TP53 STATUS AND OUTCOME IN MYELODYSPLASTIC SYNDROMES WITH COMPLEX ABERRANT KARYOTYPES
Author(s): ,
Christina Ganster
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Roxana Schaab
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Katayoon Shirneshan
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Lea Naomi Eder
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Anna Mies
Affiliations:
Dept. of Medicine I,University Hospital Carl Gustav Carus, Technical University Dresden,Dresden,Germany
,
Ulrich Germing
Affiliations:
Dept. of Hematology, Oncology and Clinical Immunology,Heinrich-Heine-University Düsseldorf,Düsseldorf,Germany
,
Ahmet Elmaagacli
Affiliations:
Dept. of Hematology Oncology and Stem Cell Transplantation,Asklepios Klinik St. Georg,Hamburg,Germany
,
Francesc Solé
Affiliations:
Universitat Autonòma de Barcelona, Josep Carreras Leukemia Research Institute (IJC),ICO-Hospital GermansTrias i Pujol,Barcelona,Spain
,
Laura Palomo
Affiliations:
Universitat Autonòma de Barcelona, Josep Carreras Leukemia Research Institute (IJC),ICO-Hospital GermansTrias i Pujol,Barcelona,Spain
,
Jennifer Kaivers
Affiliations:
Dept. of Hematology, Oncology and Clinical Immunology,Heinrich-Heine-University Düsseldorf,Düsseldorf,Germany
,
Ulrike Söling
Affiliations:
Outpatient Clinic for Hematology and Oncology,Kassel,Germany
,
Frank Lange
Affiliations:
Hufeland Klinikum,Mühlhausen,Germany
,
Nicolaus Kroeger
Affiliations:
University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Bernd Hertenstein
Affiliations:
Dept. of Hematology and Oncology,Klinikum Bremen Mitte,Bremen,Germany
,
Konstanze Döhner
Affiliations:
Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Gesine Bug
Affiliations:
Dept. of Medicine II, Hematology and Oncology,University Hospital Frankfurt,Frankfurt,Germany
,
Barbara Hildebrandt
Affiliations:
Institute of Human Genetics,Heinrich-Heine-University Düsseldorf,Düsseldorf,Germany
,
Marc Talló Parra
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Maike Nickelsen
Affiliations:
Onkologie Lerchenfeld,Hamburg,Germany
,
Bertram Glass
Affiliations:
Clinic for Hematology, Oncology, Tumorimmunology and Palliative Care,Helios Clinic Berlin-Buch,Berlin,Germany
,
Uwe Platzbecker
Affiliations:
Medical Clinic and Policlinic 1, Hematology and Cellular Therapy,University hospital Leipzig,Leipzig,Germany
,
Ulrike Bacher
Affiliations:
Dept. of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital,University of Bern,Bern,Switzerland
,
Friederike Braulke
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
,
Julie Schanz
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
Detlef Haase
Affiliations:
Clinics of Hematology and Medical Oncology,University Medicine Göttingen,Göttingen,Germany
EHA Library. Haase D. 06/12/20; 294702; EP785
Prof. Dr. Detlef Haase
Prof. Dr. Detlef Haase
Contributions
Abstract

Abstract: EP785

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
MDS with complex aberrant karyotypes (CK-MDS, ≥3 aberrations, CA) are heterogeneous in terms of genetic profile and prognosis. There is a strong association between CK-MDS and mutations in TP53 (TP53mut, Haase et al 2019). Recently, the importance of multiple TP53 hits (TP53multi) in MDS was demonstrated (Bernard et al 2019), which focused attention also on loss of heterozygosity (LOH) of 17p13 (TP53LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH).

Aims

The aim of our study was to further characterize CK-MDS and to describe the impact of the complexity of the karyotype and the TP53 status on the outcome of this group of high-risk MDS.

Methods
We included 144 pts with MDS (N=115), CMML (N=4) and sAML after MDS (≤30% blasts, N=25), all with CK. The number of CA was determined by banding analysis (144x). The karyotype was confirmed by multicolor FISH (99x). TP53LOH was verified by FISH analysis (116x) and/or molecular karyotyping (31x). TP53mut was identified by NGS (40x) or Sanger sequencing (104x). Follow-up data for survival analyses were available for all pts.

Results
The med. blast count was 11% (range 0-27%). The med. age was 71 yrs (range 30-95). The male:female ratio was 1.29:1. 82/144 pts were treated with demethylating agents (DMTi). The med. number of CA was 7 (range: 3-46). At least one TP53mut was detected in 77/144 pts and a TP53LOH was present in 52/144 pts (incl. 4x CN-LOH), resulting in 51/144 pts with TP53multi and 91/144 pts with any TP53 alteration (TP53alt).

In our cohort of CK-MDS, 117/144 pts were assigned to the very high risk group of the IPSS-R. In order to identify pts with a probably better prognosis, we analyzed parameters that might further contribute to survival (OS). The univariate analysis (Cox regression) revealed a significantly increased risk for TP53alt (HR 3.75), the number of CA (HR 3.43), anemia (Hb <10 g/dl, HR 3.41), TP53mut (HR 3.41), TP53LOH (HR 2.23), TP53multi (HR 1.93), and the blast count (HR 1.84).

