Abstract 1387

miR-155 is upregulated in aggressive subtypes of solid tumors and leukemia. In AML, higher miR-155 expression is associated with FLT3-ITD. However, whether miR-155 upregulation impacts on clinical outcome independently from FLT3-ITD and other prognosticators is unknown. We evaluated the prognostic impact of miR-155 in 363 CN-AML pts (153 age <60 y; 210 age ≥60 y) that were treated with cytarabine-daunorubicin-based regimens and had a median follow-up of 7.9 y (range, 2.3–12.9). miR-155 levels were measured in pretreatment marrow or blood by the NanoString nCounter assay quantifying expression of the encoding gene MIR155HG; other molecular markers were assessed centrally. High miR-155 expressers (miR-155) had higher WBC (P<.001) and were more often FLT3-ITD-positive (pos; P<.001), RUNX1-mutated (mut; <.001), WT1-mut (P=.03), ↑ ERG (P=.02) and ↑ BAALC (P=.002), and less often CEBPA-mut (P=.003), IDH2-mut (P=.004) and FLT3-TKD-pos (P=.08) than low expressers (↓ miR-155). ↑ miR-155 had lower CR rates (P<.001), shorter DFS (P=.001) and OS (P<.001), than ↓ miR-155. In multivariable analyses (MVA; Table), ↑ miR-155 was associated with lower CR rates (P=.007) and shorter OS (P<.001). Among younger pts, ↑ miR-155 had lower CR rates (P=.03) and shorter DFS (P<.001) and OS (P<.001) than ↓ miR-155. In MVA (Table), ↑ miR-155 status remained associated with worse CR rate (P=.06), shorter DFS (P=.003) and OS (P=.01). Among older pts, ↑ miR-155 had lower CR rates (P=.008) and shorter OS (P<.001); in MVA (Table), ↑ miR-155 remained associated with worse CR (P=.03) and shorter OS (P=.05). In the European LeukemiaNet classification, younger ↑ miR-155 in the Favorable (Fav) Genetic Group (GG; CEBPA-mut and/or NPM1-mut without FLT3-ITD) had lower CR rates (P=.03) and shorter DFS (P=.04) and OS (P=.02) than ↓ miR-155. In the younger Intermediate-I (Int-I) GG pts (with wild-type CEBPA, NPM1-mut with FLT3-ITD, or wild-type NPM1), miR-155 expression did not impact independently on outcome. In older pts, ↑ miR-155 had a shorter OS both in the Fav (P=.06) and Int-I GGs (P=.05) than ↓ miR-155. To gain biologic insights, we derived an Affymetrix gene-expression signature that comprised 196 mRNAs significantly correlated with miR-155 expression. Consistent with previous mechanistic studies, Gene Ontology analysis revealed that the ↑ miR-155-associated signature was enriched for genes involved in anti-apoptotic, proliferative and inflammatory activities (FDR<0.05). ↑ miR-155 was not significantly correlated with that of any other microRNAs (miRs) thereby supporting the unique role of miR-155 among the miRs in AML. In summary, miR-155 expression is independently associated with clinical outcome in CN-AML and may allow for better evaluation of molecular risk, especially in pts lacking FLT3-ITD, like those in the ELN Fav GG. Moreover, given its role in deregulation of fundamental mechanisms of cell homeostasis and the emergence of miR inhibitors, miR-155 may become a novel therapeutic target.

Table.

MVA in pts with primary CN-AML

GroupCRDFSOS
ORPHRPHRP
All pts   miR-155 expression not significantly associated with DFS  
    miR-155, ↑ v ↓ 0.46 .007 1.62 <.001 
    NPM1, mut v wt 2.42 .005   
    BAALC, ↑ v ↓ 0.37 .002 2.16 <.001 
    WBC, each 50 units 0.65 <.001   
    Age group, older v younger 0.43 .003 2.38 <.001 
    FLT3-ITD, pos v neg   1.78 <.001 
    Race, white v nonwhite   1.62 .03 
Pts age < 60 y       
    miR-155, ↑ v ↓ 0.39 .06 2.13 .003 1.84 .01 
    RUNX1, mut v wt 0.21 .01     
    Age, each 10 y increase 0.45 .004     
    WBC, each 50 units     1.49 <.001 
    FLT3-ITD, pos v neg   2.82 <.001 1.82 .01 
    FLT3-TKD, pos v neg   3.27 <.001   
    BAALC, ↑ v ↓   2.66 <.001 2.33 <.001 
    Race, white v nonwhite   2.81 .02   
    CEBPA, mut v wt     0.47 .02 
    WT1, mut v wt     2.25 .005 
Pts age ≥ 60 y   miR-155 expression not significantly associated with DFS   
    miR-155, ↑ v ↓ 0.46 .03 1.36 .05 
    NPM1, mut v wt 2.45 .03   
    BAALC, ↑ v ↓ 0.32 .004 2.18 <.001 
    WBC, each 50 units 0.65 .005   
    Age, each 10 y increase 0.48 .02   
    FLT3-ITD, pos v neg   1.56 .006 
GroupCRDFSOS
ORPHRPHRP
All pts   miR-155 expression not significantly associated with DFS  
    miR-155, ↑ v ↓ 0.46 .007 1.62 <.001 
    NPM1, mut v wt 2.42 .005   
    BAALC, ↑ v ↓ 0.37 .002 2.16 <.001 
    WBC, each 50 units 0.65 <.001   
    Age group, older v younger 0.43 .003 2.38 <.001 
    FLT3-ITD, pos v neg   1.78 <.001 
    Race, white v nonwhite   1.62 .03 
Pts age < 60 y       
    miR-155, ↑ v ↓ 0.39 .06 2.13 .003 1.84 .01 
    RUNX1, mut v wt 0.21 .01     
    Age, each 10 y increase 0.45 .004     
    WBC, each 50 units     1.49 <.001 
    FLT3-ITD, pos v neg   2.82 <.001 1.82 .01 
    FLT3-TKD, pos v neg   3.27 <.001   
    BAALC, ↑ v ↓   2.66 <.001 2.33 <.001 
    Race, white v nonwhite   2.81 .02   
    CEBPA, mut v wt     0.47 .02 
    WT1, mut v wt     2.25 .005 
Pts age ≥ 60 y   miR-155 expression not significantly associated with DFS   
    miR-155, ↑ v ↓ 0.46 .03 1.36 .05 
    NPM1, mut v wt 2.45 .03   
    BAALC, ↑ v ↓ 0.32 .004 2.18 <.001 
    WBC, each 50 units 0.65 .005   
    Age, each 10 y increase 0.48 .02   
    FLT3-ITD, pos v neg   1.56 .006 

↑, high expression; ↓, low expression; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; mut, mutated; neg, negative; OR, odds ratio; OS, overall survival; pos, positive; WBC, white blood count; wt, wild-type.

Odds ratios > (<) 1.0 mean higher (lower) CR rate and HRs > (<) 1.0 mean higher (lower) risk of relapse or death (DFS) or death (OS) for the higher values of continuous variables and the 1st category listed for categorical variables.

Disclosures:

No relevant conflicts of interest to declare.

This icon denotes a clinically relevant abstract

Author notes

*

Asterisk with author names denotes non-ASH members.

Sign in via your Institution