Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3747-3754 ◽  
Author(s):  
Roel G. W. Verhaak ◽  
Chantal S. Goudswaard ◽  
Wim van Putten ◽  
Maarten A. Bijl ◽  
Mathijs A. Sanders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Molecular Abnormalities ◽  
Cell Counts ◽  
Gene Expression Signatures ◽  
Acute Myeloid

Mutations in nucleophosmin NPM1 are the most frequent acquired molecular abnormalities in acute myeloid leukemia (AML). We determined the NPM1 mutation status in a clinically and molecularly well-characterized patient cohort of 275 patients with newly diagnosed AML by denaturing high-performance liquid chromatography (dHPLC). We show that NPM1 mutations are significantly underrepresented in patients younger than 35 years. NPM1 mutations positively correlate with AML with high white blood cell counts, normal karyotypes, and fms-like tyrosine kinase-3 gene (FLT3) internal tandem duplication (ITD) mutations. NPM1 mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-α (CEBPA) and NRAS mutations. With respect to gene expression profiling, we show that AML cases with an NPM1 mutation cluster in specific subtypes of AML with previously established gene expression signatures, are highly associated with a homeobox gene–specific expression signature, and can be predicted with high accuracy. We demonstrate that patients with intermediate cytogenetic risk AML without FLT3 ITD mutations but with NPM1 mutations have a significantly better overall survival (OS) and event-free survival (EFS) than those without NPM1 mutations. Finally, in multivariable analysis NPM1 mutations express independent favorable prognostic value with regard to OS, EFS, and disease-free survival (DFS).

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 971-978 ◽  
Author(s):  
Christoph Röllig ◽  
Christian Thiede ◽  
Martin Gramatzki ◽  
Walter Aulitzky ◽  
Heinrich Bodenstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Cox Model ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.

FLT3-ITD-associated gene-expression signatures in NPM1-mutated cytogenetically normal acute myeloid leukemia

2012 ◽  
Vol 96 (2) ◽  
pp. 234-240 ◽  
Author(s):  
Liang Huang ◽  
Kuangguo Zhou ◽  
Yunfan Yang ◽  
Zhen Shang ◽  
Jue Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Expression Signatures ◽  
Acute Myeloid

scholarly journals PB1740 PROGNOSTIC SIGNIFICANCE OF JAK-II GENE EXPRESSION IN ACUTE MYELOID LEUKEMIA PATIENTS

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 800-801
Author(s):  
M. El Gammal ◽  
L. Fathalla ◽  
N. Hassan ◽  
O. ElGebaly ◽  
B. Elgamal
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Acute Myeloid

Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Dorothy R. Barnard ◽  
Beverley Lange ◽  
Todd A. Alonzo ◽  
Jonathan Buckley ◽  
J. Nathan Kobrinsky ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Latency Period ◽  
Disease Free Survival ◽  
Free Survival ◽  
Cell Counts ◽  
Acute Myeloid

Abstract There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard- or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/tAML were older at presentation (P = .015), had lower white blood cell counts (P = .01), and were more likely to have MDS (21% vs 7%) (P = .02) and trisomy 8 (P = .06). Fewer had hepatomegaly (P = .02), splenomegaly (P = .03), hepatosplenomegaly (P = .02), or classic AML translocations [t(8;21), t(15;17), 16q22; P = .02]. They had a poorer induction rate (50% vs 72%,P = .016), overall survival (26% vs 47% at 3 years,P = .007), and event-free survival (21% vs 39% at 3 years, P =.023). Disease-free survival after achieving remission was similar (45% vs 53%, P = .868). Children with tMDS/tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P = .54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standard-timing induction appears less effective for this population.

Low MDR1 and BAALC expression Identifies a New Subgroup of Adult Cytogenetically Normal Acute Myeloid Leukemia with a Favorable Outcome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4312-4312
Author(s):  
Xutao Guo ◽  
Feili Chen ◽  
Pengcheng Shi ◽  
Jie Zha ◽  
Bingshan Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Long Term Outcome ◽  
Molecular Abnormalities ◽  
Mdr1 Expression ◽  
Cytogenetically Normal Aml ◽  
Low Expression ◽  
Acute Myeloid

