581
Views
9
CrossRef citations to date
0
Altmetric
Review

Investigational Janus kinase inhibitors in development for myelofibrosis

, &
Pages 723-734 | Received 27 Feb 2017, Accepted 24 Apr 2017, Published online: 08 May 2017

References

  • Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000 Apr 27;342(17):1255–1265.
  • Mehta J, Wang H, Iqbal SU, et al. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014 Mar;55(3):595–600.
  • Cervantes F, Dupriez B, Passamonti F, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol. 2012 Aug 20;30(24):2981–2987.
  • Hernandez-Boluda JC, Pereira A, Gomez M, et al. The international prognostic scoring system does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis. Haematologica. 2014 Apr;99(4):e55–7.
  • Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 19-25;365(9464):1054–1061.
  • James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144–1148.
  • Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005 Apr;7(4):387–397.
  • Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779–1790.
  • Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014 Jul;28(7):1472–1477.
  • Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014 Aug 14;124(7):1062–1069.
  • Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Plos Med. 2006 Jul;3(7):e270.
  • Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006 Nov 15;108(10):3472–3476.
  • Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379–2390.
  • Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013 Dec 19;369(25):2391–2405.
  • Elf S, Abdelfattah NS, Chen E, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016 Apr;6(4):368–381.
  • Verstovsek S, Mesa RA, Gotlib J, 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 May;161(4):508–516.
  • Anand S, Stedham F, Gudgin E, et al. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood. 2011 Aug 11;118(6):1610–1621.
  • Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014 May 29;123(22):e123–33.
  • van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508–519.
  • Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016 Mar 31;374(13):1243–1252.
  • Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017 Feb 16;376(7):652–662.
  • Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799–807.
  • Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787–798.
  • Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013 Dec 12;122(25):4047–4053.
  • Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 100(9):1139–1145.
  • Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs. best available therapy for myelofibrosis. Leukemia. 2017 Mar;31(3):775.
  • Verstovsek S, Mesa RA, Gotlib J, 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 Feb 22;10(1):55,017-0417-z.
  • Deininger M, Radich J, Burn TC, et al. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015 Sep 24;126(13):1551–1554.
  • Barosi G, Zhang MJ, Peter Gale R. Does ruxolitinib improve survival of persons with MPN-associated myelofibrosis? Should it? Leukemia. 2014 Nov;28(11):2267–2270.
  • Mascarenhas J, Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood. 2013 Jun 13;121(24):4832–4837.
  • Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010 Sep 16;363(12):1117–1127.
  • Tefferi A, Vaidya R, Caramazza D, et al. 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 Apr 1;29(10):1356–1363.
  • Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res. 2014 Apr 15;20(8):2051–2059.
  • Birgegard G. Does anything work for anaemia in myelofibrosis? Best Pract Res Clin Haematol. 2014 Jun;27(2):175–185.
  • Singer JW, Al-Fayoumi S, Ma H, et al. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive janus kinase 2 inhibitor. J Exp Pharmacol. 2016 Aug 16;8:11–19.
  • Verstovsek S, Odenike O, Singer JW, et al. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J Hematol Oncol. 2016 Dec 8;9(1):137.
  • Mesa RA, Schwager S, Radia D, et al. The myelofibrosis symptom assessment form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009 Sep;33(9):1199–1203.
  • Komrokji RS, Seymour JF, Roberts AW, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood. 2015 Apr 23;125(17):2649–2655.
  • Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996 Aug 1;88(3):1013–1018.
  • Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. 2015;33:LBA7006.
  • Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (international working group for myeloproliferative neoplasms research and treatment). Blood. 2010 Mar 4;115(9):1703–1708.
  • Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012 Nov 20;30(33):4098–4103.
  • Gale RP, Barosi G, Barbui T, et al. What are RBC-transfusion-dependence and -independence? Leuk Res. 2011 Jan;35(1):8–11.
  • Vannucchi AM, Mesa RA, Cervantes F, et al. Analysis of outcomes by patient subgroups in patients with myelofibrosis treated with pacritinib vs. best available therapy (BAT) in the phase III persist-1 trial. Blood. 2015;126(23):58.
  • Mesa RA, Egyed M, Szoke A, et al. Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): 60 week follow-up of the phase III PERSIST-1 trial. J Clin Oncol. 2016;34:7065.
  • Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Blood. 2016;128:LBA–5.
