Acute Myeloid Leukemia With t(8;21)/RUNX1-RUNX1T1 demonstrate a High Number Of Secondary Genetic Lesions: Frequency and Impact On Clinical Outcome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2565-2565
Author(s):  
Maria Theresa Krauth ◽  
Christiane Eder ◽  
Tamara Alpermann ◽  
Wolfgang Kern ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Trisomy 8 ◽  
Employment Equity ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background Translocation t(8;21) with the resulting RUNX1-RUNX1T1 rearrangement is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). Although it is generally associated with a favourable prognosis, many additional genetic lesions may impact on outcome. Aim To assess the frequency and clinical impact of additional mutations and chromosomal aberrations in AML with t(8;21)/RUNX1-RUNX1T1. Methods We analyzed 139 patients (pts) who were referred to our laboratory for diagnosis of AML between 2005 and 2012 (65 females, 74 males; median age 53.3 years, range 18.6 - 83.8 years). All pts were proven to have t(8;21)/RUNX1-RUNX1T1 by a combination of chromosome banding analysis, fluorescence in situ hybridisation and RT-PCR. Analysis of mutations in ASXL1, FLT3-TKD, KIT (D816, exon8-11), NPM1, IDH1 and IDH2, KRAS, NRAS, CBL, and JAK2 as well as of MLL-PTD and FLT3-ITD was performed in all pts. Results 107/139 pts were classified according to FAB criteria (77.0%). 34/107 had AML M1 (31.8%) and 73/107 AML M2 (68.2%). 117/139 had de novo AML (84.2%), 22/139 had therapy-related AML (t-AML) (15.8%). 69/139 (49.6%) pts had at least one molecular alteration in addition to RUNX1-RUNX1T1, 23/69 (33.3%) had two or more additional mutations. Most common were mutations (mut) in KIT (23/139; 16.5%), followed by NRAS (18/139; 12.9%) and ASXL1 (16/139; 11.5%). FLT3-ITD and mutations in FLT3-TKD, CBL, and KRAS were found in 4.3% - 5.0% of all pts, whereas mutations in IDH2 and JAK2 were detectable in 3.6% and 2.9%, respectively. IDH1 mutations were found in only 0.7% (1/139). NPM1mut and MLL-PTD were mutually exclusive of RUNX1-RUNX1T1. FLT3-ITD as well as FLT3-TKD were exclusive of ASXL1 mutations. With exception of FLT3-ITD, which was only present in de novo AML, there was no difference in mutation frequencies between de novo AML and t-AML. 69.8% (97/139) pts had at least one chromosomal aberration in addition to t(8;21)(q22;q22). Most frequent was the loss of either X- or Y-chromosome (together 46.8%), followed by del(9q) (15.1%), and trisomy 8 (5.8%). FLT3-ITD, FLT3-TKD and trisomy 8 were found to be mutually exclusive. The number of secondary chromosomal aberrations did not differ significantly between pts with de novo AML and t-AML, showing only a trend towards higher frequency of -Y, del(9q), and trisomy 8 in pts with t-AML. Survival was calculated in pts who received intensive treatment (n=111/139, 79.9%; median follow-up 26.9 months; 2-year survival rate 73.4%). With exception of KITD816 mutation, which had a negative impact on overall survival in pts with de novo AML (2-year survival rate 64.2% vs. 82.3%, p=0.03), none of the other 13 mutations significantly influenced outcome, not even in case of 2 or more coexistent mutations. Also, no influence of additional chromosomal aberrations on survival was found. In selected cases (n=21/139), we compared dynamic changes in the patterns of genetic lesions at diagnosis and at relapse. In 14/21 (66.7%) pts the initial molecular mutation pattern changed at relapse. Mutations commonly gained at relapse were KIT mutations (6/21, 28.6%), followed by ASXL1 and IDH1R132 (each 2/21, 9.5%). FLT3-ITD, CBL, NRAS and JAK2 mutations emerged in 1/21 patients (4.8%) each. Loss of a mutation at relapse has been observed in KIT, ASXL1, and NRAS (each 2/21, 9.5%), as well as in KRAS, FLT3-ITD and FLT3-TKD (each 1/21, 4.8%). Concerning chromosomal alterations at relapse, 7/21 pts (33.3%) showed a change of their initial cytogenetic pattern, mostly shifting to a more complex karyotype (gain of chromosomal aberrations: 5/21, 23.8%; loss of chromosomal aberrations: 2/21, 9.5%). In all cases, t(8;21)(q22;q22)/RUNX1-RUNX1T1 remained stable at time of relapse. Conclusions 1) 50% of t(8;21)/RUNX1-RUNX1T1 positive pts had at least one additional molecular mutation and almost 70% showed additional chromosomal abnormalities. 2) KIT was the most frequent additional molecular mutation, followed by NRAS and ASXL1. 3) The only additional genetic marker with a significant adverse prognostic impact was KITD816 mutation. Disclosures: Krauth: MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals The possible significance of trisomy 8 in acute myeloid leukemia

2017 ◽  
Vol 5 (6) ◽  
pp. 2652 ◽  
Author(s):  
Salil N. Vaniawala ◽  
Monika V. Patel ◽  
Pratik D. Chavda ◽  
Shivangi H. Zaveri ◽  
Pankaj K. Gadhia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Prognostic Significance ◽  
Chromosomal Translocation ◽  
Banding Technique ◽  
Trisomy 8 ◽  
Increased Risk ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder that results from a block in the differentiation of haematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 is the most common recurring numerical chromosomal aberrations in acute myeloid leukemia (AML). It occurs either as a sole anomaly or together with other additional chromosomal aberrations. The prognostic significance of trisomy 8 in presence of other additional chromosomal abnormality depends on clonal cytogenetic changes. The patients with trisomy 8 had shorter survival with significantly increased risk with other chromosomal abnormality.Methods: Total 139 patients were screened between January 2016 to November 2016 who were suspected of AML cases. Bone marrow cultures were set up using conventional cytogenetic methods. Chromosomal preparation was made and subjected to GTG banding technique. Banded metaphases were analysed and karyotyped for further analysis.Results: Cytogenetic evaluation of karyotyped of 139 suspected AML patients showed 52 with t(8;21)(q22;q22), 36 with t(15;17)(q22;q12), and 11 with inv(16)(p13;q22). The rest 40 cases found with additional chromosomal abnormalities, of which 16 were sole trisomy 8 and 24 cases were found with other chromosomal abnormalities In addition, only one person found with t(8;21) and trisomy 8, while  three person having t(15;17) with trisomy 8.Conclusions: AML is considered to be one of the most important cytogenetic prognostic determinants. Recurrent chromosomal translocation with trisomy 8 varying 1.9% for t(8;21) and 8.3% for t(15;17). In the present study trisomy 8 in AML with known favourable anomalies is very small. Therefore, it cannot be taken as a prognostic marker.

Assessment Of Human Equilibrative Nucleoside Transporter 1 (hENT1) – Expression By Flow Cytometry In Acute Myeloid Leukemia and Myelodysplastic Syndromes and Correlation To Clinical Outcome In Acute Myeloid Leukemia Patients Treated With Intensive Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2582-2582 ◽  
Author(s):  
Frauke Bellos ◽  
Bruce H. Davis ◽  
Naomi B. Culp ◽  
Birgitte Booij ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Molecular Genetic ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Very High ◽  
Acute Myeloid

