scholarly journals Prognostic Significance of NPM1 Mutations in the Absence of FLT3–Internal Tandem Duplication in Older Patients With Acute Myeloid Leukemia: A SWOG and UK National Cancer Research Institute/Medical Research Council Report

2015 ◽  
Vol 33 (10) ◽  
pp. 1157-1164 ◽  
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Michelle Lazenby ◽  
Elihu Estey ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Cancer Research ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Council ◽  
Medical Research Council ◽  
Prognostic Significance ◽  
Cancer Research Institute ◽  
National Cancer Research Institute ◽  
The Impact ◽  
Acute Myeloid

Purpose Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML. Patients and Methods Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype. Results Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. Conclusion NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials

Blood ◽  
2010 ◽  
Vol 116 (3) ◽  
pp. 354-365 ◽  
Author(s):  
David Grimwade ◽  
Robert K. Hills ◽  
Anthony V. Moorman ◽  
Helen Walker ◽  
Stephen Chatters ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Medical Research ◽  
Myeloid Leukemia ◽  
Research Council ◽  
Medical Research Council ◽  
Chromosomal Abnormalities ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

Abstract Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), −5, −7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11∼13;q23), other t(11q23) (excluding t(9;11)(p21∼22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), −17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated “complex” karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

scholarly journals Prognostic Significance of IDH1 and IDH2 mutations in Older Patients with Primary Cytogenetically Normal Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5058-5058 ◽  
Author(s):  
Jinghan Wang ◽  
Zhixin Ma ◽  
Qinrong Wang ◽  
Mengxia Yu ◽  
Xiufeng Yin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Old Patients ◽  
Multivariable Analyses ◽  
Idh1 Mutations ◽  
Idh1 And Idh2 Mutations ◽  
The Impact ◽  
Acute Myeloid

Abstract IDH1 and IDH2 mutations are frequently identified in older patients with AML.With the development and application of IDH inhibitor, the prognostic significance of these mutations in old patients is of primary importance. To assess the impact on clinic outcome, we analyzed 224 older (> 60 years) patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) similarly treated with intensive induction chemotherapy. Our analysis identified IDH1 and/or IDH2 (IDH1/2), IDH1 or IDH2 mutations in 63(28%), 29(12.9%) and 35(15.6%) patients, respectively. In general, IDH1 and IDH2 mutations were mutually exclusive, with only one patient having both IDH1 R132C and IDH2 R140Q mutations. IDH2 R172 mutations were exclusive with all other mutations analyzed (NPM1, CEBPA, DNMT3A, IDH1 and FLT3-ITD). There was a strong interaction between IDH2 mutation and NPM1 mutational status. Concurrent presence of IDH2 R140 and NPM1 mutations was independently associated with longer overall survival (OS; P=0.038, HR=0.42) and event free survival (EFS; P=0.034, HR=0.46) compared to the wild type counterpart in multivariable analyses. In contrast, IDH1 mutations were independently associated with shorter OS (P=0.004, HR=1.98) and EFS (P=0.014, HR=1.72) in multivariable analyses. Notably, IDH1 R132 mutations harbored higher levels of total 2-hydroxyglutarate compared to IDH2 R140Q mutations. Patients with IDH1 mutations or IDH2 R140 and NPM1 mutations harbored also distinct miRNA-expression signatures. Future studies will establish whether these difference between IDH1 and IDH2 mutations will be relevant with respect to response of the respective subsets of patients to the emerging therapies with IDH1 and IDH2 inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role and Importance of Inflammasomes and Immune Pathways in Myeloid Malignancies, Particularly Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML) to Better Understand the Disease Pathophysiology and Decipher the Scope of Therapeutic Interventions

2021 ◽  
pp. 825-867
Author(s):  
Ricardo Gobato ◽  
Abhijit Mitra
Keyword(s):  
Cancer Research ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Interventions ◽  
Tumor Spread ◽  
Cancer Research Institute ◽  
Keywords Cancer ◽  
Immune Pathways ◽  
Acute Myeloid ◽  
Research Institute

Thanks to work by researchers at the California South University (CSU) Cancer Research Institute (CRI), they may soon have new tools to treat melanoma and other cancers. In an article published last month, members of the Cancer Research Institute (CRI) introduced an intracellular complex. Involved in melanoma-mediated inflammation and leads to tumor growth and progression. The researchers found that by inhibiting NLRP3, they could reduce inflammation and tumor spread. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

scholarly journals Prognostic Significance of Expression of a Single MicroRNA,miR-181a, in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

2010 ◽  
Vol 28 (36) ◽  
pp. 5257-5264 ◽  
Author(s):  
Sebastian Schwind ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
Kelsi B. Holland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Comprehensive Cancer Center ◽  
Wild Type ◽  
The Impact ◽  
Acute Myeloid

PurposeTo evaluate the prognostic significance of expression levels of a single microRNA, miR-181a, in the context of established molecular markers in cytogenetically normal acute myeloid leukemia (CN-AML), and to gain insight into the leukemogenic role of miR-181a.Patients and MethodsmiR-181a expression was measured in pretreatment marrow using Ohio State University Comprehensive Cancer Center version 3.0 arrays in 187 younger (< 60 years) adults with CN-AML. Presence of other molecular prognosticators was assessed centrally. A gene-expression profile associated with miR-181a expression was derived using microarrays and evaluated by Gene-Ontology analysis.ResultsHigher miR-181a expression associated with a higher complete remission (CR) rate (P = .04), longer overall survival (OS; P = .01) and a trend for longer disease-free survival (DFS; P = .09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P = .009), and longer DFS (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥ 60 years) patients with CN-AML. A miR-181a-associated gene-expression profile was characterized by enrichment of genes usually involved in innate immunity.ConclusionTo our knowledge, we provide the first evidence that the expression of a single microRNA, miR-181a, is associated with clinical outcome of patients with CN-AML and may refine their molecular risk classification. Targeted treatments that increase endogenous levels of miR-181a might represent novel therapeutic strategies.

scholarly journals Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3196
Author(s):  
Francesco Mannelli ◽  
Sara Bencini ◽  
Matteo Piccini ◽  
Giacomo Gianfaldoni ◽  
Maria Ida Bonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
World Health ◽  
Erythroid Cell ◽  
Multiparameter Flow Cytometry ◽  
Prognostic Information ◽  
The Impact ◽  
Insight Into ◽  
Acute Myeloid

Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

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