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Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 6/2017

01-12-2017 | Myeloproliferative Neoplasms (B Stein, Section Editor)

Novel Therapies for Myelofibrosis

Authors: Kristen Pettit, Olatoyosi Odenike

Published in: Current Hematologic Malignancy Reports | Issue 6/2017

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Abstract

Purpose of Review

The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.

Recent Findings

Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents.

Summary

Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
Literature
1.
Mesa RA, Kiladjian JJ, Verstovsek S, Al-Ali HK, Gotlib J, Gisslinger H, et al. Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica. 2014;99(2):292–8.PubMedPubMedCentralCrossRef
2.
Mesa R, Miller CB, Thyne M, Mangan J, Goldberger S, Fazal S, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey. BMC Cancer. 2016;16:167.PubMedPubMedCentralCrossRef
3.
Geyer HL, Andreasson B, Kosiorek HE, Dueck AC, Scherber RM, Martin KA, et al. The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: an analysis by the MPN QOL International Study Group. Cancer. 2016;122(12):1888–96.PubMedCrossRef
4.
• Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7. This paper identifies high-risk molecular mutations in MF.PubMedCrossRef
5.
• 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. This paper identifies prognostic implications of driver mutations in PMF.PubMedPubMedCentralCrossRef
6.
Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667–79.PubMedCrossRef
7.
Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. American J Hematol. 1999;61(1):10–5.CrossRef
8.
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.PubMedPubMedCentralCrossRef
9.
• Verstovsek S, Mesa RA, Gotlib J, Gupta V, JF DP, 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. This paper provides a 5-year follow-up of experience with ruxolitinib on the COMFORT-1 trial in MF underscoring both ongoing benefitin some patients as well as the fact that majority of patients are off therapy at 5 years.PubMedPubMedCentralCrossRef
10.
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7.PubMedCrossRef
11.
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, 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;115(9):1703–8.PubMedCrossRef
12.
• 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. This paper provides inaugural guideline recommendations by the NCCN for the diagnostic workup and management of patients with MPNs.CrossRef
13.
Kroger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, Cervantes F, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347–50. quiz 64PubMedPubMedCentralCrossRef
14.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New Engl J Med. 2012;366(9):799–807.PubMedPubMedCentralCrossRef
15.
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. New England J Med. 2012;366(9):787–98.CrossRef
16.
Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, 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;122(25):4047–53.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
18.
Talpaz M, Paquette R, Afrin L, Hamburg SI, Prchal JT, Jamieson K, et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. J Hematol Oncol. 2013;6(1):81.PubMedPubMedCentralCrossRef
19.
Bhagwat N, Levine RL, Koppikar P. Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. Int J Hematol. 2013;97(6):695–702.PubMedCrossRef
20.
• Winter PS, Sarosiek KA, Lin KH, Meggendorfer M, Schnittger S, Letai A, et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signaling. 2014;7(357):ra122. This paper underscores the role of the RAS signaling pathway in mediating resistance to JAK inhibition.CrossRef
21.
Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708–15.PubMedCrossRef
22.
Marit MR, Chohan M, Matthew N, Huang K, Kuntz DA, Rose DR, et al. Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor. PLoS One. 2012;7(8):e43437.PubMedPubMedCentralCrossRef
23.
Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Experimental Med. 2012;209(2):259–73.CrossRef
24.
Komrokji RS, Seymour JF, Roberts AW, Wadleigh M, To LB, Scherber R, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood. 2015;125(17):2649–55.PubMedPubMedCentralCrossRef
