- Email: [email protected]
The JAK2 V617F mutational status and allele burden – authors’ reply
Thrombosis Research 136 (2015) 691–692
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Correspondence The JAK2 V617F mutational status and allele burden – authors’ reply Dear Editor, We thank Profs Shanshan Liang and Yanhong Zhou [1] for their Letter-to-the-Editor with insightful comments on methodology of our study demonstrating that the JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms (MPN Ph-) [2]. The letter concerns two main issues. The first one refers to the time of retrospective observation for thrombotic complications in patients with MPN Ph-before the MPN diagnosis was made. Which thrombotic event occurring before MPN diagnosis was linked to patient’s personal features and which was a consequence of already present MPN remains an issue. Likewise, how long the disease might have occurred before MPN diagnosis was made. It seems that the longer the time of observation for thrombotic event is, the less likely may it be connected with MPN itself. Moreover, it is difficult to make unambiguous settlement, as there is a great extent of freedom in choosing the time of observation by authors of different analyses. They range from life-long observation for thrombosis [3], of 1 year [4] to the observation exclusively in follow-up [5]. Most of the authors of studies analyzed by us choose, however, the 2 years period of observation, not only for PV, translating the knowledge that 75% of thromboses which indicate PV occur within this interval of time [6], but also for other MPN [7,8]. Therefore, our choice of 2 years enables comparability of our results with previous studies. Moreover, we believe that if we choose this period of 2 years before a diagnosis for vascular event observation, causal relation between latent MPN and the vascular event is the most probable. The readers of our article may have also an insight into medical history of life-long thrombotic complications in a cohort of our patients. We introduce a distinction between a risk factor for occurring of major thrombosis at diagnosis or at follow-up, called “previous history of thrombosis” and defined as thrombosis in patients’ medical history over 2 years before the diagnosis of MPN, which in our opinion is linked rather to patient’s personal features than MPN itself, and two outcomes in our study - “thrombosis at diagnosis” – which includes the occurrence of any thrombotic complications which directly led to diagnosis and/or occurred up to two years before a diagnosis was made - and “thrombosis in follow-up”. Additionally, our unpublished data suggest that even if we have taken into consideration patients’ life-long vascular complications, the results of JAK2 role in venous thromboembolism wouldn’t have differed from already presented in our article. All risk factors for the incidence of thromboembolic events missing by the Authors of the Letter were presented and their possible impact on thrombosis was analyzed in Supplementary Table 2 [2].
http://dx.doi.org/10.1016/j.thromres.2015.07.006 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
The second main issue is analysis of JAK2 impact on vascular complications in a whole group of MPNs patients with unbalanced distribution of MPN subtypes (53 PV vs. 114 ET vs. 11 PMF vs. 8 uMPNs). While an increasing number of studies have been exploring the influence of JAK2 mutation and allele burden on thrombosis and prognosis in MPN, the reported results are conflicting. Efforts have been previously made to classify JAK2-mutant ET and PV as a continuum of the same disease [4], while the allele burden and/or coexistence of other abnormalities influence on disease phenotype. Although our report seems to present another trial assessing the effect of JAK2 mutation on thrombosis, the biggest novelty of our paper, appreciated by Reviewers who stressed its increasing importance, was an attempt to evaluate the influence of JAK2 mutational status and allele burden on thrombosis in MPN taken as a whole group, without separation to different diseases. This approach is another step towards revised classification of MPN which would consider JAK2 mutational status among other factors and has at least four benefits: it allows the analysis of the risk of vascular complications in the presence of JAK2 V617F mutation and the clinical symptoms suggesting MPN Ph- already before making a precise diagnosis, as well as when the diagnosis remains uncertain (when differentiating between ET and the prefibrotic