Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis

Hanneke C. Kluin-Nelemans; Mohamad Jawhar; Andreas Reiter; Bjorn van Anrooij; Jason Gotlib; Karin Hartmann; Anja Illerhaus; Hanneke N.G. Oude Elberink; Aleksandra Gorska; Marek Niedoszytko; Magdalena Lange; Luigi Scaffidi; Roberta Zanotti; Patrizia Bonadonna; Cecelia Perkins; Chiara Elena; Luca Malcovati; Khalid Shoumariyeh; Nikolas von Bubnoff; Sabine Müller; Massimo Triggiani; Roberta Parente; Juliana Schwaab; Michael Kundi; Anna Belloni Fortina; Francesca Caroppo; Knut Brockow; Alexander Zink; David Fuchs; Irena Angelova-Fischer; Akif Selim Yavuz; Michael Doubek; Mattias Mattsson; Hans Hagglund; Jens Panse; Anne Simonowski; Vito Sabato; Tanja Schug; Madlen Jentzsch; Christine Breynaert; Judit Várkonyi; Vanessa Kennedy; Olivier Hermine; Julien Rossignol; Michel Arock; Peter Valent; Wolfgang R. Sperr

doi:10.7150/THNO.51872

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis

Hanneke C. Kluin-Nelemans^*, Mohamad Jawhar, Andreas Reiter, Bjorn van Anrooij, Jason Gotlib, Karin Hartmann, Anja Illerhaus, Hanneke N.G. Oude Elberink, Aleksandra Gorska, Marek Niedoszytko, Magdalena Lange, Luigi Scaffidi, Roberta Zanotti, Patrizia Bonadonna, Cecelia Perkins, Chiara Elena, Luca Malcovati, Khalid Shoumariyeh, Nikolas von Bubnoff, Sabine MüllerMassimo Triggiani, Roberta Parente, Juliana Schwaab, Michael Kundi, Anna Belloni Fortina, Francesca Caroppo, Knut Brockow, Alexander Zink, David Fuchs, Irena Angelova-Fischer, Akif Selim Yavuz, Michael Doubek, Mattias Mattsson, Hans Hagglund, Jens Panse, Anne Simonowski, Vito Sabato, Tanja Schug, Madlen Jentzsch, Christine Breynaert, Judit Várkonyi, Vanessa Kennedy, Olivier Hermine, Julien Rossignol, Michel Arock, Peter Valent, Wolfgang R. Sperr

^*Corresponding author for this work

37 Citations (Scopus)

Abstract

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

Original language	English
Journal	Theranostics
Volume	11
Issue number	1
Pages (from-to)	292-303
Number of pages	12
ISSN	1838-7640
DOIs	https://doi.org/10.7150/THNO.51872
Publication status	Published - 2020

Funding

This work was supported by the Austrian Science Fund (FWF), SFB grants F4701-B28, F4704-B28, and P32470-B (to P.V.), by the ‘Charles and Ann Johnson Foundation’ (to J.G.). V.S. is a Senior Clinical Researcher of the Research Foundation Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1804518N). C.B. is supported by the Clinical Research Fund of the University Hospital Leuven. Hanneke C. Kluin-Nelemans: institutional financial support from Novartis; honoraria from Novartis for participating in e-learning program. Andreas Reiter: Novartis Pharma – research support, advisory board, honoraria, travel reimbursement, Blueprint Medicines - advisory board, honoraria, travel reimbursement, Deciphera – advisory board, travel reimbursement. Bjorn van Anrooij: financial support from Novartis for research and advisory boards. Jason Gotlib: Funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Deciphera, Allakos. Karin Hartmann: advisory board/honoraria: Allergopharma, ALK-Abelló, Blueprint, Deciphera, Menarini, Novartis and Takeda; research grant: Euroimmun. Hanneke Oude Elberink: honoraria from ALK-Abelló, Chiesi, MEDA Pharma, Novartis, and Blueprint. Magdalena Lange: honoraria from Novartis for lectures. Chiara Elena: advisory board Novartis, Pfizer. David Fuchs, Julien Rossignol: advisory board Novartis. Khalid Shoumariyeh: travel support from Abbvie and consultancy fees from Novartis. Nikolas von Bubnoff: institutional financial support from Novartis. Massimo Triggiani: advisory board BluePrint Medicines, Deciphera, Novartis. Akif SelimYavuz: honoraria from Novartis. Jens Panse: funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Novartis. Vito Sabato: advisory board/honoraria: Blueprint Medicines, Novartis. Madlen Jentzsch: honoraria from Novartis. Olivier Hermine: Research funding support from AB science and Novartis. Advisory board of AB science. Wolfgang R. Sperr: honoraria from Novartis, Pfizer, AbbVie, Daiichi Sankyo, Amgen, Thermo Fisher, Deciphera, Incyte, Celgene and Jazz. Michel Arock: advisory board/honoraria Blueprint Medicines, Deciphera. All other authors: none.

