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Novel Therapies in Myeloproliferative Neoplasms (MPN): Beyond JAK Inhibitors

Abstract

Purpose of Review

With increased understanding of the pathobiology of myeloproliferative neoplasms (MPNs), multiple new agents are now being investigated. We aim to cover some of the current treatment options for MPNs and discuss new agents in development.

Recent Findings

The introduction of ruxolitinib improved the treatment of many patients with intermediate and higher risk myelofibrosis. However, ruxolitinib monotherapy does not benefit all patients, and not all patients can receive this therapy due to limiting cytopenias. The unraveling of new molecular abnormalities and cellular pathways led to the development of several novel targeted agents that are currently under investigation in clinical trials. These agents have different mechanisms of action and are being used either alone or in combination with ruxolitinib.

Summary

Novel targets include inhibition of apoptosis, the tumor microenvironment, telomerase enzyme action, immunotherapy, and fibrosis with associated cytokines. We comprehensively review and summarize the available preclinical and clinical trials with novel agents for MPNs.

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References

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

  1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372–5.

    PubMed  CAS  Article  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    PubMed  CAS  Article  Google Scholar 

  3. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.

    PubMed  CAS  Article  Google Scholar 

  4. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.

    PubMed  CAS  Article  Google Scholar 

  5. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.

    PubMed  CAS  Article  Google Scholar 

  6. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  8. 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.

    PubMed  CAS  Article  Google Scholar 

  9. Rampal R, Al-Shahrour F, Abdel-Wahab O, Patel JP, Brunel JP, Mermel CH, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014;123(22):e123–33.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 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.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  11. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 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.

    PubMed  Article  Google Scholar 

  13. Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood. 2017;129(7):832–7.

    PubMed  CAS  Article  Google Scholar 

  14. Boddu P, Masarova L, Verstovsek S, Strati P, Kantarjian H, Cortes J, et al. Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. Ann Hematol. 2018;97(1):109–21.

    PubMed  Article  Google Scholar 

  15. Stein BL, Saraf S, Sobol U, Halpern A, Shammo J, Rondelli D, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma. 2013;54(9):1989–95.

    PubMed  CAS  Article  Google Scholar 

  16. 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.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  17. 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.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  18. Patel KP, Newberry KJ, Luthra R, Jabbour E, Pierce S, Cortes J, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790–7.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  19. Mead AJ, Milojkovic D, Knapper S, Garg M, Chacko J, Farquharson M, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST trial. Br J Haematol. 2015;170(1):29–39.

    PubMed  CAS  Article  Google Scholar 

  20. Davis KL, Cote I, Kaye JA, Mendelson E, Gao H, Perez RJ. Real-world assessment of clinical outcomes in patients with lower-risk myelofibrosis receiving treatment with ruxolitinib. Adv Hematol. 2015;2015:848473.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 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.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  22. Palandri F, Palumbo GA, Bonifacio M, Tiribelli M, Benevolo G, Martino B, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073–86.

    PubMed  PubMed Central  Article  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125–31.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  25. Kuykendall AT, Shah S, Talati C, Al Ali N, Sweet K, Padron E, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435–41.

    PubMed  CAS  Article  Google Scholar 

  26. Fleischman AG, Aichberger KJ, Luty SB, Bumm TG, Petersen CL, Doratotaj S, et al. TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011;118(24):6392–8.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  27. Heaton WL, Senina AV, Pomicter AD, Salama ME, Clair PM, Yan D, et al. Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion. Leukemia. 2018;32(11):2399–411.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  28. 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. 2011;29(10):1356–63.

    PubMed  CAS  Article  Google Scholar 

  29. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131(4):669–81.

    PubMed  CAS  Article  Google Scholar 

  30. Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell. 2007;12(5):445–56.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  31. Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, et al. Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-kappaB activation, and is active in patient-derived xenograft models. Mol Cancer Ther. 2014;13(4):867–79.

    PubMed  CAS  Article  Google Scholar 

  32. Carter BZ, Mak DH, Morris SJ, Borthakur G, Estey E, Byrd AL, et al. XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34+38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis. 2011;16(1):67–74.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  33. Weisberg E, Ray A, Barrett R, Nelson E, Christie AL, Porter D, et al. Smac mimetics: implications for enhancement of targeted therapies in leukemia. Leukemia. 2010;24(12):2100–9.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. •• Pemmaraju NCZ, Kantarjian H, Cortes JE, Kadia TM, Garcia-Manero G, DiNardo C, et al. LCL161, an oral smac mimetic/IAP antagonist for patients with myelofibrosis (MF): novel translational findings among long-term responders in a phase 2 clinical Trial. Blood. 2018;132(1):687. LCL 161 is an investiation agent that works by promoting apoptosis and was found to have promising efficacy and safety profile in patients with myelofibrosis.

    Article  Google Scholar 

  35. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677–81.

