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Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis

Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis
Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis
The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n=102, 94%) with indolent (ISM, n=26) and advanced SM (n=83) with (n=73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, e.g. monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n=7) or mast cell leukemia (n=1) within a median of 40 months (range 2-190, P=0.04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs. 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P<0.0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM±AHN because these investigations greatly support prognostication and treatment decisions. This article is protected by copyright. All rights reserved.
1045-2257
Naumann, Nicole
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Jawhar, Mohamad
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Schwaab, Juliana
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Kluger, Sebastian
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Lübke, Johannes
aa66da00-2473-47f4-913c-f4601623ac0c
Metzgeroth, Georgia
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Popp, Henning D.
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Khaled, Nada
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Horny, Hans-Peter
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Sotlar, Karl
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Valent, Peter
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Haferlach, Claudia
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Göhring, Gudrun
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Schlegelberger, Brigitte
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Meggendorfer, Manja
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Hofmann, Wolf-Karsten
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Cross, Nicholas C.P.
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Reiter, Andreas
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Fabarius, Alice
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Naumann, Nicole
43566136-d964-415e-be36-45aeb4f88965
Jawhar, Mohamad
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Schwaab, Juliana
d63ed545-a6fc-4815-ab86-f901e55c2a2f
Kluger, Sebastian
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Lübke, Johannes
aa66da00-2473-47f4-913c-f4601623ac0c
Metzgeroth, Georgia
611ec46d-9a11-4e24-ae0f-5ac19dfd0237
Popp, Henning D.
70e7f672-f128-437e-9615-54bc8feb58b3
Khaled, Nada
ca34439b-eba7-4855-9337-3f4b327b3760
Horny, Hans-Peter
95077a3b-b869-49ba-a227-f88b2c0bad80
Sotlar, Karl
e3e96797-3fab-4c37-8728-7c77bb3ba389
Valent, Peter
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Haferlach, Claudia
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Göhring, Gudrun
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Schlegelberger, Brigitte
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Meggendorfer, Manja
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Hofmann, Wolf-Karsten
ab66838b-bf8c-4352-a0f0-3c8aafed2570
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, Andreas
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Fabarius, Alice
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Naumann, Nicole, Jawhar, Mohamad, Schwaab, Juliana, Kluger, Sebastian, Lübke, Johannes, Metzgeroth, Georgia, Popp, Henning D., Khaled, Nada, Horny, Hans-Peter, Sotlar, Karl, Valent, Peter, Haferlach, Claudia, Göhring, Gudrun, Schlegelberger, Brigitte, Meggendorfer, Manja, Hofmann, Wolf-Karsten, Cross, Nicholas C.P., Reiter, Andreas and Fabarius, Alice (2018) Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis Genes, Chromosomes and Cancer (doi:10.1002/gcc.22526).

Record type: Article

Abstract

The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n=102, 94%) with indolent (ISM, n=26) and advanced SM (n=83) with (n=73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, e.g. monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n=7) or mast cell leukemia (n=1) within a median of 40 months (range 2-190, P=0.04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs. 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P<0.0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM±AHN because these investigations greatly support prognostication and treatment decisions. This article is protected by copyright. All rights reserved.

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Accepted/In Press date: 15 January 2018
e-pub ahead of print date: 17 January 2018

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Local EPrints ID: 417184
URI: https://eprints.soton.ac.uk/id/eprint/417184
ISSN: 1045-2257
PURE UUID: 2bda5435-e719-4aad-92b1-72c15e935be7
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 24 Jan 2018 17:30
Last modified: 24 Jan 2018 17:30

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Contributors

Author: Nicole Naumann
Author: Mohamad Jawhar
Author: Juliana Schwaab
Author: Sebastian Kluger
Author: Johannes Lübke
Author: Georgia Metzgeroth
Author: Henning D. Popp
Author: Nada Khaled
Author: Hans-Peter Horny
Author: Karl Sotlar
Author: Peter Valent
Author: Claudia Haferlach
Author: Gudrun Göhring
Author: Brigitte Schlegelberger
Author: Manja Meggendorfer
Author: Wolf-Karsten Hofmann
Author: Andreas Reiter
Author: Alice Fabarius

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