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Kluin-Nelemans, H. C., Jawhar, M., Reiter, A., van Anrooij, B., Gotlib, J., Hartmann, K., Illerhaus, A., Oude Elberink, H. N. G., Gorska, A., Niedoszytko, M., Lange, M., Scaffidi, L., Zanotti, R., Bonadonna, P., Perkins, C., Elena, C., Malcovati, L., Shoumariyeh, K., von Bubnoff, N., ... Sperr, W. R. (2020). Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis. Theranostics, 11(1), 292-303. https://doi.org/10.7150/THNO.51872

@article{3707e24da19b4819977152b24f928acb,

title = "Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis",

abstract = "In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3\% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70\%; p < 0.001). Correspondingly, organomegaly (male: 23\% vs. female: 13\%, p = 0.007) was more, whereas skin involvement (male: 71\% vs. female: 86\%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10\% vs. 5\%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63\% vs. 40\%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.",

author = "Kluin-Nelemans, \{Hanneke C.\} and Mohamad Jawhar and Andreas Reiter and \{van Anrooij\}, Bjorn and Jason Gotlib and Karin Hartmann and Anja Illerhaus and \{Oude Elberink\}, \{Hanneke N.G.\} and Aleksandra Gorska and Marek Niedoszytko and Magdalena Lange and Luigi Scaffidi and Roberta Zanotti and Patrizia Bonadonna and Cecelia Perkins and Chiara Elena and Luca Malcovati and Khalid Shoumariyeh and \{von Bubnoff\}, Nikolas and Sabine M{\"u}ller and Massimo Triggiani and Roberta Parente and Juliana Schwaab and Michael Kundi and Fortina, \{Anna Belloni\} and Francesca Caroppo and Knut Brockow and Alexander Zink and David Fuchs and Irena Angelova-Fischer and Yavuz, \{Akif Selim\} and Michael Doubek and Mattias Mattsson and Hans Hagglund and Jens Panse and Anne Simonowski and Vito Sabato and Tanja Schug and Madlen Jentzsch and Christine Breynaert and Judit V{\'a}rkonyi and Vanessa Kennedy and Olivier Hermine and Julien Rossignol and Michel Arock and Peter Valent and Sperr, \{Wolfgang R.\}",

note = "Funding Information: This work was supported by the Austrian Science Fund (FWF), SFB grants F4701-B28, F4704-B28, and P32470-B (to P.V.), by the {\textquoteleft}Charles and Ann Johnson Foundation{\textquoteright} (to J.G.). V.S. is a Senior Clinical Researcher of the Research Foundation Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1804518N). C.B. is supported by the Clinical Research Fund of the University Hospital Leuven. Funding Information: Hanneke C. Kluin-Nelemans: institutional financial support from Novartis; honoraria from Novartis for participating in e-learning program. Andreas Reiter: Novartis Pharma – research support, advisory board, honoraria, travel reimbursement, Blueprint Medicines - advisory board, honoraria, travel reimbursement, Deciphera – advisory board, travel reimbursement. Bjorn van Anrooij: financial support from Novartis for research and advisory boards. Jason Gotlib: Funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Deciphera, Allakos. Karin Hartmann: advisory board/honoraria: Allergopharma, ALK-Abell{\'o}, Blueprint, Deciphera, Menarini, Novartis and Takeda; research grant: Euroimmun. Hanneke Oude Elberink: honoraria from ALK-Abell{\'o}, Chiesi, MEDA Pharma, Novartis, and Blueprint. Magdalena Lange: honoraria from Novartis for lectures. Chiara Elena: advisory board Novartis, Pfizer. David Fuchs, Julien Rossignol: advisory board Novartis. Khalid Shoumariyeh: travel support from Abbvie and consultancy fees from Novartis. Nikolas von Bubnoff: institutional financial support from Novartis. Massimo Triggiani: advisory board BluePrint Medicines, Deciphera, Novartis. Akif SelimYavuz: honoraria from Novartis. Jens Panse: funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Novartis. Vito Sabato: advisory board/honoraria: Blueprint Medicines, Novartis. Madlen Jentzsch: honoraria from Novartis. Olivier Hermine: Research funding support from AB science and Novartis. Advisory board of AB science. Wolfgang R. Sperr: honoraria from Novartis, Pfizer, AbbVie, Daiichi Sankyo, Amgen, Thermo Fisher, Deciphera, Incyte, Celgene and Jazz. Michel Arock: advisory board/honoraria Blueprint Medicines, Deciphera. All other authors: none. Publisher Copyright: {\textcopyright} The author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

doi = "10.7150/THNO.51872",

language = "English",

volume = "11",

pages = "292--303",

journal = "Theranostics",

issn = "1838-7640",

publisher = "Ivyspring International Publisher",

number = "1",

}

Kluin-Nelemans, HC, Jawhar, M, Reiter, A, van Anrooij, B, Gotlib, J, Hartmann, K, Illerhaus, A, Oude Elberink, HNG, Gorska, A, Niedoszytko, M, Lange, M, Scaffidi, L, Zanotti, R, Bonadonna, P, Perkins, C, Elena, C, Malcovati, L, Shoumariyeh, K, von Bubnoff, N, Müller, S, Triggiani, M, Parente, R, Schwaab, J, Kundi, M, Fortina, AB, Caroppo, F, Brockow, K, Zink, A, Fuchs, D, Angelova-Fischer, I, Yavuz, AS, Doubek, M, Mattsson, M, Hagglund, H, Panse, J, Simonowski, A, Sabato, V, Schug, T, Jentzsch, M, Breynaert, C, Várkonyi, J, Kennedy, V, Hermine, O, Rossignol, J, Arock, M, Valent, P & Sperr, WR 2020, 'Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis', Theranostics, vol. 11, no. 1, pp. 292-303. https://doi.org/10.7150/THNO.51872

TY - JOUR

T1 - Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis

AU - Kluin-Nelemans, Hanneke C.

