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Review

Novel Janus-kinase (JAK) Inhibitors in Myelofibrosis

ORCID Icon, ORCID Icon, ORCID Icon &
Pages 931-940 | Received 22 Jul 2023, Accepted 06 Oct 2023, Published online: 25 Oct 2023

References

  • Sureau L, Orvain C, Ianotto J-C, et al. Efficacy and tolerability of janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis. Blood Cancer J. 2021;11(7):135. doi: 10.1038/s41408-021-00526-z
  • Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016 Jun;101(6):660–671. doi: 10.3324/haematol.2015.141283
  • Kleppe M, Kwak M, Koppikar P, et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov. 2015 Mar;5(3):316–331. doi: 10.1158/2159-8290.CD-14-0736
  • Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435–441. doi: 10.1007/s00277-017-3194-4
  • 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. doi: 10.1056/NEJMoa1110557
  • Harrison CN, Vannucchi AM, Kiladjian J-J, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–1707. doi: 10.1038/leu.2016.148
  • Fonseca E, Silver RT, Kazis LE, et al. Ruxolitinib discontinuation in patients with myelofibrosis: an analysis from clinical practice. Blood. 2013;122(21):2833. doi: 10.1182/blood.V122.21.2833.2833
  • Bose P, Verstovsek S. JAK inhibition for the treatment of myelofibrosis: limitations and future perspectives. Hemasphere. 2020 Aug;4(4):e424. doi: 10.1097/HS9.0000000000000424
  • Tremblay D, Mesa R. New treatments for myelofibrosis. Curr Treat Options Oncol. 2023 Feb;24(2):61–75. doi: 10.1007/s11864-023-01052-9
  • Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023 May;98(5):801–821. doi: 10.1002/ajh.26857
  • GlaxoSmithKline. 2023 [cited 2023 Sep 15]. Available from: https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia/
  • Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):1–14. doi: 10.1186/s13045-017-0417-z
  • Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. doi: 10.1056/NEJMoa1110556
  • 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(5):643–651. doi: 10.1001/jamaoncol.2015.1590
  • Harrison C N, 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(7):e317–e324. doi: 10.1016/S2352-3026(17)30088-1
  • Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017 May;4(5):e225–e236. doi: 10.1016/S2352-3026(17)30027-3
  • 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(5):652–659. doi: 10.1001/jamaoncol.2017.5818
  • Mesa RA, Kiladjian J-J, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844–3850. doi: 10.1200/JCO.2017.73.4418
  • 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 Feb;5(2):e73–e81. doi: 10.1016/S2352-3026(17)30237-5
  • Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269–280. doi: 10.1016/S0140-6736(22)02036-0
  • Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244–248. doi: 10.1111/bjh.17727
  • Oh S, Mesa R, Harrison C, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood. 2022;140:1518–1521. doi: 10.1182/blood-2022-156936
  • Harrison CN, Gerds AT, Kiladjian J-J, et al. Pacifica: a randomized, controlled phase 3 study of Pacritinib vs. physician’s choice in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocytopenia myelofibrosis with severe thrombocytopenia (platelet count <50,000/mL). Blood. 2019;134(Supplement_1):4175–4175.
  • Reynolds SB, Pettit K. New approaches to tackle cytopenic myelofibrosis. Hematology. 2022;2022(1):235–244. doi: 10.1182/hematology.2022000340
  • 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 Mar 30;129(13):1823–1830. doi: 10.1182/blood-2016-09-740092
  • Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013 Jun;27(6):1322–1327. doi: 10.1038/leu.2013.71
  • Pardanani A, Gotlib J, Roberts AW, et al. Long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. Leukemia. 2018;32(4):1034–1037. doi: 10.1038/leu.2017.330
