HIGH EXPRESSION OF THE STEM CELL MARKER GPR56 IS ASSOCIATED WITH AN INCREASED RELAPSE INCIDENCE IN AML AFTER ALLOGENEIC STEM CELL TRANSPLANTATION
(Abstract release date: 05/19/16)
EHA Library. Jentzsch M. 06/12/16; 135314; S820
Ms. Madlen Jentzsch
Contributions
Contributions
Abstract
Abstract: S820
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Hall C15
Background
In acute myeloid leukemia (AML) leukemia initiating cells (LICs) are believed to exist within the CD34+/CD38- cell compartment. Recently, the G protein-coupled receptor 56 (GPR56) was shown to define a novel LIC compartment independent of the CD34+/CD38- phenotype. LICs are assumed to be responsible for AML maintenance & relapse & may be less immunogenic than AML bulk cells. Hematopoietic stem cell transplantation (HSCT) is a consolidating approach mainly based on immunological graft-versus-leukemia (GvL) effects & its therapeutic success is associated with the elimination of AML LICs by GvL effects.
Aims
To evaluate the clinical relevance of aberrant GPR56 expression in the context of the CD34+/CD38- burden at diagnosis in AML patients (pts) receiving HSCT.
Methods
We analyzed 148 AML pts (median age 61, range 14-75 years [y]) for whom diagnostic bone marrow aspirate material was available & who received a non-myeloablative (3x30mg Fludarabine + 2Gy total body irradiation [TBI]) or myeloablative (2x60mg Cyclophosphamide + 12Gy TBI) HSCT in 1st (69%) or 2nd (19%) complete remission (CR) or in CR with incomplete peripheral recovery (12%). At diagnosis, the mutation (mut) status of CEBPA, NPM1, presence of FLT3-ITD & expression levels of BAALC & EVI1 were evaluated. For 68 pts RUNX1mut status was available. The CD34+/CD38- burden & common surface markers expressions were determined by flow cytometry. A 5% cut-off defined pts with a high & low CD34+/CD38- burden. GPR56 was measured by qRT-PCR, normalized to ABL1 & the median normalized gene expression was used to define high & low expressers. Median follow up was 4.9y.
Results
European LeukemiaNet (ELN) classification was 24% favorable, 24% intermediate-I, 17% intermediate-II, 28% adverse & 7% unknown. At diagnosis high GPR56 expressers had lower white blood cell counts (P=.04), were less likely to have de novo AML (P=.02), core-binding factor AML (P=.01), to be NPM1mut (P=.02) & were more likely to have a del7 (P=.004), to be RUNX1mut (P=.09) by trend, to be EVI1 positive (P=.04) & to have higher BAALC (P<.001) expression. BM blasts in the high GPR56 group were less likely to be positive for myeloid markers (CD33, P=.009; CD38, P=.04; CD64, P=.04; CD15, P=.002; CD65, P=.001) & the pan-leukocyte marker CD45 (P=.03) & more likely to be positive for T-cell (CD7, P=.03; by trend CD2, P=.1), thrombocytic & erythroid (CD61, P=.005; Glykophorin A, P=.003) & immature (by trend CD34, P=.07) markers. High GPR56 expression was associated with high CD34+/CD38- cell burden at diagnosis (P=.002) & with a higher cumulative incidence of relapse (CIR, P=.04, Figure 1A) in AML pts receiving HSCT. Since GPR56 defined a novel LIC compartment independent of the CD34+/CD38- phenotype, we analyzed the impact of aberrant GPR56 expression in the low CD34+/CD38- burden pts. Similar clinical, cytogenetic & molecular associations were observed as in the entire set of pts. In the low CD34+/CD38- burden group, high GPR56 expression identified a group of AML pts with a higher CIR as compared to pts with low GPR56 expression (P=.05, Figure 1B).
