Genetic Mutations and Their Clinical Implications in Older Patients with Acute Myeloid Leukemia

2020 ◽  
pp. 1-7
Author(s):  
Xiaohong Xu ◽  
Shushu yuan ◽  
Pengcheng Xu ◽  
Zhirong Cong ◽  
Li Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
The Elderly ◽  
Genetic Alterations ◽  
Patient Specific ◽  
Genetic Mutations ◽  
Npm1 Mutation ◽  
Tp53 Mutations ◽  
Acute Myeloid

Objective：A number of leukemia-associated and patient-specific factors are related to the prognosis in older acute myeloid leukemia (AML) patients. In this study, we focus on the genetic mutations of older patients with AML and their impact on the clinical and prognosis. Methods: We retrospectively analysed the clinical, cytogenetic and laboratory data of 427 de novo non-M3 AML patients treated in our hospital from January 2000 to March 2014. We compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Then clinical curative effect survival rate of patients in two groups was observed after followed-up. Results: Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently had one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetic into three risk groups. Conclusion: Older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetic and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment.

scholarly journals Genetic Alterations and Their Clinical Implications in Older Patients with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4956-4956
Author(s):  
Cheng-Hong Tsai ◽  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Chin Lin ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
The Elderly ◽  
Genetic Alterations ◽  
Patient Specific ◽  
Intensive Chemotherapy ◽  
P53 Mutations ◽  
Acute Myeloid

Abstract Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315). Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia

Leukemia ◽  
2016 ◽  
Vol 30 (7) ◽  
pp. 1485-1492 ◽  
Author(s):  
C-H Tsai ◽  
H-A Hou ◽  
J-L Tang ◽  
C-Y Liu ◽  
C-C Lin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Clinical Implications ◽  
Acute Myeloid

scholarly journals A novel nutritional index “simplified CONUT” and the disease risk index independently stratify prognosis of elderly patients with acute myeloid leukemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hajime Senjo ◽  
Masahiro Onozawa ◽  
Daisuke Hidaka ◽  
Shota Yokoyama ◽  
Satoshi Yamamoto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nutritional Status ◽  
Risk Stratification ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
The Elderly ◽  
Genetic Alterations ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Elderly patients aged 65 or older with acute myeloid leukemia (AML) have poor prognosis. The risk stratification based on genetic alteration has been proposed in national comprehensive cancer network (NCCN) guideline but its efficacy was not well verified especially in real world elderly patients. The nutritional status assessment using controlling nutritional status (CONUT) score is a prognostic biomarker in elderly patients with solid tumors but was not examined in elderly AML patients. We performed prospective analysis of genetic alterations of 174 patients aged 65 or older with newly diagnosed AML treated without hematopoietic stem cell transplantation (HSCT) and developed simplified CONUT (sCONUT) score by eliminating total lymphocyte count from the items to adapt AML patients. In this cohort, both the NCCN 2017 risk group and sCONUT score successfully stratified the overall survival (OS) of the elderly patients. A multivariable analysis demonstrated that adverse group in NCCN 2017 and high sCONUT score were independently associated with poor 2-year OS. Both risk stratification based on NCCN 2017 and sCONUT score predict prognosis in the elderly patients with newly diagnosed AML.

FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3589-3595 ◽  
Author(s):  
Derek L. Stirewalt ◽  
Kenneth J. Kopecky ◽  
Soheil Meshinchi ◽  
Frederick R. Appelbaum ◽  
Marilyn L. Slovak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Tp53 Mutations ◽  
Ras Mutations ◽  
Cell Counts ◽  
Single Stranded Conformational Polymorphism ◽  
Acute Myeloid

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RASmutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P = .0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53mutations were associated with a worse overall survival (median 1 versus 8 months, P = .0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes.

FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1574-1574
Author(s):  
Shuhong Shen ◽  
Yin Liu ◽  
JingYan Tang ◽  
Long-Jun Gu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1574 Poster Board I-600 Introduction Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ? Patients and Methods 155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis. Results Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children. Disclosures No relevant conflicts of interest to declare.