  • CTI BioPharma provides update on clinical hold of investigational agent pacritinib and new drug application in U.S. [Internet]. Seattle, WA. 2016. [updated 2016 Feb 9; cited 2017 Feb 21]. Available from: http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=RssLanding&cat=news&id=2137027
  • CTI BioPharma announces removal of full clinical hold on pacritinib [Internet].; 2017 [updated 2016 Aug 29; cited 2016 Aug 29]. Available from: http://www.prnewswire.com/news-releases/cti-biopharma-announces-removal-of-full-clinical-hold-on-pacritinib-300386115.html.
  • Tyner JW, Bumm TG, Deininger J, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010 Jun 24;115(25):5232–5240.
  • Pardanani A, Lasho T, Smith G, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009 Aug;23(8):1441–1445.
  • Pardanani A, Gotlib JR, Gupta V, et al. Update on the long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. Blood. 2013;122:108.
  • Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the international working group for myelofibrosis research and treatment. Blood. 2009 Mar 26;113(13):2895–2901.
  • Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013 Jun;27(6):1322–1327.
  • Tefferi A, Barosi G, Mesa RA, et al. International working group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for myelofibrosis research and treatment (IWG-MRT). Blood. 2006 Sep 1;108(5):1497–1503.
  • Abdelrahman RA, Begna KH, Al-Kali A, et al. Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. Br J Haematol. 2015 Apr;169(1):77–80.
  • Pardanani A, Abdelrahman RA, Finke C, et al. Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis. Leukemia. 2015 Mar;29(3):741–744.
  • Tefferi A, Barraco D, Lasho TL, et al. Momelotinib therapy in myelofibrosis: 6-years follow-up data on safety, efficacy and the impact of mutations on overall and relapse-free survival. Blood. 2016;128:1123.
  • Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014 Apr 3;123(14):2157–2160.
  • Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015 Aug 6;126(6):790–797.
  • Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013 Sep;27(9):1861–1869.
  • Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014 Jul;28(7):1494–1500.
  • Tefferi A, Lasho TL, Finke C, et al. Type 1 vs. type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia. 2014 Jul;28(7):1568–1570.
  • Guglielmelli P, Rotunno G, Fanelli T, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J. 2015 Oct 16;5:e360.
  • Gupta V, Mesa RA, Deininger MW, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017 Jan;102(1):94–102.
  • Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: international working group-myeloproliferative neoplasms research and treatment (IWG-MRT) and European Leukemia Net (ELN) consensus report. Blood. 2013 Aug 22;122(8):1395–1398.
  • Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production and ameliorates anemia of chronic disease in rodents. Blood. 2017 Mar 30;129(13):1823–1830.
  • Bose P, Daver N, Jabbour EJ, et al. Phase-2 study of sotatercept (ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia. Blood. 2016;128:478.
  • Gilead announces top-line results from two phase 3 studies evaluating momelotinib for patients with myelofibrosis [Internet]. Foster City, CA. 2016. [updated 2016 Nov 16; cited 2017 Jan 6]. Available from: http://www.gilead.com/news/press-releases/2016/11/gilead-announces-topline-results-from-two-phase-3-studies-evaluating-momelotinib-for-patients-with-myelofibrosis
  • Nakaya Y, Shide K, Niwa T, et al. Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J. 2011 Jul;1(7):e29.
  • Nakaya Y, Shide K, Naito H, et al. Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis. Blood Cancer J. 2014 Jan 10;4:e174.
  • Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017 Feb;31(2):393–402.
  • Verstovsek S, Talpaz M, Ritchie EK, et al. Phase 1/2 study of NS-018, an oral JAK2 inhibitor, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). Blood. 2016;128:1936.
  • Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998 May 1;93(3):385–395.
  • Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789–796.
  • Tefferi A. Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms. N Engl J Med. 2012 Mar 1;366(9):844–846.
  • Mascarenhas JO, Talpaz M, Gupta V, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017 Feb;102(2):327–335.
  • Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015 Aug;1(5):643–651.
  • Verstovsek S, Hoffman R, Mascarenhas J, et al. A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis. Leuk Res. 2015 Feb;39(2):157–163.
  • Verstovsek S, Tam CS, Wadleigh M, et al. Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor. Leuk Res. 2014 Mar;38(3):316–322.
  • Hexner EO, Mascarenhas J, Prchal J, et al. Phase I dose escalation study of lestaurtinib in patients with myelofibrosis. Leuk Lymphoma. 2015;56(9):2543–2551.
  • Verstovsek S, Mesa RA, Salama ME, et al. Phase I study of LY2784544, a JAK2 selective inhibitor, in patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Blood. 2013;122(21):665.
  • Pardanani A, Roberts AW, Seymour JF, et al. BMS-911543, a selective JAK2 inhibitor: a multicenter phase 1/2a study in myelofibrosis. Blood. 2013;122(21):664.
  • Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity. 2012 Apr 20;36(4):503–514.
