patients with mutations in miR-142. All mutations were heterozygous point mutations affecting the seed region of miR-142-3p, thereby potentially changing the target specificity of miR-142. Mutations in miR-142 occurred in male and female patients. Of the five patients with mutations in miR-142, only one patient carried the diagnosis of de novo AML (0.2% in de novo AML), while two patients were diagnosed with sAML (1.2% in sAML) and two patients had MDS (0.56% in MDS, corresponding to 0.77% in MDS/AML from MDS). Apart from one patient who underwent allogeneic transplantation for sAML, all other patients with follow-up died of the disease in less than a year. 3 patients had normal cytogenetics, while one patient had a complex karyotype and one patient had a trisomy 8 with translocation t(1;4). No mutated patient showed aberrations typically associated with de novo AML (RUNX1/RUNX1T1, CBFB/MYH11, FLT3-ITD, NPM1 mutations or CEBPA mutations). However, myelodysplasia-related gene mutations such as mutations in the splicing genes or chromatin remodelling genes were found in two patients (one patient with mutated ASXL1 and SRSF2, one patient with mutated U2AF1). Furthermore, one patient had a concomitant mutation in NRAS and IDH1. Thus, the associated mutational profile suggests that miR-142 mutations play a role in the pathogenesis of MDS rather than de novo AML. Conclusion MicroRNA-142 is recurrently but infrequently mutated in MDS and secondary AML evolving from MDS, and some mutations co-occur with MDS-related gene aberrations. As miR-142 mutations affect the seed region of the miRNA the target specificity is likely changed, and the miRNA may lose its tumor suppressor function, which has been implicated from functional studies. Disclosures: Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Pretransplant comorbidity as an outcome predictor in adult patients younger than 60 years of age receiving standard induction chemotherapy for de novo acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7055-7055
Author(s):  
S. Kim ◽  
J. Lee ◽  
J. Lee ◽  
D. Kim ◽  
S. Lim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Outcome Predictor ◽  
Free Survival ◽  
Pre Treatment ◽  
De Novo Aml ◽  
Acute Myeloid

7055 Background: Comorbidity has been evaluated as an outcome predictor in elderly patients receiving induction chemotherapy for acute myeloid leukemia (AML) as well as in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematologic disorders. In this single-institute retrospective study, we investigated the prognostic significance of comorbidity in younger AML patients. Methods: A total of 276 patients, aged 14 to 59 years, who received standard induction chemotherapy consisting of cytarabine plus daunorubicin or idarubicin for de novo AML excluding M3 subtype between 2000 and 2007 were included. Pre-treatment comorbidity score, assessed by the HCT specific comorbidity index (HCT-CI), was calculated using clinico- pathologic data, which were retrieved from Asan Medical Center Leukemia Registry Database. The HCT-CI score was 0 in 113 patients (40.9%), 1 in 94 (34.1%), and ≥ 2 in 69 (25.0%). Results: In the univariate analyses, the HCT-CI score was not a significant prognostic factor for induction of complete remission (CR), whereas survival outcomes such as overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were significantly different according to the HCT-CI scores (Table). The multivariate models showed that the HCT-CI score was an independent prognostic factor for EFS (P=0.044), but not for OS (P=0.301) and RFS (P=0.119). Other independent prognostic factors were age (P=0.001 for OS, P=0.002 for RFS, P=0.006 for EFS), initial leukocyte counts (P=0.006 for CR, P<0.001 for OS, P=0.039 for RFS), initial uric acid levels (P=0.004 for RFS, P=0.001 for EFS), and cytogenetic risk groups (P=0.012 for CR, P<0.001 for OS, P<0.001 for RFS, P=0.005 for EFS). Conclusions: Pre-treatment comorbidity may provide additional prognostic information over established prognostic factors in patients younger than 60 years of age receiving standard induction chemotherapy for de novo AML. [Table: see text] No significant financial relationships to disclose.

scholarly journals TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

scholarly journals TP53 Mutation in Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66%, 13%, 9%, 9% and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50%, 17.6%, 9.2% and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22% and 27%, respectively. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P= 0.023, HR= 1.20- 7.02), whereas, WBC count> 100,000/μL (P= 0.004, HR= 1.32- 4.16) and complex karyotype (P= 0.038, HR= 1.07- 9.78) were associated with shorter OS in AML patients. Discussion: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