Abstract Background Nucleoside analogs depend on cellular hENT1 expression for entry into cells and cytotoxic activity. Studies suggest low cellular hENT1 levels correlate with poor response to such chemotherapies in solid tumors, data on AML and MDS is scarce. Aim To examine hENT1 expression by multiparameter flow cytometry (MFC) in newly diagnosed AML and MDS and correlate results to morphologic, cytogenetic (CG) and molecular genetic (MG) findings. To examine hENT1 expression with respect to clinical outcome in AML patients (pts) treated with intensive cytarabine-based chemotherapy (CHT). Methods We studied pts with newly diagnosed AML (n=145) and MDS (n=96), 133/108 male/female, median age 67.3 (AML) and 73.3 years (MDS). CG was done in 130 AML and 86 MDS. Pts included 107 de novo AML, 9 t-AML, 29 s-AML; FAB: 9 M0, 27 M1, 50 M2, 9 M3, 21 M4, 8 M4eo, 7 M5, 14 not classified; by CG (MRC): 21 favorable, 75 intermediate, 34 adverse. 91 were de novo MDS, 5 t-MDS; 1 RARS, 17 RCMD-RS, 37 RCMD, 3 5q- syndrome, 3 RAEB-1, 5 RAEB-2, 1 CMML, 24 not classified; 2 IPSS-R very low, 55 IPSS-R low, 8 IPSS-R intermediate, 8 IPSS-R high, 13 IPSS-R very high. hENT1 expression was quantified by a novel four color intracellular staining assay using monoclonal antibodies against hENT1, CD45, CD64 and myeloperoxidase. Median fluorescence intensities (MFI) of hENT1 were determined in myeloid progenitors (MP), granulocytes (G) and monocytic cells (Mo) and correlated to hENT1 MFI in lymphocytes to derive hENT1 index (index). Results No correlation of index to age, gender, hemoglobin level or counts for blasts, WBC or platelets was detected. In AML, we generally saw higher index by trend in the more favorable prognostic subgroups. M3/t(15;17)/PML-RARA+ displayed higher index in MP than non-M3 AML (4.24 vs 2.56, p<0.001). G index was lower in M0 (3.01) vs M1, M2, M4 and M4eo (5.66, 4.34, 5.35, 4.77; p=0.01, 0.028, 0.004, 0.043, respectively) and in M2 compared to M1 and M4 (4.34. vs 5.66 and 5.35, p=0.01 and 0.033, respectively). M2 showed lower MP index than M5 (2.42 vs 2.99, p=0.016). Considering CG, index in MP was higher in favorable vs intermediate and adverse pts (3.05 vs 2.58 and 2.53, p=0.034 and 0.023, respectively), Mo index was higher ín favorable vs adverse pts (3.17 vs 2.71, p=0.044). By MG, higher index in Mo and G was observed in RUNX1-RUNX1T1+ AML (4/83, 4.32 vs 3.04, p=0.01; 8.16 vs 4.60, p=0.002, respectively). Higher index for MP was found in FLT3-ITD mutated (mut) (18/111; 3.19 vs 2.62, p=0.012), CEPBA mut (4/26, 3.15 vs 2.35, p=0.004) and for Mo in NPM1 mut AML (23/104; 3.72 vs 2.84, p=0.02), whereas lower index for MP was found in RUNX1mut pts (13/65; 2.17 vs 2.59, p=0.031). De novo AML displayed higher MP index than s-AML (2.7 vs 2.28, p=0.008). Using lowest quartile of index for MP (2.1185) as cut-off, AML pts in the MRC intermediate group treated with CHT (n=38) had inferior OS if MP index was below vs above this cut-off (OS at 6 months 63% vs. 95%, p=0.017, median follow up 4.6 months). MDS showed lower Mo and MP index than AML (2.68 vs 2.96, p=0.021, 1.84 vs 2.65, p<0.001, respectively). By IPSS-R, significance was reached for higher index in Mo and MP in very low risk compared to low risk pts (3.39 vs 2.54, p=0.013 and 4.07 vs 1.78, p<0.001, respectively), MP in very low compared to intermediate and high risk pts (4.07 vs 1.95, p=0.004; 4.07 vs 1.76, p=0.002), and MP and G in very low vs very high risk pts (4.07 vs 1.71, p=0.005; 5.86 vs 3.85, p=0.001, respectively). IPSS-R intermediate vs poor and very poor showed lower G index (5.47 vs 3.59, p=0.018 and vs 3.85, p=0.034 respectively). Conclusion AML with genetic and molecular genetic good risk profile had higher hENT1 expression in MP, G and Mo, suggesting a causal mechanism for better response to CHT and better outcome. Consequently, AML with poor risk molecular genetics (RUNX1 mut) showed lower levels of hENT1 in MP. The detection of higher levels in FLT3-ITD mut pts is in line with reportedly good response to CHT, overall worse outcome being mostly due to early relapses. Strikingly, we saw differences in outcome in pts treated with CHT according to hENT1 expression with shorter OS in pts with low index for MP. Higher index in de novo AML than s-AML and MDS may be causal for better response to nucleoside-based CHT in de novo AML. Data for MDS may be interpreted accordingly, lower risk cases showing higher index in MP, G and Mo. Further analyses are needed to explore hENT1 expression in AML and MDS more comprehensively. Disclosures: Bellos: MLL Munich Leukemia Laboratory: Employment. Davis:Trillium Diagnostics, LLC: Equity Ownership. Culp:Trillium Diagnostics, LLC: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Prognostic Implication of Therapy-Related Acute Myeloid Leukemia after Comparative Analysis with De Novo acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4884-4884
