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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2012

Open Access 01-12-2012 | Review

Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

Authors: Jasleen Randhawa, Alen Ostojic, Radovan Vrhovac, Ehab Atallah, Srdan Verstovsek

Published in: Journal of Hematology & Oncology | Issue 1/2012

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Abstract

Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.
Literature
1.
Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000, 342: 1255-1265. 10.1056/NEJM200004273421706.CrossRefPubMed
2.
Hsieh PP, Olsen RJ, O'Malley DP, Konoplev SN, Hussong JW, Dunphy CH, Perkins SL, Cheng L, Lin P, Chang CC: The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders. Mod Pathol. 2007, 20: 929-935. 10.1038/modpathol.3800826.CrossRefPubMed
3.
Levine RL, Pardanani A, Tefferi A, Gilliland DG: Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007, 7: 673-683. 10.1038/nrc2210.CrossRefPubMed
4.
Verstovsek S: Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res. 2010, 16: 1988-1996. 10.1158/1078-0432.CCR-09-2836.CrossRefPubMed
5.
Mesa RA, Nagorney DS, Schwager S, Allred J, Tefferi A: Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006, 107: 361-370. 10.1002/cncr.22021.CrossRefPubMed
6.
Barosi G: Conventional and Investigational Therapy for Primary Myelofibrosis. Myeloproliferative Neoplasms: Biology and Therapy. Edited by: Verstovsek S, Tefferi A. 2011, Humana Press, New York, 117-138. Karp JE (Series Editor): Contemporary HematologyCrossRef
7.
Mesa RA: How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood. 2009, 113: 5394-5400. 10.1182/blood-2009-02-195974.CrossRefPubMed
8.
Elliott MA, Chen MG, Silverstein MN, Tefferi A: Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 1998, 103: 505-511. 10.1046/j.1365-2141.1998.00998.x.CrossRefPubMed
9.
Silverstein MN: Control of hypersplenism and painful splenomegaly in myeloid metaplasia by irradiation. Int J Radiat Oncol Biol Phys. 1977, 2: 1221-1222. 10.1016/0360-3016(77)90137-7.CrossRefPubMed
10.
Pardanani A, Brown P, Neben-Wittich M, Tobin R, Tefferi A: Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy. Am J Hematol. 2010, 85: 715-716. 10.1002/ajh.21799.CrossRefPubMed
11.
Lofvenberg E, Wahlin A: Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol. 1988, 41: 375-381.CrossRefPubMed
12.
Martinez-Trillos A, Gaya A, Maffioli M, Arellano-Rodrigo E, Calvo X, Diaz-Beya M, Cervantes F: Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol. 2010, 89: 1233-1237. 10.1007/s00277-010-1019-9.CrossRefPubMed
13.
Sirhan S, Lasho TL, Hanson CA, Mesa RA, Pardanani A, Tefferi A: The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol. 2008, 83: 363-365. 10.1002/ajh.21149.CrossRefPubMed
14.
Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odenike O, Cortes J, Wadleigh M, Solberg LA, Camoriano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Hoffman R, Cross NC, Gilliland DG, Kantarjian H: 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: 1497-1503. 10.1182/blood-2006-03-009746.CrossRefPubMed
15.
Mesa RA, Steensma DP, Pardanani A, Li CY, Elliott M, Kaufmann SH, Wiseman G, Gray LA, Schroeder G, Reeder T, Zeldis JB, Tefferi A: A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003, 101: 2534-2541. 10.1182/blood-2002-09-2928.CrossRefPubMed
16.
Thapaliya P, Tefferi A, Pardanani A, Steensma DP, Camoriano J, Wu W, Geyer S, Mesa RA: International working group for myelofibrosis research and treatment response assessment and long-term follow-up of 50 myelofibrosis patients treated with thalidomide-prednisone based regimens. Am J Hematol. 2011, 86: 96-98. 10.1002/ajh.21892.CrossRefPubMed
17.
Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL, Hogan WJ, Litzow MR, Allred JB, Jones D, Byrne C, Zeldis JB, Ketterling RP, McClure RF, Giles F, Kantarjian HM: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006, 108: 1158-1164. 10.1182/blood-2006-02-004572.CrossRefPubMed
18.
Quintas-Cardama A, Kantarjian HM, Manshouri T, Thomas D, Cortes J, Ravandi F, Garcia-Manero G, Ferrajoli A, Bueso-Ramos C, Verstovsek S: Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol. 2009, 27: 4760-4766. 10.1200/JCO.2009.22.6548.CrossRefPubMed
19.
Jabbour E, Thomas D, Kantarjian H, Zhou L, Pierce S, Cortes J, Verstovsek S: Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood. 2011, 118: 899-902. 10.1182/blood-2010-12-325589.PubMedCentralCrossRefPubMed
20.
Tefferi A, Lasho TL, Mesa RA, Pardanani A, Ketterling RP, Hanson CA: Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia. 2007, 21: 1827-1828. 10.1038/sj.leu.2404711.CrossRefPubMed
21.
Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, Gisslinger H, Paquette RL, Cervantes F, Rivera CE, Deeg HJ, Thiele J, Kvasnicka HM, Vardiman JW, Zhang Y, Bekele BN, Mesa RA, Gale RP, Kantarjian HM: Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009, 27: 4563-4569. 10.1200/JCO.2008.21.7356.CrossRefPubMed
22.
Mesa RA, Pardanani AD, Hussein K, Wu W, Schwager S, Litzow MR, Hogan WJ, Tefferi A: Phase1/-2 study of Pomalidomide in myelofibrosis. Am J Hematol. 2010, 85: 129-130.PubMed
23.
Begna KH, Mesa RA, Pardanani A, Hogan WJ, Litzow MR, McClure RF, Tefferi A: A phase-2 trial of low-dose pomalidomide in myelofibrosis. Leukemia. 2011, 25: 301-304. 10.1038/leu.2010.254.CrossRefPubMed
24.
Petti MC, Latagliata R, Spadea T, Spadea A, Montefusco E, Aloe Spiriti MA, Avvisati G, Breccia M, Pescarmona E, Mandelli F: Melphalan treatment in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002, 116: 576-581. 10.1046/j.0007-1048.2001.03331.x.CrossRefPubMed
25.
Manoharan A, Pitney WR: Chemotherapy resolves symptoms and reverses marrow fibrosis in myelofibrosis. Scand J Haematol. 1984, 33: 453-459.CrossRefPubMed
26.
Stott H, Fox W, Girling DJ, Stephens RJ, Galton DA: Acute leukaemia after busulphan. British medical journal. 1977, 2: 1513-1517. 10.1136/bmj.2.6101.1513.PubMedCentralCrossRefPubMed
27.
Finazzi G, Ruggeri M, Rodeghiero F, Barbui T: Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol. 2000, 110: 577-583. 10.1046/j.1365-2141.2000.02188.x.CrossRefPubMed
28.
Foa P, Iurlo A, Maiolo A: Renal cancer after busulphan treatment for chronic myeloid leukemia: therapeutic implications. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 1993, 4: 521-522.
29.
Quintas-Cardama A, Tong W, Kantarjian H, Thomas D, Ravandi F, Kornblau S, Manshouri T, Cortes JE, Garcia-Manero G, Verstovsek S: A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia. 2008, 22: 965-970. 10.1038/leu.2008.91.PubMedCentralCrossRefPubMed
30.
Odenike OM, Godwin JE, Van Besien K, Huo D, Sher D, Burke P, Smith SE, Green M, Melnick J, Wade JL, Lester EP, Klisovic RB, Baer MR, Larson RA, Stock W: Phase II trial of low dose, subcutaneous decitabine in myelofibrosis. Blood [ASH Annual Meeting Abstracts]. 2008, 112: 2809-
31.
Faoro LN, Tefferi A, Mesa RA: Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Eur J Haematol. 2005, 74: 117-120. 10.1111/j.1600-0609.2004.00370.x.CrossRefPubMed
32.
33.
Verstovsek S, The American Society of Clinical Oncology The American Society of Clinical Oncology, The American Society of Clinical Oncology The American Society of Clinical Oncology: Myeloproliferative disorders: JAK2 and beyond. American Society of Clinical Oncology 2011 Educational Book. 2011, The American Society of Clinical Oncology, Alexandria, VA, 256-261.
