IMPACT OF SMOKING ON JAK2V617F ALLELE BURDEN AMONG PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS TREATED WITH PEGYLATED INTERFERON ALPHA-2 OR HYDROXYUREA IN THE DALIAH TRIAL
Author(s): ,
Dustin Patel
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark;Institute for Inflammation Research (IIR),University Hospital Rigshospitalet,Copenhagen,Denmark
,
Trine Alma Knudsen
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Dennis Lund Hansen
Affiliations:
Department of Hematology,University Hospital Odense,Odense,Denmark
,
Lukas Frans Ocias
Affiliations:
Department of Hematology,University Hospital Odense,Odense,Denmark
,
Ole Weis Bjerrum
Affiliations:
Department of Hematology,University Hospital Rigshospitalet,Copenhagen,Denmark
,
Mette Brabrand
Affiliations:
Department of Hematology,University Hospital Odense,Odense,Denmark
,
Christina Ellervik
Affiliations:
Harvard Medical School,Boston,United States
,
Daniel el Fassi
Affiliations:
Department of Hematology,University Hospital Herlev,Copenhagen,Denmark
,
Mikael Frederiksen
Affiliations:
Department of Hematology,Hospital of Southern Jutland,Haderslev,Denmark
,
Lasse Kjær
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Thomas Kielsgaard Kristensen
Affiliations:
Department of Pathology,University Hospital Odense,Odense,Denmark
,
orben Kruse
Affiliations:
Department of Clinical Genetics,University Hospital Odense,Odense,Denmark
,
Hans Torben Mourits-Andersen
Affiliations:
Department of Hematology,Hospital of South West Jutland,Esbjerg,Denmark
,
Peter Møller
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Ulrik Malthe Overgaard
Affiliations:
Department of Hematology,University Hospital Rigshospitalet,Copenhagen,Denmark
,
Marianne Tang Severinsen
Affiliations:
Department of Hematology,University Hospital Aalborg,Aalborg,Denmark
,
Vibe Skov
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Anders Lindholm Sørensen
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark;Institute for Inflammation Research (IIR),University Hospital Rigshospitalet,Copenhagen,Denmark
,
Jesper Stentoft
Affiliations:
Department of Hematology,University Hospital Aarhus,Aarhus,Denmark
,
Jørn Starklint
Affiliations:
Department of Hematology,Hospital of West Jutland,Holstebro,Denmark
,
Karin de Stricker
Affiliations:
Department of Pathology,University Hospital Odense,Odense,Denmark
,
Mads Thomassen
Affiliations:
Department of Clinical Genetics,University Hospital Odense,Odense,Denmark
,
Thomas Stauffer Larsen
Affiliations:
Department of Hematology,University Hospital Odense,Odense,Denmark
Hans Carl Hasselbalch
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
EHA Library. Patel D. 05/16/19; 268120; PB2210
Dustin Patel
Dustin Patel
Contributions
Abstract

Abstract: PB2210

Type: Publication Only

Background
Smoking is linked to several malignancies, including myeloproliferative neoplasms (MPN). However, the direct impact of smoking on JAK2V617 allele burden (JAK2) has not been examined in MPN.

Aims
To compare JAK2 over time among smokers and non-smokers with MPN.

Methods

A post-hoc analysis was conducted on the DALIAH-trial (NCT01387763). The study consisted of newly diagnosed patients with either essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (pre-MF) or primary myelofibrosis (PMF) according to the WHO criteria. Patients who were naïve to cytoreductive treatment were enrolled in the study and randomized to treatment with recombinant pegylated interferon alpha-2 (r-IFNα) or hydroxyurea (HU). History of smoking prior to inclusion was collected retrospectively. Patients were defined as smokers if they had any daily tobacco consumption at baseline. JAK2 was measured by qPCR on whole blood. Molecular and clinicohematological response assessment was done using the ELN 2009 and EUMNET 2005 criteria. All patients provided written informed consent. A repeated measurements analysis was applied. JAK2 values were logit transformed for testing. Through backward elimination, the model was cleared for factors, which did not affect the model (p>0.05). The model tested for differences in predicted change of JAK2 by smoking status.

Results
A history of smoking was available for patients from 4/9 study sites (140/203 patients, Table 1). There was a more rapid predicted decrease in JAK2 among non-smokers, which was significant at 12 and 18 months (p < 0.01). Among JAK2-positive patients, 13/14 (93%) smokers received r-IFNα vs. 63/83 (76%) non-smokers, but this did not affect the model. Neither did age, sex, baseline JAK2 or diagnosis. A partial molecular response was achieved in 4/14 (28.6%) smokers vs. 32/83 (38.6%) non-smokers and a complete clinicohematological response was achieved in 14/23 (60.9%) smokers vs. 80/117 (68.4%) non-smokers. A drop-out rate of 15/23 (65.2%) among smokers and 59/117 (50.4%) among non-smokers lead to wider 95% CI with time (Figure 1). 

