scholarly journals Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification

2021 ◽  
Vol 5 (17) ◽  
pp. 3254-3265
Author(s):  
Inge van der Werf ◽  
Anna Wojtuszkiewicz ◽  
Manja Meggendorfer ◽  
Stephan Hutter ◽  
Constance Baer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Clinical Features ◽  
Myeloid Leukemia ◽  
Risk Classification ◽  
Classification Systems ◽  
Splicing Factor ◽  
Intermediate Risk ◽  
Molecular Abnormalities ◽  
Acute Myeloid

Abstract Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.

scholarly journals NEDD9, an independent good prognostic factor in intermediate-risk acute myeloid leukemia patients

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 76003-76014 ◽  
Author(s):  
Victor Pallarès ◽  
Montserrat Hoyos ◽  
M. Carmen Chillón ◽  
Eva Barragán ◽  
M. Isabel Prieto Conde ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Acute Myeloid

The Presence of FLT3/ITD Mutations Is an Independent Prognostic Factor in Acute Myeloid Leukemia Patients with Normal Karyotype.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3008-3008 ◽  
Author(s):  
Yeo-Kyeoung Kim ◽  
Je-Jung Lee ◽  
Yu-Ra Lee ◽  
Il-Kwon Lee ◽  
Hee-Nam Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Normal Karyotype ◽  
Intermediate Risk ◽  
Free Survival ◽  
Significant Difference ◽  
Acute Myeloid

Abstract An internal tandem duplication of the FLT3 gene (FLT3/ITD) has been detected in approximately 20–30% of patients with acute myeloid leukemia (AML). These are frequently associated with poor outcome in AML patients, but it is still a matter of debate whether the FLT3/ITD mutations play a role in the prognosis of AML patients independently or not. We investigated the presence of FLT3/ITD mutation in 165 patients with de novo AML, except acute promyelocytic leukemia (APL), to evaluate its clinical and prognostic significance. The FLT3/ITD mutations were studied on bone marrow samples at diagnosis using PCR assay. Of the patients, 58 patients (35.2%) demonstrated the aberrant FLT3/ITD mutations. The patients with FLT3/ITD had significantly higher WBC counts at presentation compared with patients without FLT3/ITD (52.9 ± 66.9 ×109/L vs. 32.4 ± 41.8 ×109/L, p < 0.05). However, there was no statistically significant difference in age, gender, hemoglobin level, platelet count, percentage of peripheral or bone marrow blasts, or the presence of molecular abnormalities between the patients with FLT3/ITD and the patients without FLT3/ITD. To analyze the response to or outcome of therapy, we evaluated 118 patients who received intensive induction chemotherapy. In univariate analysis, there was no significant difference in complete response rate (p = 0.21), in median duration of overall survival (13.9±3.8 ms. vs. 16.5±0 ms., p = 0.07), or in median duration of leukemic-free survival (LFS) (9.8±3.5 ms. vs. 34.6±17.9 ms., p = 0.09) between the patients with FLT3/ITD and the patients without FLT3/ITD. However, the presence of FLT3/ITD was associated with lower LFS in the patients with a cytogenetically intermediate-risk group (p < 0.05). Furthermore, in multivariate analysis, FLT3/ITD mutations were an independent prognostic factor in LFS in AML patients with normal karyotype (p < 0.05). In conclusion, this study demonstrates that the presence of FLT3/ITD mutations is a significantly poor prognostic factor for leukemic free survival in non-APL patients with a cytogenetically intermediate-risk group, especially normal karyotype.

Outcome of Adolescents and Young Adults (AYAs) with Non-M3 Acute Myeloid Leukemia (AML) Treated on Children's Oncology Group (COG) Trials Compared to Cancer and Leukemia Group B (CALGB) and Southwest Oncology Group (SWOG) Trials

