Emerging drugs for the treatment of myelofibrosis

Expert Opinion on Emerging Drugs

Volumn 20, Issue 4, 2015, Pages 663-678

  Geyer, Holly L ^a   Mesa, Ruben A ^a  

^a MAYO CLINIC   (United States)

Author keywords

antifibrosing agents; HDAC inhibitors; hedgehog inhibitors; HSP90 inhibitors; hypomethylating agents; JAK2 inhibitor; myelofibrosis; myeloproliferative neoplasms; PI3 AKT mTOR inhibitors; quality of life; symptoms; targeted therapy; telomerase inhibitors

Indexed keywords

ANTIFIBROTIC AGENT; DECITABINE; EVEROLIMUS; FEDRATINIB; FRESOLIMUMAB; GIVINOSTAT; GLASDEGIB; IMETELSTAT; LESTAURTINIB; LUMINESPIB; MOMELOTINIB; N TERT BUTYL 3 [5 METHYL 2 [4 (4 METHYL 1 PIPERAZINYL)PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; N [4 [2 [(4 MORPHOLINOPHENYL)AMINO] 4 PYRIMIDINYL]PHENYL] 2 PYRROLIDINECARBOXAMIDE; PACRITINIB; PANOBINOSTAT; PATIDEGIB; RUXOLITINIB; SIMTUZUMAB; SONIDEGIB; VISMODEGIB; VORINOSTAT;

ANEMIA; DISEASE CONTROL; DNA METHYLATION; ENZYME INHIBITION; HEALTH CARE NEED; HUMAN; MEDICAL RESEARCH; MYELOFIBROSIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SPLENOMEGALY; ALGORITHM; ANIMAL; DRUG DESIGN; LIFE EXPECTANCY; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; PRIMARY MYELOFIBROSIS; QUALITY OF LIFE; SEVERITY OF ILLNESS INDEX;

ALGORITHMS; ANIMALS; DRUG DESIGN; HUMANS; LIFE EXPECTANCY; MOLECULAR TARGETED THERAPY; PRIMARY MYELOFIBROSIS; QUALITY OF LIFE; SEVERITY OF ILLNESS INDEX; SPLENOMEGALY;

EID: 84950300715     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1517/14728214.2015.1061502     Document Type: Review

References (83)