phase of PMF [9], and, between PMF and post-ET MF or post-PV MF [10–12]); it may add an important insight into new way of understanding of MPN, particularly in the light of ongoing new molecular research and reports of phenotype dependence on genetic background; it supports consideration of the possible need to classify JAK2 V617F-positive (called “JAK-opathies” by Kiladjian [13]) and JAK2 V617F-negative entities as distinct disorders, as the different clinical course is seen in JAK2 V617F-positive patients [3,4,7]; finally, this analysis defining 4 different groups based on the allele burden makes rationale for future risk stratification and treatment decision algorithm. Our new approach was supported by the results of our study which point significant role of JAK2 mutation in vascular complications occurrence unlike the role of the distinct MPNs entities itself. Moreover, also other investigators proposed the same treatment algorithm in essential thrombocytopenia and polycythemia vera dependently from JAK2 mutational status [14]. It is why the fact that quantity of mutation was significantly higher in patients with PV in comparison with those suffering from ET or PMF has no potential impact on our results, but rather supports our hypothesis. Finally, it is also why we consider a choice of ROC analysis with the best cut-off value to assess the ability of the JAK2 V617F allele burden to predict vascular outcome to be appropriate. Last – it is difficult to discuss the size of patients study group. Similarly to the letter’s authors, we wish it was bigger. As MPN Ph- belongs to a group of rare diseases with the reported crude annual incidence rates from 1.15 to 4.99 per 100 000 [15], it is difficult to collect satisfying number of patients participating in a study. For example, in most of the studies published on the impact of JAK2 V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia the number of ET patients ranged from 13 to 414. Therefore, to draw conclusions meta-analysis studies are needed [16]. In our opinion,
692
Correspondence
however, the statistical significance of our results was high enough to raise their credibility. It is sure that the inclusion of JAK2 V617F mutant allele burden in new risk stratifications, proposed by us, requires well-planned controlled prospective trials in the future, but seems to be justified. Explaining all doubts expressed by Profs Shanshan Liang and Yanhong Zhou [1], we hope that the results of our study are confirmable and the pointed direction may be followed in the future. Conflict of Interest Statement All authors report no potential conflicts of interest. References [1] S. Liang, Y. Zhou, The JAK2 V617F mutational status and allele burden, Thromb. Res. 136 (2015) 690 (in this issue). [2] M. Borowczyk, M. Wojtaszewska, K. Lewandowski, L. Gil, M. Lewandowska, A. Lehmann-Kopydlowska, et al., The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms, Thromb. Res. 135 (2015) 272–280. [3] A. Tefferi, T.L. Lasho, S.M. Schwager, J.S. Strand, M. Elliott, R. Mesa, et al., The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera, Cancer 106 (2006) 631–635. [4] P.J. Campbell, L.M. Scott, G. Buck, K. Wheatley, C.L. East, J.T. Marsden, et al., Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study, Lancet 366 (2005) 1945–1953. [5] A. Carobbio, G. Finazzi, E. Antonioli, P. Guglielmelli, A.M. Vannucchi, C.M. Dellacasa, et al., JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera, Exp. Hematol. 37 (2009) 1016–1021. [6] P. Gis, Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia, Ann. Intern. Med. 123 (1995) 656–664. [7] A.M. Vannucchi, E. Antonioli, P. Guglielmelli, A. Rambaldi, G. Barosi, R. Marchioli, et al., Clinical profile of homozygous JAK2 617 V N F mutation in patients with polycythemia vera or essential thrombocythemia, Blood 110 (2007) 840–846. [8] V. De Stefano, T. Za, E. Rossi, A. Fiorini, A. Ciminello, C. Luzzi, et al., Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia, Haematologica 94 (2009) 733–737. [9] T. Barbui, J. Thiele, A. Carobbio, F. Passamonti, E. Rumi, M.L. Randi, et al., Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis, Blood 120 (2012) 569–571. [10] T. Barbui, J. Thiele, A.M. Vannucchi, A. Tefferi, Problems and pitfalls regarding WHOdefined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia, Leukemia 27 (2013) 1953–1958. [11] J.T. Reilly, M.F. McMullin, P.A. Beer, N. Butt, E. Conneally, A. Duncombe, et al., Guideline for the diagnosis and management of myelofibrosis, Br. J. Haematol. 158 (2012) 453–471.