34.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005, 365: 1054-1061.CrossRefPubMed
35.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005, 352: 1779-1790. 10.1056/NEJMoa051113.CrossRefPubMed
36.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer cell. 2005, 7: 387-397. 10.1016/j.ccr.2005.03.023.CrossRefPubMed
37.
Delhommeau F, Pisani DF, James C, Casadevall N, Constantinescu S, Vainchenker W: Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006, 63: 2939-2953. 10.1007/s00018-006-6272-7.CrossRefPubMed
38.
Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A, Skoda RC: Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood. 2006, 108: 1377-1380. 10.1182/blood-2005-11-009605.CrossRefPubMed
39.
Mesa RA: Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2007, 355-362.
40.
41.
Verstovsek S: Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009, 636-642.
42.
Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, Estrov Z, Fridman JS, Bradley EC, Erickson-Viitanen S, Vaddi K, Levy R, Tefferi A: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010, 363: 1117-1127. 10.1056/NEJMoa1002028.CrossRefPubMed
43.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012, 366: 799-807. 10.1056/NEJMoa1110557.CrossRefPubMed
44.
Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012, 366: 787-798. 10.1056/NEJMoa1110556.CrossRefPubMed
45.
Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J, Mak CC, Noronha G, Martin M, Ko YD, Lee BH, Soll RM, Tefferi A, Hood JD, Gilliland DG: Efficacy of TG101348, a selective JAK2 Inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer cell. 2008, 13: 311-320. 10.1016/j.ccr.2008.02.009.CrossRefPubMed
46.
Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A: TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008, 22: 1790-1792. 10.1038/leu.2008.56.CrossRefPubMed
47.
Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A: Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011, 29: 789-796. 10.1200/JCO.2010.32.8021.CrossRefPubMed
48.
Mesa RA, Yao X, Cripe LD, Li CY, Litzow M, Paietta E, Rowe JM, Tefferi A, Tallman MS: Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood. 2010, 116: 4436-4438. 10.1182/blood-2010-05-287417.PubMedCentralCrossRefPubMed
49.
Pardanani AD, Caramazza D, George G, Lasho TL, Hogan WJ, Litzow MR, Begna K, Hanson CA, McClure RF, Bavisotto LM, Smith G, Kowalski M, Sirhan S, Roberts AW, Gupta V, Gotlib J, Tefferi A: Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. J Clin Oncol. 2011, 29 (suppl; abstr 6514): 422s-
50.
Komrokji RS, Wadleigh M, Seymour JF, Roberts AW, To LB, Zhu HJ, Mesa R, To LB, Zhu HJ, Mesa RA: Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. Blood. 2011, 118: Abstract 282
51.
Santos FP, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, Kennedy D, Estrov Z, Cortes J, Verstovsek S: Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010, 115: 1131-1136. 10.1182/blood-2009-10-246363.PubMedCentralCrossRefPubMed
52.
Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, Biamonte F, Bartalucci N, Gattoni E, Lupo ML, Finazzi G, Pancrazzi A, Antonioli E, Susini MC, Pieri L, Malevolti E, Usala E, Occhini U, Grossi A, Caglio S, Paratore S, Bosi A, Barbui T, Vannucchi AM, investigators AI-GIMM: Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011, 118: 2069-2076. 10.1182/blood-2011-01-330563.PubMedCentralCrossRefPubMed
Metadata
Title
Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors
Authors
Jasleen Randhawa
Alen Ostojic
Radovan Vrhovac
Ehab Atallah
Srdan Verstovsek
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2012
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-5-43

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