References
- Passamonti F, Maffioli M. The role of JAK2 inhibitors in MPNs 7 years after approval. Blood. 2018;131(22):2426–2435. doi:10.1182/blood-2018-01-79149129650801
- Vannucchi AM, Harrison CN. Emerging treatments for classical myeloproliferative neoplasms. Blood. 2017;129(6):693–703. doi:10.1182/blood-2016-10-69596528028027
- Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667–679. doi:10.1182/blood-2016-10-69594028028029
- Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J. 2018;8(1):2. doi:10.1038/s41408-017-0041-829321520
- Szuber N, Mudireddy M, Nicolosi M, et al. 3023 mayo clinic patients with myeloproliferative neoplasms: risk-stratified comparison of survival and outcomes data among disease subgroups. Mayo Clin Proc. 2019;94(4):599–610. doi:10.1016/j.mayocp.2018.08.02230824279
- Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874–1881. doi:10.1038/leu.2013.16323739289
- Passamonti F, Cazzola M. Cytoreductive therapy for patients with essential thrombocythemia at high risk of thromboembolic complications. The difficult choice of the optimal drug. Haematologica. 2004;89(11):1284.
- 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(16):2507–2513. quiz 615. doi:10.1182/blood-2014-05-57913625037629
- 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(13):2895–2901. doi:10.1182/blood-2008-07-17044918988864
- Kim SY, Im K, Park SN, Kwon J, Kim JA, Lee DS. CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol. 2015;143(5):635–644. doi:10.1309/AJCPUAAC16LIWZMM25873496
- Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123(10):1544–1551. doi:10.1182/blood-2013-11-53909824366362
- Senin A, Fernandez-Rodriguez C, Bellosillo B, et al. Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up. Ann Hematol. 2018;97(3):443–451. doi:10.1007/s00277-017-3193-529181548
- Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv. 2016;1(1):21–30. doi:10.1182/bloodadvances.201600021629296692
- Tefferi A, Lasho TL, Finke CM, et al. Targeted deep sequencing in primary myelofibrosis. Blood Adv. 2016;1(2):105–111. doi:10.1182/bloodadvances.201600020829296803
- Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93(12):1551–1560. doi:10.1002/ajh.v93.1230039550
- James C, Ugo V, Le Couédic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–1148. doi:10.1038/nature0354615793561
- Ward AC, Touw I, Yoshimura A. The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood. 2000;95(1):19–29. doi:10.1182/blood.V95.1.1910607680
- Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–1061. doi:10.1016/S0140-6736(05)71142-915781101
- Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–1790. doi:10.1056/NEJMoa05111315858187
- Bewersdorf JP, Ardasheva A, Podoltsev NA. et al. From clonal hematopoiesis to myeloid leukemia and what happens in between: will improved understanding lead to new therapeutic and preventive opportunities? Blood Rev;2019 100587. doi:10.1016/j.blre.2019.10058731400824
- Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;117(10):2813–2816. doi:10.1182/blood-2010-11-31681021224469
- Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–468. doi:10.1056/NEJMoa06520217267906
- 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/NEJMoa111055722375971
- 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/NEJMoa111055622375970
- 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):55. doi:10.1186/s13045-017-0417-z28228106
- 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(1):156. doi:10.1186/s13045-017-0527-728962635
- 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(7):e317–e24. doi:10.1016/S2352-3026(17)30088-128602585
- Pardanani A, Tefferi A, Jamieson C, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015;5:e335. doi:10.1038/bcj.2015.6326252788
- 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.2015.159026181658
- Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–796. doi:10.1200/JCO.2010.32.802121220608
- Bose P, Alfayez M, Verstovsek S. New concepts of treatment for patients with myelofibrosis. Curr Treat Options Oncol. 2019;20(1):5. doi:10.1007/s11864-019-0604-y30675650
- Bose P, Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood. 2017;130(2):115–125. doi:10.1182/blood-2017-04-74228828500170
- Singer JW, Al-Fayoumi S, Taylor J, Velichko S, O’Mahony A. Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS One. 2019;14(9):e0222944–e. doi:10.1371/journal.pone.022294431560729
