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Drugs
Published in: Drugs 3/2015

01-02-2015 | Adis Drug Evaluation

Ruxolitinib: A Review of Its Use in Patients with Myelofibrosis

Author: Greg L. Plosker

Published in: Drugs | Issue 3/2015

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Abstract

Ruxolitinib (Jakavi®, Jakafi®) is an orally administered inhibitor of Janus kinases (JAK) 1 and 2 used in the management of patients with myelofibrosis. Clinical trials with ruxolitinib, notably the phase III COMFORT-I and -II studies and their extensions, have demonstrated marked and durable clinical benefits in terms of reductions in splenomegaly and disease-related symptoms in patients with intermediate-2 or high-risk myelofibrosis. Ruxolitinib was also associated with improvements in health-related quality of life and functioning. Despite the crossover of patients in control groups to ruxolitinib, results of the COMFORT studies and their extensions indicate a survival advantage for patients randomized to ruxolitinib. The beneficial effects of ruxolitinib were observed across subgroups of myelofibrosis patients, including those not harbouring the JAK2V617F mutation. Improvements in splenomegaly and disease-related symptoms were also observed in a trial in Japanese/Asian patients with myelofibrosis and in myelofibrosis patients with a low baseline platelet count. Dose-related anaemia and thrombocytopenia were common in clinical trials with ruxolitinib, but rarely led to discontinuation of therapy and were managed with dosage modifications and/or transfusions of packed red blood cells. In addition to the USA and EU, ruxolitinib is now approved in a number of other countries, including Japan, and remains the only approved drug for the treatment of myelofibrosis, although various other agents are undergoing investigation. Appropriate monitoring and dosage titration are important to achieve optimal clinical benefits of ruxolitinib. Further research, including studies evaluating ruxolitinib-based combination therapy, may also help to optimise treatment.
Literature
1.
Gregory SA, Mesa RA, Hoffman R, et al. Clinical and laboratory features of myelofibrosis and limitations of current therapies. Clin Adv Hematol Oncol. 2011;9(9 Suppl 22):1–16.PubMed
2.
Mughal TI, Vaddi K, Sarlis NJ, et al. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89–101.PubMedCentralPubMed
3.
Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22(1):14–22.CrossRefPubMed
4.
Mehta J, Wang H, Iqbal SU, et al. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595–600.CrossRefPubMed
5.
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(13):2895–901.CrossRefPubMed
6.
7.
8.
Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19(26):4399–413.CrossRefPubMedCentralPubMed
9.
Santos FP, Verstovsek S. JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation? Anticancer Agents Med Chem. 2012;12(9):1098–109.CrossRefPubMed
10.
Oh ST, Gotlib J. JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Rev Hematol. 2010;3(3):323–37.CrossRefPubMed
11.
Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol. 2011;29(5):573–82.CrossRefPubMed
12.
Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.CrossRefPubMedCentralPubMed
13.
Yang LPH, Keating GM. Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012;72(16):2117–27.CrossRefPubMed
14.
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(15):3109–17.CrossRefPubMedCentralPubMed
15.
16.
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(12):1117–27.CrossRefPubMed
17.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807 [plus supplementary appendix].
18.
Vannucchi A, Kiladjian JJ, Gisslinger H, et al. Reductions in Jak2v617f allele burden with ruxolitinib treatment in Comfort-II, a phase III study comparing the safety and efficacy of ruxolitinib to best available therapy (BAT) [abstract no. 0373]. In: 17th Congress of the European Haematology Association. 2012.
19.
Quintas-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10(2):127–40.CrossRefPubMed
20.
21.
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(12):1644–54.CrossRefPubMed
22.
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(11):2023–31.CrossRefPubMed
23.
Chen X, Williams WV, Sandor V, et al. 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(7):721–30.CrossRefPubMed
24.
Ogama Y, Mineyama T, Yamamoto A, et al. A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers. Int J Hematol. 2013;97(3):351–9.CrossRefPubMed
25.
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(6):809–18.CrossRefPubMed
26.
Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120(6):1202–9.CrossRefPubMedCentralPubMed
27.
Kvasnicka HM, 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 [abstract no. 4055]. Blood. 2013;122(21).
28.
Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013;98(12):1865–71.CrossRefPubMedCentralPubMed
29.
Verstovsek S, Mesa RA, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I [abstract no. 396]. Blood. 2013;122(21).
30.
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;161(4):508–16.CrossRefPubMedCentralPubMed
31.
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;31(10):1285–92.CrossRefPubMed
32.
Mesa RA, Verstovsek S, Gupta V, et al. Improvement in weight and total cholesterol and their association with survival in ruxolitinib-treated patients with myelofibrosis from COMFORT-I [abstract no. 1733]. Blood. 2012;120(21).
33.
Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013;6(1).
34.