  • Gangat N, Begna KH, Al-Kali A, et al. Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival. Am J Hematol. 2023;98(2):282–289. doi: 10.1002/ajh.26778
  • Gupta V, Mesa RA, Deininger MW, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017 Jan;102(1):94–102. doi: 10.3324/haematol.2016.148924
  • Tefferi A, Barraco D, Lasho TL, et al. Momelotinib therapy for myelofibrosis: a 7-year follow-up. Blood Cancer J. 2018 Mar 7;8(3):29. doi: 10.1038/s41408-018-0067-6
  • Gerds A, Verstovsek S, Vannucchi A, et al. MPN-483 thrombocytopenic myelofibrosis (MF) patients Previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib (MMB) versus Danazol (DAN) [MOMENTUM]. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S340.
  • Liu J, Lv B, Yin H, et al. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple ascending dose and food effect study to evaluate the tolerance, pharmacokinetics of jaktinib, a New selective janus kinase inhibitor in healthy Chinese volunteers. Front Pharmacol. 2020;11:604314. doi: 10.3389/fphar.2020.604314
  • Zhang Y, Zhou H, Jiang Z, et al. Safety and efficacy of jaktinib in the treatment of janus kinase inhibitor-naïve patients with myelofibrosis: results of a phase II trial. Am J Hematol. 2022 Dec;97(12):1510–1519. doi: 10.1002/ajh.26709
  • Cargnin S, Serafini M, Pirali T. A primer of deuterium in drug design. Future Med Chem. 2019 Aug;11(16):2039–2042. doi: 10.4155/fmc-2019-0183
  • Tefferi A, Gangat N, Pardanani A. Jaktinib (JAK1/2 inhibitor): a momelotinib derivative with similar activity and optimized dosing schedule. Am J Hematol. 2022 Dec;97(12):1507–1509. doi: 10.1002/ajh.26712
  • Zhang Y, Zhou H, Duan M, et al. Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: a single-arm, open-label, phase 2, multicenter study. Am J Hematol. 2023 Jul 20;98(10):1588–1597. doi: 10.1002/ajh.27033
  • Zhang Y, Zhou H, Zhuang J, et al. A randomized, double-blind, phase 3 study of jaktinib versus hydroxyurea (HU) in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF). J Clin Oncol. 2023;41(16_suppl):7015–7015. doi: 10.1200/JCO.2023.41.16_suppl.7015
  • Covington M, He X, Scuron M, et al. Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases. Eur J Pharmacol. 2020;885:173505. doi: 10.1016/j.ejphar.2020.173505
  • 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 Apr 15;115(15):3109–3117. doi: 10.1182/blood-2009-04-214957
  • 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):1117–1127. doi: 10.1056/NEJMoa1002028
  • Mascarenhas J. Selective janus associated kinase 1 inhibition as a therapeutic target in myelofibrosis. Leukemia Lymphoma. 2015;56(9):2493–2497. doi: 10.3109/10428194.2015.1004670
  • Mascarenhas JO, Talpaz M, Gupta V, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017 Feb;102(2):327–335. doi: 10.3324/haematol.2016.151126
  • A study of itacitinib in combination with low-dose ruxolitinib or itacitinib alone following ruxolitinib in participants with myelofibrosis: ClinicalTrials.Gov; 2022 [cited 2023 Sep 19].
  • Moyo TK, Mendler JH, Itzykson R, et al. The ABNL-MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes [journal article]. BMC Cancer. 2022;22(1). doi: 10.1186/s12885-022-10073-w
  • Hexner EO, Serdikoff C, Jan M, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008;111(12):5663–5671. doi: 10.1182/blood-2007-04-083402
  • Hexner E, Goldberg JD, Prchal JT, et al. A multicenter, open label phase I/II study of CEP701 (lestaurtinib) in adults with myelofibrosis; a report on phase I: a study of the myeloproliferative Disorders research Consortium (MPD-RC). Blood. 2009;114(22):754–754. doi: 10.1182/blood.V114.22.754.754
  • Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010 Feb 11;115(6):1131–1136. doi: 10.1182/blood-2009-10-246363