Conclusion
High GPR56 expression was associated with a higher relapse rate & worse outcome predictors. Among pts with low CD34+/CD38- burden high GPR56 expression defined a subgroup with higher CIR after HSCT possibly due to an independent GPR56-defined LIC population. HSCT-associated therapeutic GvL effects might be insufficient to control the disease in pts with high LIC burden defined by the CD34+/CD38-phenotype & GPR56 expression status at diagnosis.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Allogeneic hematopoietic stem cell transplant, AML, Leukemic stem cell, Prognosis
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Hall C15
Background
In acute myeloid leukemia (AML) leukemia initiating cells (LICs) are believed to exist within the CD34+/CD38- cell compartment. Recently, the G protein-coupled receptor 56 (GPR56) was shown to define a novel LIC compartment independent of the CD34+/CD38- phenotype. LICs are assumed to be responsible for AML maintenance & relapse & may be less immunogenic than AML bulk cells. Hematopoietic stem cell transplantation (HSCT) is a consolidating approach mainly based on immunological graft-versus-leukemia (GvL) effects & its therapeutic success is associated with the elimination of AML LICs by GvL effects.
Aims
To evaluate the clinical relevance of aberrant GPR56 expression in the context of the CD34+/CD38- burden at diagnosis in AML patients (pts) receiving HSCT.
Methods
We analyzed 148 AML pts (median age 61, range 14-75 years [y]) for whom diagnostic bone marrow aspirate material was available & who received a non-myeloablative (3x30mg Fludarabine + 2Gy total body irradiation [TBI]) or myeloablative (2x60mg Cyclophosphamide + 12Gy TBI) HSCT in 1st (69%) or 2nd (19%) complete remission (CR) or in CR with incomplete peripheral recovery (12%). At diagnosis, the mutation (mut) status of CEBPA, NPM1, presence of FLT3-ITD & expression levels of BAALC & EVI1 were evaluated. For 68 pts RUNX1mut status was available. The CD34+/CD38- burden & common surface markers expressions were determined by flow cytometry. A 5% cut-off defined pts with a high & low CD34+/CD38- burden. GPR56 was measured by qRT-PCR, normalized to ABL1 & the median normalized gene expression was used to define high & low expressers. Median follow up was 4.9y.
Results
European LeukemiaNet (ELN) classification was 24% favorable, 24% intermediate-I, 17% intermediate-II, 28% adverse & 7% unknown. At diagnosis high GPR56 expressers had lower white blood cell counts (P=.04), were less likely to have de novo AML (P=.02), core-binding factor AML (P=.01), to be NPM1mut (P=.02) & were more likely to have a del7 (P=.004), to be RUNX1mut (P=.09) by trend, to be EVI1 positive (P=.04) & to have higher BAALC (P<.001) expression. BM blasts in the high GPR56 group were less likely to be positive for myeloid markers (CD33, P=.009; CD38, P=.04; CD64, P=.04; CD15, P=.002; CD65, P=.001) & the pan-leukocyte marker CD45 (P=.03) & more likely to be positive for T-cell (CD7, P=.03; by trend CD2, P=.1), thrombocytic & erythroid (CD61, P=.005; Glykophorin A, P=.003) & immature (by trend CD34, P=.07) markers. High GPR56 expression was associated with high CD34+/CD38- cell burden at diagnosis (P=.002) & with a higher cumulative incidence of relapse (CIR, P=.04, Figure 1A) in AML pts receiving HSCT. Since GPR56 defined a novel LIC compartment independent of the CD34+/CD38- phenotype, we analyzed the impact of aberrant GPR56 expression in the low CD34+/CD38- burden pts. Similar clinical, cytogenetic & molecular associations were observed as in the entire set of pts. In the low CD34+/CD38- burden group, high GPR56 expression identified a group of AML pts with a higher CIR as compared to pts with low GPR56 expression (P=.05, Figure 1B).