1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6:372-5
2. Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol 1999;61:10-15
3. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer 2007;109:68-76
4. 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;30:4098-103
5. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood 2008;111:3383-7
6. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005;23:2224-32
7. Barbui T, Carobbio A, Cervantes F, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 2010;115:778-82
8. Gangat N, Caramazza D, Vaidya R, 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;29:392-7
9. Cervantes F, Tassies D, Salgado C, et al. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol 1991;85:124-7
10. Okamura T, Kinukawa N, Niho Y, et al. Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients. Int J Hematol 2001;73:194-8
11. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a singleinstitution experience with 91 cases. Blood 2005;105:973-7
12. Wang H, Mehta J, Iqbal U, et al. Analysis of the Impact and Burden of Illness of Myelofibrosis in the US [abstract 972]. Blood (ASH Annual Meeting Abstracts) 2012
13. Mesa R, Miller CB, Thyne M, et al. Impact of myeloproliferative neoplasms (MPNs) on patients' overall health and productivity: results from the MPN LANDMARK SURVEY in the United States. 56th ASH Annual Meeting and Exposition; 6-9 December 2014; San Francisco CA; 2014
14. Kerbauy DM, Gooley TA, Sale GE, et al. Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant 2007;13:355-65
15. Martinez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol 2010;89:1233-7
16. Sirhan S, Lasho TL, Hanson CA, et al. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol 2008;83:363-5
17. Santos FP, Tam CS, Kantarjian H, et al. Splenectomy in patients with myeloproliferative neoplasms: efficacy, complications and impact on survival and transformation. Leuk Lymphoma 2014;55:121-7
18. Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer 2001;92:1684-8
19. Diehn F, Tefferi A. Pruritus in polycythaemia vera: prevalence, laboratory correlates and management. Br J Haematol 2001;115:619-21
20. Koch CA, Li CY, Mesa RA, et al. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003;78:1223-33
21. 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;113:2895-901
22. Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol 2009;27:4563-9
23. Begna KH, Mesa RA, Pardanani A, et al. A phase-2 trial of low-dose pomalidomide in myelofibrosis. Leukemia 2011;25:301-4
24. 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;33:1199-203
25. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood 2011;118:401-8
26. Geyer HL, Emanuel RM, Dueck AC, et al. Distinct clustering of symptomatic burden amongst myeloproliferative neoplasm patients: retrospective assessment in 1470 patients. Blood 2014;123(24):3803-10
27. Geyer H, Dueck AC, Emanuel RM, et al. Insomnia, Quality Of Life and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG). Blood 2013;122:4087
28. Geyer H, Dueck AC, Emanuel RM, et al. Sexuality Challenges, Intimacy, and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG). Blood 2013;122:4088
29. Tefferi A, Jimma T, Sulai NH, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 2012;26:475-80
30. Groopman JE. The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med 1980;92:857-8
31. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Ruxolitinib-induced modulation of bone marrow microenvironment in patients with myelofibrosis is associated with inflammatory cytokine levels. 2014
32. Wang JC, Chen C, Dumlao T, et al. Enhanced histone deacetylase enzyme activity in primary myelofibrosis. Leuk Lymphoma 2008;49:2321-7
33. Glozak MA, Sengupta N, Zhang X, et al. Acetylation and deacetylation of nonhistone proteins. Gene 2005;363:15-23
34. Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010;28:605-13
35. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood 2012;119:2196-204
36. Lin TL, Matsui W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. Onco Targets Ther 2012;5:47-58
37. Pearl LH, Prodromou C, Workman P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J 2008;410:439-53
38. Wang Y, Fiskus W, Chong DG, 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;114:5024-33
39. George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005;105:1768-76
40. Jacobson RJ, Salo A, Fialkow PJ. Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis. Blood 1978;51:189-94
41. Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 2005;23:8520-30
42. Kimura A, Katoh O, Kuramoto A. Effects of platelet derived growth factor, epidermal growth factor and transforming growth factor-beta on the growth of human marrow fibroblasts. Br J Haematol 1988;69:9-12
43. Bedekovics J, Kiss A, Beke L, et al. Platelet derived growth factor receptorbeta (PDGFRbeta) expression is limited to activated stromal cells in the bone marrow and shows a strong correlation with the grade of myelofibrosis. Virchows Arch 2013;463:57-65
44. Hodes R. Molecular targeting of cancer: telomeres as targets. Proc Natl Acad Sci U S A 2001;98:7649-51
45. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62
46. Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-75
47. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003;4:257-62