Table 1: Patient characteristics. Data are median (IQR) and n

Non-smokers (n=117)

Smokers (n=23)

Age

62 (50-67)

62 (45-69)

Sex, men/women

64/53

14/9

Type of treatment, HU/r-IFNα

23/94

4/19

Diagnosis, ET / PV / PreMF/PMF

45/46/10/16

9/8/3/3

Mutation, JAK2V617F/CALR/MPL/Triple-negative

83/20/2/12

14/3/1/5

JAK2, %

33 (18-49)

33 (16-49)

Hemoglobin, mmol/L

9.1 (8.4-10.5)

9.2 (8.8-10)

Leukocytes, 10^9/L

9.2 (7.7-11.1)

12.3 (10.1-13.9)

Thrombocytes, 10^9/L

672 (460-880)

662 (513-863)

Conclusion
Non-smokers are more likely to have a more rapid decrease in JAK2 particularly in the initial phase of treatment (12 and 18 months, p < 0.01) compared to smokers. Although statistical testing was not performed, partial molecular response and complete clinicohematological response were more incident among non-smokers and drop-out was lower among non-smokers. The study was limited by several factors: (1) The post-hoc design. (2) The few smokers. (3) Smoking status might change in relation to a diagnosis of MPN, thus rendering the initial grouping unprecise. (4) The study design was not powered to detect factors affecting the model. Still, the resulting model was rather conservative. Hence the finding was surprising, and it needs confirmation in additional studies.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Molecular markers, Molecular response, Myeloproliferative disorder

Abstract: PB2210

Type: Publication Only

Background
Smoking is linked to several malignancies, including myeloproliferative neoplasms (MPN). However, the direct impact of smoking on JAK2V617 allele burden (JAK2) has not been examined in MPN.

Aims
To compare JAK2 over time among smokers and non-smokers with MPN.

Methods

A post-hoc analysis was conducted on the DALIAH-trial (NCT01387763). The study consisted of newly diagnosed patients with either essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (pre-MF) or primary myelofibrosis (PMF) according to the WHO criteria. Patients who were naïve to cytoreductive treatment were enrolled in the study and randomized to treatment with recombinant pegylated interferon alpha-2 (r-IFNα) or hydroxyurea (HU). History of smoking prior to inclusion was collected retrospectively. Patients were defined as smokers if they had any daily tobacco consumption at baseline. JAK2 was measured by qPCR on whole blood. Molecular and clinicohematological response assessment was done using the ELN 2009 and EUMNET 2005 criteria. All patients provided written informed consent. A repeated measurements analysis was applied. JAK2 values were logit transformed for testing. Through backward elimination, the model was cleared for factors, which did not affect the model (p>0.05). The model tested for differences in predicted change of JAK2 by smoking status.

Results
A history of smoking was available for patients from 4/9 study sites (140/203 patients, Table 1). There was a more rapid predicted decrease in JAK2 among non-smokers, which was significant at 12 and 18 months (p < 0.01). Among JAK2-positive patients, 13/14 (93%) smokers received r-IFNα vs. 63/83 (76%) non-smokers, but this did not affect the model. Neither did age, sex, baseline JAK2 or diagnosis. A partial molecular response was achieved in 4/14 (28.6%) smokers vs. 32/83 (38.6%) non-smokers and a complete clinicohematological response was achieved in 14/23 (60.9%) smokers vs. 80/117 (68.4%) non-smokers. A drop-out rate of 15/23 (65.2%) among smokers and 59/117 (50.4%) among non-smokers lead to wider 95% CI with time (Figure 1). 

Table 1: Patient characteristics. Data are median (IQR) and n

Non-smokers (n=117)

Smokers (n=23)

Age

62 (50-67)

62 (45-69)

Sex, men/women

64/53

14/9

Type of treatment, HU/r-IFNα

23/94

4/19

Diagnosis, ET / PV / PreMF/PMF

45/46/10/16

9/8/3/3

Mutation, JAK2V617F/CALR/MPL/Triple-negative

83/20/2/12

14/3/1/5

JAK2, %

33 (18-49)

33 (16-49)

Hemoglobin, mmol/L

9.1 (8.4-10.5)

9.2 (8.8-10)

Leukocytes, 10^9/L

9.2 (7.7-11.1)

12.3 (10.1-13.9)

Thrombocytes, 10^9/L

672 (460-880)

662 (513-863)

Conclusion
Non-smokers are more likely to have a more rapid decrease in JAK2 particularly in the initial phase of treatment (12 and 18 months, p < 0.01) compared to smokers. Although statistical testing was not performed, partial molecular response and complete clinicohematological response were more incident among non-smokers and drop-out was lower among non-smokers. The study was limited by several factors: (1) The post-hoc design. (2) The few smokers. (3) Smoking status might change in relation to a diagnosis of MPN, thus rendering the initial grouping unprecise. (4) The study design was not powered to detect factors affecting the model. Still, the resulting model was rather conservative. Hence the finding was surprising, and it needs confirmation in additional studies.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Molecular markers, Molecular response, Myeloproliferative disorder

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies