ASSOCIATION OF MIR29 RNA WITH RESPONSE AND SURVIVAL IN OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) TREATED WITH AZACITIDINE (AZA) OR CONVENTIONAL CARE REGIMENS (CCR)
(Abstract release date: 05/21/15)
EHA Library. J.MacBeth K. 06/14/15; 103171; S797
Kyle J.MacBeth
Contributions
Contributions
Abstract
Abstract: S797
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room C1
Background
DNA methyltransferases (DNMTs) mediate DNA methylation and contribute to epigenetic aberrancy in myeloid malignancies. The miR29 family of microRNAs directly inhibit the expression of DNMT-3A and -3B (Fabbri, PNAS, 2007). In a small study (N=23) of older patients (pts) with AML, higher levels of miR29b were significantly associated with response to decitabine (Blum, PNAS, 2010). The large (N=488) phase 3 randomized AZA-AML-001 study compared AZA and CCR treatment (Tx) in older pts with AML. AZA prolonged median overall survival (OS) by ~4 months (mos) (10.4 vs 6.5 mos; p<0.101) and improved 1-year survival (46.5% vs 34.2%) vs CCR (Dombret, EHA, 2014).
Aims
To investigate the relationship between miR29 family RNA levels and clinical endpoints (response and OS) in AZA-AML-001 pts.
Methods
Eligible pts were age ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts) and had ECOG PS of 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. Pts received AZA (75mg/m2/day [d] x7d/28d cycle) or a preselected CCR: intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20mg SC BID x10d/28d cycle), or best supportive care only. RNA was isolated from BM mononuclear cells collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate BM mononuclear cells for analysis. Experimental miRNAs (miR29a, b, c) and control RNAs (RNU44, miR-16) were quantified by qRT-PCR. Associations between miR levels and response (IWG 2003) were assessed, defining responders as pts who achieved complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi), and nonresponders as pts with partial response (PR), stable disease (SD), or progressive disease (PD) as their best response. Differences in baseline miRNA expression were compared by T-test within the AZA and CCR Tx arms. A 2-way ANOVA model was used to test the interaction between miR expression and Tx. miR expression as a continuous variable was also fit in a Cox model with and without strata in separate arms.
Results
The biomarker cohort comprised 156 of all 488 pts (32%; AZA n=83, CCR n=73). Baseline characteristics were well-matched in the biomarker vs non-biomarker groups, respectively, with median age 75 years in both groups, median BM blasts 50.5% vs 52.0%, and cytogenetic risks of intermediate 63.8% vs 66.5%, and poor 36.3% vs 33.5%. Baseline miR29a and miR29b expression levels were significantly higher in responders (CR+CRi) vs nonresponders (PR+SD+PD) with AZA Tx (p<0.004 & p<0.029, respectively), but not with CCR Tx (Figure). This difference for miR29a was confirmed in the 2-way ANOVA analysis of response and Tx (p<0.054). miR29a levels were also associated with OS (p<0.044) in the AZA arm, but not in the CCR arm, in stratified survival analysis. No significant associations between miR29b or miR29c levels and OS were seen in either Tx arm.
Summary
In this exploratory analysis, higher expression levels of miR29a and miR29b were significantly associated with response to AZA Tx, and the association of miR29a levels with response was specific to AZA. Higher miR29a levels were also associated with improved OS in pts treated with AZA, but not in pts treated with CCR. As miR29a is implicated in regulating DNMT levels, an AZA target, these data are consistent with the concept that reduced pretreatment DNMT levels due to higher miR29a expression can improve response and survival with hypomethylating agents.
Keyword(s): Acute myeloid leukemia, DNA methylation, Epigenetic
Session topic: AML: Molecular profile and targeting
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room C1
Background
DNA methyltransferases (DNMTs) mediate DNA methylation and contribute to epigenetic aberrancy in myeloid malignancies. The miR29 family of microRNAs directly inhibit the expression of DNMT-3A and -3B (Fabbri, PNAS, 2007). In a small study (N=23) of older patients (pts) with AML, higher levels of miR29b were significantly associated with response to decitabine (Blum, PNAS, 2010). The large (N=488) phase 3 randomized AZA-AML-001 study compared AZA and CCR treatment (Tx) in older pts with AML. AZA prolonged median overall survival (OS) by ~4 months (mos) (10.4 vs 6.5 mos; p<0.101) and improved 1-year survival (46.5% vs 34.2%) vs CCR (Dombret, EHA, 2014).
