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RAS PATHWAY HYPERACTIVATION IS ASSOCIATED WITH INFERIOR SURVIVAL IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA
Author(s): ,
Klaus Geissler
Affiliations:
5th Medical Department with Oncology,Hospital Hietzing,Vienna,Austria
,
Agnes Barna
Affiliations:
Austrian Red Cross, Blood Transfusion Service for Upper Austria ,Linz,Austria
,
Eva Jäger
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Michael Gurbisz
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Temeida Alendar
Affiliations:
5th Medical Department with Oncology,Hospital Hietzing,Vienna,Austria
,
Elmir Ljubuncic
Affiliations:
5th Medical Department with Oncology,Hospital Hietzing,Vienna,Austria
,
Bojana Borjan
Affiliations:
Internal Medicine V, Hematology and Oncology, Labor für Tumorbiologie und Angiogenese,Medical University of Innsbruck,Innsbruck,Austria
,
Ruth Jilch
Affiliations:
Department of Laboratory Medicine,Hospital Hietzing,Vienna,Austria
,
Thomas Nösslinger
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Michael Pfeilstöcker
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Heinz Tüchler
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Regina Reisner
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Thamer Sliwa
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Felix Keil
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Christoph Geissler
Affiliations:
3rd Medical Department,Hospital Hanusch,Vienna,Austria
,
Peter Bettelheim
Affiliations:
1st Medical Department with Hematology, Stem Cell Transplantation, Hemostasis and Medical Oncology,Elisabethinen Hospital,Linz,Austria
,
Sigrid Machherndl-Spandl
Affiliations:
1st Medical Department with Hematology, Stem Cell Transplantation, Hemostasis and Medical Oncology,Elisabethinen Hospital,Linz,Austria
,
Otto Zach
Affiliations:
1st Medical Department with Hematology, Stem Cell Transplantation, Hemostasis and Medical Oncology,Elisabethinen Hospital,Linz,Austria
,
Ansgar Weltermann
Affiliations:
1st Medical Department with Hematology, Stem Cell Transplantation, Hemostasis and Medical Oncology,Elisabethinen Hospital,Linz,Austria
,
Sonja Burgstaller
Affiliations:
Department of Internal Medicine IV,Hospital Wels-Grieskirchen,Wels,Austria
,
Josef Thaler
Affiliations:
Department of Internal Medicine IV,Hospital Wels-Grieskirchen,Wels,Austria
,
Armin Zebisch
Affiliations:
Department of Hematology,Medical University of Graz,Graz,Austria
,
Heinz Sill
Affiliations:
Department of Hematology,Medical University of Graz,Graz,Austria
,
Reinhard Stauder
Affiliations:
Internal Medicine V, Hematology and Oncology,Medical University of Innsbruck,Innsbruck,Austria
,
Rajko Kusec
Affiliations:
University Hospital Dubrava, School of Medicine,University of Zagreb,Zagreb,Croatia
,
Ernst Ulsperger
Affiliations:
Department of Internal Medicine,Country Hospital Horn,Horn,Austria
,
Bruno Schneeweiss
Affiliations:
Department of Internal Medicine,Hospital Kirchdorf,Kirchdorf,Austria
,
Jörg Berger
Affiliations:
Department of Internal Medicine,Hospital Schwarzach,Schwarzach,Austria
,
Leopold Öhler
Affiliations:
Department of Internal Medicine/Oncology,Hospital St.Josef,Vienna,Austria
,
Ulrich Germing
Affiliations:
Department of Hematology, Oncology, and Clinical Immunology,Heinrich-Heine-University Düsseldorf,Düsseldorf,Germany
,
Wolfgang R. Sperr
Affiliations:
Division of Hematology and Hemostaseology, Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Paul Knöbl
Affiliations:
Division of Hematology and Hemostaseology, Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Ilse Schwarzinger
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Gregor Hörmann
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Ulrich Jäger
Affiliations:
Division of Hematology and Hemostaseology, Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
Peter Valent
Affiliations:
Division of Hematology and Hemostaseology, Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
(Abstract release date: 05/17/18) EHA Library. Geissler K. 06/16/18; 214472; S880
Klaus Geissler
Klaus Geissler
Contributions
Abstract

Abstract: S880

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15

Location: Room A7

Background
Although patients with chronic myelomonocytic leukemia (CMML) have surprisingly diverse genomic alterations, these events tend to occur in a limited number of pathways. The prognostic impact of pathway activation in CMML is poorly investigated. Recently we were able to show that the spontaneous in vitro growth of myeloid colonies (CFU-GM) may be a useful functional parameter of RAS pathway activation (Geissler K et al, Leukemia 2016).