[12] N. Sangle, J. Cook, S. Perkins, C.J. Teman, D. Bahler, K. Hickman, et al., Myelofibrotic transformations of polycythemia vera and essential thrombocythemia are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis, Appl. Immunohistochem. Mol. Morphol. 22 (2014) 663–668. [13] J.J. Kiladjian, The spectrum of JAK2-positive myeloproliferative neoplasms, Hematology Am. Soc. Hematol. Educ. Program. 2012 (2012) 561–566. [14] A. Tefferi, T. Barbui, New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera, Am. J. Hematol. 90 (2015) 683–685. [15] L.A. Anderson, M.F. McMullin, Epidemiology of MPN: what do we know? Curr. Hematol. Malig. Rep. 9 (2014) 340–349. [16] Y. Qin, X. Wang, C. Zhao, C. Wang, Y. Yang, The impact of JAK2V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia: a metaanalysis, Int. J. Hematol. (2015) http://dx.doi.org/10.1007/s12185-015-1808-y (Epub ahead of print).
Martyna Borowczyk⁎ Marzena Wojtaszewska Krzysztof Lewandowski Lidia Gil Maria Lewandowska Agata Lehmann-Kopydłowska Renata Kroll-Balcerzak Andrzej Balcerzak Małgorzata Iwoła Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, 84 Szamarzewski Street, 60–569, Poznań, Poland ⁎Corresponding author. E-mail address: [email protected] (M. Borowczyk). Michał Michalak Department of Computer Science and Statistics, Poznań University of Medical Sciences, 79 Dabrowski Street, 60–529, Poznań, Poland Mieczysław Komarnicki Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, 84 Szamarzewski Street, 60–569, Poznań, Poland 15 June 2015
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Correspondence The JAK2 V617F mutational status and allele burden – authors’ reply Dear Editor, We thank Profs Shanshan Liang and Yanhong Zhou [1] for their Letter-to-the-Editor with insightful comments on methodology of our study demonstrating that the JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms (MPN Ph-) [2]. The letter concerns two main issues. The first one refers to the time of retrospective observation for thrombotic complications in patients with MPN Ph-before the MPN diagnosis was made. Which thrombotic event occurring before MPN diagnosis was linked to patient’s personal features and which was a consequence of already present MPN remains an issue. Likewise, how long the disease might have occurred before MPN diagnosis was made. It seems that the longer the time of observation for thrombotic event is, the less likely may it be connected with MPN itself. Moreover, it is difficult to make unambiguous settlement, as there is a great extent of freedom in choosing the time of observation by authors of different analyses. They range from life-long observation for thrombosis [3], of 1 year [4] to the observation exclusively in follow-up [5]. Most of the authors of studies analyzed by us choose, however, the 2 years period of observation, not only for PV, translating the knowledge that 75% of thromboses which indicate PV occur within this interval of time [6], but also for other MPN [7,8]. Therefore, our choice of 2 years enables comparability of our results with previous studies. Moreover, we believe that if we choose this period of 2 years before a diagnosis for vascular event observation, causal relation between latent MPN and the vascular event is the most probable. The readers of our article may have also an insight into medical history of life-long thrombotic complications in a cohort of our patients. We introduce a distinction between a risk factor for occurring of major thrombosis at diagnosis or at follow-up, called “previous history of thrombosis” and defined as thrombosis in patients’ medical history over 2 years before the diagnosis of MPN, which in our opinion is linked rather to patient’s personal features than MPN itself, and two outcomes in our study - “thrombosis at diagnosis” – which includes the occurrence of any thrombotic complications which directly led to diagnosis and/or occurred up to two years before a diagnosis was made - and “thrombosis in follow-up”. Additionally, our unpublished data suggest that even if we have taken into consideration patients’ life-long vascular complications, the results of JAK2 role in venous thromboembolism wouldn’t have differed from already presented in our article. All risk factors for the incidence of thromboembolic events missing by the Authors of the Letter were presented and their possible impact on thrombosis was analyzed in Supplementary Table 2 [2].