  • Hexner EO, Mascarenhas J, Prchal J, et al. Phase I dose escalation study of lestaurtinib in patients with myelofibrosis. Leuk Lymphoma. 2015;56(9):2543–2551. doi: 10.3109/10428194.2014.1001986
  • Mascarenhas J, Baer MR, Kessler C, et al. Phase II trial of lestaurtinib, a JAK2 inhibitor, in patients with myelofibrosis. Leuk Lymphoma. 2019 May;60(5):1343–1345. doi: 10.1080/10428194.2018.1532509
  • Rosenthal A, Mesa RA. Janus kinase inhibitors for the treatment of myeloproliferative neoplasms. Expert Opin Pharmacother. 2014 Jun;15(9):1265–1276. doi: 10.1517/14656566.2014.913024
  • Ma L, Clayton JR, Walgren RA, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013 Apr 12;3(4):e109. doi: 10.1038/bcj.2013.6
  • Verstovsek S, Mesa RA, Salama ME, et al. A phase 1 study of the janus kinase 2 (JAK2)(V617F) inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Leuk Res. 2017 Oct;61:89–95.
  • Berdeja J, Palandri F, Baer MR, et al. Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms. Leuk Res. 2018 Aug;71:82–88.
  • Purandare AV, McDevitt TM, Wan H, et al. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280–288. doi: 10.1038/leu.2011.292
  • Wan H, Schroeder GM, Hart AC, et al. Discovery of a highly selective JAK2 inhibitor, BMS-911543, for the treatment of myeloproliferative neoplasms. ACS Med Chem Lett. 2015 Aug 13;6(8):850–855. doi: 10.1021/acsmedchemlett.5b00226
  • Pomicter AD, Eiring AM, Senina AV, et al. Limited efficacy of BMS-911543 in a murine model of janus kinase 2 V617F myeloproliferative neoplasm. Exp Hematol. 2015 Jul;43(7):537-45.e1–11. doi: 10.1016/j.exphem.2015.03.006
  • Tyner JW, Bumm TG, Deininger J, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115(25):5232–5240. doi: 10.1182/blood-2009-05-223727
  • Pardanani A, Roberts AW, Seymour JF, et al. BMS-911543, a selective JAK2 inhibitor: a multicenter phase 1/2a study in myelofibrosis. Blood. 2013;122(21):664. doi: 10.1182/blood.V122.21.664.664
  • Gangat N, Begna KH, Al-Kali A, et al. Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor. Blood Cancer J. 2023 Jan 4;13(1):3. doi: 10.1038/s41408-022-00780-9
  • Pettit K, Rezazadeh A, Atallah EL, et al. Management of Myeloproliferative Neoplasms in the molecular era: from research to practice. Am Soc Clin Oncol Educ Book. 2022 Apr;42:1–19.
  • Nakaya Y, Shide K, Naito H, et al. Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis. Blood Cancer J. 2014 Jan 10;4(1):e174. doi: 10.1038/bcj.2013.73
  • Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017 Feb;31(2):393–402. doi: 10.1038/leu.2016.215
  • Verstovsek S, Talpaz M, Ritchie EK, et al. Phase 1/2 study of NS-018, an oral JAK2 inhibitor, in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF). Blood. 2016;128(22):1936. doi: 10.1182/blood.V128.22.1936.1936
  • Zhang W, Liu J, Shi Z, et al. P1004: effect and molecular mechanism of TQ05105, a novel small molecule inhibitor of JAK2 in myeloproliferative neoplasm. Hemasphere. 2022;6(Suppl):894–895. doi: 10.1097/01.HS9.0000846884.97738.71
  • Yang T, Hu M, Qi W, et al. Discovery of potent and orally effective dual janus kinase 2/FLT3 inhibitors for the treatment of acute myelogenous Leukemia and Myeloproliferative Neoplasms. J Med Chem. 2019;62(22):10305–10320. doi: 10.1021/acs.jmedchem.9b01348
  • Zhu J, Yang T, Tang M, et al. Studies on the anti-psoriasis effects and its mechanism of a dual JAK2/FLT3 inhibitor flonoltinib maleate. Biomed Pharmacother. 2021;137:111373. doi: 10.1016/j.biopha.2021.111373
  • Hu M, Yang T, Yang L, et al. Preclinical studies of flonoltinib maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2(V617F)-induced myeloproliferative neoplasms. Blood Cancer J. 2022 Mar 7;12(3):37. doi: 10.1038/s41408-022-00628-2

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