Vol 9, No 2 (2018)
Review paper
Published online: 2018-08-17
Place of ruxolitinib in myelofibrosis treatment.
Hematologia 2018;9(2):90-99.
Abstract
Ruxolitinib – inhibitor JAK1/JAK2 kinases has been the only drug approved for the treatment of patients with myelofibrosis. It reduces spleen size as well as constitutional symptoms, such as pruritus, night sweats, and weight loss. The main adverse events of the drug are thrombocytopenia and anemia. Non-hematologic side effects results from immunosuppression: increased risk of infections, including opportunistic ones. Ruxolitinib may be indicated before allogeneic transplantation due to its effect on constitutional symptoms and reduction of spleen size. In Poland ruxolitinib has been approved for patients with intermediate-2 and high risk myelofibrosis.
Keywords: myelofibrosisJAK inhibitorsruxolitinib
References
- Incyte Corporation. Jakafi (ruxolitinib) tablets [prescribing information]. http://www ema europa eu/ema/index jsp?curl=pages/medicines/human/medicines/002464/human_med_001568 jsp&mid=WC0b01ac058001d124 2014 (12.06.2018).
- Novartis Pharma GmbH. Jakavi Charakterystyka Produktu Leczniczego. http://www ema europa eu/ema/index jsp?curl=pages/medicines/human/medicines/002464/human_med_001568 jsp&mid=WC0b01ac058001d124 2012 (12.06.2018).
- 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(33): 4098–4103.
- Kuter DJ, Bain B, Mufti G, et al. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007; 139(3): 351–362.
- 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; 123(22): e123–e133.
- Campbell PJ, Scott LM, Baxter EJ, et al. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464): 1054–1061.
- Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7): e270.
- Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013; 369(25): 2391–2405.
- Tefferi A, Wassie EA, Lasho TL, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28(7): 1472–1477.
- Funakoshi-Tago M, Pelletier S, Matsuda T, et al. The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv Immunol. 1995; 60(52): 1–35.
- 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; 28(7): 1494–1500.
- Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell. 2001; 8(6): 1327–1338.
- Toms AV, Deshpande A, McNally R, et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol. 2013; 20(10): 1221–1223.
- Leroy E, Constantinescu SN, Leroy E, et al. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition. Leukemia. 2017; 31(5): 1023–1038.
- Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012; 489(7414): 155–159.
- Bhagwat N, Levine RL, Koppikar P. Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. Int J Hematol. 2013; 97(6): 695–702.
- 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): 1644–1654.
- 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): 809–818.
- Verstovsek S, Mesa RA, Gotlib J, et al. COMFORT-I investigators, COMFORT Investigators, COMFORT-I investigators. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010; 363(12): 1117–1127.
- Kvasnicka HM, Thiele J, Bueso-Ramos C. 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.
- Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol. 2018; 11(1): 42.
- Verstovsek S, Mesa RA, Gotlib J, et al. COMFORT-I investigators. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366(9): 799–807.
- Tefferi A, Barosi G, Mesa RA, et al. IWG for Myelofibrosis Research and Treatment (IWG-MRT). 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; 108(5): 1497–1503.
- 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): 1865–1871.
- 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): 1285–1292.
- 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): 508–516.
- 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): 787–798.
- 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): 229–239.
- Cervantes F, Vannucchi AM, Kiladjian JJ, et al. COMFORT-II investigators. 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): 4047–4053.
- Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015; 100(9): 1139–1145.
- Marchetti M, Barosi G, Cervantes F, et al. Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Leukemia. 2017; 31(4): 882–888.
- Martí-Carvajal AJ, Anand V, Solà I. Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis. Cochrane Database Syst Rev. 2015(4): CD010298.
- Barosi G, Rosti V, Gale RP. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis. Onco Targets Ther. 2015; 8: 1091–1102.
- Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood. 2017; 129(7): 832–837.
- Guglielmelli P, Biamonte F, Rotunno G, et al. COMFORT-II Investigators, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) Investigators. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014; 123(14): 2157–2160.
- Passamonti F, Caramazza D, Maffioli M. JAK inhibitor in CALR-mutant myelofibrosis. N Engl J Med. 2014; 370(12): 1168–1169.
- Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017; 8(45): 79073–79086.
- Pieri L, Paoli C, Arena U, et al. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms. Am J Hematol. 2017; 92(2): 187–195.
- Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016; 101(9): 1065–1073.
- Mead AJ, Milojkovic D, Knapper S, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015; 170(1): 29–39.
- Lancman G, Mascarenhas J. Should we be treating lower risk myelofibrosis patients with a JAK2 inhibitor? Expert Rev Hematol. 2017; 10(1): 23–28.
- Bjørn ME, Holmström MO, Hasselbalch HC. Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. Leuk Lymphoma. 2016; 57(1): 125–128.
- Grunwald MR, Spivak JL. Ruxolitinib enhances platelet production in patients with thrombocytopenic myelofibrosis. J Clin Oncol. 2016; 34(5): e38–e40.
- Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013; 122(7): 1192–1202.
- 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): 225–227.
- Colomba C, Rubino R, Siracusa L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes. 2012; 5: 552.
- Hopman RK, Lawrence SJ, Oh ST. Disseminated tuberculosis associated with ruxolitinib. Leukemia. 2014; 28(8): 1750–1751.
- Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest. 2013; 143(5): 1478–1479.
- Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013; 369(7): 681–683.
- Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013; 369(2): 197–198.
- Lussana F, Cattaneo M, Rambaldi A, et al. Ruxolitinib-associated infections: A systematic review and meta-analysis. Am J Hematol. 2018; 93(3): 339–347.
- Gupta V, Gotlib J, Radich JP, et al. Janus kinase inhibitors and allogeneic stem cell transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2014; 20(9): 1274–1281.
- Masarova L, Popat UR, Bose P, et al. Allogeneic stem cell transplantation versus medical therapy in patients with advanced myelofibrosis: matched survival analysis and the effect of JAK2 inhibitor therapy. Blood. 2016; 128: 4687.
- Shanavas M, Popat U, Michaelis LC, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 Inhibitors. Biol Blood Marrow Transplant. 2016; 22(3): 432–440.
- 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): 179–184.
- 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; 28(8): 1736–1738.
- Kröger N, Giorgino T, Scott BL, 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 3364.
- Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015; 29(11): 2126–2133.
