Ruxolitinib: a Potent and Selective Janus Kinase 1 and 2 Inhibitor in Patients with Myelofibrosis. An Update for Clinicians

Overview

Journal Ther Adv Hematol

Specialty Hematology

Date 2013 Apr 23

PMID 23606937

Citations 22

Authors

Claire Harrison

Alessandro M Vannucchi

Affiliations

Soon will be listed here.

Abstract

Ruxolitinib became the first US Food and Drug Administration approved therapy for myelofibrosis in 2011 and EU approval is anticipated in summer 2012. Two large phase III trials (known as the COMFORT studies) were the basis for this approval and were published recently. In this review article we discuss the challenges in managing myelofibrosis, the information to date about ruxolitinib and speculate as to the future direction with this and similar agents.

Citing Articles

Shaping the Future of Myeloproliferative Neoplasm Therapy: Immune-Based Strategies and Targeted Innovations.

Carturan A, More S, Poloni A, Rupoli S, Morsia E Cancers (Basel). 2024; 16(23).

PMID: 39682299 PMC: 11640548. DOI: 10.3390/cancers16234113.

Trans-vaccenic acid reprograms CD8 T cells and anti-tumour immunity.

Fan H, Xia S, Xiang J, Li Y, Ross M, Lim S Nature. 2023; 623(7989):1034-1043.

PMID: 37993715 PMC: 10686835. DOI: 10.1038/s41586-023-06749-3.

Lupus Nephritis: New and Emerging Biologic and Targeted Therapies.

Kale A, Lech M, Anders H, Gaikwad A BioDrugs. 2023; 37(4):463-475.

PMID: 37093522 DOI: 10.1007/s40259-023-00597-3.

New approaches to tackle cytopenic myelofibrosis.

Reynolds S, Pettit K Hematology Am Soc Hematol Educ Program. 2022; 2022(1):235-244.

PMID: 36485113 PMC: 9820710. DOI: 10.1182/hematology.2022000340.

Immune response and possible therapeutics in COVID-19.

Dutta A, Roy A, Roy L, Chattopadhyay S, Chatterjee S RSC Adv. 2022; 11(2):960-977.

PMID: 35423713 PMC: 8693424. DOI: 10.1039/d0ra08901j.

References

Baxter E, Scott L, Campbell P, East C, Fourouclas N, Swanton S . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-61. DOI: 10.1016/S0140-6736(05)71142-9. View

Wernig G, Mercher T, Okabe R, Levine R, Lee B, Gilliland D . Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006; 107(11):4274-81. PMC: 1895786. DOI: 10.1182/blood-2005-12-4824. View

Tyner J, Bumm T, Deininger J, Wood L, Aichberger K, Loriaux M . CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010; 115(25):5232-40. PMC: 2892953. DOI: 10.1182/blood-2009-05-223727. View

Kiladjian J, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M . Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008; 112(8):3065-72. DOI: 10.1182/blood-2008-03-143537. View

Passamonti F, Cervantes F, Vannucchi A, Morra E, Rumi E, Pereira A . 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. 2009; 115(9):1703-8. DOI: 10.1182/blood-2009-09-245837. View

Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S . 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. 2010; 29(4):392-7. DOI: 10.1200/JCO.2010.32.2446. View

Harutyunyan A, Klampfl T, Cazzola M, Kralovics R . p53 lesions in leukemic transformation. N Engl J Med. 2011; 364(5):488-90. DOI: 10.1056/NEJMc1012718. View

Santos F, Kantarjian H, Jain N, Manshouri T, Thomas D, Garcia-Manero G . Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2009; 115(6):1131-6. PMC: 4081385. DOI: 10.1182/blood-2009-10-246363. View

Pikman Y, Lee B, Mercher T, McDowell E, Ebert B, Gozo M . MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7):e270. PMC: 1502153. DOI: 10.1371/journal.pmed.0030270. View

10.

Grand F, Hidalgo-Curtis C, Ernst T, Zoi K, Zoi C, McGuire C . Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009; 113(24):6182-92. DOI: 10.1182/blood-2008-12-194548. View

11.

James C, Ugo V, Le Couedic J, Staerk J, Delhommeau F, Lacout C . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005; 434(7037):1144-8. DOI: 10.1038/nature03546. View

12.

Harrison C, Kiladjian J, Al-Ali H, Gisslinger H, Waltzman R, Stalbovskaya V . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366(9):787-98. DOI: 10.1056/NEJMoa1110556. View

13.

Lu M, Wang J, Li Y, Berenzon D, Wang X, Mascarenhas J . Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon α specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells. Blood. 2010; 116(20):4284-7. PMC: 2993627. DOI: 10.1182/blood-2010-04-279125. View

14.

Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M . EZH2 mutational status predicts poor survival in myelofibrosis. Blood. 2011; 118(19):5227-34. DOI: 10.1182/blood-2011-06-363424. View

15.

DeAngelo D, Mesa R, Fiskus W, Tefferi A, Paley C, Wadleigh M . Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. Br J Haematol. 2013; 162(3):326-35. DOI: 10.1111/bjh.12384. View

16.

Verstovsek S, Kantarjian H, Mesa R, Pardanani A, Cortes-Franco J, Thomas D . Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010; 363(12):1117-27. PMC: 5187954. DOI: 10.1056/NEJMoa1002028. View

17.

Fridman J, Scherle P, Collins R, Burn T, Li Y, Li J . Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010; 184(9):5298-307. DOI: 10.4049/jimmunol.0902819. View

18.

Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C . Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012; 119(20):4614-8. PMC: 4081383. DOI: 10.1182/blood-2011-12-400051. View

19.

Vannucchi A . From palliation to targeted therapy in myelofibrosis. N Engl J Med. 2010; 363(12):1180-2. DOI: 10.1056/NEJMe1005856. View

20.

Hexner E, Serdikoff C, Jan M, Swider C, Robinson C, Yang S . Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2007; 111(12):5663-71. PMC: 2424161. DOI: 10.1182/blood-2007-04-083402. View