Current Hematologic Malignancy Reports

, Volume 14, Issue 5, pp 460–468 | Cite as

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

  • Minas P. Economides
  • Srdan Verstovsek
  • Naveen PemmarajuEmail author
Myeloproliferative Neoplasms (B Stein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Myeloproliferative Neoplasms


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.


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.


Ruxolitinib Myeloproliferative neoplasms Novel therapies JAK inhibitors Novel drugs 



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

Compliance with Ethical Standards

Conflict of Interest

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.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372–5.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.PubMedPubMedCentralGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedPubMedCentralGoogle Scholar
  6. 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.PubMedPubMedCentralGoogle Scholar
  7. 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.PubMedPubMedCentralGoogle Scholar
  8. 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.PubMedPubMedCentralGoogle Scholar
  9. 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.PubMedPubMedCentralGoogle Scholar
  10. 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.PubMedPubMedCentralGoogle Scholar
  11. 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.PubMedPubMedCentralGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 13.
    Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood. 2017;129(7):832–7.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedPubMedCentralGoogle Scholar
  17. 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.PubMedPubMedCentralGoogle Scholar
  18. 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.PubMedPubMedCentralGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedPubMedCentralGoogle Scholar
  21. 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.PubMedPubMedCentralGoogle Scholar
  22. 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.PubMedPubMedCentralGoogle Scholar
  23. 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.Google Scholar
  24. 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.PubMedPubMedCentralGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedPubMedCentralGoogle Scholar
  27. 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.PubMedPubMedCentralGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedPubMedCentralGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedPubMedCentralGoogle Scholar
  33. 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.PubMedPubMedCentralGoogle Scholar
  34. 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. Google Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Bullinger L, Dohner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934–46.PubMedGoogle Scholar
  40. 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.PubMedPubMedCentralGoogle Scholar
  41. 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.PubMedPubMedCentralGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.Google Scholar
  48. 48.
    Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res. 2012;18(1):64–76.PubMedPubMedCentralGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31.PubMedGoogle Scholar
  53. 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.PubMedPubMedCentralGoogle Scholar
  54. 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.PubMedPubMedCentralGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Groopman JE. The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med. 1980;92(6):857–8.PubMedGoogle Scholar
  59. 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.PubMedPubMedCentralGoogle Scholar
  60. 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.PubMedPubMedCentralGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.PubMedPubMedCentralGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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. Google Scholar
  70. 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.PubMedPubMedCentralGoogle Scholar
  71. 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.Google Scholar
  72. 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.PubMedGoogle Scholar
  73. 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.PubMedGoogle Scholar
  74. 74.
    Roth A, Harley CB, Baerlocher GM. Imetelstat (GRN163L)--telomerase-based cancer therapy. Recent Results Cancer Res. 2010;184:221–34.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 77.
    Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012;12(7):465–77.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54(5):728–36.PubMedGoogle Scholar
  79. 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.PubMedPubMedCentralGoogle Scholar
  80. 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.PubMedPubMedCentralGoogle Scholar
  81. 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.PubMedPubMedCentralGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 83.
    Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13(5):337–56.PubMedGoogle Scholar
  84. 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.PubMedPubMedCentralGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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. PubMedPubMedCentralGoogle Scholar
  88. 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.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Minas P. Economides
    • 1
  • Srdan Verstovsek
    • 2
  • Naveen Pemmaraju
    • 2
    Email author
  1. 1.Department of Internal MedicineThe University of Texas School of Health Sciences at HoustonHoustonUSA
  2. 2.Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonUSA

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