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The Rationale for Immunotherapy in Myeloproliferative Neoplasms

Abstract

Purpose of Review

The classic, chronic Philadelphia chromosome negative myeloproliferative neoplasms (MPN)—essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)—are clonal malignancies of hematopoietic stem cells and are associated with myeloproliferation, organomegaly, and constitutional symptoms. Expanding knowledge that chronic inflammation and a dysregulated immune system are central to the pathogenesis and progression of MPNs serves as a driving force for the development of agents affecting the immune system as therapy for MPN. This review describes the rationale and potential impact of anti-inflammatory, immunomodulatory, and targeted agents in MPNs.

Recent Findings

The advances in molecular insights, especially the discovery of the Janus kinase 2 (JAK2) V617F mutation and its role in JAK-STAT pathway dysregulation, led to the development of the JAK inhibitor ruxolitinib, which currently represents the cornerstone of medical therapy in MF and hydroxyurea-resistant/intolerant PV. However, there remain significant unmet needs in the treatment of these patients, and many agents continue to be investigated. Novel, more selective JAK inhibitors might offer reduced myelosuppression or even improvement of blood counts. The recent approval of a novel, long-acting interferon for PV patients in Europe, might eventually lead to its broader clinical use in all MPNs. Targeted immunotherapy involving monoclonal antibodies, checkpoint inhibitors, or therapeutic vaccines against selected MPN epitopes could further enhance tumor-specific immune responses.

Summary

Immunotherapeutic approaches are expanding and hopefully will extend the therapeutic armamentarium in patients with myeloproliferative neoplasms.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905–14. https://doi.org/10.1038/leu.2008.72.

    CAS  Article  PubMed  Google Scholar 

  2. Barosi G, Rosti V, Bonetti E, Campanelli R, Carolei A, Catarsi P, et al. Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis. PLoS One. 2012;7(4):e35631. https://doi.org/10.1371/journal.pone.0035631.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90. https://doi.org/10.1056/NEJMoa051113.

    CAS  Article  PubMed  Google Scholar 

  4. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90. https://doi.org/10.1056/NEJMoa1311347.

    CAS  Article  PubMed  Google Scholar 

  5. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270. https://doi.org/10.1371/journal.pmed.0030270.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Milosevic Feenstra JD, Nivarthi H, Gisslinger H, Leroy E, Rumi E, Chachoua I, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016;127(3):325–32. https://doi.org/10.1182/blood-2015-07-661835.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Viny AD, Levine RL. Genetics of myeloproliferative neoplasms. Cancer J. 2014;20(1):61–5. https://doi.org/10.1097/ppo.0000000000000013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Rumi E, Pietra D, Pascutto C, Guglielmelli P, Martinez-Trillos A, Casetti I, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7):1062–9. https://doi.org/10.1182/blood-2014-05-578435.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A, et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood. 2006;108(4):1377–80. https://doi.org/10.1182/blood-2005-11-009605.

    CAS  Article  PubMed  Google Scholar 

  10. Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14):2220–8. https://doi.org/10.1182/blood-2013-11-537167.

    CAS  Article  PubMed  Google Scholar 

  11. Barbui T, Vannucchi AM, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 2015;5:e369. https://doi.org/10.1038/bcj.2015.94.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. PharmaEssentia. PharmaEssentia and AOP orphan receive EU approval of Besremi™ (ropeginterferon alfa-2b) for treatment of polycythemia Vera (PV) in EU. 2018. Available from: https://www.prnewswire.com/news-releases/pharmaessentia-and-aop-orphan-receive-eu-approval-of-besremi-ropeginterferon-alfa-2b-for-treatment-of-polycythemia-vera-pv-in-eu-300800079.html. Accessed April 2019.

  13. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood. 2012;120(7):1367–79. https://doi.org/10.1182/blood-2012-05-399048.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Kroger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126–33. https://doi.org/10.1038/leu.2015.233.

    CAS  Article  PubMed  Google Scholar 

  15. • Bose P, Alfayez M, Verstovsek S. New concepts of treatment for patients with myelofibrosis. Curr Treat Options in Oncol. 2019;20(1):5. https://doi.org/10.1007/s11864-019-0604-y Comprehensive reviews of novel therapeutic approaches in MPN.

    Article  Google Scholar 

  16. • Pettit K, Odenike O. Novel therapies for myelofibrosis. Curr Hematol Malig Rep. 2017;12(6):611–24. https://doi.org/10.1007/s11899-017-0403-0 Comprehensive reviews of novel therapeutic approaches in MPN.

    Article  PubMed  PubMed Central  Google Scholar 

  17. • Bose P, Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood. 2017;130(2):115–25. https://doi.org/10.1182/blood-2017-04-742288 Comprehensive reviews of novel therapeutic approaches in MPN.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. •• Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood. 2012;119(14):3219–25. https://doi.org/10.1182/blood-2011-11-394775 Excellent review about inflammation and deregulated immune system in MPNs.

    CAS  Article  PubMed  Google Scholar 

  19. •• Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev. 2013;24(2):133–45. https://doi.org/10.1016/j.cytogfr.2013.01.004 Excellent review about inflammation and deregulated immune system in MPNs.

    CAS  Article  PubMed  Google Scholar 

  20. •• Lussana F, Rambaldi A. Inflammation and myeloproliferative neoplasms. J Autoimmun. 2017;85:58–63. https://doi.org/10.1016/j.jaut.2017.06.010 Excellent review about inflammation and deregulated immune system in MPNs.

