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Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 6/2020

01-12-2020 | Wernicke's Encephalopathy | Myeloproliferative Neoplasms (B Stein, Section Editor)

The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib

Authors: Anand A. Patel, Olatoyosi Odenike

Published in: Current Hematologic Malignancy Reports | Issue 6/2020

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Abstract

Purpose of Review

Ruxolitinib is the first FDA-approved JAK inhibitor for the treatment of myeloproliferative neoplasms and is an effective means of controlling symptom burden and improving splenomegaly. However, a majority of patients will develop disease progression with long-term use. Fedratinib, momelotinib, and pacritinib are three newer-generation JAK inhibitors being prospectively evaluated and we will discuss their roles in the treatment of myeloproliferative neoplasms.

Recent Findings

Fedratinib has a role in both JAK-inhibitor naive intermediate-/high-risk myelofibrosis patients and in patients that have previously received ruxolitinib. It has recently received FDA approval for these indications as well. Momelotinib does not appear to have an advantage over ruxolitinib with regards to improving splenomegaly in intermediate-/high-risk JAK-inhibitor naive myelofibrosis. However, increased rates of transfusion independence have been noted with momelotinib. Pacritinib has been studied in myelofibrosis patients with significant baseline anemia and thrombocytopenia; these trials support the use of pacritinib in myelofibrosis patients with significant thrombocytopenia.