Author(s):  
Jae-Ho Yoon ◽  
Byung-Sik Cho ◽  
Hee-Je Kim ◽  
Seung-Ah Yahng ◽  
Seung-Hwan Shin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Survival Outcome ◽  
Poor Survival ◽  
Poor Survival Outcome ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Therapy-related acute myeloid leukemia (t-AML) is regarded as a complication after cytotoxic chemotherapy and/or radiation therapy, and also considered to have a poor survival outcome compared to de novo AML. We still have a question whether t-AML itself indicates a poor prognosis or whether the inferior outcome results from the association with such an adverse characteristics including cytogenetic risk or age or underlying malignancies. Methods: In this single center retrospective study, 1825 patients (median 46 years old [range, 17-92]) with variable karyotypes were enrolled from 2002 to 2013. Fifty-four (3.0%) patients had previous malignancies or autoimmune diseases, and all of them were treated with radiation or toxic chemotherapy before diagnosis of t-AML with a median duration of 36.3 months (range, 2.9-280.5). We analyzed clinical outcomes compared to 1771 de novo AML patients who were not related with any toxic therapies before. Results: Among 54 t-AML patients, 42 (77.8%) was in remission of prior malignant disease and 8 were in stable disease and 4 were in relapsed disease. In t-AML subgroup, median age was older (50 vs. 46 years old, p =0.119), leukocyte and bone marrow blast counts were significantly lower than de novo AML subgroup. There were more female patients in t-AML subgroup (70.3% vs. 45.4%, p=0.003). Among 38 female t-AML patients, 13 (34.2%) patients had breast cancer, 10 patients had hematological malignancies (i.e. APL in 5, lymphoma in 3, multiple myeloma in 2), and 8 (21.1%) had gynecological malignancies (i.e. ovarian and cervical cancer etc.). One or more chromosomal abnormalities (82.6% vs. 68.3%, p=0.015) and more adverse-risk karyotypes (41.2% vs. 20.0%, p<.001) were in t-AML subgroup. Especially, t-AML had more 5 or 7 chromosomal abnormalities (7.8% vs. 2.0%, p=.004) and complex karyotypes (27.5% vs. 7.6%, p<.001) which also included abnormal 5 or 7 chromosomes. Smaller number of t-AML patients received induction chemotherapy (74.1% vs. 87.6%, p=0.006) and early death rate was higher in t-AML group (22.2% vs. 13.7%, p=.083). After median follow-up of 70 months (range: 5.6-165.0), t-AML showed inferior 5-year overall survival (OS) compared to de novo AML (23.8% vs. 39.0%, p <.001). The result was more significant in intermediate to poor-risk group (9.2% vs. 30.0%, p<.001), but it was similar in favorable-risk group (75.0% VS. 62.8%, p=.532). In treated cohort, however, remission rate (70.0% vs. 79.3%, p =.149) and relapse rate (28.8% vs. 35.9%, p =.544) was not different, and multivariate analysis showed t-AML did not affect OS (HR=1.25, p=.185), while age >50 years old (HR=1.48, p<.001), hematopoietic cell transplantation (HCT, HR=0.37, p<.001), favorable-risk karyotype (HR=0.48, p<.001), and post-induction remission status (HR=0.26, p<.001) did. Five-year OS of t-AML patients treated with HCT (n=16) was 50.0%, and for intermediate to poor-risk subgroup treated with HCT, 5-year OS was 33.3%. Conclusion: In this study, t-AML was related with a larger proportion of adverse-risk karyotype, and many patients could not start induction chemotherapy due to old age, and remained prior malignant disease, which might result in poor survival outcome. On the other hand, response to induction chemotherapy of t-AML was similar with de novo AML consistent with a recent report (Kayser et al. Blood 2011). Therefore, if previous malignancy is in remission or in stable disease, aggressive treatment strategy using HCT may overcome poor survival outcome of t-AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cytogenetic and Morphological Analysis of De Novo Acute Myeloid Leukemia in Adults: A Single Center Study in Jordan