The Prognostic Impact Of Complex Gene Mutation In The Intermediate Risk Karyotype Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1418-1418
Author(s):  
Satoshi Wakita ◽  
Hiroki Yamaguchi ◽  
Takeshi Ryotokuji ◽  
Tuneaki Hirakawa ◽  
Ikuko Omori ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Nippon Medical School ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background Many gene mutations were detected and overlapped in de novo acute myeloid leukemia (AML), but the prognosis of complex gene mutation remains to be unclear. In this study, we analyzed the prognostic impact of complex gene mutation in de novo AML patients with the intermediate risk karyotype. Methods We analyzed 143 samples from de novo AML patients with the intermediate risk karyotype diagnosed at Nippon Medical School Hospital from 2000 to 2012. Bone marrow or peripheral blood samples containing 20% or more blast cells were used for analyses. Mutation analyses were performed using PCR method for FLT3-ITD, FLT3-TKD and MLL-PTD, and direct sequence for NPM1, C/EBPα, DNMT3a, IDH1/2, TET2 and N/K-RAS. Results The NPM1 (39.9%), DNMT3a (26.6%), FLT3-ITD (24.5%), IDH1/2 (18.9%), TET2 (17.5%), C/EBPα (14.7%), N/K-RAS (14.0%) and MLL-PTD (6.3%) mutations were detected in our cohort, respectively. When we performed prognostic analyses for mutations of these genes, DNMT3 mutation and FLT3-ITD were isolated as a poor prognostic factor in overall survival (OS) , respectively (DNMT3a mutation positive: n=39, 3yOS 17.9%. negative: n=104, 3yOS 33.2%. p=.0056) (FLT3-ITD positive: n=35, 3yOS 12.2%. negative: n=108, 3yOS 35.0%. p=.0077). Moreover, in the FLT3-ITD positive cases, OS of patients with DNMT3a R882 mutation was significantly shorter than those without R882 mutation (R882 positive: n=20, 3yOS: 0%. negative: n=15, 3yOS 25.0%. p<.0256). Interestingly, High rate of patients with FLT3-ITD (91.4%), NPM1 (89.5%), DNMT3a (92.1%), TET2 (84.0%), and IDH1/2 (88.9%) mutations were detected other overlapped mutations, respectively. The frequency of the overlapped mutations in patients with DNMT3a mutation, especially with mutations on R882, was significantly higher than those in patients without them (DNMT3a: p=.0001, R882: p<.0001). For total cohort, the rates of and OS and relapse free survival (RFS) in patients with three or more overlapping mutations (complex gene mutation: CGM) were significantly lower than those in patients without them (CGM+: n=36, 3yOS 5.6%. CGM-: n=107, 3yOS 37.7%. p<.0001) (CGM+: n=12, 3yRFS: 8.3%. CGM-: n=57, 3yRFS: 36.0%. p=.0013). Moreover, among the patients without FLT3-ITD, the rates of RFS and OS at 3 years in patients with complex gene mutation were significantly lower than those in patients without them (CGM+: n=11, 3yOS 5.6%. CGM-: n=96, 3yOS 37.7%. p<.0408) (CGM+: n=4, 3yRFS: 8.3%. CGM-: n=51, 3yRFS: 36.0%. p=.0179). Conclusions Our study revealed that the gene mutations appeared to be overlapped, and the complex gene mutation significantly affected the prognosis of de novo AML with the intermediate risk karyotype. Intriguingly the DNMT3a mutation may contribute to an occurrence of complex gene mutation by giving genetic instability to AML cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunohistochemical Expression of CD123 Is Associated with an Inferior Clinical Outcome in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2887-2887
Author(s):  
Nana Arai ◽  
Bungo Saito ◽  
Maasa Abe ◽  
Megumi Watanuki ◽  
So Murai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Clinical Outcome ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
P53 Expression ◽  
De Novo Aml ◽  
Induction Failure ◽  
Acute Myeloid