48. Ugo V, Marzac C, Teyssandier I, et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol 2004;32:179-87
49. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144-8
50. Ghaffari S, Kitidis C, Zhao W, et al. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation. Blood 2006;107:1888-91
51. Grimwade LF, Happerfield L, Tristram C, et al. Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. Br J Haematol 2009;147:495-506
52. Bogani C, Bartalucci N, Martinelli S, et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One 2013;8:e54826
53. Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 2010;115:3109-17
54. Verstovsek S KH, Pardanani AD, Thomas D, et al. The JAK inhibitor INCB018424 demonstrates durable and marked clinical reponses in primary myelofibrosis (PMF) and postpolycythemia/essential thrombocythemia myelofibrosis (post-PV/ET-MF). Blood 2008;112(Suppl)):abstract 1762
55. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807
56. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787-98
57. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015;372:426-35
58. 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;122:4047-53
59. Hagop K, Kiladjian J-J, Gotlib J, et al. A Pooled Overall Survival Analysis of The COMFORT Studies: 2 Randomized Phase 3 Trials of Ruxolitinib For The Treatment of Myelofibrosis. Blood 2013;122:2820
60. Kvasnicka H, Thiele J, Bueso-Ramos CE, et al. Effects Of Five-Years Of Ruxolitinib Therapy On Bone Marrow Morphology In Patients With Myelofibrosis and Comparison With Best Available Therapy. Blood 2013;122:4055
61. Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 2013;27:1322-7
62. Pardanani AGG, Lasho TL, Hogan W, et al. A Phase I/II study of CYT387, an oral JAK-1/2 Inhibitor, in myelofibrosis: significant response rates in anemia, splenomegaly, and constitutional symptoms. Blood 2010;116(Suppl):abstract 460
63. Abdelrahman RA, Begna K, Al-Kali A, et al. Momelotinib treatment-associated neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. Br J Haematol 2015;169(1):77-80
64. 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;125(17):2649-55
65. Verstovsek S, Dean JP, Cernohous P, et al. Pacritinib, a Dual JAK2/FLT3 Inhibitor: An Integrated Efficacy and Safety Analysis Of Phase II Trial Data In Patients With Primary and Secondary Myelofibrosis (MF) and Platelet Counts 100,000/l. Blood 2013;122:395
66. Mascarenhas J, Lu M, Li T, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and postpolycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF). Br J Haematol 2013;161:68-75
67. DeAngelo DJ, Mesa RA, Fiskus W, et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and postpolycythaemia vera myelofibrosis. Br J Haematol 2013;162:326-35
68. Kiladjian J-J, Heidel FH, Vannucchi AM, et al. Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis. 56th ASH Annual Meeting and Exposition; 6-9 December 2014; San Francisco CA; 2014
69. Andersen CL, Mortensen NB, Klausen TW, et al. A phase II study of vorinostat (MK-0683) in patients with primary myelofibrosis and postpolycythemia vera myelofibrosis. Haematologica 2014;99:e5-7
70. Guerini V, Barbui V, Spinelli O, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia 2008;22:740-7
71. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010;150:446-55
72. Quintas-Cardama A, Tong W, Kantarjian H, et al. A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia 2008;22:965-70
73. Mesa RA, Verstovsek S, Rivera C, et al. 5-Azacitidine has limited therapeutic activity in myelofibrosis. Leukemia 2009;23:180-2
74. Odenike O, Godwin J, Besien K, et al. Phase II Trial of low dose, subcutaneous decitabine in myelofibrosis. Blood (ASH Annual Meeting Abstracts)2010: 2010 Abstract 2809 2809
75. Jamieson C, Cortes JE, Oehler V, et al. Phase I dose-escalation study of PF-04449913, an oral Hedgehog (Hh) inhibitor, in patients with select hematologic malignancies [abstract 2804]. Blood (ASH Annual Meeting Abstracts) 2010;2011:118
76. Gupta V, Koschmieder S, Harrison CN, et al. Phase 1b dose-escalation study of sonidegib (LDE225) in combination with ruxolitinib (INC424) in patients with myelofibrosis. 56th ASH Annual Meeting and Exposition, San Francisco CA, 6-9 December 2014; 2014
77. Fiskus W, Verstovsek S, Manshouri T, et al. Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells. Clin Cancer Res 2011;17:7347-58
78. Baerlocher G, Leibundgut E, Ayran C, et al. Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results. Blood ASH Annual Meeting 2012. 179
79. Tefferi A, LaPlant B, Benga K, et al. Imetelstat, a Telomerase Inhibitor, Therapy for Myelofibrosis: A Pilot Study. Blood ASH Annual Meeting 2014. 634
80. Guglielmelli P, Barosi G, Rambaldi A, 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;118:2069-76
81. Pardanini A, Harrison CN, Cortes JE, et al. Results Of a Randomized, Double-Blind, Placebo-Controlled Phase III Study (JAKARTA) Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF). Blood 2013;122:393
82. Harrison CN, Schaap NP, Zweegman S, et al. Efficacy and Safety Of Fedratinib (SAR302503/TG101348) In Patients With Intermediate-Or High-Risk Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Or Post-Essential Thrombocythemia (ET) MF Previously Treated With Ruxolitinib: Interim Results From a Phase II Study (JAKARTA-2). Blood 2013;122:661
83. 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;42:1656-62