Conclusion
High GPR56 expression was associated with a higher relapse rate & worse outcome predictors. Among pts with low CD34+/CD38- burden high GPR56 expression defined a subgroup with higher CIR after HSCT possibly due to an independent GPR56-defined LIC population. HSCT-associated therapeutic GvL effects might be insufficient to control the disease in pts with high LIC burden defined by the CD34+/CD38-phenotype & GPR56 expression status at diagnosis.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Allogeneic hematopoietic stem cell transplant, AML, Leukemic stem cell, Prognosis
Abstract: S820
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Hall C15
Background
In acute myeloid leukemia (AML) leukemia initiating cells (LICs) are believed to exist within the CD34+/CD38- cell compartment. Recently, the G protein-coupled receptor 56 (GPR56) was shown to define a novel LIC compartment independent of the CD34+/CD38- phenotype. LICs are assumed to be responsible for AML maintenance & relapse & may be less immunogenic than AML bulk cells. Hematopoietic stem cell transplantation (HSCT) is a consolidating approach mainly based on immunological graft-versus-leukemia (GvL) effects & its therapeutic success is associated with the elimination of AML LICs by GvL effects.
Aims
To evaluate the clinical relevance of aberrant GPR56 expression in the context of the CD34+/CD38- burden at diagnosis in AML patients (pts) receiving HSCT.
Methods
We analyzed 148 AML pts (median age 61, range 14-75 years [y]) for whom diagnostic bone marrow aspirate material was available & who received a non-myeloablative (3x30mg Fludarabine + 2Gy total body irradiation [TBI]) or myeloablative (2x60mg Cyclophosphamide + 12Gy TBI) HSCT in 1st (69%) or 2nd (19%) complete remission (CR) or in CR with incomplete peripheral recovery (12%). At diagnosis, the mutation (mut) status of CEBPA, NPM1, presence of FLT3-ITD & expression levels of BAALC & EVI1 were evaluated. For 68 pts RUNX1mut status was available. The CD34+/CD38- burden & common surface markers expressions were determined by flow cytometry. A 5% cut-off defined pts with a high & low CD34+/CD38- burden. GPR56 was measured by qRT-PCR, normalized to ABL1 & the median normalized gene expression was used to define high & low expressers. Median follow up was 4.9y.
Results
European LeukemiaNet (ELN) classification was 24% favorable, 24% intermediate-I, 17% intermediate-II, 28% adverse & 7% unknown. At diagnosis high GPR56 expressers had lower white blood cell counts (P=.04), were less likely to have de novo AML (P=.02), core-binding factor AML (P=.01), to be NPM1mut (P=.02) & were more likely to have a del7 (P=.004), to be RUNX1mut (P=.09) by trend, to be EVI1 positive (P=.04) & to have higher BAALC (P<.001) expression. BM blasts in the high GPR56 group were less likely to be positive for myeloid markers (CD33, P=.009; CD38, P=.04; CD64, P=.04; CD15, P=.002; CD65, P=.001) & the pan-leukocyte marker CD45 (P=.03) & more likely to be positive for T-cell (CD7, P=.03; by trend CD2, P=.1), thrombocytic & erythroid (CD61, P=.005; Glykophorin A, P=.003) & immature (by trend CD34, P=.07) markers. High GPR56 expression was associated with high CD34+/CD38- cell burden at diagnosis (P=.002) & with a higher cumulative incidence of relapse (CIR, P=.04, Figure 1A) in AML pts receiving HSCT. Since GPR56 defined a novel LIC compartment independent of the CD34+/CD38- phenotype, we analyzed the impact of aberrant GPR56 expression in the low CD34+/CD38- burden pts. Similar clinical, cytogenetic & molecular associations were observed as in the entire set of pts. In the low CD34+/CD38- burden group, high GPR56 expression identified a group of AML pts with a higher CIR as compared to pts with low GPR56 expression (P=.05, Figure 1B).
