MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, GENOTYPIC AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL
Author(s): ,
Klaus Geissler
Affiliations:
Sigmund Freud University,Vienna,Austria;5th Medical Department with Hematology, Oncology and Palliative Medicine,Hospital Hietzing,Vienna,Austria
,
Eva Jäger
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Agnes Barna
Affiliations:
Blood Transfusion Service for Upper Austria,Austrian Red Cross,Linz,Austria
,
Michael Gurbisz
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Renate Marschon
Affiliations:
Labor für Molekularbiologie,Hospital Barmherzige Schwestern,Linz,Austria
,
Temeida Graf
Affiliations:
5th Medical Department with Hematology, Oncology and Palliative Medicine,Hospital Hietzing,Vienna,Austria
,
Elmir Graf
Affiliations:
5th Medical Department with Hematology, Oncology and Palliative Medicine,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
,
Christoph Geissler
Affiliations:
Department of Laboratory Medicine,Hospital Hietzing,Vienna,Austria
,
Gregor Hörmann
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Harald Esterbauer
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Ilse Schwarzinger
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Thomas Nösslinger
Affiliations:
3rd Medical Department,Hanusch Hospital,Vienna,Austria
,
Michael Pfeilstöcker
Affiliations:
3rd Medical Department,Hanusch Hospital,Vienna,Austria
,
Heinz Tüchler
Affiliations:
3rd Medical Department,Hanusch Hospital,Vienna,Austria
,
Regina Reisner
Affiliations:
3rd Medical Department,Hanusch Hospital,Vienna,Austria
,
Thamer Sliwa
Affiliations:
3rd Medical Department,Hanusch Hospital,Vienna,Austria
,
Felix Keil
Affiliations:
3rd Medical Department,Hanusch Hospital,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 Heibl
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
,
Gerald Webersinke
Affiliations:
Labor für Molekularbiologie,Hospital Barmherzige Schwestern,Linz,Austria
,
Andreas Petzer
Affiliations:
Department of Internal Medicine I with Oncology and Hematology,Hospital Barmherzige Schwestern,Linz,Austria
,
Rajko Kusec
Affiliations:
University Hospital Dubrava,School of Medicine, University of Zagreb,Zagreb,Croatia
,
Ernst Ulsperger
Affiliations:
Department of Internal Medicine,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,St. Josef Hospital,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
,
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
EHA Library. Geissler K. Jun 15, 2019; 266948; PS1331
Prof. Dr. Klaus Geissler
Prof. Dr. Klaus Geissler
Contributions
Abstract

Abstract: PS1331

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Normal hematopoietic function is maintained by a well controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations. This balance may be skewed during pathologic conditions such as hematological malignancies, infections and autoimmunity. Moreover skewed hematopoiesis can be found in aged hematopoiesis. Myelomonocytic skewing has been described in chronic myelomonocytic leukemia (CMML) (Itzykson R et al, Blood 2013) but the role of this phenomen has not been investigated in a large cohort of patients. Since semisolid in vitro cultures from peripheral blood mononuclear cells (PBMNC) of normal individuals usually contain a higher concentration of erythroid colonies (BFU-E) as compared to myelomonocytic colony forming units (CFU-GM) this test may be useful for investigating skewed differentiation towards the myelomonocytic over erythroid committment in patients.

Aims
Our aim was to study the role myelomonocytic skewing in patients with CMML.

Methods
In the Austrian Biodatabase for CMML (ABCMML) real life data from CMML patients who are treated in different centers are collected centrally. Biologic assays are carried out in one laboratory in which in vitro cell cultures are performed. In this retrospective study data from the ABCMML were used to determine the frequency of myelomonocytic skewing, its correlation to hematologic and molecular parameters, and its prognostic impact in patients with CMML.  146 CMML patients were found in whom semisolid in vitro cell cultures from PBMNC have been performed between 1990 and 2018. The concentration of BFU-E and CFU-GM, respectively, was assessed as previously described (Geissler K et al, Blood 1996). For molecular characterization, we used NGS with amplicon-based target enrichment. Assuming that clones that are too small are unlikely to significantly impact hematopoiesis, only mutations with an allele burden of 20% or higher were considered as positive for analysis.

Results
There was a high prevalence of myelomonocytic skewing as indicated by an inverse ratio of BFU-E/CFU-GM in CMML patients (120/146, 82%) whereas this phenomenon was rare in normal individuals (2/54, 4%). There was no difference in patients with and without myelomonocytic skewing with regard to age and male predominance. CMML patients with myelomonocytic skewing had higher WBC counts (17.7 x 109/L [2.8-156] vs 8.3 [3.1-38], p=0.0008) and PB blast cell percentages (0% [0-17] vs 0 [0-2], p=0.0178), and lower platelet values (100 x 109/L [5-867] vs 160 [35-689], p=0.0015). In semisolid cultures myelomonocytic skewing was associated with a higher growth factor independent formation of CFU-GM (11.5/105PBMNC [0-1127] vs 2 [0-167], p=0071). Regarding the mutational profile, there were no differences in the frequency of mutations in genes of the epigenetic machinery (such as TET2, SRSF2and ASXL1) but a higher frequency of mutations in RASopathy genes including NRAS, KRAS, NF1, CBLand PTPN11, respectively, in CMML patients with (45%) as compared to patients without myelomonocytic skewing (13%, p=0.0153). Interestingly, the lack of myelomonocytic skewing discriminated CMML patients with a particularly favorable prognosis (Figure 1, 60 vs 19 months, p=0.0030).

Conclusion
The results of this study show that the in vitro assessment of myelomonocytic skewing can discriminate subgroups of patients with CMML with a different hematologic phenotype, a different genotype and different prognosis. Our findings may be important for the understanding and management of CMML.

Session topic: 9. Myelodysplastic syndromes - Biology & Translational Research

Keyword(s): Chronic myelomonocytic leukemia, Genotype, Phenotype, Prognosis

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