    CAS  Article  PubMed  Google Scholar 

  21. •• Barosi G. An immune dysregulation in MPN. Curr Hematol Malig Rep. 2014;9(4):331–9. https://doi.org/10.1007/s11899-014-0227-0 Excellent review about inflammation and deregulated immune system in MPNs.

    Article  PubMed  Google Scholar 

  22. •• Hasselbalch HC. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res. 2013;37(2):214–20. https://doi.org/10.1016/j.leukres.2012.10.020 Excellent review about inflammation and deregulated immune system in MPNs.

    CAS  Article  PubMed  Google Scholar 

  23. Delhommeau FDS, Tonetti C, Massé A, et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007;109:71–7.

    CAS  Article  PubMed  Google Scholar 

  24. Pourcelot E, Trocme C, Mondet J, Bailly S, Toussaint B, Mossuz P. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp Hematol. 2014;42(5):360–8. https://doi.org/10.1016/j.exphem.2014.01.006.

    CAS  Article  PubMed  Google Scholar 

  25. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. 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 Off J Am Soc Clin Oncol. 2011;29(10):1356–63. https://doi.org/10.1200/jco.2010.32.9490.

    CAS  Article  Google Scholar 

  26. Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(33):8520–30. https://doi.org/10.1200/jco.2004.00.9316.

    CAS  Article  Google Scholar 

  27. Le Bousse-Kerdiles MC, Chevillard S, Charpentier A, Romquin N, Clay D, Smadja-Joffe F, et al. Differential expression of transforming growth factor-beta, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia. Blood. 1996;88(12):4534–46.

    PubMed  Google Scholar 

  28. Bock O, Hoftmann J, Theophile K, Hussein K, Wiese B, Schlue J, et al. Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. Am J Pathol. 2008;172(4):951–60. https://doi.org/10.2353/ajpath.2008.071030.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Flamant L, Toffoli S, Raes M, Michiels C. Hypoxia regulates inflammatory gene expression in endothelial cells. Exp Cell Res. 2009;315(5):733–47. https://doi.org/10.1016/j.yexcr.2008.11.020.

    CAS  Article  PubMed  Google Scholar 

  30. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;44(7203):436–44. https://doi.org/10.1038/nature07205.

    CAS  Article  Google Scholar 

  31. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62. https://doi.org/10.1038/nrm909.

    CAS  Article  PubMed  Google Scholar 

  32. Boissinot M, Cleyrat C, Vilaine M, Jacques Y, Corre I, Hermouet S. Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F. Oncogene. 2011;30(8):990–1001. https://doi.org/10.1038/onc.2010.479.

    CAS  Article  PubMed  Google Scholar 

  33. •• Kleppe M, Kwak M, Koppikar P, Riester M, Keller M, Bastian L, et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov. 2015;5(3):316–31. https://doi.org/10.1158/2159-8290.cd-14-0736 Excellent paper about JAK/STAT pathway in MPN pathogenesis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Zhan H, Ma Y, Lin CH, Kaushansky K. JAK2(V617F)-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation. Leukemia. 2016;30(12):2332–41. https://doi.org/10.1038/leu.2016.114.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Lataillade JJ, Pierre-Louis O, Hasselbalch HC, Uzan G, Jasmin C, Martyre MC, et al. Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence. Blood. 2008;112(8):3026–35. https://doi.org/10.1182/blood-2008-06-158386.

    CAS  Article  PubMed  Google Scholar 

  36. Corre-Buscail I, Pineau D, Boissinot M, Hermouet S. Erythropoietin-independent erythroid colony formation by bone marrow progenitors exposed to interleukin-11 and interleukin-8. Exp Hematol. 2005;33(11):1299–308. https://doi.org/10.1016/j.exphem.2005.07.002.

    CAS  Article  PubMed  Google Scholar 

  37. Skov V, Larsen TS, Thomassen M, Riley CH, Jensen MK, Bjerrum OW, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res. 2012;36(11):1387–92. https://doi.org/10.1016/j.leukres.2012.07.009.

    CAS  Article  PubMed  Google Scholar 

  38. Zhao WB, Li Y, Liu X, Zhang LY, Wang X. Involvement of CD4+CD25+ regulatory T cells in the pathogenesis of polycythaemia vera. Chin Med J. 2008;121(18):1781–6.

    CAS  Article  PubMed  Google Scholar 

  39. Skov V, Riley CH, Thomassen M, Larsen TS, Jensen MK, Bjerrum OW, et al. Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Lymphoma. 2013;54(10):2269–73. https://doi.org/10.3109/10428194.2013.764417.

    CAS  Article  PubMed  Google Scholar 

  40. Marty C, Lacout C, Droin N, Le Couedic JP, Ribrag V, Solary E, et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia. 2013;27(11):2187–95. https://doi.org/10.1038/leu.2013.102.

    CAS  Article  PubMed  Google Scholar 

  41. Bjorn ME, Hasselbalch HC. The role of reactive oxygen species in myelofibrosis and related neoplasms. Mediat Inflamm. 2015:648090. https://doi.org/10.1155/2015/648090.

  42. Wang JC, Kundra A, Andrei M, Baptiste S, Chen C, Wong C, et al. Myeloid-derived suppressor cells in patients with myeloproliferative neoplasm. Leuk Res. 2016;43:39–43. https://doi.org/10.1016/j.leukres.2016.02.004.