Abstract Background: The aberrant expression of the interleukin-3 receptor (IL3RA or CD123) alpha chain is frequently observed in a subset of leukemic disorders, including acute myeloid leukemia (AML), particularly in leukemia stem cells. Using flow cytometric (FCM) analysis, studies have shown that increased CD123 expression is associated with a poor prognosis of AML. Although FCM is a sensitive technique, the analysis may be limited in a clinical setting because live leukemia cells are required. Immunohistochemistry (IHC) is a more useful alternative compared with FCM because it can be tested long after specimens are collected; however, it is less sensitive. Here we evaluated the impact of blast CD123 expression via IHC analysis for the prognosis of AML. Patients and methods: This study was performed as a retrospective analysis of 70 patients who were diagnosed with de novo AML (M0-M5, n = 48) and AML with myelodysplasia-related changes (MRC) (n = 22) at our hospital from February 2008 to September 2015. The median age at diagnosis was 64.5 years (range: 21-93 years). The median follow-up period was 498 days (range: 2-3052 days). Morphological findings were obtained using HE stains of 3-µm sections. Formalin-fixed, paraffin-embedded specimens were used for immunohistochemical analysis. We analyzed the relationships between the patients' clinical outcome and CD123, p53, CD34, CD71, CD56, and c-kit expressions. [(CD123, CD34, CD71, CD56, and c-kit immunostained slides were defined as positive if >10% of the blast cells had a moderate to strong membranous staining. p53 was evaluated as positive when more than 5% of the cells were positively stained. For each case, the following data were obtained: patient age (>60 years or <60 years), sex, karyotype (good, intermediate, or poor), SCT (undergone or not), 1st induction (failure or complete remission (CR), and overall survival (OS)]. Results: Of the 70 cases, percentages of the positive immunohistochemical study dates were as follows: CD123: 25.7%; p53: 30%; CD34: 52.8%; CD71: 46.3%; CD56: 25.7%; and c-kit: 77.1%. There were 48 cases with de novo AML: CD123: 29.1%; p53: 75%; CD34: 52%; CD71: 37.5%; CD56: 27%; and c-kit: 79.1%. Moreover, there were 22 cases with MRC: CD123: 18.1%; p53: 31.8%; CD34: 54.5%; CD71: 66.6%; CD56: 22.7%; and c-kit: 72.7%. CD71 is highly expressed in MRC than de novo AML (P = 0.036). Among all patients, the CR rate following first induction therapy was 62.3%. Age (≥60 years), high p53 expression, disease (MRC), and poor karyotype were associated with induction failure (P = 0.011, P = 0.002, P <0.001, and P = 0.008, respectively). Among patients with de novo AML, only elevated CD123 expression was associated with the failure to obtain a CR following the first remission induction chemotherapy (P = 0.044). In contrast, among patients with MRC, CD123 expression was not associated with any clinical data or the CR rate. The 2-year OS rates were 45.9%. Age (≥60), high p53 expression, MRC, poor karyotype were significantly associated with poor OS (P = 0.003, P = 0.036, P <0.001, and P = 0.002, respectively). In Multivariate analysis, age (≥60 years), MRC, poor karyotype are significantly associated with poor OS (P = 0.028, P = 0.001, and P = 0.014, respectively). Among de novo AML patients, CD123 expression, p53 expression, and induction failure were independently associated with poor OS (P = 0.036, 0.003 and P < 0.001, respectively), and increased p53 expression and induction failure was associated with poor OS in the multivariate analysis (P = 0.001 and P = 0.002). Among patients with MRC, only induction failure was associated with the OS (P = 0.026). Conclusion: This is the first study to demonstrate that CD123 expression using IHC is associated with poor a CR rate and OS in de novo AML patients; however, this association was not observed in MRC patients. Our results suggest that CD123 expression may predict the refractory to induction therapy and poor OS in de novo AML. Moreover, these results support previous reports using FCM. Therefore, CD123 expression may become one of the important factors used to characterize leukemia blasts and predict the prognosis of AML. In addition, novel therapy with antibodies targeting CD123 is currently under development. Therefore, we suggest that an analysis of CD123 expression using IHC is a clinically important assessment for de novo AML patients at the time of diagnosis. Disclosures No relevant conflicts of interest to declare.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

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