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IMPACT OF CALR AND ASXL1 MUTATIONS ON SURVIVAL AND DISEASE COMPLICATIONS IN ESSENTIAL THROMBOCYTHEMIA AND PREFIBROTIC PRIMARY MYELOFIBROSIS STRICTLY DIAGNOSED ACCORDING TO THE WHO-CLASSIFICATION
Author(s): ,
Martin Schalling
Affiliations:
Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Bettina Gisslinger
Affiliations:
Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Georg Jeryczynski
Affiliations:
Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Tiina Berg
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Ashot Harutyunyan
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Jelena Milosevic
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Klaudia Bagienski
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Nicole Them
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Fiorella Schischlik
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Veronika Buxhofer-Ausch
Affiliations:
Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Günther Nirnberger
Affiliations:
Institute for Bioconsulting,Breitenfurth,Austria
,
Ana-Iris Schiefer
Affiliations:
Institute of Pathology,Medical University of Vienna,Vienna,Austria
,
Leonhard Müllauer
Affiliations:
Institute of Pathology,Medical University of Vienna,Vienna,Austria
,
Robert Kralovics
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria;Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
,
Jürgen Thiele
Affiliations:
Institute of Pathology,University of Cologne,Cologne,Germany
Heinz Gisslinger
Affiliations:
Department of Internal Medicine I,Medical University of Vienna,Vienna,Austria
(Abstract release date: 05/21/15) EHA Library. Gisslinger H. 06/13/15; 100810; P669 Disclosure(s): This project was partly supported by a grant from Novartis Pharma GmbH, Austria to the Medical University of Vienna.
Prof. Dr. Heinz Gisslinger
Prof. Dr. Heinz Gisslinger
Contributions
Abstract
Abstract: P669

Type: Poster Presentation

Presentation during EHA20: From 13.06.2015 17:15 to 13.06.2015 18:45

Location: Poster area (Hall C)

Background

In 2013, the landscape of myeloproliferative neoplasms (MPN) was altered dramatically by the identification of somatic mutations in the calreticulin (CALR) gene. With this discovery molecular information, in addition to the JAK2V617F mutation, can be implemented as an affirmative variable for discrimination of MPNs from reactive myeloid proliferations for the first time. Previously, the clinical course of essential thrombocythemia (ET) or primary myelofibrosis (PMF) in patients carrying the CALR mutation has been reported to be more indolent than in JAK2 positive patients and was associated with increased survival.



Aims

Our aim was to investigate the different impacts of CALR mutations on the prognosis and clinical outcome in prefibrotic PMF (prePMF) and WHO-classified ET (WHO-ET). Additionally, the same investigations were made concerning ASXL1 (exon12) mutations, with ASXL1 being one of the most common bystander mutated genes in MPNs.



Methods

In a cohort of 348 patients with the clinical diagnosis of either WHO-ET or PMF, mutational analysis for CALR was available.  For study entry, the following eligibility criteria had to be fulfilled: a) availability of mutation analysis for JAK2, MPL and CALR; b) availability of representative, treatment-naive bone marrow biopsy; c) availability of a histological and clinical consensus on the diagnosis; d) complete long-term documentation of clinical data and outcome.



Results

Consenting clinico-pathological findings were consistent with 115 cases of WHO-ET and 85 patients with prePMF. In contrast to the most recent publications, the present study revealed a different CALR mutation frequency in ET (table 1). This discrepancy in the frequencies of CALR positivity in our ET cohort may be due to our strict adherence to the WHO criteria for diagnosis of ET. Regarding prePMF, we observed CALR mutations in 39% of the patients. 92% of the JAK2/MPL wt subgroup carried the CALR mutation, with JAK2, MPL and CALR wt being observed in only 3% of prePMF. The most striking differences between WHO-ET and prePMF were seen in the comparison of the overall survival (figure 1A, 1B). While the CALR mutation did not have any beneficial influence on survival in WHO-ET, it was associated with a superior overall survival in prePMF. Such a difference was not seen in the time to transformation into overt MF, and there was only a slightly shorter time to progression to fibrosis in CALR wt prePMFs. There was a trend showing that CALR mutated prePMF patients have shorter thrombosis-free survival compared to CALR wt prePMF patients. No impact of the CALR mutations on thrombosis-free survival in WHO-ET was observed. ASXL1 (exon12) mutations revealed no impact on overall survival (figure 1C).


