JAK-Inhibitoren für die Behandlung hämatoonkologischer Erkrankungen

Einleitung

Der deregulierte und aktivierte Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-Signalweg spielt nicht nur eine Schlüsselrolle in der Pathogenese von Autoimmunerkrankungen wie rheumatoider Arthritis (RA), systemischem Lupus erythematodes, chronisch-entzündlicher Darmerkrankungen und Vaskulitiden [1], sondern ist auch ein wesentlicher Treiber für die myeloproliferativen Neoplasien (MPN), speziell der Polycythaemia vera (PV), der essentiellen Thrombozythämie (ET) und der primären sowie sekundären (post-PV- und post-ET-) Myelofibrose (MF) [2]. Zudem wird die inflammatorische Aktivität der Graft-versus-Host-Erkrankung (GvHD) nach allogener hämatopoetischer Stammzelltransplantation (allo-HSCT) zu einem überwiegenden Teil über den JAK-STAT-Signalweg vermittelt [3]. Durch pharmakologische Hemmung der JAK-Proteine lässt sich die Aktivität dieses Signalwegs herabregulieren, sodass sowohl die genannten entzündlich-rheumatischen Erkrankungen als auch die hämatoonkologischen Entitäten wirksam therapiert werden können. Für die rheumatologische Indikation RA sind in Europa die JAK-Inhibitoren Baricitinib, Upadacitinib und Tofacitinib zugelassen, letzteres zudem bei Colitis ulcerosa und Psoriasis-Arthritis [4]. Die Zulassung für Filgotinib wird darüber hinaus in Kürze erwartet.