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(9):787–98 [plus supplementary appendix].
35.
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(25):4047–53.CrossRefPubMed
36.
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-2 cohorts. Blood. 2014;123(12):1833–5.CrossRefPubMed
37.
Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med. 2011;365(15):1455–7.CrossRefPubMed
38.
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;123(14):2157–60.CrossRefPubMed
39.
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(2):229–39.CrossRefPubMed
40.
Harrison C, Kiladjian JJ, Gisslinger H, et al. Multivariate analysis of the association of cytokine levels and reductions in spleen size in COMFORT-II, a phase 3 study comparing ruxolitinib to best available therapy (BAT) [abstract no. P269]. In: 18th Congress of the European Haematology Association. 2013.
41.
Harrison C, Kiladjian JJ, Gisslinger H, et al. Association of cytokine levels and reductions in spleen size in COMFORT-II, a phase 3 study comparing ruxolitinib to best available therapy (BAT) [abstract no. 0379]. In: 17th Congress of the European Haematology Association. 2012.
42.
Squires M, Harrison CN, Barosi G, et al. The relationship between cytokine levels and symptoms in patients (pts) with myelofibrosis (MF) from COMFORT-II, a phase 3 study of ruxolitinib (RUX) vs best available therapy (BAT) [abstract no. 4070]. Blood. 2013;122(21).
43.
Vannucchi AM, Hagop K, Kiladjian JJ, et al. A pooled overall survival analysis of the COMFORT studies: 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis [abstract no. 2820]. Blood. 2013;122(21).
44.
Jabbour E, Kantarjian HM, Ning J, et al. Prognostic factors for outcome in patients (pts) with myelofibrosis (MF) treated with ruxolitinib (Rux) [abstract no. 4050]. Blood. 2013;122(21).
45.
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.CrossRefPubMedCentralPubMed
46.
Verstovsek S, Kiladjian JJ, Mesa RA, et al. Effect of ruxolitinib on the incidence of splenectomy in patients with myelofibrosis: a retrospective analysis of data from ruxolitinib clinical trials [abstract no. 2847]. Blood. 2012;120(21).
47.
Jung CW, Shih LY, Xiao Z, et al. Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis. Leuk Lymphoma. 2014:1–22.
48.
Oritani K, Okamoto S, Tauchi T, et al. Efficacy and safety of ruxolitinib in Japanese patients with myelofibrosis (MF) [abstract no. OS-2-49]. In: 76th Annual Meeting of the Japanese Society of Hematology. 2014.
49.
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.CrossRefPubMedCentralPubMed
50.
Andreoli A, Rey J, Dauriac C, et al. Ruxolitinib therapy in myelofibrosis: Analysis of 241 patients treated in compassionate use (French “ATU” program) by the French intergroup of myeloproliferative neoplasms (FIM) [abstract no. 2841]. Blood. 2012;120(21).
51.
Alzate MA, Osorio MJM, Barreyro P, et al. Ruxolitinib in myelofibrosis (MF) patients through compassionate use program (CUP). Argentinian experience [abstract no. 5247]. Blood. 2013;122(21).
52.
Tabarroki A, Lindner D, Visconte V, et al. Modified dose escalation of ruxolitinib: a feasible therapeutic approach in the management of myelofibrosis [abstract no. 1586]. Blood. 2013;122(21).
53.
Harrison CN, Clark RE, Chacko J, et al. Response to ruxolitinib in patients with intermediate-1, intermediate-2 and high-risk myelofibrosis: interim results of the UK Robust Trial [abstract no. 2826]. Blood. 2013;122(21).
54.
Galli S, McLornan D, Harrison C. Safety evaluation of ruxolitinib for treating myelofibrosis. Expert Opin Drug Saf. 2014;13(7):967–76.CrossRefPubMed
55.
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.CrossRefPubMedCentralPubMed
56.
Al-Ali HK, Stalbovskaya V, Gopalakrishna P, et al. Ruxolitinib overcomes the adverse prognostic effect of anemia in patients with myelofibrosis (MF) [abstract] In: 56th American Society of Hematology Annual Meeting and Exposition. 2014.
57.
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(1):225–7.CrossRefPubMed
58.
Tong LX, Jackson J, Kerstetter J, et al. Reactivation of herpes simplex virus infection in a patient undergoing ruxolitinib treatment. J Am Acad Dermatol. 2014;70(3):e59–60.CrossRefPubMed
59.
Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1, 2 inhibitor. Chest. 2013;143(5):1478–9.CrossRefPubMed
60.
Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013;369(7):681–3.CrossRefPubMed
61.
Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86(12):1188–91.CrossRefPubMedCentralPubMed
62.
63.
Harrison CN, Bennett M. Orphan drugs for myelofibrosis. Expert Opin Orphan Drugs. 2014;2(4):391–405.CrossRef
64.
Qureshi MR, MacLean C, McMullin MF, et al. Management of myelofibrosis: a survey of current practice in the United Kingdom. J Clin Pathol. 2012;65(12):1124–7.CrossRefPubMed
65.
66.
Mascarenhas J. Rationale for combination therapy in myelofibrosis. Best Pract Res Clin Haematol. 2014;27(2):197–208.CrossRefPubMed
67.
Stubig 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;28(8):1736–8.CrossRefPubMed
68.
Jaekel N, Behre G, Behning A, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. Bone Marrow Transplant. 2014;49(2):179–84.CrossRefPubMed
Metadata
Title
Ruxolitinib: A Review of Its Use in Patients with Myelofibrosis
Author
Greg L. Plosker
Publication date
01-02-2015
Publisher
Springer International Publishing
Published in
Drugs / Issue 3/2015
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-015-0351-8

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