    PubMed  CAS  Article  Google Scholar 

  36. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–53.

    PubMed  CAS  Article  Google Scholar 

  37. Rivenbark AG, Coleman WB. Field cancerization in mammary carcinogenesis - implications for prevention and treatment of breast cancer. Exp Mol Pathol. 2012;93(3):391–8.

    PubMed  CAS  Article  Google Scholar 

  38. Munkley J, Vodak D, Livermore KE, James K, Wilson BT, Knight B, et al. Glycosylation is an androgen-regulated process essential for prostate cancer cell viability. EBioMedicine. 2016;8:103–16.

    PubMed  PubMed Central  Article  Google Scholar 

  39. Bullinger L, Dohner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934–46.

    PubMed  CAS  Article  Google Scholar 

  40. Gravina GL, Senapedis W, McCauley D, Baloglu E, Shacham S, Festuccia C. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7:85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27(12):2357–65.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  42. Tan DS, Bedard PL, Kuruvilla J, Siu LL, Razak AR. Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. Cancer Discov. 2014;4(5):527–37.

    PubMed  CAS  Article  Google Scholar 

  43. Garnache-Ottou F, Feuillard J, Ferrand C, Biichle S, Trimoreau F, Seilles E, et al. Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia. Br J Haematol. 2009;145(5):624–36.

    PubMed  CAS  Article  Google Scholar 

  44. Elliott MA, Verstovsek S, Dingli D, Schwager SM, Mesa RA, Li CY, et al. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leuk Res. 2007;31(11):1503–9.

    PubMed  CAS  Article  Google Scholar 

  45. Frankel AE, Ramage J, Kiser M, Alexander R, Kucera G, Miller MS. Characterization of diphtheria fusion proteins targeted to the human interleukin-3 receptor. Protein Eng. 2000;13(8):575–81.

    PubMed  CAS  Article  Google Scholar 

  46. Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628–37.

    PubMed  CAS  Article  Google Scholar 

  47. Pemmaraju N, Gupta V, Schiller GJ, Lee S, Yacoub A, Ali H, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate or high risk relapsed/refractory myelofibrosis. Blood. 2018;132(1):1773.

    Article  Google Scholar 

  48. Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res. 2012;18(1):64–76.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  49. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425(6956):407–10.

    PubMed  CAS  Article  Google Scholar 

  50. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005;280(29):26729–34.

    PubMed  CAS  Article  Google Scholar 

  51. Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009;114(24):5024–33.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  52. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31.

    PubMed  CAS  Article  Google Scholar 

  53. Chen J, Wu X, Lin J, Levine AJ. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol Cell Biol. 1996;16(5):2445–52.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  54. Reis B, Jukofsky L, Chen G, Martinelli G, Zhong H, So WV, et al. Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica. 2016;101(5):e185–8.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  55. Thiele J, Kvasnicka HM. Grade of bone marrow fibrosis is associated with relevant hematological findings-a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann Hematol. 2006;85(4):226–32.

    PubMed  CAS  Article  Google Scholar 

  56. Vener C, Fracchiolla NS, Gianelli U, Calori R, Radaelli F, Iurlo A, et al. Prognostic implications of the European consensus for grading of bone marrow fibrosis in chronic idiopathic myelofibrosis. Blood. 2008;111(4):1862–5.

    PubMed  CAS  Article  Google Scholar 

  57. 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.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  58. Groopman JE. The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med. 1980;92(6):857–8.

    PubMed  CAS  Article  Google Scholar 

  59. Verstovsek S, Manshouri T, Pilling D, Bueso-Ramos CE, Newberry KJ, Prijic S, et al. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med. 2016;213(9):1723–40.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  60. Nakagawa N, Barron L, Gomez IG, Johnson BG, Roach AM, Kameoka S, et al. Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease. JCI Insight. 2016;1(20):e87446.

    PubMed  PubMed Central  Article  Google Scholar 

  61. Le Bousse-Kerdiles MC, Martyre MC. Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis. Ann Hematol. 1999;78(10):437–44.

    PubMed  Article  Google Scholar 

  62. Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V, Hoffman R. Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol. 2013;41(2):155–66 e17.

    PubMed  CAS  Article  Google Scholar 

  63. Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol. 2014;165(6):870–82.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  64. Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med. 2014;20(4):398–407.

    PubMed  CAS  Article  PubMed Central  Google Scholar 

  65. Ear J, Huang H, Wilson T, Tehrani Z, Lindgren A, Sung V, et al. RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1. Blood. 2015;126(7):880–90.

    PubMed  CAS  Article  Google Scholar 

  66. Langdon JM, Barkataki S, Berger AE, Cheadle C, Xue QL, Sung V, et al. RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice. Am J Hematol. 2015;90(1):8–14.

    PubMed  CAS  Article  Google Scholar 

  67. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408–14.