http://dx.doi.org/10.1016/j.thromres.2015.07.006 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
The second main issue is analysis of JAK2 impact on vascular complications in a whole group of MPNs patients with unbalanced distribution of MPN subtypes (53 PV vs. 114 ET vs. 11 PMF vs. 8 uMPNs). While an increasing number of studies have been exploring the influence of JAK2 mutation and allele burden on thrombosis and prognosis in MPN, the reported results are conflicting. Efforts have been previously made to classify JAK2-mutant ET and PV as a continuum of the same disease [4], while the allele burden and/or coexistence of other abnormalities influence on disease phenotype. Although our report seems to present another trial assessing the effect of JAK2 mutation on thrombosis, the biggest novelty of our paper, appreciated by Reviewers who stressed its increasing importance, was an attempt to evaluate the influence of JAK2 mutational status and allele burden on thrombosis in MPN taken as a whole group, without separation to different diseases. This approach is another step towards revised classification of MPN which would consider JAK2 mutational status among other factors and has at least four benefits: it allows the analysis of the risk of vascular complications in the presence of JAK2 V617F mutation and the clinical symptoms suggesting MPN Ph- already before making a precise diagnosis, as well as when the diagnosis remains uncertain (when differentiating between ET and the prefibrotic phase of PMF [9], and, between PMF and post-ET MF or post-PV MF [10–12]); it may add an important insight into new way of understanding of MPN, particularly in the light of ongoing new molecular research and reports of phenotype dependence on genetic background; it supports consideration of the possible need to classify JAK2 V617F-positive (called “JAK-opathies” by Kiladjian [13]) and JAK2 V617F-negative entities as distinct disorders, as the different clinical course is seen in JAK2 V617F-positive patients [3,4,7]; finally, this analysis defining 4 different groups based on the allele burden makes rationale for future risk stratification and treatment decision algorithm. Our new approach was supported by the results of our study which point significant role of JAK2 mutation in vascular complications occurrence unlike the role of the distinct MPNs entities itself. Moreover, also other investigators proposed the same treatment algorithm in essential thrombocytopenia and polycythemia vera dependently from JAK2 mutational status [14]. It is why the fact that quantity of mutation was significantly higher in patients with PV in comparison with those suffering from ET or PMF has no potential impact on our results, but rather supports our hypothesis. Finally, it is also why we consider a choice of ROC analysis with the best cut-off value to assess the ability of the JAK2 V617F allele burden to predict vascular outcome to be appropriate. Last – it is difficult to discuss the size of patients study group. Similarly to the letter’s authors, we wish it was bigger. As MPN Ph- belongs to a group of rare diseases with the reported crude annual incidence rates from 1.15 to 4.99 per 100 000 [15], it is difficult to collect satisfying number of patients participating in a study. For example, in most of the studies published on the impact of JAK2 V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia the number of ET patients ranged from 13 to 414. Therefore, to draw conclusions meta-analysis studies are needed [16]. In our opinion,
692
Correspondence