- Zhang M, Xu CR, Shamiyeh E, et al. A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol. 2014;54(4):415–421. doi:10.1002/jcph.v54.424165976
- Zhang M, Xu C, Ma L, et al. Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): results from two phase I studies in healthy volunteers. Clin Pharmacol Drug Dev. 2015;4(4):315–321. doi:10.1002/cpdd.v4.427136912
- Ogasawara K, Zhou S, Krishna G, Palmisano M, Li Y. Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia. Cancer Chemother Pharmacol. 2019;84(4):891–898. doi:10.1007/s00280-019-03929-931444617
- Abba C, Campanelli R, Catarsi P, et al. Constitutive STAT5 phosphorylation in CD34+ cells of patients with primary myelofibrosis: correlation with driver mutation status and disease severity. PLoS One. 2019;14(8):e0220189. doi:10.1371/journal.pone.022018931369569
- RISUM M, MADELUNG A, BONDO H, et al. The JAK2V617F allele burden and STAT3- and STAT5 phosphorylation in myeloproliferative neoplasms: early prefibrotic myelofibrosis compared with essential thrombocythemia, polycythemia vera and myelofibrosis. APMIS. 2011;119(8):498–504. doi:10.1111/apm.2011.119.issue-821749449
- Teofili L, Martini M, Cenci T, et al. Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation. Blood. 2007;110(1):354–359. doi:10.1182/blood-2007-01-06923717376889
- Harrison C, Schaap N, Vannucchi A, et al. Fedratinib induces spleen responses in patients with Myeloproliferative Neoplasm (MPN)-associated intermediate- or high-risk myelofibrosis (MF) resistant or intolerant to ruxolitinib: an updated analysis of the phase II JAKARTA2 study. Clin Lymphoma Myeloma Leuk. 2019;19:S356. doi:10.1016/j.clml.2019.07.375
- Harrison C, Schaap N, Vannucchi A, et al. Fedratinib induces spleen responses and reduces symptom burden as first-line or salvage therapy in patients with myeloproliferative neoplasm-associated intermediate- or high-risk myelofibrosis (MF) and low platelet counts. Clin Lymphoma Myeloma Leuk. 2019;19:S355. doi:10.1016/j.clml.2019.07.374
- 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(10):1656–1662. doi:10.1124/dmd.114.05888325063672
- 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;642:163–167. doi:10.1016/j.neulet.2017.01.04128109775
- NCCN. NCCN guidelines version 3.2019: myeloproliferative neoplasms; 2019 [cited 1111, 2019]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf.
- Stahl M, Zeidan AM. Improved JAK inhibition in myelofibrosis—the long road ahead. JAMA Oncol. 2018;4(5):659–660. doi:10.1001/jamaoncol.2017.580229522105
- 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(2):e73–e81. doi:10.1016/S2352-3026(17)30237-529275119
- 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(34):3844–3850. doi:10.1200/JCO.2017.73.441828930494
- 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):1035–1038. doi:10.1038/leu.2017.33029263442
- Tefferi A, Barraco D, Lasho TL, et al. Momelotinib therapy for myelofibrosis: a 7-year follow-up. Blood Cancer J. 2018;8(3):29. doi:10.1038/s41408-018-0067-629515114
- Gupta V, Mesa RA, Deininger MWN, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017;102(1):94–102. doi:10.3324/haematol.2016.14892427634203
- 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(13):1823–1830. doi:10.1182/blood-2016-09-74009228188131
- Diaz AE, Mesa RA. Pacritinib and its use in the treatment of patients with myelofibrosis who have thrombocytopenia. Future Oncol. 2018;14(9):797–807. doi:10.2217/fon-2017-049429235894
- 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.2017.581829522138
- 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;4(5):e225–e36. doi:10.1016/S2352-3026(17)30027-328336242
- Mascarenhas J, Virtgaym E, Stal M, et al. Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study. Ann Hematol. 2018;97(8):1369–1374. doi:10.1007/s00277-018-3309-629616317
- Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11–19. doi:10.2147/JEP.S11070227574472
- Pardanani A, Tefferi A. How I treat myelofibrosis after failure of JAK inhibitors. Blood. 2018;132(5):492–500. doi:10.1182/blood-2018-02-78592329866811
- Gerds AT, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib. Blood. 2019;134(Supplement_1):667.
- 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.