Summary

While ruxolitinib is effective in reducing the symptom burden and splenomegaly of patients with myeloproliferative neoplasms, a majority of patients will ultimately progress on therapy. Newer-generation JAK inhibitors including fedratinib, momelotinib, and pacritinib are being prospectively evaluated to determine their appropriate roles in the management of myeloproliferative neoplasms. In addition, both combination therapies with JAK inhibitors and novel investigational therapies are being actively explored.
Literature
1.
Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372–5.CrossRef
2.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.CrossRef
3.
James C, Ugo V, Le Couédic J-P, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.CrossRef
4.
Kralovics R, Passamonti F, Buser AS, Teo S-S, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.CrossRef
5.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJP, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.CrossRef
6.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.CrossRef
7.
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.CrossRef
8.
Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459–68.CrossRef
9.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.CrossRef
10.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.CrossRef
11.
• Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017;129:680–92. Comprehensive review detailing Ph-negative MPNs, the molecular features of these diseases, risk stratification, and how to best evaluate for response.
12.
Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109–17.CrossRef
13.
• Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807. Double-blind RCT establishing ruxolitinib as a treatment strategy compared to placebo in symptomatic, advanced-risk myelofibrosis patients with splenomegaly.
14.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100:479–88.CrossRef
15.
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, 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;10:55.CrossRef
16.
• Harrison C, Kiladjian J-J, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98. RCT establishing ruxolitinib as a treatment strategy compared to best available therapy in symptomatic, advanced-risk myelofibrosis patients with splenomegaly.
17.
Harrison CN, Vannucchi AM, Kiladjian J-J, Al-Ali HK, Gisslinger H, Knoops L, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30:1701–7.CrossRef
18.
• Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426–35. RCT establishing ruxolitinib as a treatment strategy compared to standard therapy in polycythemia vera patients with an inadequate response to hydroxyurea.
19.
Kiladjian J-J, Zachee P, Hino M, Pane F, Masszi T, Harrison CN, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020; Available from: https://​doi.​org/​10.​1016/​S2352-3026(19)30207-8.
20.
Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614–8.CrossRef
21.
Pemmaraju N, Kantarjian H, Kadia T, Cortes J, Borthakur G, Newberry K, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:171–6.CrossRef
22.
• Odenike O. How I treat the blast phase of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood. 2018;132:2339–50. Comprehensive review of treatment strategies in myeloproliferative neoplasms that have progressed to blast phase.
23.
•• Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1:643–51. RCT demonstrating the efficacy of fedratinib in symptomatic, advanced-risk, JAK-inhibitor naive myelofibrosis patients with compared to placebo.
24.
•• Harrison CN, Schaap N, Vannucchi AM, Kiladjian J-J, Tiu RV, Zachee P, 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:e317–24. Single-arm open-label trial demonstrating efficacy of fedratinib in symptomatic, advanced-risk, myelofibrosis patients that had previously received ruxolitinib.
25.
•• Mesa RA, Kiladjian J-J, Catalano JV, Devos T, Egyed M, Hellmann A, 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;35:3844–50. RCT demonstrating non-inferiority of momelotinib when compared to ruxolitinib in symptomatic, advanced-risk, myelofibrosis patients.
26.
•• Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, 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:e73–81. RCT demonstrating that momelotinib was not superior to best available therapy in symptomatic, advanced-risk, myelofibrosis patients that had previously received ruxolitinib.
27.
•• Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov 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;4:e225–36. RCT demonstrating superiority of pacritinib compared to best available therapy excluding JAK inhibition in symptomatic, advanced-risk, JAK-inhibitor naive myelofibrosis irrespective of baseline cytopenias.
28.
•• Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4:652–9. RCT demonstrating superiorty of pacritinib compared to best available therapy including ruxolitinib in symptomatic, advanced-risk, myelofibrosis with thrombocytopenia.
29.
Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29:789–96.CrossRef
30.
Jamieson C, Hasserjian R, Gotlib J, Cortes J, Stone R, Talpaz M, et al. Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis. J Transl Med. 2015;13:294.CrossRef
31.
• Harrison CN, Mesa RA, Jamieson C, Hood J, Bykowski J, Zuccoli G, et al. Case series of potential Wernicke’s encephalopathy in patients treated with fedratinib. Blood. Am Soc Hematol. 2017;130:4197–7. Case series establishing that the risk of Wernicke's encephalopathy with fedratinib was quite low.
32.
Zhang Q, Zhang Y, Diamond S, Boer J, Harris JJ, Li Y, 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;42:1656–62.CrossRef
33.
Hazell AS, Afadlal S, Cheresh DA, Azar A. Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke’s encephalopathy. Neurosci Lett. 2017;642:163–7.CrossRef
34.
Hood J, Hazell A. Fedratinib does not inhibit thiamine uptake or induce experimental Wernicke’s encephalopathy in nonclinical studies. Blood Am Soc Hematol. 2017;130:4993–3.
35.
36.
Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, et al. 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;108:1497–503.CrossRef
37.
Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27:1322–7.CrossRef
38.
Abdelrahman RA, Begna KH, Al-Kali A, Hogan WJ, Litzow MR, Pardanani A, et al. Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. Br J Haematol. 2015;169:77–80.CrossRef
39.
Gupta V, Mesa RA, Deininger MWN, Rivera CE, Sirhan S, Brachmann CB, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017;102:94–102.CrossRef
40.
Verstovsek S, Odenike O, Singer JW, Granston T, Al-Fayoumi S, Deeg HJ. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J Hematol Oncol. 2016;9:137.CrossRef
41.
Komrokji RS, Seymour JF, Roberts AW, Wadleigh M, To LB, Scherber R, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood. 2015;125:2649–55.CrossRef
42.
Emanuel RM, Dueck AC, Geyer HL, Kiladjian J-J, Slot S, Zweegman S, 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;30:4098–103.CrossRef
43.
Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, et al. The myeloproliferative neoplasm symptom assessment form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118:401–8.CrossRef
44.
• Leroy E, Constantinescu SN. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition. Leukemia. 2017;31:1023–38. Comprehensive review detailing novel strategies of JAK inhibition.
45.
Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489:155–9.CrossRef
46.
Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell. 2015;28:15–28.CrossRef
47.
Deshpande A, Reddy MM, Schade GOM, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26:708–15.CrossRef
48.
Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673–83.CrossRef
49.
Winter PS, Sarosiek KA, Lin KH, Meggendorfer M, Schnittger S, Letai A, et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7:ra122.CrossRef
50.
Khan I, Huang Z, Wen Q, Stankiewicz MJ, Gilles L, Goldenson B, et al. AKT is a therapeutic target in myeloproliferative neoplasms. Leukemia. 2013;27:1882–90.CrossRef
51.
Stivala S, Codilupi T, Brkic S, Baerenwaldt A, Ghosh N, Hao-Shen H, et al. Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. J Clin Invest. 2019;130:1596–611.CrossRef
52.
Patel AA, Cahill K, Charnot-Katsikas A, Liu H, Gurbuxani S, Thirman M, et al. Clinical outcomes of IDH2-mutated advanced-phase Ph-negative myeloproliferative neoplasms treated with enasidenib. Br J Haematol. 2020; Available from:. https://​doi.​org/​10.​1111/​bjh.​16709.
53.
• Pettit K, Odenike O. Novel therapies for myelofibrosis. Curr Hematol Malig Rep. 2017;12:611–24. Comprehensive review of novel therapies in myelofibrosis moving beyond JAK inhibition.
Metadata
Title
The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib
Authors
Anand A. Patel
Olatoyosi Odenike
Publication date
01-12-2020
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 6/2020
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-020-00596-z
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