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The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients
The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients
We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of five 'prognostically-detrimental' mutated genes (ASXL1, EZH2, SRSF2, IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had 2 or more mutated genes. The presence of 2 or more mutations predicted the worst survival: median 2.6 years (HR 3.8, 95%CI 2.6-5.7) vs 7.0 years (HR 1.9, 95%CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of IPSS (HR 2.4, 95% CI 1.6-3.6) and DIPSS-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. CALR mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.
primary myelofibrosis, mutations, prognosis, calreticulin, ASXL1
0887-6924
1804-1810
Guglielmelli, Paola
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Lasho, Terra L.
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Rotunno, Giada
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Score, Joannah
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Mannarelli, Carmela
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Pancrazzi, Alessandro
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Biamonte, Flavia
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Pardanani, Animesh
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Zoi, Katerina
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Reiter, Andreas
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Duncombe, Andrew
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Fanelli, Tiziana
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Pietra, Daniela
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Rumi, Elisa
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Finke, Christy
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Gangat, Naseema
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Ketterling, Rhett P.
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Knudson, Ryan A.
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Hanson, Curt A.
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Bosi, Alberto
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Pereira, Arturo
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Manfredini, Rossella
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Cervantes, Francisco
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Barosi, Giovanni
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Cazzola, Marie
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Cross, Nicholas C. P.
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Vannucchi, Alessandro M.
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Tefferi, Ayalew
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Guglielmelli, Paola
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Lasho, Terra L.
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Rotunno, Giada
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Score, Joannah
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Mannarelli, Carmela
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Pancrazzi, Alessandro
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Biamonte, Flavia
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Pardanani, Animesh
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Zoi, Katerina
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Reiter, Andreas
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Duncombe, Andrew
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Fanelli, Tiziana
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Pietra, Daniela
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Rumi, Elisa
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Finke, Christy
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Gangat, Naseema
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Ketterling, Rhett P.
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Knudson, Ryan A.
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Hanson, Curt A.
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Bosi, Alberto
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Pereira, Arturo
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Manfredini, Rossella
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Cervantes, Francisco
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Barosi, Giovanni
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Cazzola, Marie
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Cross, Nicholas C. P.
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Vannucchi, Alessandro M.
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Tefferi, Ayalew
772fe8d4-f061-4e7c-af13-91959ea634e5

Guglielmelli, Paola, Lasho, Terra L., Rotunno, Giada, Score, Joannah, Mannarelli, Carmela, Pancrazzi, Alessandro, Biamonte, Flavia, Pardanani, Animesh, Zoi, Katerina, Reiter, Andreas, Duncombe, Andrew, Fanelli, Tiziana, Pietra, Daniela, Rumi, Elisa, Finke, Christy, Gangat, Naseema, Ketterling, Rhett P., Knudson, Ryan A., Hanson, Curt A., Bosi, Alberto, Pereira, Arturo, Manfredini, Rossella, Cervantes, Francisco, Barosi, Giovanni, Cazzola, Marie, Cross, Nicholas C. P., Vannucchi, Alessandro M. and Tefferi, Ayalew (2014) The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia, 28 (9), 1804-1810. (doi:10.1038/leu.2014.76). (PMID:24549259)

Record type: Article

Abstract

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of five 'prognostically-detrimental' mutated genes (ASXL1, EZH2, SRSF2, IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had 2 or more mutated genes. The presence of 2 or more mutations predicted the worst survival: median 2.6 years (HR 3.8, 95%CI 2.6-5.7) vs 7.0 years (HR 1.9, 95%CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of IPSS (HR 2.4, 95% CI 1.6-3.6) and DIPSS-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. CALR mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

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More information

Accepted/In Press date: 14 February 2014
e-pub ahead of print date: 7 March 2014
Published date: September 2014
Keywords: primary myelofibrosis, mutations, prognosis, calreticulin, ASXL1
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 362357
URI: http://eprints.soton.ac.uk/id/eprint/362357
ISSN: 0887-6924
PURE UUID: 0f881a4f-a683-4ae9-8943-3e098d7f3c3a
ORCID for Nicholas C. P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 21 Feb 2014 12:54
Last modified: 17 Dec 2019 01:51

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Contributors

Author: Paola Guglielmelli
Author: Terra L. Lasho
Author: Giada Rotunno
Author: Joannah Score
Author: Carmela Mannarelli
Author: Alessandro Pancrazzi
Author: Flavia Biamonte
Author: Animesh Pardanani
Author: Katerina Zoi
Author: Andreas Reiter
Author: Andrew Duncombe
Author: Tiziana Fanelli
Author: Daniela Pietra
Author: Elisa Rumi
Author: Christy Finke
Author: Naseema Gangat
Author: Rhett P. Ketterling
Author: Ryan A. Knudson
Author: Curt A. Hanson
Author: Alberto Bosi
Author: Arturo Pereira
Author: Rossella Manfredini
Author: Francisco Cervantes
Author: Giovanni Barosi
Author: Marie Cazzola
Author: Alessandro M. Vannucchi
Author: Ayalew Tefferi

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