- Schlenk RF, Stegelmann F, Reiter A, et al. Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2017;31(4):889–895. doi:10.1038/leu.2016.29927774990
- Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009;27(27):4563–4569. doi:10.1200/JCO.2008.21.735619652059
- Tefferi A, Al-Ali HK, Barosi G, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31(4):896–902. doi:10.1038/leu.2016.30027773929
- Daver N, Cortes J, Newberry K, et al. Ruxolitinib in combination with lenalidomide as therapy for patients with myelofibrosis. Haematologica. 2015;100(8):1058–1063. doi:10.3324/haematol.2015.12682126088933
- Bose P, Daver N, Jabbour EJ, et al. Phase-2 study of sotatercept (ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia. Blood. 2016;128(22):478. doi:10.1182/blood.V128.22.478.478
- Stegelmann F, Bangerter M, Heidel FH, et al. A phase-Ib/II study of ruxolitinib plus pomalidomide in myelofibrosis. Blood. 2015;126(23):826. doi:10.1182/blood.V126.23.826.82626473196
- Jacquelin S, Straube J, Cooper L, et al. Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation. Blood. 2018;132(26):2707–2721. doi:10.1182/blood-2018-04-84622030366920
- Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111(50):E5401–E5410. doi:10.1073/pnas.140779211125516983
- Masarova L, Verstovsek S, Hidalgo-Lopez JE, et al. A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis. Blood. 2018;132(16):1664–1674. doi:10.1182/blood-2018-04-84662630185431
- Greenberg PL, Stone RM, Al-Kali A, et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(1):60–87. doi:10.6004/jnccn.2017.000728040720
- Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms. Blood Adv. 2018;2(24):3572–3580. doi:10.1182/bloodadvances.201801966130563881
- Tibes R, Mesa RA. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies. J Hematol Oncol. 2014;7:18. doi:10.1186/1756-8722-7-1824598114
- Shallis RM, Bewersdorf JP, Boddu PC, Zeidan AM. Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia. Expert Rev Anticancer Ther. 2019;19(8):717–729. doi:10.1080/14737140.2019.165209531422721
- Gerds AT, Tauchi T, Ritchie E, et al. Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. Leuk Res. 2019;79:38–44. doi:10.1016/j.leukres.2019.02.01230849661
- Couban S, Benevolo G, Donnellan W, et al. A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis. J Hematol Oncol. 2018;11(1):122. doi:10.1186/s13045-018-0661-x30249277
- DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi:10.1182/blood-2018-08-86875230361262
- Wei AH, Strickland SA Jr., Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277–1284. doi:10.1200/JCO.18.0160030892988
- Harrison CN, Garcia JS, Mesa RA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Blood. 2019;134(Supplement_1):671.
- Saenz DT, Fiskus W, Qian Y, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31(9):1951–1961. doi:10.1038/leu.2016.39328042144
- Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), as monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019;134(Supplement_1):670.
- Cortes AA, Diaz RA, Hernandez-Campo P, et al. Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. Haematologica. 2019;104(5):937–946. doi:10.3324/haematol.2018.20103830545926
- Wang X, Hu CS, Petersen B, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. 2018;2(18):2378–2388. doi:10.1182/bloodadvances.201802201230242099
- Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373(10):908–919. doi:10.1056/NEJMoa131052326332545
- Barosi G, Klersy C, Villani L, et al. JAK2V617F allele burden ≥50% is associated with response to ruxolitinib in persons with MPN-associated myelofibrosis and splenomegaly requiring therapy. Leukemia. 2016;30(8):1772–1775. doi:10.1038/leu.2016.4526975727
- Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790–797. doi:10.1182/blood-2015-03-63340426124496
- Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK–STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155–159. doi:10.1038/nature1130322820254
- Stahl M, Zeidan AM. Management of myelofibrosis: JAK inhibition and beyond. Expert Rev Hematol. 2017;10(5):459–477. doi:10.1080/17474086.2017.131759028395559
- Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.000000000000005431723778
- Pettit K, Gerds AT, Yacoub A, et al. A phase 2a study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of myelofibrosis. Blood. 2019;134(Supplement_1):556.
- Pemmaraju N, Carter BZ, Kantarjian HM, et al. LCL161, an oral smac mimetic/IAP antagonist for patients with myelofibrosis (MF): novel translational findings among long-term responders in a phase 2 clinical trial. Blood. 2018;132(Supplement 1):687. doi:10.1182/blood-2018-99-119753