Conclusion
High GPR56 expression was associated with a higher relapse rate & worse outcome predictors. Among pts with low CD34+/CD38- burden high GPR56 expression defined a subgroup with higher CIR after HSCT possibly due to an independent GPR56-defined LIC population. HSCT-associated therapeutic GvL effects might be insufficient to control the disease in pts with high LIC burden defined by the CD34+/CD38-phenotype & GPR56 expression status at diagnosis.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Allogeneic hematopoietic stem cell transplant, AML, Leukemic stem cell, Prognosis
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Hall C15
Background
In acute myeloid leukemia (AML) leukemia initiating cells (LICs) are believed to exist within the CD34+/CD38- cell compartment. Recently, the G protein-coupled receptor 56 (GPR56) was shown to define a novel LIC compartment independent of the CD34+/CD38- phenotype. LICs are assumed to be responsible for AML maintenance & relapse & may be less immunogenic than AML bulk cells. Hematopoietic stem cell transplantation (HSCT) is a consolidating approach mainly based on immunological graft-versus-leukemia (GvL) effects & its therapeutic success is associated with the elimination of AML LICs by GvL effects.
Aims
To evaluate the clinical relevance of aberrant GPR56 expression in the context of the CD34+/CD38- burden at diagnosis in AML patients (pts) receiving HSCT.
Methods
We analyzed 148 AML pts (median age 61, range 14-75 years [y]) for whom diagnostic bone marrow aspirate material was available & who received a non-myeloablative (3x30mg Fludarabine + 2Gy total body irradiation [TBI]) or myeloablative (2x60mg Cyclophosphamide + 12Gy TBI) HSCT in 1st (69%) or 2nd (19%) complete remission (CR) or in CR with incomplete peripheral recovery (12%). At diagnosis, the mutation (mut) status of CEBPA, NPM1, presence of FLT3-ITD & expression levels of BAALC & EVI1 were evaluated. For 68 pts RUNX1mut status was available. The CD34+/CD38- burden & common surface markers expressions were determined by flow cytometry. A 5% cut-off defined pts with a high & low CD34+/CD38- burden. GPR56 was measured by qRT-PCR, normalized to ABL1 & the median normalized gene expression was used to define high & low expressers. Median follow up was 4.9y.
Results
European LeukemiaNet (ELN) classification was 24% favorable, 24% intermediate-I, 17% intermediate-II, 28% adverse & 7% unknown. At diagnosis high GPR56 expressers had lower white blood cell counts (P=.04), were less likely to have de novo AML (P=.02), core-binding factor AML (P=.01), to be NPM1mut (P=.02) & were more likely to have a del7 (P=.004), to be RUNX1mut (P=.09) by trend, to be EVI1 positive (P=.04) & to have higher BAALC (P<.001) expression. BM blasts in the high GPR56 group were less likely to be positive for myeloid markers (CD33, P=.009; CD38, P=.04; CD64, P=.04; CD15, P=.002; CD65, P=.001) & the pan-leukocyte marker CD45 (P=.03) & more likely to be positive for T-cell (CD7, P=.03; by trend CD2, P=.1), thrombocytic & erythroid (CD61, P=.005; Glykophorin A, P=.003) & immature (by trend CD34, P=.07) markers. High GPR56 expression was associated with high CD34+/CD38- cell burden at diagnosis (P=.002) & with a higher cumulative incidence of relapse (CIR, P=.04, Figure 1A) in AML pts receiving HSCT. Since GPR56 defined a novel LIC compartment independent of the CD34+/CD38- phenotype, we analyzed the impact of aberrant GPR56 expression in the low CD34+/CD38- burden pts. Similar clinical, cytogenetic & molecular associations were observed as in the entire set of pts. In the low CD34+/CD38- burden group, high GPR56 expression identified a group of AML pts with a higher CIR as compared to pts with low GPR56 expression (P=.05, Figure 1B).
Conclusion
High GPR56 expression was associated with a higher relapse rate & worse outcome predictors. Among pts with low CD34+/CD38- burden high GPR56 expression defined a subgroup with higher CIR after HSCT possibly due to an independent GPR56-defined LIC population. HSCT-associated therapeutic GvL effects might be insufficient to control the disease in pts with high LIC burden defined by the CD34+/CD38-phenotype & GPR56 expression status at diagnosis.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Allogeneic hematopoietic stem cell transplant, AML, Leukemic stem cell, Prognosis
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