    CAS  Article  PubMed  Google Scholar 

  43. • Prestipino A, Emhardt AJ, Aumann K, O'Sullivan D, Gorantla SP, Duquesne S, et al. Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med. 2018;10(429). https://doi.org/10.1126/scitranslmed.aam7729 Interesting paper about the role of JAK2 in PD-L1 overexpression.

  44. •• Holmstrom MO, Hjortso MD, Ahmad SM, Met O, Martinenaite E, Riley C, et al. The JAK2V617F mutation is a target for specific T cells in the JAK2V617F-positive myeloproliferative neoplasms. Leukemia. 2017;31(2):495–8. https://doi.org/10.1038/leu.2016.290 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    CAS  Article  PubMed  Google Scholar 

  45. •• Holmstrom MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413–6. https://doi.org/10.1038/leu.2016.233 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    CAS  Article  PubMed  Google Scholar 

  46. •• Holmstrom MO, Riley CH, Skov V, Svane IM, Hasselbalch HC, Andersen MH. Spontaneous T-cell responses against the immune check point programmed-death-ligand 1 (PD-L1) in patients with chronic myeloproliferative neoplasms correlate with disease stage and clinical response. Oncoimmunology. 2018;7(6):e1433521. https://doi.org/10.1080/2162402x.2018.1433521 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. •• Holmstrom MO, Hasselbalch HC, Andersen MH. The JAK2V617F and CALR exon 9 mutations are shared immunogenic neoantigens in hematological malignancy. Oncoimmunology. 2017;6(11):e1358334. https://doi.org/10.1080/2162402x.2017.1358334 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. •• Elf SAN, Chen E, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016;6(4):368–81 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. •• Pecquet Ch BT, Chachoua I, Roy A, Vertenoeil G, et al. Secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor activation specifically in CALR mutated cells: perspectives for MPN therapy. Blood. 2018;132:4 Very interesting data about the potential use of JAK2 and CALR as neo-antigens for cancer vaccines.

    Article  Google Scholar 

  50. •• Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68–76. https://doi.org/10.1002/cncr.22365 Important study about symptoms burden in patients with MPN.

    Article  PubMed  Google Scholar 

  51. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89–101. https://doi.org/10.2147/ijgm.s51800.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Mesa R, Jamieson C, Bhatia R, Deininger MW, Gerds AT, Gojo I, et al. Myeloproliferative neoplasms, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14(12):1572–611.

    CAS  Article  Google Scholar 

  53. Mesa RA, Jamieson C, Bhatia R, Deininger MW, Fletcher CD, Gerds AT, et al. NCCN guidelines insights: myeloproliferative neoplasms, version 2.2018. J Natl Compr Cancer Netw. 2017;15(10):1193–207. https://doi.org/10.6004/jnccn.2017.0157.

    Article  Google Scholar 

  54. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood. 2011;117(18):4706–15. https://doi.org/10.1182/blood-2010-08-258772.

    CAS  Article  PubMed  Google Scholar 

  55. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5(5):375–86. https://doi.org/10.1038/nri1604.

    CAS  Article  PubMed  Google Scholar 

  56. Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, et al. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis. 2003;8(3):237–49.

    CAS  Article  PubMed  Google Scholar 

  57. Wang Q, Miyakawa Y, Fox N, Kaushansky K. Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Blood. 2000;96(6):2093–9.

    CAS  PubMed  Google Scholar 

  58. Peschel C, Aulitzky WE, Huber C. Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders. Leuk Lymphoma. 1996;22(Suppl 1):129–34. https://doi.org/10.3109/10428199609074370.

    Article  PubMed  Google Scholar 

  59. Dai CHPJ, et al. Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon gamma to produce erythroid cell apoptosis. Blood. 1998;91(4):1235–42.

    CAS  PubMed  Google Scholar 

  60. Kanfer EJ, Price CM, Gordon AA, Barrett AJ. The in vitro effects of interferon-gamma, interferon-alpha, and tumour-necrosis factor-alpha on erythroid burst-forming unit growth in patients with non-leukaemic myeloproliferative disorders. Eur J Haematol. 1993;50(5):250–4.

    CAS  Article  PubMed  Google Scholar 

  61. Aman MJ, Bug G, Aulitzky WE, Huber C, Peschel C. Inhibition of interleukin-11 by interferon-alpha in human bone marrow stromal cells. Exp Hematol. 1996;24(8):863–7.

    CAS  PubMed  Google Scholar 

  62. Carlo-Stella C, Cazzola M, Gasner A, Barosi G, Dezza L, Meloni F, et al. Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia. Blood. 1987;70(4):1014–9.

    CAS  PubMed  Google Scholar 

  63. Indraccolo S. Interferon-alpha as angiogenesis inhibitor: learning from tumor models. Autoimmunity. 2010;43(3):244–7. https://doi.org/10.3109/08916930903510963.

    CAS  Article  PubMed  Google Scholar 

  64. Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904–8. https://doi.org/10.1038/nature07815.

    CAS  Article  PubMed  Google Scholar 

  65. Lu M, Zhang W, Li Y, Berenzon D, Wang X, Wang J, et al. Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp Hematol. 2010;38(6):472–80. https://doi.org/10.1016/j.exphem.2010.03.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Riley CH, Jensen MK, Brimnes MK, Hasselbalch HC, Bjerrum OW, Straten PT, et al. Increase in circulating CD4(+)CD25(+)Foxp3(+) T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-alpha. Blood. 2011;118(8):2170–3. https://doi.org/10.1182/blood-2011-03-340992.