25.
• 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. This paper underscores activity of pacritinib in some patients with MF irrespective of baseline cytopenias.PubMedCrossRef
26.
Mascarenhas J, Hoffman R, Talpaz M. Results of the persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients with myelofibrosis (MF) and platelet counts <100,000/μL. Blood. 2016;128:LBA-5.CrossRef
27.
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.PubMedPubMedCentralCrossRef
28.
Mesa RA, Kiladjian JJ, Catalano JV. Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF). J Clin Oncol. 2017;35:7000.
29.
Harrison C. Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX). J Clin Oncol. 2017;35:7001.
30.
Verstovsek S, Talpaz M, Ritchie EK. Phase 1/2 study of NS-018, an oral JAK2 inhibitor, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (postPV MF), or post-essential thrombocythemia myelofibrosis (postET MF). Blood. 2016;634:1936.
31.
Mascarenhas JO, Talpaz M, Gupta V, Foltz LM, Savona MR, Paquette R, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017;102(2):327–35.PubMedPubMedCentralCrossRef
32.
33.
Wang JC, Chen W, Nallusamy S, Chen C, Novetsky AD. Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation. Brit J Haematol. 2002;116(3):582–6.CrossRef
34.
Kumagai T, Tefferi A, Jones L, Koeffler HP. Methylation analysis of the cell cycle control genes in myelofibrosis with myeloid metaplasia. Leukemia Res. 2005;29(5):511–5.CrossRef
35.
Quintas-Cardama A, Tong W, Kantarjian H, Thomas D, Ravandi F, Kornblau S, et al. A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia. 2008;22(5):965–70.PubMedPubMedCentralCrossRef
36.
Mesa RA, Verstovsek S, Rivera C, Pardanani A, Hussein K, Lasho T, et al. 5-Azacitidine has limited therapeutic activity in myelofibrosis. Leukemia. 2009;23(1):180–2.PubMedCrossRef
37.
Odenike O, Godwin J, van Besien KM. Phase II trial of low dose, subcutaneous decitabine in myelofibrosis. Blood. 2008;112:2809.
38.
Badar T, Kantarjian HM, Ravandi F, Jabbour E, Borthakur G, Cortes JE, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leukemia Res. 2015;39(9):950–6.CrossRef
39.
Danilov AV, Relias V, Feeney DM, Miller KB. Decitabine is an effective treatment of idiopathic myelofibrosis. Br J Haematol. 2009;145(1):131–2.PubMedCrossRef
40.
Tabarroki A, Saunthararajah Y, Visconte V, Cinalli T, Colaluca K, Rogers HJ, et al. Ruxolitinib in combination with DNA methyltransferase inhibitors: clinical responses in patients with symptomatic myelofibrosis with cytopenias and elevated blast(s) counts. Leukemia Lymphoma. 2015;56(2):497–9.PubMedCrossRef
41.
Daver N, Cortes J, Pemmaraju N. Ruxolitinib (RUX) in combination with 5-azacytidine (AZA) as therapy for patients (pts) with myelofibrosis (MF). Blood. 2016;128:1127.CrossRef
42.
Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010;116(19):3735–42.PubMedCrossRef
43.
Mascarenhas J, Navada S, Malone A, Rodriguez A, Najfeld V, Hoffman R. Therapeutic options for patients with myelofibrosis in blast phase. Leukemia Res. 2010;34(9):1246–9.CrossRef
44.
Bose P, Verstovsek S, Gasior Y. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results. Blood. 2016;128:4262.
45.
Rampal R, Mascarenhas J, Kosiorek HE. Safety and efficacy of combined ruxolitinib and decitabine in patients with blast-phase MPN and post-MPN AML: results of a phase I study (Myeloproliferative Disorders Research Consortium 109 trial). Blood. 2016;128:1124.
46.
Andersen CL, Mortensen NB, Klausen TW, Vestergaard H, Bjerrum OW, Hasselbalch HC. A phase II study of vorinostat (MK-0683) in patients with primary myelofibrosis and post-polycythemia vera myelofibrosis. Haematologica. 2014;99(1):e5–7.PubMedPubMedCentralCrossRef
47.
DeAngelo DJ, Mesa RA, Fiskus W, Tefferi A, Paley C, Wadleigh M, et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. Br J Haematol. 2013;162(3):326–35.PubMedCrossRef
48.
Mascarenhas J, Lu M, Li T, Petersen B, Hochman T, Najfeld V, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF). Br J Haematol. 2013;161(1):68–75.PubMedCrossRef
49.
Mascarenhas J, Sandy L, Lu M, Yoon J, Petersen B, Zhang D, et al. A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF). Leukemia Res. 2017;53:13–9.CrossRef
50.
Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, et al. A pilot study of the histone-deacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010;150(4):446–55.PubMed
51.
Quintas-Cardama A, Kantarjian H, Estrov Z, Borthakur G, Cortes J, Verstovsek S. Therapy with the histone deacetylase inhibitor pracinostat for patients with myelofibrosis. Leukemia Res. 2012;36(9):1124–7.CrossRef
52.
Harrison C, Kiladjian JJ, Heidel FH. 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;126:4060.
53.
Grimwade LF, Happerfield L, Tristram C, McIntosh G, Rees M, Bench AJ, et al. Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. Brit J Haematol. 2009;147(4):495–506.CrossRef
54.
Bartalucci N, Tozzi L, Bogani C, Martinelli S, Rotunno G, Villeval JL, et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. J Cellular Mol Med. 2013;17(11):1385–96.CrossRef
55.
Fiskus W, Verstovsek S, Manshouri T, Smith JE, Peth K, Abhyankar S, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12(5):577–88.PubMedCrossRef
56.
Khan I, Huang Z, Wen Q, Stankiewicz MJ, Gilles L, Goldenson B, et al. AKT is a therapeutic target in myeloproliferative neoplasms. Leukemia. 2013;27(9):1882–90.PubMedPubMedCentralCrossRef
57.
Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011;118(8):2069–76.PubMedPubMedCentralCrossRef
58.
Durrant ST, Nagler A, Vannucchi AM. 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;126:827.CrossRef
59.
McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia. 2008;22(4):708–22.PubMedCrossRef
60.
Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008;22(4):686–707.PubMedCrossRef
61.
Oku S, Takenaka K, Kuriyama T, Shide K, Kumano T, Kikushige Y, et al. JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation. Br J Haematol. 2010;150(3):334–44.PubMedCrossRef
62.
Nguyen TK, Tata P, Brooks S. The MEK/ERK inhibitor trametinib reduces fibrosis in a transduction-transplantation model of mutated calreticulin. Blood. 2016;128:635.
63.
Kong G, Wunderlich M, Yang D, Ranheim EA, Young KH, Wang J, et al. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. J Clin Investig. 2014;124(6):2762–73.PubMedPubMedCentralCrossRef
64.
Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014;20(2):490–8.PubMedCrossRef
65.
Borthakur G, Popplewell L, Boyiadzis M, Foran J, Platzbecker U, Vey N, et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer. 2016;122(12):1871–9.PubMedCrossRef
66.
McGowan SE, McCoy DM. Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation. Am J Physiol Lung Cellular Mol Physiol. 2013;305(3):L229–39.CrossRef
67.
68.
Gerds A, Tauchi T, Ritchie E. Phase I/II trial of glasdegib in patients with primary or secondary myelofibrosis. J Clin Oncol. 2017;35(suppl):abstr 7061.
69.
Gupta V, Harrison C, Hasselbalch H. Phase 1b/2 study of the efficacy and safety of sonidegib (LDE225) in combination with ruxolitinib (INC424) in patients with myelofibrosis. Blood. 2015;126:825.CrossRef
70.
Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, tetrahymena and yeast to human cancer and aging. Nat Med. 2006;12(10):1133–8.PubMedCrossRef
71.
Asai A, Oshima Y, Yamamoto Y, Uochi TA, Kusaka H, Akinaga S, et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. 2003;63(14):3931–9.PubMed
72.
Herbert BS, Gellert GC, Hochreiter A, Pongracz K, Wright WE, Zielinska D, et al. Lipid modification of GRN163, an N3’-->P5’ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 2005;24(33):5262–8.PubMedCrossRef
73.
• Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. New England J Med. 2015;373(10):908–19. This paper documents the potential activity of the telomerase inhibitor imetelstat in myelofibrosis and underscores the need for additional studies.CrossRef
74.
Baerlocher GM, Burington B, Snyder DS. Telomerase inhibitor imetelstat in essential thrombocythemia and myelofibrosis. New England J Med. 2015;373(26):2580.
75.
Dillingh MR, van den Blink B, Moerland M, van Dongen MG, Levi M, Kleinjan A, et al. Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis. Pulmonary Pharmacol Therap. 2013;26(6):672–6.CrossRef
76.
77.
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 Experimental Med. 2016;213(9):1723–40.CrossRef
78.
Verstovsek S, Mesa R, Foltz L. Phase 2 trial of PRM-151, an anti-fibrotic agent, in patients with myelofibrosis: stage 1 results. Blood. 2014;124:713.