AU - Jawhar, Mohamad

AU - Reiter, Andreas

AU - van Anrooij, Bjorn

AU - Gotlib, Jason

AU - Hartmann, Karin

AU - Illerhaus, Anja

AU - Oude Elberink, Hanneke N.G.

AU - Gorska, Aleksandra

AU - Niedoszytko, Marek

AU - Lange, Magdalena

AU - Scaffidi, Luigi

AU - Zanotti, Roberta

AU - Bonadonna, Patrizia

AU - Perkins, Cecelia

AU - Elena, Chiara

AU - Malcovati, Luca

AU - Shoumariyeh, Khalid

AU - von Bubnoff, Nikolas

AU - Müller, Sabine

AU - Triggiani, Massimo

AU - Parente, Roberta

AU - Schwaab, Juliana

AU - Kundi, Michael

AU - Fortina, Anna Belloni

AU - Caroppo, Francesca

AU - Brockow, Knut

AU - Zink, Alexander

AU - Fuchs, David

AU - Angelova-Fischer, Irena

AU - Yavuz, Akif Selim

AU - Doubek, Michael

AU - Mattsson, Mattias

AU - Hagglund, Hans

AU - Panse, Jens

AU - Simonowski, Anne

AU - Sabato, Vito

AU - Schug, Tanja

AU - Jentzsch, Madlen

AU - Breynaert, Christine

AU - Várkonyi, Judit

AU - Kennedy, Vanessa

AU - Hermine, Olivier

AU - Rossignol, Julien

AU - Arock, Michel

AU - Valent, Peter

AU - Sperr, Wolfgang R.

N1 - Funding Information: This work was supported by the Austrian Science Fund (FWF), SFB grants F4701-B28, F4704-B28, and P32470-B (to P.V.), by the ‘Charles and Ann Johnson Foundation’ (to J.G.). V.S. is a Senior Clinical Researcher of the Research Foundation Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1804518N). C.B. is supported by the Clinical Research Fund of the University Hospital Leuven. Funding Information: Hanneke C. Kluin-Nelemans: institutional financial support from Novartis; honoraria from Novartis for participating in e-learning program. Andreas Reiter: Novartis Pharma – research support, advisory board, honoraria, travel reimbursement, Blueprint Medicines - advisory board, honoraria, travel reimbursement, Deciphera – advisory board, travel reimbursement. Bjorn van Anrooij: financial support from Novartis for research and advisory boards. Jason Gotlib: Funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Deciphera, Allakos. Karin Hartmann: advisory board/honoraria: Allergopharma, ALK-Abelló, Blueprint, Deciphera, Menarini, Novartis and Takeda; research grant: Euroimmun. Hanneke Oude Elberink: honoraria from ALK-Abelló, Chiesi, MEDA Pharma, Novartis, and Blueprint. Magdalena Lange: honoraria from Novartis for lectures. Chiara Elena: advisory board Novartis, Pfizer. David Fuchs, Julien Rossignol: advisory board Novartis. Khalid Shoumariyeh: travel support from Abbvie and consultancy fees from Novartis. Nikolas von Bubnoff: institutional financial support from Novartis. Massimo Triggiani: advisory board BluePrint Medicines, Deciphera, Novartis. Akif SelimYavuz: honoraria from Novartis. Jens Panse: funding to support conduct of clinical trial: Blueprint Medicines, Deciphera; advisory board/honoraria: Blueprint Medicines, Novartis. Vito Sabato: advisory board/honoraria: Blueprint Medicines, Novartis. Madlen Jentzsch: honoraria from Novartis. Olivier Hermine: Research funding support from AB science and Novartis. Advisory board of AB science. Wolfgang R. Sperr: honoraria from Novartis, Pfizer, AbbVie, Daiichi Sankyo, Amgen, Thermo Fisher, Deciphera, Incyte, Celgene and Jazz. Michel Arock: advisory board/honoraria Blueprint Medicines, Deciphera. All other authors: none. Publisher Copyright: © The author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020

Y1 - 2020

N2 - In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

AB - In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

UR - https://www.scopus.com/pages/publications/85094590768

U2 - 10.7150/THNO.51872

DO - 10.7150/THNO.51872

M3 - Journal articles

C2 - 33391475

AN - SCOPUS:85094590768

SN - 1838-7640

VL - 11

SP - 292

EP - 303

JO - Theranostics

JF - Theranostics

IS - 1

ER -

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis

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