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 183-183 ◽  
Author(s):  
Anna R.K. Franklin ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Kathleen Donohue ◽  
Megan Othus ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Classification Systems ◽  
Cooperative Group ◽  
Cooperative Groups ◽  
Oncology Group ◽  
Molecular Abnormalities ◽  
Younger Age ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Abstract 183 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy AYAs with acute lymphoblastic leukemia have superior survival when treated with intensive pediatric regimens compared to regimens used for older adults. To determine if a similar benefit occurred in AYAs with AML, we performed a retrospective analysis of 517 patients (pts) with AML ages 16 to 21 years (yrs), comparing outcomes between patients treated on COG (n=281), CALGB (n=149) and SWOG (n=87) studies from 1986 to 2008. We also performed stratified analyses, comparing younger to older patients (16-18 vs 19–21 yrs) and comparing early and later studies. Early studies included those before 1996 (COG: 2861, 2891; CALGB: 8525, 9022, 9222, SWOG 8600). Later studies included COG 2941, 2961 and AML03P1, CALGB 9621, 19808 and SWOG 9500 and S0106. The median age was 18.0 yrs. However, the COG cohort (17.2 yrs) was significantly younger than CALGB (20.1 yrs) and SWOG (19.8 yrs) (p<0.001); 94% of COG pts were <19 yrs. The median white blood cell count, percent bone marrow blasts, FAB classification and overall complete remission rates did not differ between the Groups. The analysis of cytogenetics is ongoing as we reconcile differences between varying cooperative group classification systems. Assessment of the cumulative incidence of relapse is ongoing as well. Data on molecular abnormalities were incomplete and not analyzed. At eight years from the time of study entry, overall survival (OS) was first noted to be significantly higher for the COG cohort than for the combined CALGB/SWOG cohort (45+6% vs. 36+7%) (p<0.001). Combining the patients from the three cooperative groups, the OS in younger AYAs was 43±6% vs 32±8% in older AYAs at 10 yrs (p<0.05). Within each cooperative group, there was no difference in the OS of younger and older AYAs. Combining the patients from the three cooperative groups, the 5 yr OS improved from 38+6% in early studies to 48+6% for AYAs on later studies (p=0.045). Data on all patients from the 3 cooperative groups showed younger AYAs had a higher 5 yr EFS than older AYAs (37%+5% vs 26%+7% (p=0.015). Younger AYAs in COG had improved EFS compared to older AYAs in COG (39%+6% vs 17%+18%)(p=0.053). There was no significant difference in EFS between younger and older AYAs in CALGB or SWOG, where EFS was 28%+8% vs 27%+10%, respectively. Overall, the 5 year EFS of the COG AYAs (38%+6%) was higher than CALGB and SWOG combined (27%+6%) (p=0.006), although the younger age of the COG cohort is confounding. Combining the data from the 3 cooperative groups, 5 yr EFS has improved from 30+6% in earlier studies to 36+6% in later studies (p=0.039). One marked distinction between the cooperative groups was the significantly higher treatment-related mortality (TRM) on COG trials. TRM was 29 + 5% at 5 yrs on COG trials compared to 7 + 4% for CALGB and SWOG patients combined (p<0.001). Changes to supportive care guidelines in COG AML trials in 2000 have subsequently led to a decrease in TRM. Combining pts from all 3 cooperative groups, younger AYAs had increased 5 yr TRM of 25+5% compared to 8+4% of older AYAs (p<0.001). However, there were no differences in TRM between younger and older AYAs within each cooperative group, which may be due to the younger age of the COG cohort. Overall, 5 yr TRM has increased from 13+4% on early studies to 24+5% on later studies. In summary, younger AYAs have improved OS and 5 yr EFS in comparison to older AYAs. Age is a confounding variable in this cohort making it difficult to compare outcomes for AYAs treated on pediatric and adult studies. Even within the small 6-year age span of these AYAs, there are marked differences in the ages of patients treated by pediatric and adult cooperative groups. OS and EFS have increased for AYAs in more recent studies; unfortunately TRM has increased as well. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes

2020 ◽  
Vol 11 ◽  
pp. 204062072096612
Author(s):  
Sotirios G. Papageorgiou ◽  
Ioannis Kotsianidis ◽  
Anthi Bouchla ◽  
Argyris Symeonidis ◽  
Athanasios Galanopoulos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Serum Ferritin ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Risk Classification ◽  
Classification Systems ◽  
Ecog Ps ◽  
Acute Myeloid

Background: 5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied. Methods: This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA. Results: The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system. Conclusions: ECOG PS and SF levels > 520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores’ predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.

scholarly journals TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3803-3810 ◽  
Author(s):  
Wen-Chien Chou ◽  
Sheng-Chieh Chou ◽  
Chieh-Yu Liu ◽  
Chien-Yuan Chen ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Disease Evolution ◽  
Unfavorable Prognostic Factor ◽  
Tet2 Mutation ◽  
Acute Myeloid

Abstract The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1+/FLT3-ITD− or CEBPA+). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution.

scholarly journals High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Li ◽  
Zheng Ge
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Adverse Outcomes ◽  
High Expression ◽  
Micro Rnas ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

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