    PubMed  CAS  Article  Google Scholar 

  68. Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338–47.

    PubMed  CAS  Article  Google Scholar 

  69. • Fenaux PPU, Mufti GJ, Garcia-Manero-G, Buckstein R, Santini V, Diez-Campelo M, et al. The medalist trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (rs) who require red blood cell (RBC) transfusions. Blood. 2018;132(1):1. Luspatercept is an investigational erythroid maturation agent that decreases red blood cell transfusion requirements when compared with placebo in patients with myelodysplastic syndromes.

    Article  Google Scholar 

  70. Wen QJ, Yang Q, Goldenson B, Malinge S, Lasho T, Schneider RK, et al. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med. 2015;21(12):1473–80.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. Gangat N, Marinaccio C, Swords R, Watts JM, Gurbuxani S, Rademaker A, et al. Aurora kinase a inhibition provides clinical benefit, normalizes megakaryocytes and reduces bone marrow fibrosis in patients with myelofibrosis. Clin Cancer Res. 2019.

  72. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011–5.

    PubMed  CAS  Article  Google Scholar 

  73. Chiappori AA, Kolevska T, Spigel DR, Hager S, Rarick M, Gadgeel S, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol. 2015;26(2):354–62.

    PubMed  CAS  Article  Google Scholar 

  74. Roth A, Harley CB, Baerlocher GM. Imetelstat (GRN163L)--telomerase-based cancer therapy. Recent Results Cancer Res. 2010;184:221–34.

    PubMed  Article  CAS  Google Scholar 

  75. Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, et al. Telomerase inhibitor Imetelstat in patients with essential thrombocythemia. N Engl J Med. 2015;373(10):920–8.

    PubMed  CAS  Article  Google Scholar 

  76. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A pilot study of the telomerase inhibitor Imetelstat for myelofibrosis. N Engl J Med. 2015;373(10):908–19.

    PubMed  CAS  Article  Google Scholar 

  77. Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012;12(7):465–77.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  78. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54(5):728–36.

    PubMed  CAS  Article  Google Scholar 

  79. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–34.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  80. Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell. 2015;58(2):362–70.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  81. Roe JS, Mercan F, Rivera K, Pappin DJ, Vakoc CR. BET bromodomain inhibition suppresses the function of hematopoietic transcription factors in acute myeloid leukemia. Mol Cell. 2015;58(6):1028–39.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  82. Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res. 2015;21(7):1628–38.

    PubMed  CAS  Article  Google Scholar 

  83. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13(5):337–56.

    PubMed  CAS  Article  Google Scholar 

  84. Fiskus W, Sharma S, Qi J, Shah B, Devaraj SG, Leveque C, et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014;13(10):2315–27.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  85. Dawson MA, Gudgin EJ, Horton SJ, Giotopoulos G, Meduri E, Robson S, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2):311–20.

    PubMed  CAS  Article  Google Scholar 

  86. Saenz DT, Fiskus W, Manshouri T, Rajapakshe K, Krieger S, Sun B, et al. BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells. Leukemia. 2017;31(3):678–87.

    PubMed  CAS  Article  Google Scholar 

  87. • Fiskus W, Cai T, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;9(2):4. Bromodomain inhibition is a new target in cancer therapy. Bromodomain inhibitor in combination with BCL2 inhibitor was highly effective in AML cells.

    PubMed  PubMed Central  Article  Google Scholar 

  88. Mesa RA, Miller CB, Thyne M, Mangan J, Goldberger S, Fazal S, et al. Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: findings from the MPN landmark survey. Cancer. 2017;123(3):449–58.

    PubMed  Article  Google Scholar 

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Funding

This research is supported in part by the M. D. Anderson Cancer Center Support Grant P30 CA016672.

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Correspondence to Naveen Pemmaraju.

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Minas P. Economides declares no conflict of interest.

Srdan Verstovsek declares the following: Consulting/honorarium from Constellation, Pragmatist, Sierra, Incyte Corporation, Novartis, and Celgene. Research funding/clinical trials support from Incyte Corporation, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma Corp., Genentech, Blueprint Medicines Corp., and Novartis.

Naveen Pemmaraju declares the following: Consulting/honorarium from Celgene, Stemline, Incyte Corporation, Novartis, MustangBio, Roche Diagnostics, and LFB. Research funding/clinical trials support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and SagerStrong Foundation.

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Economides, M.P., Verstovsek, S. & Pemmaraju, N. Novel Therapies in Myeloproliferative Neoplasms (MPN): Beyond JAK Inhibitors. Curr Hematol Malig Rep 14, 460–468 (2019). https://doi.org/10.1007/s11899-019-00538-4

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  • DOI: https://doi.org/10.1007/s11899-019-00538-4

Keywords

  • Ruxolitinib
  • Myeloproliferative neoplasms
  • Novel therapies
  • JAK inhibitors
  • Novel drugs