however, the statistical significance of our results was high enough to raise their credibility. It is sure that the inclusion of JAK2 V617F mutant allele burden in new risk stratifications, proposed by us, requires well-planned controlled prospective trials in the future, but seems to be justified. Explaining all doubts expressed by Profs Shanshan Liang and Yanhong Zhou [1], we hope that the results of our study are confirmable and the pointed direction may be followed in the future. Conflict of Interest Statement All authors report no potential conflicts of interest. References [1] S. Liang, Y. Zhou, The JAK2 V617F mutational status and allele burden, Thromb. Res. 136 (2015) 690 (in this issue). [2] M. Borowczyk, M. Wojtaszewska, K. Lewandowski, L. Gil, M. Lewandowska, A. Lehmann-Kopydlowska, et al., The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms, Thromb. Res. 135 (2015) 272–280. [3] A. Tefferi, T.L. Lasho, S.M. Schwager, J.S. Strand, M. Elliott, R. Mesa, et al., The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera, Cancer 106 (2006) 631–635. [4] P.J. Campbell, L.M. Scott, G. Buck, K. Wheatley, C.L. East, J.T. Marsden, et al., Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study, Lancet 366 (2005) 1945–1953. [5] A. Carobbio, G. Finazzi, E. Antonioli, P. Guglielmelli, A.M. Vannucchi, C.M. Dellacasa, et al., JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera, Exp. Hematol. 37 (2009) 1016–1021. [6] P. Gis, Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia, Ann. Intern. Med. 123 (1995) 656–664. [7] A.M. Vannucchi, E. Antonioli, P. Guglielmelli, A. Rambaldi, G. Barosi, R. Marchioli, et al., Clinical profile of homozygous JAK2 617 V N F mutation in patients with polycythemia vera or essential thrombocythemia, Blood 110 (2007) 840–846. [8] V. De Stefano, T. Za, E. Rossi, A. Fiorini, A. Ciminello, C. Luzzi, et al., Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia, Haematologica 94 (2009) 733–737. [9] T. Barbui, J. Thiele, A. Carobbio, F. Passamonti, E. Rumi, M.L. Randi, et al., Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis, Blood 120 (2012) 569–571. [10] T. Barbui, J. Thiele, A.M. Vannucchi, A. Tefferi, Problems and pitfalls regarding WHOdefined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia, Leukemia 27 (2013) 1953–1958. [11] J.T. Reilly, M.F. McMullin, P.A. Beer, N. Butt, E. Conneally, A. Duncombe, et al., Guideline for the diagnosis and management of myelofibrosis, Br. J. Haematol. 158 (2012) 453–471.
[12] N. Sangle, J. Cook, S. Perkins, C.J. Teman, D. Bahler, K. Hickman, et al., Myelofibrotic transformations of polycythemia vera and essential thrombocythemia are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis, Appl. Immunohistochem. Mol. Morphol. 22 (2014) 663–668. [13] J.J. Kiladjian, The spectrum of JAK2-positive myeloproliferative neoplasms, Hematology Am. Soc. Hematol. Educ. Program. 2012 (2012) 561–566. [14] A. Tefferi, T. Barbui, New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera, Am. J. Hematol. 90 (2015) 683–685. [15] L.A. Anderson, M.F. McMullin, Epidemiology of MPN: what do we know? Curr. Hematol. Malig. Rep. 9 (2014) 340–349. [16] Y. Qin, X. Wang, C. Zhao, C. Wang, Y. Yang, The impact of JAK2V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia: a metaanalysis, Int. J. Hematol. (2015) http://dx.doi.org/10.1007/s12185-015-1808-y (Epub ahead of print).
Martyna Borowczyk⁎ Marzena Wojtaszewska Krzysztof Lewandowski Lidia Gil Maria Lewandowska Agata Lehmann-Kopydłowska Renata Kroll-Balcerzak Andrzej Balcerzak Małgorzata Iwoła Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, 84 Szamarzewski Street, 60–569, Poznań, Poland ⁎Corresponding author. E-mail address: [email protected] (M. Borowczyk). Michał Michalak Department of Computer Science and Statistics, Poznań University of Medical Sciences, 79 Dabrowski Street, 60–529, Poznań, Poland Mieczysław Komarnicki Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, 84 Szamarzewski Street, 60–569, Poznań, Poland 15 June 2015