Abstract Abstract 4312 OBJECTIVE: Cytogenetically normal acute myeloid leukemia (AML) is a heterogeneous disease, in terms of genetic/molecular abnormalities resulting into marked differences in outcome. We demonstrated that MDR1, BAALC expression was of prognostic significance and high MDR1 expression correlated with a high BAALC expression (r=0.487, P<0.001) in cytogenetically normal AML in the prophase study then we hypothesized that MDR1 and BAALC expression together would better identify the patient's risk profile. METHODS: Pretreatment bone marrow samples from 92 cytogenetically normal AML patients were analyzed for MDR1 and BAALC mRNA expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into low MDR1 and BAALC expression group and combined group (high MDR1 and/or high BAALC expression) according to MDR1 and BAALC levels and were compared for clinical outcome. RESULTS: 73 cases of 92 cytogenetically normal AML patients got CR after the first block with a CR rate being 79.3%. However, 29 cases of the CR patients relapsed with the relapsed rate being 39.7%. In contrast, Patients with low expression of both MDR1 and BAALC had a higher CR rate (93.3%vs72.6%, P=0.021), lower relapse rate (7.1% vs. 42.5%, P=0.000), longer OS (50.3% vs 17.8%,P=0.001) than high MDR1 and/or high BAALC expression (combined group) in cytogenecally normal AML. Results showed no statistical difference in CR rate (93.3%vs85.7%, P=0.341),relapse rate (7.1% vs. 8.8%, P=0.000) and OS (50.3% vs 63.1%,P=0.431) for cytogenetically normal patients with both MDR1 and BAALC low expression comparing to those with low-risk cytogenetically abnormal. CONCLUSION: The combined assessment of BAALC and MDR1 expression can improve treatment stratification in adult cytogenetically normal AML. Low expression of both MDR1 and BAALC identifies cytogenetically normal AML patients with a favorable long-term outcome. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of β-2 Microglobulin Levels in Acute Myeloid Leukemia: Analysis of 1293 Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 802-802
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
Susan O’Brien ◽  
Sijin Wen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Uric Acid ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Elevated Serum ◽  
Cell Counts ◽  
Younger Age ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: β-2 Microglobulin (β2M) is a single polypeptide chain that is linked non-covalently to the major histocompatibility complex class I cell surface antigen. Its specific function is unknown, but serum β2M levels reflect membrane turnover (tumor mass and growth rate) and renal function. Elevated serum β2M levels are associated with poor survival in several hematologic malignancies, but its prognostic significance in acute myeloid leukemia (AML) is unknown. The purpose of this study was to determine the association between β2M levels and pretreatment characteristics and clinical outcomes in newly diagnosed AML. Patients and Methods: From 1990 to 2005, β2M levels were prospectively measured in 1293 patients with AML. Serum β2M was quantified by radioimmunoassay (normal range, 0.7–2.0 mg/L). Results: The median patient age was 61 yrs (range, 16–89 yrs); 54% were &gt;60 yrs. Cytogenetics were favorable in 7% of patients, intermediate in 60%, poor-risk in 29%, and 4% of patients had insufficient metaphases. Zubrod performance status (PS) was 0–1 in 73% of patients, 2 in 20%, and 3–4 in 7%. Eighty-five percent had de novo AML, and 91% received Ara-C-based therapy. High β2M levels were more common in patients who were older (cor=0.22); had high early risk of mortality (ERM) score (cor =0.33); high levels of creatinine (cor=0.63), and uric acid (cor=0.29), high white blood cell counts (cor=0.26), or circulating monocytes (cor = 0.23); prolonged prothrombin time (PT) (cor=0.26); worse PS (cor=0.27); and low albumin levels (cor=−0.22)(p&lt;0.001 for all variables). High β2M levels were correlated with worse-risk cytogenetics (p=0.03), RAS mutation (p=0.003), baseline infection (p=0.04), and secondary AML (p=0.01). The median follow-up of surviving patients was 3.8 yrs. In multivariate analysis, independent factors predicting response were younger age (p&lt;0.0001), better-risk cytogenetics (p&lt;0.0001), Ara-C-based therapy (p&lt;0.0001), lower levels of β2M (p=0.0001), shorter PT (p=0.006), de novo AML (p=0.007), lower LDH levels (p=0.02), and lower bilirubin levels (p=0.03). Factors independently prognostic of longer survival were younger age (p&lt;0.0001), better-risk cytogenetics (p&lt;0.0001), better PS (p&lt;0.0001), de novo AML (p&lt;0.0001), lower serum uric acid levels (p=0.0001), lower LDH levels (p=0.0007), shorter PT (p=0.0009), lower β2M levels (p=0.003), higher hemoglobin levels (p=0.005), Ara-C-based therapy (p=0.007), and lower bilirubin levels (p=0.02). Factors independently prognostic of longer event-free survival (EFS) were younger age (p&lt;0.0001), better-risk cytogenetics (p&lt;0.0001), Ara-C-based therapy (p&lt;0.0001), de novo AML (p=0.0001), better PS (p=0.0003), lower uric acid levels (p=0.0004), lower LDH levels (p=0.001), lower β2M levels (p=0.002), higher hemoglobin levels (p=0.003), shorter PT (p=0.02), and lower bilirubin levels (p=0.045). Conclusions: Elevated serum β2M levels are an independent adverse prognostic factor for response, survival, and EFS in the context of established prognostic factors for AML. Outcomes by β2M levels β2M (mg/L) &lt;2.0 2.0–2.9 3.0–3.9 ≥4.0 p-value No. pts. 251 448 260 334 CR, % 67 66 54 39 &lt;0.0001 Median EFS (yrs) 0.69 0.58 0.31 0.15 &lt;0.0001 Median Survival (yrs) 1.33 1.19 0.63 0.42 &lt;0.0001

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