Acute Myeloid Leukemia with Normal Karyotype: Analysis of FLT3, NPM1, MLL and CEBPA Gene Abnormalities.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4245-4245
Author(s):  
Fernanda Trigo ◽  
Fatima Torres ◽  
Patricia Guimaraes ◽  
Pedro Silva-Coelho ◽  
Ines Carvalhais ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Agarose Gel ◽  
Coding Region ◽  
Rt Pcr ◽  
Npm1 Mutation ◽  
Clinicopathological Findings ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with normal karyotype (AML-NK) is markedly heterogeneous depending on the presence or absence of certain genetic alterations. We studied the prevalence of different abnormalities, namely of the FLT3, NPM1, CEBPA and MLL genes, in AML-NK patients and tried to correlate them with clinicopathological findings. Techniques used were as follows: FLT3-ITD (internal tandem duplications), PCR using fluorescent primers, analysis in automatic sequencer; FLT3-TKD (D385), PCR, fragment cut with EcoRV restriction enzyme run in agarose gel; NPM1, RT-PCR and automatic sequencing of a fragment containing exon 12; CEBPA, PCR and automatic sequencing of the entire coding region; MLL-PTD, RT-PCR with analysis in agarose gel. The following data from patients were recorded: sex, age, FAB classification, WBC and platelet count, hemoglobin and LDH level, response to induction, survival time and cause of death. The incidence of FLT3 alterations (all ITDs) was 10/23 (43.5%), varying from 1 to 10 ITDs; NPM1 was mutated in 12/24 cases (50.0%) and MLL-PTD in 2/24 patients (8.3%); for CEBPA, of the 10 cases in which all 3 amplicons (1A, 2B, 3C) were analysed, 6 had a mutation mostly in amplicon 2B (5 cases). More than one genetic abnormality was present in 9 cases: six showed coexistence of FLT3-ITD and NPM1 mutation, one of MLL and CEBPA mutations, one of FLT3-ITD and CEBPA mutation and one of FLT3-ITD, NPM1 and CEBPA. Regardind correlation with clinical characteristics, we observed that 72.7% of nucleophosmin mutated (NPM1+) cases were CD34 negative and 91.7% of CD34+ patients were NPM1 negative (p=0.003). There is a tendency, although not significant, for CEBPA+ cases to correlate with low WBC counts and for patients with high WBC count to be NPM1+ and FLT3-ITD+ (odds ratio of 3.0 and 3.33, respectively). All NPM1+ patients treated with appropriate induction therapy achieved complete remission; 22.2% of NPM1 negative patients were refractory to therapy. No significant correlation was observed between survival and presence or absence of any of the genetic alterations. This work was funded by an unrestricted grant from Roche Farmaceutica - Portugal.

scholarly journals Therapeutic Choice in Older Patients with Acute Myeloid Leukemia: A Matter of Fitness

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 120
Author(s):  
Raffaele Palmieri ◽  
Giovangiacinto Paterno ◽  
Eleonora De Bellis ◽  
Lisa Mercante ◽  
Elisa Buzzatti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Standard Of Care ◽  
The Elderly ◽  
Treatment Choice ◽  
Conditioning Treatment ◽  
Approved Drugs ◽  
Acute Myeloid

Acute myeloid leukemia (AML), with an incidence increasing with age, is the most common acute leukemia in adults. Concurrent comorbidities, mild to severe organ dysfunctions, and low performance status (PS) are frequently found in older patients at the onset, conditioning treatment choice and crucially influencing the outcome. Although anthracyclines plus cytarabine-based chemotherapy, also called “7 + 3” regimen, remains the standard of care in young adults, its use in patients older than 65 years should be reserved to selected cases because of higher incidence of toxicity. These adverse features of AML in the elderly underline the importance of a careful patient assessment at diagnosis as a critical tool in the decision-making process of treatment choice. In this review, we will describe selected recently approved drugs as well as examine prognostic algorithms that may be helpful to assign treatment in elderly patients properly.