    CAS  Article  PubMed  Google Scholar 

  67. Riley CH, Hansen M, Brimnes MK, Hasselbalch HC, Bjerrum OW, Straten PT, et al. Expansion of circulating CD56bright natural killer cells in patients with JAK2-positive chronic myeloproliferative neoplasms during treatment with interferon-alpha. Eur J Haematol. 2015;94(3):227–34. https://doi.org/10.1111/ejh.12420.

    CAS  Article  PubMed  Google Scholar 

  68. Rizza P, Moretti F, Belardelli F. Recent advances on the immunomodulatory effects of IFN-alpha: implications for cancer immunotherapy and autoimmunity. Autoimmunity. 2010;43(3):204–9. https://doi.org/10.3109/08916930903510880.

    CAS  Article  PubMed  Google Scholar 

  69. Xiong Z, Yan Y, Liu E, Silver RT, Verstovsek S, Yang F, et al. Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. Clin Immunol. 2007;122(3):279–87. https://doi.org/10.1016/j.clim.2006.10.006.

    CAS  Article  PubMed  Google Scholar 

  70. Skov V, Riley CH, Thomassen M, Kjaer L, Stauffer Larsen T, Bjerrum OW, et al. The impact of interferon-alpha2 on HLA genes in patients with polycythemia vera and related neoplasms. Leuk Lymphoma. 2017;58(8):1914–21. https://doi.org/10.1080/10428194.2016.1262032.

    CAS  Article  PubMed  Google Scholar 

  71. Skov VRC, Thomassen M, Lasse Kjær L, et al. Interferon-alfa2 treatment of patients with polycythemia vera and related neoplasms impacts deregulation of oxidative stress genes and antioxidative defence mechanisms. Potential implications of IFN-alfa induced changes in TP53, NRF2 and CXCR4 for genomic instability and CD34+ mobilisation. Blood. 2018;132:4326.

    Google Scholar 

  72. Radin AI, Kim HT, Grant BW, Bennett JM, Kirkwood JM, Stewart JA, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer. 2003;98(1):100–9. https://doi.org/10.1002/cncr.11486.

    CAS  Article  PubMed  Google Scholar 

  73. Gowin K, Thapaliya P, Samuelson J, Harrison C, Radia D, Andreasson B, et al. Experience with pegylated interferon alpha-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients. Haematologica. 2012;97(10):1570–3. https://doi.org/10.3324/haematol.2011.061390.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Gowin KLJT, Kosiorek HE, Camoriano J, Tibes R, Palmer J, Mesa RA. Pegylated interferon alpha-2a in 75 patients with myeloproliferative neoplasms: a single center experience. Blood. 2015;126:2818.

    Google Scholar 

  75. Stauffer Larsen T, Iversen KF, Hansen E, Mathiasen AB, Marcher C, Frederiksen M, et al. Long term molecular responses in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelofibrosis treated with recombinant interferon alpha. Leuk Res. 2013;37(9):1041–5. https://doi.org/10.1016/j.leukres.2013.06.012.

    CAS  Article  PubMed  Google Scholar 

  76. Larsen TS, Moller MB, de Stricker K, Norgaard P, Samuelsson J, Marcher C, et al. Minimal residual disease and normalization of the bone marrow after long-term treatment with alpha-interferon2b in polycythemia vera. A report on molecular response patterns in seven patients in sustained complete hematological remission. Hematology. 2009;14(6):331–4. https://doi.org/10.1179/102453309x12473408860587.

    CAS  Article  PubMed  Google Scholar 

  77. Yacoub AMJ, Kosiorek HE, et al. Single-arm salvage therapy with pegylated interferon alfa-2a for patients with high-risk polycythemia vera or high-risk essential thrombocythemia who are either hydroxyurea-resistant or intolerant: final results of the myeloproliferative disorders-research consortium (MPD-RC) protocol 111 global phase II trial. Blood. 2017;130:321.

    Google Scholar 

  78. Masarova L, Patel KP, Newberry KJ, Cortes J, Borthakur G, Konopleva M, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165–75. https://doi.org/10.1016/s2352-3026(17)30030-3.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Masarova L, Yin CC, Cortes JE, Konopleva M, Borthakur G, Newberry KJ, et al. Histomorphological responses after therapy with pegylated interferon alpha-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Exp Hematol Oncol. 2017;6:30. https://doi.org/10.1186/s40164-017-0090-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Knudsen AT HD, Ocias LF, Bjerrum OW, Brabrand M, et al. Three-year analysis of the DALIAH trial - a randomized controlled phase III clinical trial comparing recombinant interferon alpha-2 vs. hydroxyurea in patients with myeloproliferative neoplasms. EHA learning center S1609. 2019.

  81. Mascarenhas JKH, Prchal J, Rambaldi A, et al. Results of the myeloproliferative neoplasms - research consortium (MPN-RC) 112 randomized trial of pegylated interferon alfa-2a (PEG) versus hydroxyurea (HU) therapy for the treatment of high risk polycythemia vera (PV) and high risk essential thrombocythemia (ET). Blood. 2018;132:577.

    Google Scholar 

  82. • Mikkelsen SU, Kjaer L, Bjorn ME, Knudsen TA, Sorensen AL, Andersen CBL, et al. Safety and efficacy of combination therapy of interferon-alpha2 and ruxolitinib in polycythemia vera and myelofibrosis. Cancer Med. 2018;7(8):3571–81. https://doi.org/10.1002/cam4.1619 Interesting study of combination of ruxolitinib and interferon in PV and MF.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. •• Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer. 2006;107(3):451–8. https://doi.org/10.1002/cncr.22026 Important study of interferon in PV.