 

Total cohort (N=200)

WHO-ET (N=115)

prePMF (N=85)

P

Age at diagnosis, years

 

 

 

0,04

   Median (range)

58,85 (19-88)

56,4 (19-84)

60,7 (27-88)

 

Sex

 

 

 

0,587

   Male/female

78/122

43/72

35/50

 

Observation period, years

 

 

 

0,066

   Median (range)

8 (0-30)

8,5 (0-28)

7,4 (0-30)

 

CALR positive

 

 

 

0,001

   No. (%)

54 (27)

21 (18,3)

33 (38,8)

 

ASXL1(ex12) positive

(N=190)

(N=108)

(N=82)

0,0868

   No. (%)

17 (8,9)

13 (12)

4 (4,9)

 



Summary

The present data confirm that WHO-ET and prePMF are biologically different sub-entities of MPNs. In prePMF, almost all patients are now associated with known disease-causing mutations. Our data support the classical approach in the diagnosis of thrombocytosis, using BM histology to differentiate WHO-ET from prePMF and more accurately estimate the outcome of the disease.



Keyword(s): Essential Thrombocytemia, Mutation analysis, Myelofibrosis, WHO classification



Session topic: Myeloproliferative neoplasms - Clinical 2
Abstract: P669

Type: Poster Presentation

Presentation during EHA20: From 13.06.2015 17:15 to 13.06.2015 18:45

Location: Poster area (Hall C)

Background

In 2013, the landscape of myeloproliferative neoplasms (MPN) was altered dramatically by the identification of somatic mutations in the calreticulin (CALR) gene. With this discovery molecular information, in addition to the JAK2V617F mutation, can be implemented as an affirmative variable for discrimination of MPNs from reactive myeloid proliferations for the first time. Previously, the clinical course of essential thrombocythemia (ET) or primary myelofibrosis (PMF) in patients carrying the CALR mutation has been reported to be more indolent than in JAK2 positive patients and was associated with increased survival.



Aims

Our aim was to investigate the different impacts of CALR mutations on the prognosis and clinical outcome in prefibrotic PMF (prePMF) and WHO-classified ET (WHO-ET). Additionally, the same investigations were made concerning ASXL1 (exon12) mutations, with ASXL1 being one of the most common bystander mutated genes in MPNs.



Methods

In a cohort of 348 patients with the clinical diagnosis of either WHO-ET or PMF, mutational analysis for CALR was available.  For study entry, the following eligibility criteria had to be fulfilled: a) availability of mutation analysis for JAK2, MPL and CALR; b) availability of representative, treatment-naive bone marrow biopsy; c) availability of a histological and clinical consensus on the diagnosis; d) complete long-term documentation of clinical data and outcome.



Results

Consenting clinico-pathological findings were consistent with 115 cases of WHO-ET and 85 patients with prePMF. In contrast to the most recent publications, the present study revealed a different CALR mutation frequency in ET (table 1). This discrepancy in the frequencies of CALR positivity in our ET cohort may be due to our strict adherence to the WHO criteria for diagnosis of ET. Regarding prePMF, we observed CALR mutations in 39% of the patients. 92% of the JAK2/MPL wt subgroup carried the CALR mutation, with JAK2, MPL and CALR wt being observed in only 3% of prePMF. The most striking differences between WHO-ET and prePMF were seen in the comparison of the overall survival (figure 1A, 1B). While the CALR mutation did not have any beneficial influence on survival in WHO-ET, it was associated with a superior overall survival in prePMF. Such a difference was not seen in the time to transformation into overt MF, and there was only a slightly shorter time to progression to fibrosis in CALR wt prePMFs. There was a trend showing that CALR mutated prePMF patients have shorter thrombosis-free survival compared to CALR wt prePMF patients. No impact of the CALR mutations on thrombosis-free survival in WHO-ET was observed. ASXL1 (exon12) mutations revealed no impact on overall survival (figure 1C).


 

Total cohort (N=200)

WHO-ET (N=115)

prePMF (N=85)

P

Age at diagnosis, years

 

 

 

0,04

   Median (range)

58,85 (19-88)

56,4 (19-84)

60,7 (27-88)

 

Sex

 

 

 

0,587

   Male/female

78/122

43/72

35/50

 

Observation period, years

 

 

 

0,066

   Median (range)

8 (0-30)

8,5 (0-28)

7,4 (0-30)

 

CALR positive

 

 

 

0,001

   No. (%)

54 (27)

21 (18,3)

33 (38,8)

 

ASXL1(ex12) positive

(N=190)

(N=108)

(N=82)

0,0868

   No. (%)

17 (8,9)

13 (12)

4 (4,9)

 



Summary

The present data confirm that WHO-ET and prePMF are biologically different sub-entities of MPNs. In prePMF, almost all patients are now associated with known disease-causing mutations. Our data support the classical approach in the diagnosis of thrombocytosis, using BM histology to differentiate WHO-ET from prePMF and more accurately estimate the outcome of the disease.



Keyword(s): Essential Thrombocytemia, Mutation analysis, Myelofibrosis, WHO classification



Session topic: Myeloproliferative neoplasms - Clinical 2

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