The OS did not significantly differ between TP53multi and a single TP53 alteration (253 days/N=53 vs 160 days/N=24) in the whole cohort. As a trend towards shorter OS in TP53multi (N=3, OS 107 days) compared to single TP53 alterations (N=6, OS 491 days, P=0.16) was just observed in pts with <5 CA, TP53alt was used for further analyses.

First, adding TP53alt as a differentiating feature to the IPSS-R (by subtracting/adding 2 points for TP53alt absent/present to the raw IPSS-R score) increased the prognostic power of the IPSS-R (Dxy 0.13 vs 0.30).

Second, creating a simplified prognostic scoring system for CK-MDS where one scoring point each was assigned to the 3 parameters with the greatest impact on OS in the multivariate model (anemia (Hb <10 g/dl), HR 2.95; TP53alt, HR 2.69; ≥5 CA, HR 2.24) also improved prognostication (Dxy 0.39).

Conclusion
Our data imply that TP53 and the complexity of the karyotype are independent prognostic marker in CK-MDS. TP53multi was of reduced informative value in our cohort, but might be useful in non CK-MDS, e.g. with 5q-. In addition, a positive impact of DMTi on TP53multi could affect this parameter in our cohort of intensely treated pts. Adding TP53alt as differentiating feature to the IPSS-R may enhance its prognostic significance in CK-MDS. The suggested simplified model fits well to our cohort of CK-MDS. But as overfitting cannot be excluded it should be tested in an independent cohort. In summary, considering additional parameters for predicting the prognosis of CK-MDS will allow to better tailor treatment decisions for individual pts with CK-MDS.

Session topic: 09. Myelodysplastic syndromes - Biology & Translational Research

Keyword(s): Cytogenetics, Mutation analysis

Abstract: EP785

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
MDS with complex aberrant karyotypes (CK-MDS, ≥3 aberrations, CA) are heterogeneous in terms of genetic profile and prognosis. There is a strong association between CK-MDS and mutations in TP53 (TP53mut, Haase et al 2019). Recently, the importance of multiple TP53 hits (TP53multi) in MDS was demonstrated (Bernard et al 2019), which focused attention also on loss of heterozygosity (LOH) of 17p13 (TP53LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH).

Aims

The aim of our study was to further characterize CK-MDS and to describe the impact of the complexity of the karyotype and the TP53 status on the outcome of this group of high-risk MDS.

Methods
We included 144 pts with MDS (N=115), CMML (N=4) and sAML after MDS (≤30% blasts, N=25), all with CK. The number of CA was determined by banding analysis (144x). The karyotype was confirmed by multicolor FISH (99x). TP53LOH was verified by FISH analysis (116x) and/or molecular karyotyping (31x). TP53mut was identified by NGS (40x) or Sanger sequencing (104x). Follow-up data for survival analyses were available for all pts.

Results
The med. blast count was 11% (range 0-27%). The med. age was 71 yrs (range 30-95). The male:female ratio was 1.29:1. 82/144 pts were treated with demethylating agents (DMTi). The med. number of CA was 7 (range: 3-46). At least one TP53mut was detected in 77/144 pts and a TP53LOH was present in 52/144 pts (incl. 4x CN-LOH), resulting in 51/144 pts with TP53multi and 91/144 pts with any TP53 alteration (TP53alt).

In our cohort of CK-MDS, 117/144 pts were assigned to the very high risk group of the IPSS-R. In order to identify pts with a probably better prognosis, we analyzed parameters that might further contribute to survival (OS). The univariate analysis (Cox regression) revealed a significantly increased risk for TP53alt (HR 3.75), the number of CA (HR 3.43), anemia (Hb <10 g/dl, HR 3.41), TP53mut (HR 3.41), TP53LOH (HR 2.23), TP53multi (HR 1.93), and the blast count (HR 1.84).

The OS did not significantly differ between TP53multi and a single TP53 alteration (253 days/N=53 vs 160 days/N=24) in the whole cohort. As a trend towards shorter OS in TP53multi (N=3, OS 107 days) compared to single TP53 alterations (N=6, OS 491 days, P=0.16) was just observed in pts with <5 CA, TP53alt was used for further analyses.

First, adding TP53alt as a differentiating feature to the IPSS-R (by subtracting/adding 2 points for TP53alt absent/present to the raw IPSS-R score) increased the prognostic power of the IPSS-R (Dxy 0.13 vs 0.30).

Second, creating a simplified prognostic scoring system for CK-MDS where one scoring point each was assigned to the 3 parameters with the greatest impact on OS in the multivariate model (anemia (Hb <10 g/dl), HR 2.95; TP53alt, HR 2.69; ≥5 CA, HR 2.24) also improved prognostication (Dxy 0.39).

Conclusion
Our data imply that TP53 and the complexity of the karyotype are independent prognostic marker in CK-MDS. TP53multi was of reduced informative value in our cohort, but might be useful in non CK-MDS, e.g. with 5q-. In addition, a positive impact of DMTi on TP53multi could affect this parameter in our cohort of intensely treated pts. Adding TP53alt as differentiating feature to the IPSS-R may enhance its prognostic significance in CK-MDS. The suggested simplified model fits well to our cohort of CK-MDS. But as overfitting cannot be excluded it should be tested in an independent cohort. In summary, considering additional parameters for predicting the prognosis of CK-MDS will allow to better tailor treatment decisions for individual pts with CK-MDS.

Session topic: 09. Myelodysplastic syndromes - Biology & Translational Research

Keyword(s): Cytogenetics, Mutation analysis

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