    CAS  Article  PubMed  Google Scholar 

  84. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–72. https://doi.org/10.1182/blood-2008-03-143537.

    CAS  Article  PubMed  Google Scholar 

  85. Kiladjian JJ, Cassinat B, Turlure P, Cambier N, Roussel M, Bellucci S, et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood. 2006;108(6):2037–40. https://doi.org/10.1182/blood-2006-03-009860.

    CAS  Article  PubMed  Google Scholar 

  86. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, et al. Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126(15):1762–9. https://doi.org/10.1182/blood-2015-04-637280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Gisslinger HB-AV, Josef Thaler J, Forjan E, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera – final phase I/II Peginvera Study results. Blood. 2018;132:3030.

    Google Scholar 

  88. •• Gisslinger HKC, Georgiev P, et al. Evidence for superior efficacy and disease modification after three years of prospective randomized controlled treatment of polycythemia vera patients with ropeginterferon alfa-2b vs. HU/BAT. Blood. 2018;130:579 Important study showing superiority of long term monopegylated interferon to hydrea.

  89. Gisslinger HKC, Georgiev P, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients. Blood. 2016;128(22):475.

    Google Scholar 

  90. Verger E, Cassinat B. Clinical and molecular response to interferon-alpha therapy in essential thrombocythemia patients with CALR mutations. 2015;126(24):2585–91. https://doi.org/10.1182/blood-2015-07-659060.

  91. Silver RT, Vandris K. Recombinant interferon alpha (rIFN alpha-2b) may retard progression of early primary myelofibrosis. Leukemia. 2009;23(7):1366–9. https://doi.org/10.1038/leu.2009.90.

    CAS  Article  PubMed  Google Scholar 

  92. Silver RT, Barel AC, Lascu E, Ritchie EK, Roboz GJ, Christos PJ, et al. The effect of initial molecular profile on response to recombinant interferon-alpha (rIFNalpha) treatment in early myelofibrosis. Cancer. 2017;123(14):2680–7. https://doi.org/10.1002/cncr.30679.

    CAS  Article  PubMed  Google Scholar 

  93. Ianotto JC, Kiladjian JJ, Demory JL, Roy L, Boyer F, Rey J, et al. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d'Etudes des Myelofibroses (GEM) and France Intergroupe des syndromes Myeloproliferatifs (FIM). Br J Haematol. 2009;146(2):223–5. https://doi.org/10.1111/j.1365-2141.2009.07745.x.

    CAS  Article  PubMed  Google Scholar 

  94. Ianotto JC, Chauveau A, Boyer-Perrard F, Gyan E, Laribi K, Cony-Makhoul P, et al. Benefits and pitfalls of pegylated interferon-alpha2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis: a French Intergroup of Myeloproliferative neoplasms (FIM) study. Haematologica. 2018;103(3):438–46. https://doi.org/10.3324/haematol.2017.181297.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Gisslinger HGB, Schalling M, Krejcy K, et al. Effect of Ropeginterferon alfa-2b in Prefibrotic primary myelofibrosis. Blood. 2018;132:3029.

    Google Scholar 

  96. Samuelsson J, Hasselbalch H, Bruserud O, Temerinac S, Brandberg Y, Merup M, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer. 2006;106(11):2397–405. https://doi.org/10.1002/cncr.21900.

    CAS  Article  PubMed  Google Scholar 

  97. Silver RT, Vandris K, Goldman JJ. Recombinant interferon-alpha may retard progression of early primary myelofibrosis: a preliminary report. Blood. 2011;117(24):6669–72. https://doi.org/10.1182/blood-2010-11-320069.

    CAS  Article  PubMed  Google Scholar 

  98. Turlure PCN, Roussel M, Bellucci S, et al. Complete hematological, molecular and histological remissions without cytoreductive treatment lasting after Pegylated-interferon α-2a (peg-IFNα-2a) therapy in polycythemia vera (PV): long term results of a phase 2 trial. Blood. 2011;118:280.

    Google Scholar 

  99. Knudsen ATHD, Ocias LF, Bjerrum OW, Brabrand M, et al. Long-term efficacy and safety of recombinant interferon Alpha-2 vs. hydroxyurea in polycythemia Vera: preliminary results from the three-year analysis of the Daliah trial - a randomized controlled phase III clinical trial. Blood. 2018;132:580.

    Google Scholar 

  100. Muller GW, Chen R, Huang SY, Corral LG, Wong LM, Patterson RT, et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett. 1999;9(11):1625–30.

    CAS  Article  PubMed  Google Scholar 

  101. Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother. 2009;58(7):1033–45. https://doi.org/10.1007/s00262-008-0620-4.

    CAS  Article  PubMed  Google Scholar 

  102. Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer. 2002;87(10):1166–72. https://doi.org/10.1038/sj.bjc.6600607.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Elliott MA, Mesa RA, Li CY, Hook CC, Ansell SM, Levitt RM, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;117(2):288–96.

    CAS  Article  PubMed  Google Scholar 

  104. Marchetti M, Barosi G, Balestri F, Viarengo G, Gentili S, Barulli S, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(3):424–31. https://doi.org/10.1200/jco.2004.08.160.