2012 ◽  
Vol 15 (1) ◽  
pp. 5-10
Author(s):  
M Ayesh ◽  
B Khassawneh ◽  
I Matalkah ◽  
K Alawneh ◽  
S Jaradat
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Morphological Analysis ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Single Center ◽  
Trisomy 8 ◽  
Single Center Study ◽  
Acute Myeloid ◽  
Center Study

Cytogenetic and Morphological Analysis of De Novo Acute Myeloid Leukemia in Adults: A Single Center Study in JordanAcute myeloid leukemia (AML) in adults is known to be a heterogeneous disease with diverse chromosomal abnormalities. Some of these abnormalities are found with a high incidence in specific ethnic groups and in certain geographical areas. We report the results of cytogenetic studies of 35 adult Jordanian Arab patients withde novoAML diagnosed according to the French-American-British (FAB) criteria. Four patients did not have metaphases secondary to hypocellular bone marrow. The most common morphological subtype was M5 (55%) followed by M3 (19%). Cytogenetic abnormalities were present in 20 patients (65%); t(15;17) translocation in six patients (19%), inv(16) in four patients (13%), t(11;17) in two patients (4%), and the t(8;21) translocation was not present in any patient. Trisomy 8 was the most common numerical chromosomal abnormality [four patients (13%)].There were variations and similarities with similar ethninc Arab populations. The most common chromosomal abnormalities were t(15;17), +8 and inv(16). Further and larger crossborder studies are needed.

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.

IDH Mutations and Trisomy 8 In Myelodysplastic Syndromes and Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4009-4009
Author(s):  
Domenica Caramazza ◽  
Terra Lasho ◽  
Christy Finke ◽  
Naseema Gangat ◽  
David Dingli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Trisomy 8 ◽  
Idh Mutations ◽  
De Novo Aml ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals De novo adult acute myeloid leukemia with two new mutations in juxtatransmembrane domain of the FLT3 gene: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ismael F. Alarbeed ◽  
Abdulsamad Wafa ◽  
Faten Moassass ◽  
Bassel Al-Halabi ◽  
Walid Al-Achkar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Molecular Genetic ◽  
Type A ◽  
Chemotherapeutic Treatment ◽  
Acute Myeloid ◽  
New Mutations

Abstract Background Approximately 30% of adult acute myeloid leukemia (AML) acquire within fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (FLT3/ITDs) in their juxtamembrane domain (JMD). FLT3/ITDs range in size from three to hundreds of nucleotides, and confer an adverse prognosis. Studies on a possible relationship between of FLT3/ITDs length and clinical outcomes in those AML patients were inconclusive, yet. Case presentation Here we report a 54-year-old Arab male diagnosed with AML who had two FLT3-ITD mutations in addition to NPM1 mutation. Cytogenetic approaches (banding cytogenetics) and fluorescence in situ hybridization (FISH) using specific probes to detect translocations t(8;21), t(15;17), t(16;16), t(12;21), and deletion del(13q)) were applied to exclude chromosomal abnormalities. Molecular genetic approaches (polymerase chain reaction (PCR) and the Sanger sequencing) identified a yet unreported combination of two new mutations in FLT3-ITDs. The first mutation induced a frameshift in JMD, and the second led to a homozygous substitution of c.1836T>A (p.F612L) also in JMD. Additionally a NPM1 type A mutation was detected. The first chemotherapeutic treatment was successful, but 1 month after the initial diagnosis, the patient experienced a relapse and unfortunately died. Conclusions To the best of our knowledge, a combination of two FLT3-ITD mutations in JMD together with an NPM1 type A mutation were not previously reported in adult AML. Further studies are necessary to prove or rule out whether the size of these FLT3-ITDs mutations and potential other double mutations in FLT3-ITD are correlated with the observed adverse outcome.

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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