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KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis

KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis
KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis

KIT D816 mutations (KIT D816mut) are strongly associated with systemic mastocytosis (SM) but are also detectable in acute myeloid leukemia (AML), where they represent an adverse prognostic factor in combination with core binding factor (CBF) fusion genes. Here, we evaluated the clinical and molecular features of KIT D816mut/CBF-negative (CBFneg) AML, a previously uncharacterized combination. All KIT D816mut/CBFneg cases (n = 40) had histologically proven SM with associated AML (SM-AML). Molecular analyses revealed at least one additional somatic mutation (median, n = 3) beside KIT D816 (e.g., SRSF2, 38%; ASXL1, 31%; RUNX1, 34%) in 32/32 (100%) patients. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm. Longitudinal molecular and cytogenetic analyses revealed the acquisition of new mutations and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Median overall survival (OS) was 5.4 months. A screen of two independent AML databases (AMLdatabases) revealed remarkable similarities between KIT D816mut/CBFneg SM-AML and KIT D816mut/CBFneg AMLdatabases (n = 69) with regard to KIT D816mut variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AMLdatabases patients. Bone marrow histology and reclassification as SM-AML has important clinical implications regarding prognosis and potential inclusion of KIT inhibitors in treatment concepts.

0887-6924
1134-1134
Jawhar, Mohamad
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Döhner, Konstanze
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Kreil, Sebastian
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Schwaab, Juliana
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Shoumariyeh, Khalid
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Meggendorfer, Manja
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Span, Lambert L.F.
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Fuhrmann, Stephan
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Naumann, Nicole
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Horny, Hans Peter
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Sotlar, Karl
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Kubuschok, Boris
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von Bubnoff, Nikolas
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Spiekermann, Karsten
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Heuser, Michael
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Metzgeroth, Georgia
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Fabarius, Alice
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Klein, Stefan
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Hofmann, Wolf Karsten
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Kluin-Nelemans, Hanneke C.
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Haferlach, Torsten
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Cross, Nicholas C.P.
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Sperr, Wolfgang R.
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Valent, Peter
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Reiter, Andreas
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Jawhar, Mohamad
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Döhner, Konstanze
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Kreil, Sebastian
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Schwaab, Juliana
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Shoumariyeh, Khalid
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Meggendorfer, Manja
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Span, Lambert L.F.
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Fuhrmann, Stephan
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Naumann, Nicole
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Horny, Hans Peter
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Sotlar, Karl
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Kubuschok, Boris
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von Bubnoff, Nikolas
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Spiekermann, Karsten
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Heuser, Michael
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Metzgeroth, Georgia
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Fabarius, Alice
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Klein, Stefan
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Hofmann, Wolf Karsten
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Kluin-Nelemans, Hanneke C.
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Haferlach, Torsten
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Döhner, Hartmut
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Cross, Nicholas C.P.
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Sperr, Wolfgang R.
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Valent, Peter
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Reiter, Andreas
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Jawhar, Mohamad, Döhner, Konstanze, Kreil, Sebastian, Schwaab, Juliana, Shoumariyeh, Khalid, Meggendorfer, Manja, Span, Lambert L.F., Fuhrmann, Stephan, Naumann, Nicole, Horny, Hans Peter, Sotlar, Karl, Kubuschok, Boris, von Bubnoff, Nikolas, Spiekermann, Karsten, Heuser, Michael, Metzgeroth, Georgia, Fabarius, Alice, Klein, Stefan, Hofmann, Wolf Karsten, Kluin-Nelemans, Hanneke C., Haferlach, Torsten, Döhner, Hartmut, Cross, Nicholas C.P., Sperr, Wolfgang R., Valent, Peter and Reiter, Andreas (2019) KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis. Leukemia, 33 (5), 1134-1134. (doi:10.1038/s41375-018-0346-z).

Record type: Article

Abstract

KIT D816 mutations (KIT D816mut) are strongly associated with systemic mastocytosis (SM) but are also detectable in acute myeloid leukemia (AML), where they represent an adverse prognostic factor in combination with core binding factor (CBF) fusion genes. Here, we evaluated the clinical and molecular features of KIT D816mut/CBF-negative (CBFneg) AML, a previously uncharacterized combination. All KIT D816mut/CBFneg cases (n = 40) had histologically proven SM with associated AML (SM-AML). Molecular analyses revealed at least one additional somatic mutation (median, n = 3) beside KIT D816 (e.g., SRSF2, 38%; ASXL1, 31%; RUNX1, 34%) in 32/32 (100%) patients. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm. Longitudinal molecular and cytogenetic analyses revealed the acquisition of new mutations and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Median overall survival (OS) was 5.4 months. A screen of two independent AML databases (AMLdatabases) revealed remarkable similarities between KIT D816mut/CBFneg SM-AML and KIT D816mut/CBFneg AMLdatabases (n = 69) with regard to KIT D816mut variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AMLdatabases patients. Bone marrow histology and reclassification as SM-AML has important clinical implications regarding prognosis and potential inclusion of KIT inhibitors in treatment concepts.

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Accepted/In Press date: 6 November 2018
e-pub ahead of print date: 11 January 2019
Published date: 1 May 2019

Identifiers

Local EPrints ID: 427508
URI: https://eprints.soton.ac.uk/id/eprint/427508
ISSN: 0887-6924
PURE UUID: 3342d3e7-5dac-419b-86d6-916f06f3f4fa
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 22 Jan 2019 17:30
Last modified: 24 May 2019 00:36

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Contributors

Author: Mohamad Jawhar
Author: Konstanze Döhner
Author: Sebastian Kreil
Author: Juliana Schwaab
Author: Khalid Shoumariyeh
Author: Manja Meggendorfer
Author: Lambert L.F. Span
Author: Stephan Fuhrmann
Author: Nicole Naumann
Author: Hans Peter Horny
Author: Karl Sotlar
Author: Boris Kubuschok
Author: Nikolas von Bubnoff
Author: Karsten Spiekermann
Author: Michael Heuser
Author: Georgia Metzgeroth
Author: Alice Fabarius
Author: Stefan Klein
Author: Wolf Karsten Hofmann
Author: Hanneke C. Kluin-Nelemans
Author: Torsten Haferlach
Author: Hartmut Döhner
Author: Wolfgang R. Sperr
Author: Peter Valent
Author: Andreas Reiter

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