    CAS  Article  Google Scholar 

  105. Barosi G, Grossi A, Comotti B, Musto P, Gamba G, Marchetti M. Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2001;114(1):78–83.

    CAS  Article  PubMed  Google Scholar 

  106. Mesa RA, Elliott MA, Schroeder G, Tefferi A. Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc. 2004;79(7):883–9. https://doi.org/10.1016/s0025-6196(11)62154-x.

    CAS  Article  PubMed  Google Scholar 

  107. Thapaliya P, Tefferi A, Pardanani A, Steensma DP, Camoriano J, Wu W, et al. International working group for myelofibrosis research and treatment response assessment and long-term follow-up of 50 myelofibrosis patients treated with thalidomide-prednisone based regimens. Am J Hematol. 2011;86(1):96–8. https://doi.org/10.1002/ajh.21892.

    CAS  Article  PubMed  Google Scholar 

  108. Weinkove R, Reilly JT, McMullin MF, Curtin NJ, Radia D, Harrison CN. Low-dose thalidomide in myelofibrosis. Haematologica. 2008;93(7):1100–1. https://doi.org/10.3324/haematol.12416.

    CAS  Article  PubMed  Google Scholar 

  109. Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006;108(4):1158–64. https://doi.org/10.1182/blood-2006-02-004572.

    CAS  Article  PubMed  Google Scholar 

  110. Mesa RA, Yao X, Cripe LD, Li CY, Litzow M, Paietta E, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood. 2010;116(22):4436–8. https://doi.org/10.1182/blood-2010-05-287417.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Chihara D, Masarova L, Newberry KJ, Maeng H, Ravandi F, Garcia-Manero G, et al. Long-term results of a phase II trial of lenalidomide plus prednisone therapy for patients with myelofibrosis. Leuk Res. 2016;48:1–5. https://doi.org/10.1016/j.leukres.2016.06.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, Gisslinger H, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(27):4563–9. https://doi.org/10.1200/jco.2008.21.7356.

    CAS  Article  Google Scholar 

  113. Mesa RA, Pardanani AD, Hussein K, Wu W, Schwager S, Litzow MR, et al. Phase1/-2 study of Pomalidomide in myelofibrosis. Am J Hematol. 2010;85(2):129–30. https://doi.org/10.1002/ajh.21598.

    CAS  Article  PubMed  Google Scholar 

  114. Daver N, Shastri A, Kadia T, Newberry K, Pemmaraju N, Jabbour E, et al. Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia. Leuk Res. 2014;38(9):1126–9. https://doi.org/10.1016/j.leukres.2014.06.015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. Begna KH, Pardanani A, Mesa R, Litzow MR, Hogan WJ, Hanson CA, et al. Long-term outcome of pomalidomide therapy in myelofibrosis. Am J Hematol. 2012;87(1):66–8. https://doi.org/10.1002/ajh.22233.

    CAS  Article  PubMed  Google Scholar 

  116. Masarova LDN, Kadia T, Pemmaraju N, et al. Efficacy and safety of pomalidomide in combination with prednisone in patients with myelofibrosis and anemia — final results of a prospective phase 2 study. Blood. 2018;132:1764.

    Article  Google Scholar 

  117. Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2016. https://doi.org/10.1038/leu.2016.300.

  118. •• Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. https://doi.org/10.1056/NEJMoa1110557 COMFORT studies of ruxolitinib in patients with MF.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. •• Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98. https://doi.org/10.1056/NEJMoa1110556 COMFORT studies of ruxolitinib in patients with MF.

    CAS  Article  PubMed  Google Scholar 

  120. Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. https://doi.org/10.1186/s13045-017-0417-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. Passamonti FKJ, Vannucchi AM, Reiter A, et al. ReTHINK: a randomized, double-blind, placebo-controlled, multicenter, phase 3 study of ruxolitinib in early myelofibrosis patients. J Clin Oncol. 2016;34:TPS7080.

    Article  Google Scholar 

  122. Al-Ali HK, Griesshammer M, le Coutre P, Waller CF, Liberati AM, Schafhausen P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065–73. https://doi.org/10.3324/haematol.2016.143677.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7. https://doi.org/10.1038/leu.2016.148.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. •• Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35. https://doi.org/10.1056/NEJMoa1409002 RESPONSE studies of ruxolitinib in patients with PV.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. •• Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88–99. https://doi.org/10.1016/s1470-2045(16)30558-7 RESPONSE studies of ruxolitinib in patients with PV.

    CAS  Article  PubMed  Google Scholar 

  126. Kiladjian JJPZP, Hino M, Pane F, et al. Long-term efficacy and safety (5 years) in RESPONSE, a phase 3 study comparing ruxolitinib (rux) with best available therapy (BAT) in hydroxyurea (HU)-resistant/intolerant patients (pts) with polycythemia vera (PV). Blood. 2018;132:1753.

    Google Scholar 

  127. Passamonti FPF, Saydam G, Benevolo G, et al. Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 156-week follow-up from the phase 3 response-2 study. Blood. 2018;132:1754.

    Google Scholar 

  128. Foltz LPGM, Zerazhi H, Droogenbroeck JV, et al. Updated results from an open-label, multicenter, expanded treatment protocol (ETP) phase (Ph) 3b study of Ruxolitinib (RUX) in patients (pts) with polycythemia vera (PV) who were hydroxyurea (HU) resistant or intolerant and for whom no alternative treatment (Tx) was available. Blood. 2018;132:1774.