Publication History

Article published online:
07 April 2021

• Literatur

• 1 You H, Xu D, Zhao J. et al JAK Inhibitors: Prospects in Connective Tissue Diseases. Clin Rev Allergy Immunol 2020; (Online ahead of print)
• 2 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: e123-e133
• 3 Zeiser R, Burchert A, Lengerke C. et al. Ruxolitinib in corticosteroidrefractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29: 2062-2068
• 4 Witte T. JAK-Inhibitoren in der Rheumatologie. Dtsch Med Wochenschr 2019; 144: 748-752
• 5 Ajayi S, Becker H, Reinhardt H. et al. Ruxolitinib. Recent Results Cancer Res 2018; 212: 119-132
• 6 Tefferi A. Myeloproliferative neoplasms: A decade of discoveries and treatment advances. Am J Hematol 2016; 91: 50-58
• 7 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391-2405
• 8 Tremblay D, Schwartz M, Bakst R. et al. Modern management of splenomegaly in patients with myelofibrosis. Ann Hematol 2020; 99: 1441-1451
• 9 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: 2126-2133
• 10 Iurlo A, Cattaneo D, Gianelli U. Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options. Int J Mol Sci 2019; 20: 1839
• 11 Tallarico M, Odenike O. Secondary acute myeloid leukemias arising from Philadelphia chromosome negative myeloproliferative neoplasms: pathogenesis, risk factors, and therapeutic strategies. Curr Hematol Malig Rep 2015; 10: 112-117
• 12 Kennedy JA, Atenafu EG, Messner HA. et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood 2013; 121: 2725-2733
• 13 Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci 2018; 27: 1984-2009
• 14 Tiong IS, Casolari DA, Moore S. et al. Apparent ‘JAK2-negative’ polycythaemia vera due to compound mutations in exon 14. Br J Haematol 2017; 178: 333-336
• 15 Greenfield G, McPherson S, Mills K. et al. The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms. J Transl Med 2018; 16: 360
• 16 Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 2017; 129: 667-679
• 17 Nangalia J, Grinfeld J, Green AR. Pathogenesis of Myeloproliferative Disorders. Annu Rev Pathol 2016; 11: 101-126
• 18 Tefferi A, Guglielmelli P, Larson DR. et al Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124: 2507-2513 . quiz 2615
• 19 Milosevic Feenstra JD, Nivarthi H, Gisslinger H. et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 2016; 127: 325-332
• 20 Rumi E, Barate C, Benevolo G. et al. Myeloproliferative and lymphoproliferative disorders: State of the art. Hematol Oncol 2020; 38: 121-128
• 21 Harrison CN, Schaap N, Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann Hematol 2020; 99: 1177-1191
• 22 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: 2895-2901
• 23 Passamonti F, Cervantes F, Vannucchi AM. et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115: 1703-1708
• 24 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: 392-397
• 25 Guglielmelli P, Lasho TL, Rotunno G. et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol 2018; 36: 310-318
• 26 Tefferi A, Guglielmelli P, Lasho TL. et al. MIPSS70 + Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol 2018; 36: 1769-1770
• 27 Tefferi A, Guglielmelli P, Nicolosi M. et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia 2018; 32: 1631-1642
• 28 Barbui T, Tefferi A, Vannucchi AM. et al. Philadelphia chromosomenegative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 2018; 32: 1057-1069
• 29 Vannucchi AM, Kiladjian JJ, Griesshammer M. et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 426-435
• 30 DGHO. Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO). Leitlinienportal Onkopedia. Verfügbar unter. https://www.onkopedia.com/de/onkopedia/guidelines Zugegriffen: 02.09.2020
• 31 Tiribelli M, Palandri F, Sant’Antonio E. et al. The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review. Bone Marrow Transplant 2020; 55: 708-716
• 32 McLornan DP, Yakoub-Agha I, Robin M. et al. State-of-the-art review: allogeneic stem cell transplantation for myelofibrosis in 2019. Haematologica 2019; 104: 659-668
• 33 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: 432-440
• 34 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: 508-516
• 35 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: 1117-1127
• 36 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
• 37 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: 787-798
• 38 Al-Ali HK, Griesshammer M, Foltz L. et al. Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Br J Haematol 2020; 189: 888-903
• 39 Verstovsek S, Gotlib J, Mesa RA. et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol 2017; 10: 156
• 40 Quintás-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: 3109-3117
• 41 Bose P, Verstovsek S. JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives. Hemasphere 2020; 4: e424
• 42 Rudolph J, Heine A, Quast T. et al. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia 2016; 30: 2119-2123
• 43 Pemmaraju N, Kantarjian H, Nastoupil L. et al. Characteristics of patients with myeloproliferative neoplasms with lymphoma, with or without JAK inhibitor therapy. Blood 2019; 133: 2348-2351
• 44 Porpaczy E, Tripolt S, Hoelbl-Kovacic A. et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood 2018; 132: 694-706
• 45 Rumi E, Zibellini S. JAK inhibitors and risk of B-cell lymphomas. Blood 2019; 133: 2251-2253
• 46 Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86: 1188-1191
• 47 Coltro G, Mannelli F, Guglielmelli P. et al. A life-threatening ruxolitinib discontinuation syndrome. Am J Hematol 2017; 92: 833-838
• 48 Newberry KJ, Patel K, Masarova L. et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood 2017; 130: 1125-1131
• 49 Palandri F, Breccia M, Bonifacio M. et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 2020; 126: 1243-1252
• 50 Pardanani A, Harrison C, Cortes JE. et al. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol 2015; 1: 643-651
• 51 Harrison CN, Schaap N, Vannucchi AM. et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol 2017; 4: e317-e324
• 52 Mullally A, Hood J, Harrison C. et al. Fedratinib in myelofibrosis. Blood Adv 2020; 4: 1792-1800
• 53 Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia 2020; (Online ahead of print)
• 54 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: 1656-1662
• 55 Iurlo A, Cattaneo D, Bucelli C. Management of Myelofibrosis: from Diagnosis to New Target Therapies. Curr Treat Options Oncol 2020; 21: 46
• 56 Singer JW, Al-Fayoumi S, Ma H. et al. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol 2016; 8: 11-19
• 57 Mascarenhas J, Hoffman R, Talpaz M. et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol 2018; 4: 652-659
• 58 Asshoff M, Petzer V, Warr MR. et al. Momelotinib inhibits ACVR1 / ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood 2017; 129: 1823-1830
• 59 Mesa RA, Kiladjian JJ, Catalano JV. et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients With Myelofibrosis. J Clin Oncol 2017; 35: 3844-3850
• 60 Harrison CN, Vannucchi AM, Platzbecker U. et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol 2018; 5: e73-e81
• 61 Daver N, Cortes J, Newberry K. et al. Ruxolitinib in combination with lenalidomide as therapy for patients with myelofibrosis. Haematologica 2015; 100: 1058-1063
• 62 Martin PJ, Rizzo JD, Wingard JR. et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012; 18: 1150-1163
• 63 Zeiser R, Blazar BR. Acute Graft-versus-Host Disease − Biologic Process, Prevention, and Therapy. N Engl J Med 2017; 377: 2167-2179
• 64 Zhang L, Yu J, Wei W. Advance in Targeted Immunotherapy for Graft-Versus-Host Disease. Front Immunol 2018; 9: 1087
• 65 Khoury HJ, Wang T, Hemmer MT. et al. Improved survival after acute graft-versus-host disease diagnosis in the modern era. Haematologica 2017; 102: 958-966
• 66 Spoerl S, Mathew NR, Bscheider M. et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123: 3832-3842
• 67 Jagasia M, Perales MA, Schroeder MA. et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood 2020; 135: 1739-1749
• 68 Przepiorka D, Luo L, Subramaniam S. et al. FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease. Oncologist 2020; 25: e328-e334
• 69 Zeiser R, von Bubnoff N, Butler J. et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 2020; 382: 1800-1810
• 70 Zeiser R, Socié G. The development of ruxolitinib for glucocorticoidrefractory acute graft-versus-host disease. Blood Adv 2020; 4: 3789-3794
• 71 Modi B, Hernandez-Henderson M, Yang D. et al. Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 2019; 25: 265-269
• 72 Jagasia M, Zeiser R, Arbushites M. et al. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy 2018; 10: 391-402
• 73 Khoury HJ, Langston AA, Kota VK. et al. Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 2018; 53: 826-831
• 74 Abedin S, McKenna E, Chhabra S. et al. Efficacy, Toxicity, and Infectious Complications in Ruxolitinib-Treated Patients with Corticosteroid-Refractory Graft-versus-Host Disease after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2019; 25: 1689-1694
• 75 Mannina D, Kröger N. Janus Kinase Inhibition for Graft-Versus-Host Disease: Current Status and Future Prospects. Drugs 2019; 79: 1499-1509