scholarly journals Correlative Biomarkers of Response to Venetoclax in Combination with Chemotherapy or Hypomethylating Agents in Elderly Untreated Patients with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1709-1709 ◽  
Author(s):  
Brenda Chyla ◽  
Relja Popovic ◽  
Jalaja Potluri ◽  
John Hayslip ◽  
Xin Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Peripheral Blood ◽  
Rna Splicing ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Hypomethylating Agents ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Background: We recently reported encouraging antileukemic activity of venetoclax, an orally available selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA; NCT02203773) or low dose cytarabine (LDAC; NCT02287233) in patients aged ≥65 years with treatment-naive acute myeloid leukemia (AML) who are not fit for standard induction therapy [Pollyea et al, ASCO 2016 (abstract 7009); Lin et al, ASCO 2016 (abstract 7007)]. Here we present the genetic and molecular markers observed in this patient population, and their correlation with responses. Methods: The data cut-off dates were: 10FEB2016 (venetoclax+HMA study), and 15FEB2016 (venetoclax+LDAC study). Patient responses were assessed according to the IWG criteria for AML. Given the selectivity of venetoclax to inhibit BCL-2, but not BCL-xL, the baseline expression of BCL-2 and BCL-xL proteins in blasts isolated from peripheral blood was determined by flow cytometry. The expression levels of BCL-2 were compared between those who achieved a response [complete remission (CR), CR with incomplete marrow recovery (CRi), partial remission (PR), morphologically leukemia free state (MLFS)] and those who did not achieve a response by the data cut-off dates [resistant disease (RD), progressive disease (PD)]. Next-generation sequencing (NGS) was performed on the blasts from bone marrow aspirates to identify recurrent mutations in genes associated with AML. Patients were classified into the following molecular subgroups based on the mutations data and site reported cytogenetics: (i) chromatin-RNA splicing group consisting of mutations in chromatin remodeling factors (ASXL1, EZH2), in splicing factors (SRSF2, SF3B1, ZRSR2), and/or in the transcription factor, RUNX1 (ii) NPM1 mutation (iii) MLL translocation (iv) TP53 mutations or >3 chromosomal aberrations (Papaemmanuil et al. NEJM 2016). Results: Data from 45 patients enrolled in the venetoclax+HMA study and 26 patients enrolled in the venetoclax+LDAC study are reported here. The demographic and baseline characteristics are summarized in Table 1. BCL-2 and BCL-xL protein expression were determined in 16/45 (36%) patients from the venetoclax+HMA study and 11/26 (42%) patients from the venetoclax+LDAC study. Remaining 44/71 (62%) patients were not included in this analysis for the following reasons: not evaluable for clinical response (n=7), non-availability of the specimen (n=8), and insufficient blasts in peripheral blood (n=29). The percentage of blasts expressing BCL-xL was low (range 0-22%, median 0.6%), whereas the percentage of blasts expressing BCL-2 (BCL-2+) varied (6-99%, median 75%). 16/27 (59%) evaluable patients who achieved a response of CR/CRi/PR/MLFS had an average of 78% blasts BCL-2+. The remaining 11/27 (41%) patients who have not yet achieved a response had an average of 64% blasts BCL-2+ and were separated into two groups: a low percent of BCL-2+ blasts (median 11%, n=5) and a high percent of BCL-2+ blasts (median 82%, n=6) (Figure 1). Pre-treatment bone marrow aspirates were available for NGS analysis from 40/45 patients (venetoclax+HMA study) and 21/26 patients (venetoclax+LDAC study). The data are summarized in Table 2. The chromatin-RNA splicing group comprised the largest subset of patients (n=28), of which 19 (68%) patients achieved a CR/CRi. Majority [10/11 (91%)] of the patients with NPM1 mutation had a CR/CRi. Conversely, 3/12 (25%) patients with TP53 aneuploidy or >3 chromosomal aberrations and 2/6 (33%) with MLL translocation achieved a CR/CRi to date. IDH1/2 mutations were identified in 11/45 (24%) patients in the venetoclax+HMA trial and 7/21 (33%) patients in venetoclax+LDAC trial. 10/11 (91%) patients from the venetoclax+HMA trial and 5/7 (71%) patients from the venetoclax+LDAC trial were responders. Conclusions: The results from this small data set showed that patients who achieved a response to venetoclax plus HMA or LDAC had a higher percent of blasts with BCL-2+. Among patients classified as non-responders, it remains to be determined if those with high percent of BCL-2+ blasts (n=6) will achieve a response with longer time on venetoclax therapy. Patients with specific genetic alterations such as chromatin-RNA splicing and NPM1 mutation may correlate with better odds of response to a venetoclax containing regimen. Samples are being analyzed to confirm these early findings as the two studies continue to enroll more patients. Disclosures Chyla: AbbVie Inc.: Employment, Other: may own stock. Popovic:AbbVie Inc.: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock. Huang:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Mabry:AbbVie Inc.: Employment, Other: May own stock. Bhathena:AbbVie Inc.: Employment, Other: may own stock.

Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients

2007 ◽  
Vol 25 (14) ◽  
pp. 1908-1915 ◽  
Author(s):  
Elihu Estey
Keyword(s):  
Acute Myeloid Leukemia ◽  
Natural History ◽  
Lower Risk ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Specific Treatment ◽  
Risk Groups ◽  
The Elderly ◽  
History Of ◽  
Acute Myeloid

The median age of patients with acute myeloid leukemia (AML) is 65 to 70 years. The majority of older patients with AML probably do not receive specific treatment, and those who receive standard regimens have a median survival time of less than 1 year. This suggests that, in general, older patients should receive investigational therapy; however, factors other than age influence survival after administration of standard treatment and need to be accounted for when making treatment recommendations. In some cases where investigational therapy is unavailable, palliative care may be the best option. Like AML, myelodysplastic syndrome (MDS) is a disease of the elderly. It is divided into higher and lower risk groups. The natural history of high-risk MDS (eg, > 10% marrow blasts) bears more resemblance to that of AML than to that of an indolent disorder; accordingly, similar therapeutic considerations apply. The more benign natural history of lower risk MDS leads to consideration of reduction in transfusion needs and improvement in quality of life as primary goals of therapy. Lenalidomide, azacitidine, and decitabine, each recently approved by the US Food and Drug Administration, are useful in achieving these objectives.

Comprehensive Analysis of Genetic Alterations in Acute Myeloid Leukemia According to the WHO Classification.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4311-4311
Author(s):  
Yuichi Ishikawa ◽  
Hitoshi Kiyoi ◽  
Akane Tsujimura ◽  
Yasusi Miyazaki ◽  
Masao Tomonaga ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
P53 Mutation ◽  
Npm1 Mutation ◽  
Multilineage Dysplasia ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and is thought to be the consequence of two broad complementation classes of mutations: those that confer a proliferative and/or survival advantage to hematopoietic progenitors, and those that impair hematopoietic differentiation and confer properties of self-renewal. To date, several genetic alterations, which are involved in the pathophysiology of the AML development, have been apparent, and some of them have been disclosed to have an impact on the clinical management. Therefore, it is required to establish the detailed classification of AML according to the genetic status. In this study, we comprehensively analyzed the genetic alterations in AML patients in comparison with the WHO classification. The study population included 115 newly diagnosed AML patients consisting of 25 recurrent genetic abnormalities, 25 multilineage dysplasia, 7 therapy-related and 56 not otherwise categorized WHO subcategories. Bone marrow samples were obtained from the patients after obtaining informed consent for banking and molecular analyses. Mutations in FLT3, cKIT, NPM1, N-RAS, p53, C/EBPa, AML1 and AKT1 genes were analyzed as previously described. In consistent with previous reports, FLT3 (20.9%), NPM1 (14.8%) and C/EBPa (13.0%) mutations were frequently observed, while no AKT1 mutation was found. Furthermore, NPM1 mutation was not found in AML with recurrent genetic abnormalities and C/EBPa mutation was not found in AML with recurrent genetic abnormalities or therapy related. Nine cases have double mutations of FLT3 and NPM1 genes, and 3 have FLT3 and C/EBPa mutations. Of note is that 15 of 25 (60%) AML with multilineage dysplasia cases have at least one mutation in p53, NPM1, C/EBPa, FLT3, N-RAS and AML1 genes and that p53 mutation was selectively found in the cases with complex karyotype. However, 4 AML with multilineage dysplasia cases with normal karyotype did not have any mutations in the analyzed genes. Comprehensive genetic analysis clarifies the detailed molecular base of AML and could make the subdivision of the WHO classification by combining the analysis for clinical impacts. Especially, mutation status in p53, NPM1 and C/EBPa genes seems to be useful for the subdivision of the AML with multilineage dysplasia, which is the most heterogeneous subcategory in the WHO classification.

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