    Google Scholar 

  129. Mesa R, Vannucchi AM, Yacoub A, Zachee P, Garg M, Lyons R, et al. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. 2017;176(1):76–85. https://doi.org/10.1111/bjh.14382.

    CAS  Article  PubMed  Google Scholar 

  130. Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rumi E, Gattoni E, et al. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood. 2017;130(15):1768–71. https://doi.org/10.1182/blood-2017-02-765032.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889–97. https://doi.org/10.1182/blood-2017-05-785790.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11–9. https://doi.org/10.2147/jep.s110702.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225–e36. https://doi.org/10.1016/s2352-3026(17)30027-3.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652–9. https://doi.org/10.1001/jamaoncol.2017.5818.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823–30. https://doi.org/10.1182/blood-2016-09-740092.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(34):3844–50. https://doi.org/10.1200/jco.2017.73.4418.

    CAS  Article  Google Scholar 

  137. Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73–81. https://doi.org/10.1016/s2352-3026(17)30237-5.

    Article  PubMed  Google Scholar 

  138. Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643–51. https://doi.org/10.1001/jamaoncol.2015.1590.

    Article  PubMed  Google Scholar 

  139. Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317–e24. https://doi.org/10.1016/s2352-3026(17)30088-1.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Zhang Q, Zhang Y, Diamond S, Boer J, Harris JJ, Li Y, et al. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy. Drug Metab Dispos. 2014;42(10):1656–62. https://doi.org/10.1124/dmd.114.058883.

    Article  PubMed  Google Scholar 

  141. Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27. https://doi.org/10.1056/NEJMoa1002028.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Harrison CN, Mesa RA, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol. 2013;162(2):229–39. https://doi.org/10.1111/bjh.12375.

    CAS  Article  PubMed  Google Scholar 

  143. Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(10):1285–92. https://doi.org/10.1200/jco.2012.44.4489.

    CAS  Article  Google Scholar 

  144. Mesa RA, Shields A, Hare T, Erickson-Viitanen S, Sun W, Sarlis NJ, et al. Progressive burden of myelofibrosis in untreated patients: assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study. Leuk Res. 2013;37(8):911–6. https://doi.org/10.1016/j.leukres.2013.04.017.

    Article  PubMed  Google Scholar 

  145. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, phase III study in patients with myelofibrosis. Br J Haematol. 2013;161(4):508–16. https://doi.org/10.1111/bjh.12274.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. Mesa RA, Scherber RM, Geyer HL. Reducing symptom burden in patients with myeloproliferative neoplasms in the era of Janus kinase inhibitors. Leuk Lymphoma. 2015;56(7):1989–99. https://doi.org/10.3109/10428194.2014.983098.

    CAS  Article  PubMed  Google Scholar 

  147. Mesa RAVS, Gupta V, et al. Improvement in weight and total cholesterol and their association with survival in ruxolitinib-treated patients with myelofibrosis from COMFORT-I. Blood. 2012;120(21):1733.

    Google Scholar 

  148. Mascarenhas J, Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood. 2013;121(24):4832–7. https://doi.org/10.1182/blood-2013-02-482232.

    CAS  Article  PubMed  Google Scholar 

  149. Kvasnicka HM, Thiele J, Bueso-Ramos CE, Sun W, Cortes J, Kantarjian HM, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol. 2018;11(1):42. https://doi.org/10.1186/s13045-018-0585-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. Vannucchi AM, Verstovsek S, Guglielmelli P, Griesshammer M, Burn TC, Naim A, et al. Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study. Ann Hematol. 2017;96(7):1113–20. https://doi.org/10.1007/s00277-017-2994-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Deininger M, Radich J, Burn TC, Huber R, Paranagama D, Verstovsek S. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015;126(13):1551–4. https://doi.org/10.1182/blood-2015-03-635235.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Verstovsek SGV, Gotlib JR, et al. A pooled overall survival (OS) analysis of 5-year data from the COMFORT-I and COMFORT-II trials of ruxolitinib for the treatment of myelofibrosis (MF). Blood. 2016;128(22):3110–311.

    Google Scholar 

  153. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122(7):1192–202. https://doi.org/10.1182/blood-2013-03-484642.

    CAS  Article  PubMed  Google Scholar 

  154. Rudolph J, Heine A, Quast T, Kolanus W, Trebicka J, Brossart P, et al. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia. 2016;30(10):2119–23. https://doi.org/10.1038/leu.2016.155.

    CAS  Article  PubMed  Google Scholar 

  155. Massa M, Rosti V, Campanelli R, Fois G, Barosi G. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia. 2014;28(2):449–51. https://doi.org/10.1038/leu.2013.296.

    CAS  Article  PubMed  Google Scholar 

  156. Keohane C, Kordasti S, Seidl T, Perez Abellan P, Thomas NS, Harrison CN, et al. JAK inhibition induces silencing of T helper cytokine secretion and a profound reduction in T regulatory cells. Br J Haematol. 2015;171(1):60–73. https://doi.org/10.1111/bjh.13519.

    CAS  Article  PubMed  Google Scholar 

  157. Parampalli Yajnanarayana S, Stubig T, Cornez I, Alchalby H, Schonberg K, Rudolph J, et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol. 2015;169(6):824–33. https://doi.org/10.1111/bjh.13373.

    CAS  Article  PubMed  Google Scholar 

  158. Schonberg K, Rudolph J, Vonnahme M, Parampalli Yajnanarayana S, Cornez I, Hejazi M, et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res. 2015;75(11):2187–99. https://doi.org/10.1158/0008-5472.can-14-3198.