Aims
To investigate the relationship between miR29 family RNA levels and clinical endpoints (response and OS) in AZA-AML-001 pts.
Methods
Eligible pts were age ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts) and had ECOG PS of 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. Pts received AZA (75mg/m2/day [d] x7d/28d cycle) or a preselected CCR: intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20mg SC BID x10d/28d cycle), or best supportive care only. RNA was isolated from BM mononuclear cells collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate BM mononuclear cells for analysis. Experimental miRNAs (miR29a, b, c) and control RNAs (RNU44, miR-16) were quantified by qRT-PCR. Associations between miR levels and response (IWG 2003) were assessed, defining responders as pts who achieved complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi), and nonresponders as pts with partial response (PR), stable disease (SD), or progressive disease (PD) as their best response. Differences in baseline miRNA expression were compared by T-test within the AZA and CCR Tx arms. A 2-way ANOVA model was used to test the interaction between miR expression and Tx. miR expression as a continuous variable was also fit in a Cox model with and without strata in separate arms.
Results
The biomarker cohort comprised 156 of all 488 pts (32%; AZA n=83, CCR n=73). Baseline characteristics were well-matched in the biomarker vs non-biomarker groups, respectively, with median age 75 years in both groups, median BM blasts 50.5% vs 52.0%, and cytogenetic risks of intermediate 63.8% vs 66.5%, and poor 36.3% vs 33.5%. Baseline miR29a and miR29b expression levels were significantly higher in responders (CR+CRi) vs nonresponders (PR+SD+PD) with AZA Tx (p<0.004 & p<0.029, respectively), but not with CCR Tx (Figure). This difference for miR29a was confirmed in the 2-way ANOVA analysis of response and Tx (p<0.054). miR29a levels were also associated with OS (p<0.044) in the AZA arm, but not in the CCR arm, in stratified survival analysis. No significant associations between miR29b or miR29c levels and OS were seen in either Tx arm.
Summary
In this exploratory analysis, higher expression levels of miR29a and miR29b were significantly associated with response to AZA Tx, and the association of miR29a levels with response was specific to AZA. Higher miR29a levels were also associated with improved OS in pts treated with AZA, but not in pts treated with CCR. As miR29a is implicated in regulating DNMT levels, an AZA target, these data are consistent with the concept that reduced pretreatment DNMT levels due to higher miR29a expression can improve response and survival with hypomethylating agents.
Keyword(s): Acute myeloid leukemia, DNA methylation, Epigenetic
Session topic: AML: Molecular profile and targeting
Abstract: S797
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room C1
Background
DNA methyltransferases (DNMTs) mediate DNA methylation and contribute to epigenetic aberrancy in myeloid malignancies. The miR29 family of microRNAs directly inhibit the expression of DNMT-3A and -3B (Fabbri, PNAS, 2007). In a small study (N=23) of older patients (pts) with AML, higher levels of miR29b were significantly associated with response to decitabine (Blum, PNAS, 2010). The large (N=488) phase 3 randomized AZA-AML-001 study compared AZA and CCR treatment (Tx) in older pts with AML. AZA prolonged median overall survival (OS) by ~4 months (mos) (10.4 vs 6.5 mos; p<0.101) and improved 1-year survival (46.5% vs 34.2%) vs CCR (Dombret, EHA, 2014).
Aims
To investigate the relationship between miR29 family RNA levels and clinical endpoints (response and OS) in AZA-AML-001 pts.
Methods
Eligible pts were age ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts) and had ECOG PS of 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. Pts received AZA (75mg/m2/day [d] x7d/28d cycle) or a preselected CCR: intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20mg SC BID x10d/28d cycle), or best supportive care only. RNA was isolated from BM mononuclear cells collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate BM mononuclear cells for analysis. Experimental miRNAs (miR29a, b, c) and control RNAs (RNU44, miR-16) were quantified by qRT-PCR. Associations between miR levels and response (IWG 2003) were assessed, defining responders as pts who achieved complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi), and nonresponders as pts with partial response (PR), stable disease (SD), or progressive disease (PD) as their best response. Differences in baseline miRNA expression were compared by T-test within the AZA and CCR Tx arms. A 2-way ANOVA model was used to test the interaction between miR expression and Tx. miR expression as a continuous variable was also fit in a Cox model with and without strata in separate arms.
Results
The biomarker cohort comprised 156 of all 488 pts (32%; AZA n=83, CCR n=73). Baseline characteristics were well-matched in the biomarker vs non-biomarker groups, respectively, with median age 75 years in both groups, median BM blasts 50.5% vs 52.0%, and cytogenetic risks of intermediate 63.8% vs 66.5%, and poor 36.3% vs 33.5%. Baseline miR29a and miR29b expression levels were significantly higher in responders (CR+CRi) vs nonresponders (PR+SD+PD) with AZA Tx (p<0.004 & p<0.029, respectively), but not with CCR Tx (Figure). This difference for miR29a was confirmed in the 2-way ANOVA analysis of response and Tx (p<0.054). miR29a levels were also associated with OS (p<0.044) in the AZA arm, but not in the CCR arm, in stratified survival analysis. No significant associations between miR29b or miR29c levels and OS were seen in either Tx arm.
Summary
In this exploratory analysis, higher expression levels of miR29a and miR29b were significantly associated with response to AZA Tx, and the association of miR29a levels with response was specific to AZA. Higher miR29a levels were also associated with improved OS in pts treated with AZA, but not in pts treated with CCR. As miR29a is implicated in regulating DNMT levels, an AZA target, these data are consistent with the concept that reduced pretreatment DNMT levels due to higher miR29a expression can improve response and survival with hypomethylating agents.
Keyword(s): Acute myeloid leukemia, DNA methylation, Epigenetic
Session topic: AML: Molecular profile and targeting
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room C1
Background
DNA methyltransferases (DNMTs) mediate DNA methylation and contribute to epigenetic aberrancy in myeloid malignancies. The miR29 family of microRNAs directly inhibit the expression of DNMT-3A and -3B (Fabbri, PNAS, 2007). In a small study (N=23) of older patients (pts) with AML, higher levels of miR29b were significantly associated with response to decitabine (Blum, PNAS, 2010). The large (N=488) phase 3 randomized AZA-AML-001 study compared AZA and CCR treatment (Tx) in older pts with AML. AZA prolonged median overall survival (OS) by ~4 months (mos) (10.4 vs 6.5 mos; p<0.101) and improved 1-year survival (46.5% vs 34.2%) vs CCR (Dombret, EHA, 2014).
Aims
To investigate the relationship between miR29 family RNA levels and clinical endpoints (response and OS) in AZA-AML-001 pts.
Methods
Eligible pts were age ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts) and had ECOG PS of 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. Pts received AZA (75mg/m2/day [d] x7d/28d cycle) or a preselected CCR: intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20mg SC BID x10d/28d cycle), or best supportive care only. RNA was isolated from BM mononuclear cells collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate BM mononuclear cells for analysis. Experimental miRNAs (miR29a, b, c) and control RNAs (RNU44, miR-16) were quantified by qRT-PCR. Associations between miR levels and response (IWG 2003) were assessed, defining responders as pts who achieved complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi), and nonresponders as pts with partial response (PR), stable disease (SD), or progressive disease (PD) as their best response. Differences in baseline miRNA expression were compared by T-test within the AZA and CCR Tx arms. A 2-way ANOVA model was used to test the interaction between miR expression and Tx. miR expression as a continuous variable was also fit in a Cox model with and without strata in separate arms.
Results
The biomarker cohort comprised 156 of all 488 pts (32%; AZA n=83, CCR n=73). Baseline characteristics were well-matched in the biomarker vs non-biomarker groups, respectively, with median age 75 years in both groups, median BM blasts 50.5% vs 52.0%, and cytogenetic risks of intermediate 63.8% vs 66.5%, and poor 36.3% vs 33.5%. Baseline miR29a and miR29b expression levels were significantly higher in responders (CR+CRi) vs nonresponders (PR+SD+PD) with AZA Tx (p<0.004 & p<0.029, respectively), but not with CCR Tx (Figure). This difference for miR29a was confirmed in the 2-way ANOVA analysis of response and Tx (p<0.054). miR29a levels were also associated with OS (p<0.044) in the AZA arm, but not in the CCR arm, in stratified survival analysis. No significant associations between miR29b or miR29c levels and OS were seen in either Tx arm.
Summary
In this exploratory analysis, higher expression levels of miR29a and miR29b were significantly associated with response to AZA Tx, and the association of miR29a levels with response was specific to AZA. Higher miR29a levels were also associated with improved OS in pts treated with AZA, but not in pts treated with CCR. As miR29a is implicated in regulating DNMT levels, an AZA target, these data are consistent with the concept that reduced pretreatment DNMT levels due to higher miR29a expression can improve response and survival with hypomethylating agents.
Keyword(s): Acute myeloid leukemia, DNA methylation, Epigenetic
Session topic: AML: Molecular profile and targeting
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