79.
Tadmor T, Bejar J, Attias D, Mischenko E, Sabo E, Neufeld G, et al. The expression of lysyl-oxidase gene family members in myeloproliferative neoplasms. Am J Hematol. 2013;88(5):355–8.PubMedCrossRef
80.
Eliades A, Papadantonakis N, Bhupatiraju A, Burridge KA, Johnston-Cox HA, Migliaccio AR, et al. Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. J Biol Chem. 2011;286(31):27630–8.PubMedPubMedCentralCrossRef
81.
Verstovsek S, Savona MR, Mesa RA, Dong H, Maltzman JD, Sharma S, et al. A phase 2 study of simtuzumab in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Br J Haematol. 2017;176(6):939–49.PubMedCrossRef
82.
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.PubMedCrossRef
83.
Bose P, Daver N, Jabbour E. Phase-2 study of sotatercept (ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia. Blood. 2016;128:478.
84.
Mascarenhas J, Li T, Sandy L, Newsom C, Petersen B, Godbold J, et al. Anti-transforming growth factor-beta therapy in patients with myelofibrosis. Leukemia Lymphoma. 2014;55(2):450–2.PubMedCrossRef
85.
Ditschkowski M, Elmaagacli AH, Trenschel R, Gromke T, Steckel NK, Koldehoff M, et al. Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. Haematologica. 2012;97(10):1574–81.PubMedPubMedCentralCrossRef
86.
Scott BL, Gooley TA, Sorror ML, Rezvani AR, Linenberger ML, Grim J, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood. 2012;119(11):2657–64.PubMedPubMedCentralCrossRef
87.
Alchalby H, Yunus DR, Zabelina T, Kobbe G, Holler E, Bornhauser M, et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol. 2012;157(1):75–85.PubMedCrossRef
88.
Gupta V, Malone AK, Hari PN, Ahn KW, Hu ZH, Gale RP, et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplantation. 2014;20(1):89–97.CrossRef
89.
• Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M, et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014;124(7):1183–91. This paper documents the potential for reduced intensity conditioning to induce durable remssions post-allogeneic stem cell transplantation for myelofibrosis.PubMedPubMedCentralCrossRef
90.
Choi DC, Tremblay D, Iancu-Rubin C, Mascarenhas J. Programmed cell death-1 pathway inhibition in myeloid malignancies: implications for myeloproliferative neoplasms. Ann Hematol. 2017;96(6):919–27.PubMedCrossRef
91.
Garcia-Manero G, Tallman M, Martinelli G. Pembrolizumab, a PD-1 inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of hypomethylating agent treatment. Oral Abstract American Society of Hematology Annual Meeting Dec 4, 2016.
92.
Garcia-Manero G, Daver N, Montalban-Bravo G. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in Pts with previously treated or untreated myelodysplastic syndromes (MDS). Oral Abstract American Society of Hematology Annual Meeting Dec 4, 2016.
93.
Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. New Engl J Med. 2016;375(2):143–53.PubMedPubMedCentralCrossRef
94.
Rashidi A, Walter RB. Antigen-specific immunotherapy for acute myeloid leukemia: where are we now, and where do we go from here? Exp Rev Hematol. 2016;9(4):335–50.CrossRef
95.
Nikiforow S, Werner L, Murad J. Safety data from a first-in-human phase 1 trial of NKG2D chimeric antigen receptor-T cells in AML/MDS and multiple myeloma. Poster Abstract American Society of Hematology Annual Meeting Dec 5, 2016.
96.
Brault L, Gasser C, Bracher F, Huber K, Knapp S, Schwaller J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95(6):1004–15.PubMedPubMedCentralCrossRef
97.
Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB. Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 2005;105(11):4477–83.PubMedPubMedCentralCrossRef
98.
Berns A, Mikkers H, Krimpenfort P, Allen J, Scheijen B, Jonkers J. Identification and characterization of collaborating oncogenes in compound mutant mice. Cancer Res. 1999 Apr 01;59(7 Suppl):1773s–7s.PubMed
99.
Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nature Rev Cancer. 2011;11(1):23–34.CrossRef
100.
Wernig G, Gonneville JR, Crowley BJ, Rodrigues MS, Reddy MM, Hudon HE, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood. 2008;111(7):3751–9.PubMedPubMedCentralCrossRef
101.
Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, Reuther GW. The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget. 2015;6(37):40141–57.PubMedPubMedCentralCrossRef