Aims
To investigate the prognostic impact of RAS pathway activation in patients with CMML.

Methods
In this study we analyzed CMML patient samples which were collected in the “Austrian Biodatabase for CMML” (ABCMML) with regard to the presence of molecular aberrations in RASopathy genes by targeted next generation sequencing (NGS) and the presence of high spontaneous myeloid colony  formation using semisolid in vitro cultures as described previously (Geissler K et al, J Exp Med 1996). From 225 CMML patients 288 samples (BMMNC or PBMNC) were analyzed by NGS and 207 samples (PBMNC) were used for in vitro cultures. Mutations with a VAF >5% were considered as positive in this study and autonomous CFU-GM formation >100/105 PBMNC was considered as high colony growth. Survival analysis was calculated from the sampling date. Molecular and functional data were correlated with patient survival using Cox regression analysis. 

Results
Fig 1a shows the Kaplan-Meier plots, hazard ratios and p-values of the prognostic impact of RASopathy gene mutations including NRAS (23.3%), KRAS (11.6%), CBL (16.5%), NF1 (10.2%), and PTPN11 (8.0%), respectively. If the presence of a mutation in at least one of the RASopathy genes was used as a composite molecular parameter (55.5%) the prognostic impact was most significant with a p value = 0.00006. The prognostic impact of RAS pathway activation could be also demonstrated at a functional level. As shown in Fig 1b high autonomous colony formation (CFU-GM >100/105 PBMNC; 27.0%) was significantly associated with inferior survival (p <0.00001).

Conclusion
Our data show that RAS pathway hyperactivation, which was demonstrated at the molecular and at the functional level, is associated with inferior survival in patients with CMML. These data may be important for better understanding the pathogenesis of CMML, for improving risk stratification of individual patients and for the design of targeted treatment concepts.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Chronic myelomonocytic leukemia, Colony assay, Ras

Abstract: S880

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15

Location: Room A7

Background
Although patients with chronic myelomonocytic leukemia (CMML) have surprisingly diverse genomic alterations, these events tend to occur in a limited number of pathways. The prognostic impact of pathway activation in CMML is poorly investigated. Recently we were able to show that the spontaneous in vitro growth of myeloid colonies (CFU-GM) may be a useful functional parameter of RAS pathway activation (Geissler K et al, Leukemia 2016).

Aims
To investigate the prognostic impact of RAS pathway activation in patients with CMML.

Methods
In this study we analyzed CMML patient samples which were collected in the “Austrian Biodatabase for CMML” (ABCMML) with regard to the presence of molecular aberrations in RASopathy genes by targeted next generation sequencing (NGS) and the presence of high spontaneous myeloid colony  formation using semisolid in vitro cultures as described previously (Geissler K et al, J Exp Med 1996). From 225 CMML patients 288 samples (BMMNC or PBMNC) were analyzed by NGS and 207 samples (PBMNC) were used for in vitro cultures. Mutations with a VAF >5% were considered as positive in this study and autonomous CFU-GM formation >100/105 PBMNC was considered as high colony growth. Survival analysis was calculated from the sampling date. Molecular and functional data were correlated with patient survival using Cox regression analysis. 

Results
Fig 1a shows the Kaplan-Meier plots, hazard ratios and p-values of the prognostic impact of RASopathy gene mutations including NRAS (23.3%), KRAS (11.6%), CBL (16.5%), NF1 (10.2%), and PTPN11 (8.0%), respectively. If the presence of a mutation in at least one of the RASopathy genes was used as a composite molecular parameter (55.5%) the prognostic impact was most significant with a p value = 0.00006. The prognostic impact of RAS pathway activation could be also demonstrated at a functional level. As shown in Fig 1b high autonomous colony formation (CFU-GM >100/105 PBMNC; 27.0%) was significantly associated with inferior survival (p <0.00001).

Conclusion
Our data show that RAS pathway hyperactivation, which was demonstrated at the molecular and at the functional level, is associated with inferior survival in patients with CMML. These data may be important for better understanding the pathogenesis of CMML, for improving risk stratification of individual patients and for the design of targeted treatment concepts.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Chronic myelomonocytic leukemia, Colony assay, Ras

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