Safety evaluation of ruxolitinib for treating myelofibrosis

Expert Opinion on Drug Safety

Volumn 13, Issue 7, 2014, Pages 967-976

  Galli, Sofia ^a   McLornan, Donal ^a   Harrison, Claire ^a  

^a GUY S HOSPITAL   (United Kingdom)

Author keywords

JAK; Myelofibrosis; Ruxolitinib; Safety

Indexed keywords

JANUS KINASE INHIBITOR; RUXOLITINIB; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE;

ANEMIA; ARTICLE; BRAIN DISEASE; CANCER SURVIVAL; DIZZINESS; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG SURVEILLANCE PROGRAM; DRUG TOLERABILITY; EVALUATION STUDY; GENE; GENE MUTATION; HEMATOLOGY; HUMAN; INFECTION; JAK2 GENE; KIDNEY DISEASE; LIVER DISEASE; MYELOFIBROSIS; PHASE 3 CLINICAL TRIAL (TOPIC); PREGNANT WOMAN; SKIN BRUISING; THROMBOCYTOPENIA; PRIMARY MYELOFIBROSIS; SAFETY;

CLINICAL TRIALS, PHASE III AS TOPIC; HUMANS; PRIMARY MYELOFIBROSIS; PROTEIN KINASE INHIBITORS; PYRAZOLES; SAFETY;

EID: 84902686517     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2014.916273     Document Type: Article

References (58)

1. Cross NC. Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011;2011: 208-14
2. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-405
3. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-90
4. United States full prescribing information. Jakafi (ruxolitinib). 2011. Available from: http:/www.accessdata.fda.gov/drugsatfda-docs/label/2011/ 202192lbl.pdf
5. EMA Summary of Product Characteristics. Jakavi. Novartis Pharmaceuticals U K Ltd. Available from: http://www.ema. europa.eu/docs/en-GB/document-library/ EPAR-Product-Information/human/002464/WC500133223.pdf [Accessed 12 March 2014]
6. 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
7. Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787-98
8. 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
9. Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 2012;489:155-9
10. Deshpande A, Reddy MM, Schade GO, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia 2012;26:708-15
11. Shi JG, Chen X, McGee RF, et al. The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers. J Clin Pharmacol 2011;51:1644-54
12. Chen X, Williams WV, Sandor V, Yeleswaram S. Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF). J Clin Pharmacol 2013;53:721-30
13. Shilling AD, Nedza FM, Emm T, et al. Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab Dispos 2010;38:2023-31
14. Shi JG, Chen X, Emm T, et al. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol 2012;52:809-18
15. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I. Blood 2013;122:abstract 396
16. 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
17. Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-II cohorts. Blood 2014. [Epub ahead of print]
18. Vannucchi AM, KantarjIan H, Kiladjian J-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
19. Thiele J, Bueso-Ramos CE, Sun W, 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
20. Wilkins BS, Radia D, Woodley C, et al. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica 2013;98:1872-6
21. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014;120:513-20
22. Spiekermann K, Biethahn S, Wilde S, et al. Constitutive activation of STAT transcription factors in acute myelogenous leukemia. Eur J Haematol 2001;67(2):63-71
23. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012;119:4614-18
24. Maude SL, Tasian SK, Vincent T, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia (ALL). Blood 2012;120(17):3510-18
25. Ghoreschi K, Gadina M. Jakpot! new small molecules in autoimmune and inflammatory diseases. Exp Dermatol 2014;23:7-11
26. Aittomaki S, Pesu M. Therapeutic targeting of the Jak/STAT pathway. Basic Clin Pharmacol Toxicol 2014;114:18-23
27. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther 2013;7:13-21
28. Talpaz M, Paquette R, Afrin L, et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. J Hematol Oncol 2013;6:81
29. Harrison CN, Gisslinger H, Miller CB, et al. Expand: a phase 1b, open-label, dose-finding study of ruxolitinib in patients with myelofibrosis and baseline platelet counts between 50 x 109/L and 99 x 109/L. ASH Annual Meeting Abstracts 2012;120:177
30. 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;363:1117-27
31. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011;86:1188-91
32. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1, 2 inhibitor. Chest 2013;143:1478-9
33. Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med 2013;369:681-3
34. Caocci G, Murgia F, Podda L, et al. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia 2014;28:225-7
35. Shen CH, Hwang CE, Chen YY, Chen CC. Hepatitis B virus reactivation associated with ruxolitinib. Ann Hematol 2013. [Epub ahead of print]
36. Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med 2013;369:197-8
37. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013;122:1192-202
38. Massa M, Rosti V, Campanelli R, et al. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia 2014;28:449-51
39. Stuebig T, Wolschke C, Alchalby H, et al. The Pan-JAK inhibitor ruxolitinib impairs T-cell activation, cytokine production and proliferation in vivo and in vitro. Blood 2013;122:2001
40. Yajnanarayana SP, Cornez I, Heine A, et al. CD4+ T cell functions are potently suppressed by the janus kinase 1/2 (JAK1/JAK2) inhibitor ruxolitinib. Blood 2013;122:2281
41. Keohane C, Kordasti SY, Seidl T, et al. JAK inhibition reduces CD25 high CD27+ FOXp3+ T regulatory cells and causes a silencing of T effector cells in patients with myeloproliferative neoplasms whilst promoting a TH17 phenotype. Blood 2013;122:4092
42. Schonberg K, Rudolph J, Cornez I, et al. The JAK1/JAK2 inhibitor ruxolitinib substantially affects NK cell biology. Blood 2013;122:16
43. Flynn JL, Chan J, Triebold KJ, et al. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993;178(6): 2249-54
44. Kim Y-K, Lee SR, Park Y, et al. Efficacy of ruxolitinib in Korean myelofibrosis patients and cases complicated TB lymphadenitis during the treatment. Blood 2013;122:1596
45. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood 2013;122:3843-4
46. Harrison CN, Mesa RA, Kiladjian JJ, et al. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol 2013;162:229-39
47. Mesa RA, Kiladjian JJ, Verstovsek S, 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
48. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European LeukemiaNet (ELN) consensus report. Blood 2013;122(8):1395-8
49. Jovanovic JV, Ivey A, Vannucchi AM, et al. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study. Leukemia 2013;27:2032-9
50. Wade R, Rose M, Neilson AR, et al. Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal. Pharmacoeconomics 2013;31: 841-52
51. 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
52. Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 2010;148:961-3
53. 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(8):2069-76
54. Mascarenhas J, Lu M, Li T, 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;161:68-75
55. Harrison CN, Heidel FH, Kiladjian J-J, et al. A phase 1b, dose-finding study of ruxolitinib plus panobinostat in patients with primary myelofibrosis (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF): identification of the recommended phase 2 dose. Blood 2013;122:4045
56. McLornan DP, Mead AJ, Jackson G, Harrison CN. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol 2012;157:413-25
57. Robin M, Francois S, Huynh A, et al. Ruxolitinib before allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis: a preliminary descriptive report of the JAK ALLO study, a phase II trial sponsored by goelams-FIM in collaboration with the Sfgmtc. Blood 2013;122:306
58. Stübig T, Alchalby H, Ditschkowski M, et al. JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis. Leukemia 2014. [Epub ahead of print]