102.
Huang SM, Wang A, Greco R, Li Z, Barberis C, Tabart M, et al. Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance. Oncotarget. 2014;5(10):3362–74.PubMedPubMedCentralCrossRef
103.
Silva M, Richard C, Benito A, Sanz C, Olalla I, Fernandez-Luna JL. Expression of Bcl-x in erythroid precursors from patients with polycythemia vera. New England J Med. 1998;338(9):564–71.CrossRef
104.
Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999;98(2):181–91.PubMedCrossRef
105.
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Disc. 2016;6(10):1106–17.CrossRef
106.
Parikh SA, Kantarjian H, Schimmer A, Walsh W, Asatiani E, El-Shami K, et al. Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leukemia. 2010;10(4):285–9.CrossRef
107.
Waibel M, Solomon VS, Knight DA, Ralli RA, Kim SK, Banks KM, et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 2013;5(4):1047–59.PubMedPubMedCentralCrossRef
108.
Brown JC, Winters-Stone K, Lee A, Schmitz KH. Cancer, physical activity, and exercise. Comprehens Physiol. 2012;2(4):2775–809.
109.
Bade BC, Thomas DD, Scott JB, Silvestri GA. Increasing physical activity and exercise in lung cancer: reviewing safety, benefits, and application. J Thor Oncol. 2015;10(6):861–71.CrossRef
110.
Eckert R, Huberty J, Gowin K, Mesa R, Marks L. Physical activity as a nonpharmacological symptom management approach in myeloproliferative neoplasms: recommendations for future research. Integr Cancer Ther. 2016.
111.
Huberty J, Eckert R, Gowin K. Online-streamed yoga as a non-pharmacologic symptom management approach in myeloproliferative neoplasms. Blood. 2016;128:5478.
112.
Arthur AE, Peterson KE, Shen J, Djuric Z, Taylor JM, Hebert JR, et al. Diet and proinflammatory cytokine levels in head and neck squamous cell carcinoma. Cancer. 2014;120(17):2704–12.PubMedPubMedCentralCrossRef
113.
Lucas R, Parikh SJ, Sridhar S, Guo DH, Bhagatwala J, Dong Y, et al. Cytokine profiling of young overweight and obese female African American adults with prediabetes. Cytokine. 2013;64(1):310–5.PubMedPubMedCentralCrossRef
114.
Olendzki BC, Silverstein TD, Persuitte GM, Ma Y, Baldwin KR, Cave D. An anti-inflammatory diet as treatment for inflammatory bowel disease: a case series report. Nutr J. 2014;13:5.PubMedPubMedCentralCrossRef
115.
Scherber RM, Kosiorek HE, Senyak Z, Dueck AC, Clark MM, Boxer MA, et al. Comprehensively understanding fatigue in patients with myeloproliferative neoplasms. Cancer. 2016;122(3):477–85.PubMedCrossRef
116.
Hulbert-Williams NJ, Storey L, Wilson KG. Psychological interventions for patients with cancer: psychological flexibility and the potential utility of Acceptance and Commitment Therapy. European J Cancer Care. 2015;24(1):15–27.CrossRef
117.
Feros DL, Lane L, Ciarrochi J, Blackledge JT. Acceptance and Commitment Therapy (ACT) for improving the lives of cancer patients: a preliminary study. Psycho-Oncol. 2013;22(2):459–64.
118.
Kangas M, McDonald S, Williams JR, Smee RI. Acceptance and commitment therapy program for distressed adults with a primary brain tumor: a case series study. Supportive Care Cancer. 2015;23(10):2855–9.CrossRef
119.
• Leroy E, Constantinescu SN. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile janus kinase inhibition. Leukemia. 2017;31(5):1023–38. This paper provides a comprehensive review of strategies under development for more specific JAK inhibitors.PubMedCrossRef
120.
Smith C, Abalde-Atristain L, He C, Brodsky BR, Braunstein EM, Chaudhari P, et al. Efficient and allele-specific genome editing of disease loci in human iPSCs. Mol Ther. 2015;23(3):570–7.PubMedCrossRef
121.
• Mead AJ, Mullally A. Myeloproliferative neoplasm stem cells. Blood. 2017;129(12):1607–16. This paper provides a contemporary review of driver mutations in MPN pathogenesis and clonal expansion and novel strategies and approaches under consideration for targeting MPN stem cells.PubMedCrossRef
122.
Metadata
Title
Novel Therapies for Myelofibrosis
Authors
Kristen Pettit
Olatoyosi Odenike
Publication date
01-12-2017
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 6/2017
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-017-0403-0

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