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Vol. 40. Núm. 2.Abril - Junho 2018
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Vol. 40. Núm. 2.Abril - Junho 2018
Páginas 99-198
Scientific Comment
DOI: 10.1016/j.htct.2018.01.005
Inflammatory picture of Philadelphia-negative myeloproliferative neoplasms
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Katia Borgia Barbosa Pagnano
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kborgia@unicamp.br

Correspondence to: Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas (Unicamp), Rua Carlos Chagas 480, Cidade Universitária Zeferino Vaz, 13092-801 Campinas, SP, Brazil.
Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
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hematol Transfus Cell Ther 2018;40:120-3110.1016/j.htct.2017.12.003
Maira da Costa Cacemiro, Juçara Gastaldi Cominal, Raquel Tognon, Natalia de Souza Nunes, Belinda Pinto Simões, Lorena Lôbo de Figueiredo-Pontes, Luiz Fernando Bazzo Catto, Fabíola Traina, Elizabeth Xisto Souto, Fabiana Albani Zambuzi, Fabiani Gai Frantz, Fabíola Attié de Castro
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In this issue of the Hematology, Transfusion and Cell Therapy Journal, Cacemiro et al. evaluated the plasma cytokine profile of 47 patients with Ph-negative myeloproliferative neoplasms (MPN) [essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV)] and of healthy subjects.1 They demonstrated increased levels of pro-inflammatory cytokines in MPN patients and higher levels of interferon (IFN)-γ-induced protein 10 (IP-10) in PMF patients with the JAK2 V617F mutation. They found differences in the cytokine profile among the three MPN disorders, including increased levels of IL-12p70, IL-17A, and RANTES in PMF, showing that MPN, in particular PMF, have altered inflammatory profiles. However, their sample population did not make clinical and prognostic implications of their findings possible.

What is the clinical relevance of the altered cytokine levels in MPN? Are they related to constitutional symptoms, transformation or evolution to fibrosis? Do they have an impact on the risk of thrombosis or response to JAK-2 inhibitors?

In a cohort of patients with ET and PV, Pourcelot et al. showed increased plasma levels of inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-12, TNFα and IFN-γ). The levels of the growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) were also elevated. They observed that a subgroup of PV patients with vascular complications had significantly different concentrations of IL-12 (p70) and GM-CSF compared to patients with no vascular complications.2 A study by Tefferi et al. evaluated the cytokine plasma levels of 127 patients with PMF, and observed significantly higher levels of several cytokines and decreased levels of IFN-γ. Increased levels of IL-8, IL-2R, IL-12 and IL-15 were predictive of inferior survival in the multivariate analysis. IL-8 levels predicted leukemia-free survival, which was also associated with ≥1% circulating blasts. These authors also found an association of IL-8 levels with constitutional symptoms and IL-2R and IL-12 levels with transfusion needs. Stratification of patients identified lower survival rates in patients with increased IL-8/IL2R levels. Patients with intermediate-1 and intermediate-2 risk according to the Dynamic International Prognostic Scoring System plus model also showed that cytokine levels influence survival.3

Other authors showed that targeting MF-associated cytokines with JAK-2 inhibitors such as ruxolitinib caused reductions in plasma levels of C-reactive protein, IL-1Rra, MIP-1β, TNF-α and IL-6, and was associated with improvements of constitutional symptoms and splenomegaly.4

Regarding the evolution of fibrosis, increased levels of IL-8, oncostatin-M, lipocalin-2, transforming growth factor (TGF)-β1, PDGF, FGF, VEGF and inhibitors of matrix metalloproteinases have been associated with the development of fibrosis.5,6 Megakaryocytes produce PDGF and VEGF, which lead to bone marrow fibrosis and collagen production.7

Finally, two inflammatory biomarkers, which are markers of thrombosis and atherogenesis in the general population, were recently identified as prognostic markers in MPN. Barbui et al. evaluated 244 patients with ET and PV and found that the thrombosis rate was higher in the tertile with the highest C-reactive protein levels and lower in patients with the highest pentraxin-3 levels.8 Lussana et al. demonstrated a strong correlation between the JAK2 V617F allele burden and PTX3 levels.9

In summary, Cacemiro et al. showed that increased cytokine levels are associated with MPN physiopathology.1 These markers may be useful for risk stratification of Ph-negative MPN and help in the clinical management and by combining treatments that target clonal hematopoiesis and inflammation.

Conflicts of interest

The author declares no conflicts of interest

References
[1]
M.C. Cacemiro,J.G. Cominal,R. Tognon,N.S. Nunes,B.P. Simões,L.L. Pontes
Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation
Hematol Transfus Cell Ther, 40 (2018), pp. 120-131
[2]
E. Pourcelot,C. Trocme,J. Mondet,S. Bailly,B. Toussaint,P. Mossuz
Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications
Exp Hematol, 42 (2014), pp. 360-368 http://dx.doi.org/10.1016/j.exphem.2014.01.006
[3]
A. Tefferi,R. Vaidya,D. Caramazza,C. Finke,T. Lasho,A. Pardanani
Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study
J Clin Oncol, (2011), pp. 1356-1363
[4]
S. Verstovsek,H. Kantarjian,R.A. Mesa,A.D. Pardanani,J. Cortes-Franco,D.A. Thomas
Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis
N Engl J Med, 363 (2010), pp. 1117-1127 http://dx.doi.org/10.1056/NEJMoa1002028
[5]
G. Hoermann,S. Cerny-Reiterer,H. Herrmann,K. Blatt,M. Bilban,H. Gisslinger
Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms
FASEB J, 26 (2012), pp. 894-906 http://dx.doi.org/10.1096/fj.11-193078
[6]
A. Tefferi
Pathogenesis of myelofibrosis with myeloid metaplasia
J Clin Oncol, 23 (2005), pp. 8520-8530 http://dx.doi.org/10.1200/JCO.2004.00.9316
[7]
O. Leiva,S.K. Ng,S. Chitalia,A. Balduini,S. Matsuura,K. Ravid
The role of the extracellular matrix in primary myelofibrosis
Blood Cancer J, 7 (2017), pp. e525 http://dx.doi.org/10.1038/bcj.2017.6
[8]
T. Barbui,A. Carobbio,G. Finazzi,A.M. Vannucchi,G. Barosi,E. Antonioli
Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3
Haematologica, 96 (2011), pp. 315-318 http://dx.doi.org/10.3324/haematol.2010.031070
[9]
F. Lussana,A. Carobbio,S. Salmoiraghi,P. Guglielmelli,A.M. Vannucchi,B. Bottazzi
Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera
J Hematol Oncol, 10 (2017), pp. 54 http://dx.doi.org/10.1186/s13045-017-0425-z

See paper by Maira da Costa Cacemiro et al. on pages [120–131].

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