    Article  PubMed  Google Scholar 

  159. Colomba C, Rubino R, Siracusa L, Lalicata F, Trizzino M, Titone L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes. 2012;5:552. https://doi.org/10.1186/1756-0500-5-552.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest. 2013;143(5):1478–9. https://doi.org/10.1378/chest.12-1604.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia. 2014;28(1):225–7. https://doi.org/10.1038/leu.2013.235.

    CAS  Article  PubMed  Google Scholar 

  162. Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013;369(7):681–3. https://doi.org/10.1056/NEJMc1302895.

    CAS  Article  PubMed  Google Scholar 

  163. Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369(2):197–8. https://doi.org/10.1056/NEJMc1302135.

    CAS  Article  PubMed  Google Scholar 

  164. Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629–40.e2. https://doi.org/10.1016/j.jaci.2016.11.022.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. Porpaczy ETS, Hoelbl-Kovacic A, et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood. 2018;132(7):694–706. Blood. 2019;133(7):768. https://doi.org/10.1182/blood-2019-01-895136.

    CAS  Article  PubMed  Google Scholar 

  166. Pemmaraju N, Kantarjian H, Nastoupil L, Dupuis M, Zhou L, Pierce S, et al. Characteristics of patients with myeloproliferative neoplasms with lymphoma, with or without JAK inhibitor therapy. Blood. 2019. https://doi.org/10.1182/blood-2019-01-897637.

  167. Bjorn ME, de Stricker K, Kjaer L, Ellemann K, Hasselbalch HC. Combination therapy with interferon and JAK1-2 inhibitor is feasible: proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera. Leuk Res Rep. 2014;3(2):73–5. https://doi.org/10.1016/j.lrr.2014.05.003.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. •• Koschmieder S, Mughal TI, Hasselbalch HC, Barosi G, Valent P, Kiladjian JJ, et al. Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both. Leukemia. 2016;30(5):1018–24. https://doi.org/10.1038/leu.2016.12 Excellent review of immunological dysregulation in MPNs.

    CAS  Article  PubMed  Google Scholar 

  169. Kiladjian JJ, Soret-Dulphy J, Resche-Rigon M, et al. Ruxopeg, a multi-center Bayesian phase 1/2 adaptive randomized trial of the combination of ruxolitinib and pegylated interferon alpha 2a in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis. Blood. 2018;132:581.

    Google Scholar 

  170. Daver N, Cortes J, Newberry K, Jabbour E, Zhou L, Wang X, et al. Ruxolitinib in combination with lenalidomide as therapy for patients with myelofibrosis. Haematologica. 2015;100(8):1058–63. https://doi.org/10.3324/haematol.2015.126821.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. Rampal R VS, Devlin S, Stein E, et al. Early results of he phase II study of combined ruxolitinib and thalidomide in patients with myelofibrosis. EHA Learning Center PS1467. 2019.

  172. Masarova L, Verstovsek S, Kantarjian H, Daver N. Immunotherapy based approaches in myelofibrosis. Expert Rev Hematol. 2017;10(10):903–14. https://doi.org/10.1080/17474086.2017.1366853.

    CAS  Article  PubMed  Google Scholar 

  173. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.

    CAS  Article  PubMed  Google Scholar 

  174. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. https://doi.org/10.1038/nrc3239.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. https://doi.org/10.1038/nm730.

    CAS  Article  PubMed  Google Scholar 

  176. Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114(8):1528–36. https://doi.org/10.1182/blood-2008-09-179697.

    CAS  Article  PubMed  Google Scholar 

  177. Craig RTS, Deininger M, Salama ME. Programmed death ligand (PD-L1) expression is increased in spleens of myelofibrosis patients United States and Canadian Academy of 2016 Annual meeting, Abstract 1353.

  178. Lasho TFC, Kimlinger TK, Zblewski D, Chen D, Patnaik MM, Hanson CA, et al. Expression of CD123 (IL-3R-alpha), a therapeutic target of SL-401, on myeloproliferative neoplasms. Blood. 2014;124:5577.

    Google Scholar 

  179. Pemmaraju NAH, Gupta V, Schiller GJ, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate or high risk relapsed/refractory myelofibrosis. J Clin Oncol. 2019;37(15_suppl):7058.

    Google Scholar 

  180. Schischlik FJR, Rosebrock F, et al. Mutational landscape of the transcriptome offers a rich neoantigen resource for immunotherapy of myeloproliferative neoplasms. Blood. 2018;132:3058.

    Google Scholar 

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Correspondence to Lucia Masarova.

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Lucia Masarova reports no conflict of interest.

Prithviraj Bose reports research support from Incyte Corp., Celgene, Astellas, Pfizer, Blueprint Pharmaceuticals, Kartos Therapeutics, Constellation Pharmaceuticals, CTI BioPharma, NS Pharma, and Promedior, and honoraria from Incyte Corp., Celgene, and Blueprint Pharmaceuticals.

Srdan Verstovsek reports research support and grants from Incyte Corp.

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Masarova, L., Bose, P. & Verstovsek, S. The Rationale for Immunotherapy in Myeloproliferative Neoplasms. Curr Hematol Malig Rep 14, 310–327 (2019). https://doi.org/10.1007/s11899-019-00527-7

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Keywords

  • Interferon
  • JAK inhibitors
  • Immunotherapy
  • Myeloproliferative neoplasms