  • Zhang Q, Zhang Y, Diamond S, 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 Oct;42(10):1656–1662.
  • Kretz A, Happold CJ, Marticke JK, et al. Erythropoietin promotes regeneration of adult CNS neurons via JAK2/STAT3 and PI3K/AKT pathway activation. Mol Cell Neurosci. 2005 Aug;29(4):569–579.
  • Weng Z, Signore AP, Gao Y, et al. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem. 2007 Nov 23;282(47):34479–34491.
  • Mesa RA, Komrokji RS, Verstovsek S. Ruxolitinib dose management as a key to long-term treatment success. Int J Hematol. 2016 Oct;104(4):420–429.
  • Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016 Dec;101(12):e482–4.
  • Langdon JM, Barkataki S, Berger AE, et al. RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice. Am J Hematol. 2015 Jan;90(1):8–14.
  • Pardanani A, Finke C, Abdelrahman RA, et al. Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. Am J Hematol. 2013 Apr;88(4):312–316.
  • Tam CS, Kantarjian H, Cortes J, et al. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol. 2009 Nov 20;27(33):5587–5593.
  • Verstovsek S, Mesa RA, Foltz LM, et al. Phase 2 trial of PRM-151, an anti-fibrotic agent, in patients with myelofibrosis: stage 1 results. Blood. 2014;124:713.
  • Verstovsek S, Mesa RA, Foltz LM, et al. PRM-151 in myelofibrosis: durable efficacy and safety at 72 weeks. Blood. 2015;126(23):56.
  • Pemmaraju N, Carter BZ, Kantarjian HM, et al. Results for phase II clinical trial of LCL161, a SMAC mimetic, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocytosis myelofibrosis (post-ET MF). Blood. 2016;128:3105.
  • Mesa RA, Gotlib J, Gupta V, 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. 2013 Apr 1;31(10):1285–1292.
  • Andraos R, Qian Z, Bonenfant D, et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov. 2012 Jun;2(6):512–523.
  • Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012 Sep 6;489(7414):155–159.
  • Meyer SC, Keller MD, Chiu S, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell. 2015 Jul 13;28(1):15–28.
  • Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001 Aug 3;293(5531):876–880.
  • Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286–2294.
  • Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017 Mar 30;543(7647):733–737.
  • Neuman LL, Ward R, Arnold D, et al. First-in-human phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of the noncovalent Bruton tyrosine kinase (BTK) inhibitor SNS-062 in healthy subjects. Blood. 2016;128:2032.
  • Durrant S, Nagler A, Vannucchi AM, et al. An open-label, multicenter, 2-arm, dose-finding, phase 1b study of the combination of ruxolitinib and buparlisib (BKM120) in patients with myelofibrosis: results from HARMONY study. Blood. 2015;126(23):827.
  • Gupta V, Harrison CN, Hasselbalch HC, et al. Phase 1b/2 study of the efficacy and safety of sonidegib (LDE225) in combination with ruxolitinib (INC424) in patients with myelofibrosis. Blood. 2015;126(23):825.
  • Harrison CN, Kiladjian JJ, Heidel FH, et al. Efficacy, safety, and confirmation of the recommended phase 2 starting dose of the combination of ruxolitinib (RUX) and panobinostat (PAN) in patients (pts) with myelofibrosis (MF). Blood. 2015;126(23):4060.
  • Daver N, Cortes JE, Pemmaraju N, et al. Ruxolitinib (RUX) in combination with 5-azacytidine (AZA) as therapy for patients (pts) with myelofibrosis (MF). Blood. 2016;128:1127.
  • Moyo TK, Sochacki A, Ayers GD, et al. Preliminary results from a phase I dose escalation trial of ruxolitinib and the PI3Kδ inhibitor TGR-1202 in myelofibrosis. Blood. 2016;128:1125.
  • Bhagwat N, Koppikar P, Keller M, et al. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014 Mar 27;123(13):2075–2083.
  • Marubayashi S, Koppikar P, Taldone T, et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010 Oct;120(10):3578–3593.
  • Weigert O, Lane AA, Bird L, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012 Feb 13;209(2):259–273.
  • Rampal R, Pinzon-Ortiz M, Varshini HSA, et al. Synergistic therapeutic efficacy of combined JAK1/2, pan-PIM, and CDK4/6 inhibition in myeloproliferative neoplasms. Blood. 2016;128(22):634.
  • Yan D, Tantravahi SK, Pomicter AD, et al. Selective inhibition of nuclear cytoplasmic transport as a new treatment paradigm in myelofibrosis. Blood. 2016;128(22):636.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.