The role of pacritinib in the management of myelofibrosis

Expert Review of Hematology

Volumn 7, Issue 3, 2014, Pages 325-332

  Duong, Vu H ^a   Komrokji, Rami S ^b  

^a UNIVERSITY OF MARYLAND GREENEBAUM CANCER CENTER   (United States)

^b H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

Author keywords

Essential thrombocythemia; FLT3 inhibitor; JAK2 inhibitor; Myelofibrosis; Myeloproliferative neoplasms; Pacritinib; Polycythemia vera; Ruxolitinib; SB1518

Indexed keywords

5 CHLORO N2 [1 (5 FLUORO 2 PYRIMIDINYL)ETHYL] N4 (5 METHYL 1H PYRAZOL 3 YL) 2,4 PYRIMIDINEDIAMINE; ANTIDIARRHEAL AGENT; ANTIEMETIC AGENT; BMS 911543; FEDRATINIB; GANDOTINIB; JANUS KINASE 2; JANUS KINASE INHIBITOR; LESTAURTINIB; MOMELOTINIB; PACRITINIB; STAT3 PROTEIN; STAT5 PROTEIN; UNCLASSIFIED DRUG; 11-(2-PYRROLIDIN-1-YLETHOXY)-14,19-DIOXA-5,7,26-TRIAZATETRACYCLO(19.3.1.1(2,6).1(8,12))HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE; BRIDGED COMPOUND; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; RUXOLITINIB;

ABDOMINAL PAIN; ANTINEOPLASTIC ACTIVITY; ARTICLE; CLINICAL TRIAL (TOPIC); DIARRHEA; DIZZINESS; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG METABOLISM; DRUG PENETRATION; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; FLATULENCE; GENE MUTATION; HUMAN; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR WEIGHT; MYELOFIBROSIS; NAUSEA; NEUTROPENIA; NONHUMAN; PHARMACODYNAMICS; PHYSICAL EXAMINATION; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SPLENOMEGALY; SYMPTOM; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; VOMITING; ANIMAL; ENZYMOLOGY; METABOLISM; PATHOLOGY; PRIMARY MYELOFIBROSIS;

ANIMALS; BRIDGED COMPOUNDS; CLINICAL TRIALS AS TOPIC; HUMANS; JANUS KINASE 2; PRIMARY MYELOFIBROSIS; PYRAZOLES; PYRIMIDINES;

EID: 84900859210     PISSN: 17474086     EISSN: 17474094     Source Type: Journal    
DOI: 10.1586/17474086.2014.905200     Document Type: Article

References (49)

1. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia 2008;22(5): 905-14
2. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365(9464): 1054-61
3. 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):1779-90
4. Levine RL,Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4): 387-97
5. Akada H, Yan D, Zou H, et al. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood 2010; 115(17):3589-97
6. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434(7037):1144-8
7. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106(6):2162-8
8. Anand S, Stedham F, Gudgin E, et al. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood 2011;118(6): 1610-21
9. 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
10. 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(9):787-98
11. William AD, Lee AC, Blanchard S, et al. Discovery of the macrocycle 11-(2- pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26- triaza-tetracyclo[19.3.1.1(2, 6). 1(8,12)] heptacosa-1(25),2(26),3,5,8,10,12 (27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem 2011;54(13):4638-58
12. Marsault E, Peterson ML. Macrocycles are great cycles: Applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J Med Chem 2011;54(7): 1961-2004
13. Driggers EM, Hale SP, Lee J, Terrett NK. The exploration of macrocycles for drug discovery - An underexploited structural class. Nat Rev Drug Discov 2008;7(7): 608-24
14. Hart S, Goh KC, Novotny-Diermayr V, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 2011;25(11): 1751-9
15. Grandage VL, Everington T, Linch DC, Khwaja A. Go6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells. Br J Haematol 2006;135(3): 303-16
16. Derenzini E, Lemoine M, Buglio D, et al. The JAK inhibitor AZD1480 regulates proliferation and immunity in hodgkin lymphoma. Blood Cancer J 2011;1(12): E46
17. Hart S, Goh KC, Novotny-Diermayr V, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J 2011; 1(11):e44
18. Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thrombocythemia/polycythemia vera myelofibrosis. ASH Annual Meeting Abstracts 2009. 114(22): 3905
19. Seymour JF, To B, Goh A, et al. First report of the phase I study of the novel oral JAK2 inhibitor SB1518 in patients with myelofibrosis. Congress of the European Hematology Association 2010;95(Suppl 2): Abstract 1144
20. Younes A, Romaguera J, Fanale M, et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: Evidence of clinical and biologic activity in multiple lymphoma subtypes. J Clin Oncol 2012;30(33): 4161-7
21. Seymour JF, Scott B, Roberts AW, et al. Long-term safety and efficacy analysis of the two Phase 1 Studies of SB1518, a novel oral JAK2 inhibitor, in patient with advanced myeloid malignancies. Congress of the European Hematology Association 2011; 96(Suppl 2):Abstract 0907
22. Komrokji RS, Wadleigh M, Seymour JF, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. ASH Annual Meeting Abstracts 2011. 118(21): 282
23. Deeg HJ, Odenike O, Scott BL, et al. Phase II study of SB1518, an orally available novel JAK2 inhibitor, in patients with myelofibrosis. ASCO Meeting Abstracts 2011;29(Suppl 15): 6515
24. Tefferi A. 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(5):1497-503
25. Verstovsek S, Dean JP, Cernohous P, et al. Pacritinib, a dual JAK2/FLT3 inhibitor: An integrated efficacy and safety analysis of phase II trial data in patients with primary and secondary myelofibrosis (MF) and platelet counts '100,000/ml. Blood 2013; 122(21):395
26. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: Durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. ASH Annual Meeting Abstracts 2012. 120(21): 800
27. Cervantes F, Kiladjian J-J, Niederwieser D, et al. Long-term safety, efficacy, and survival findings from COMFORT-II, a Phase 3 Study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). ASH Annual Meeting Abstracts 2012. 120(21):801
28. Kvasnicka H-M, Thiele J, Bueso-Ramos CE, et al. Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis. ASCO Meeting Abstracts 2013;31(Suppl 15):7030
29. Campbell PJ, Griesshammer M, Dohner K, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood 2006;107(5): 2098-100
30. Alchalby H, Badbaran A, Zabelina T, et al. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood 2010;116(18):3572-81
31. Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 2007;110(12): 4030-6
32. Barosi G, Poletto V, Massa M, et al. JAK2 V617F genotype is a strong determinant of blast transformation in primary myelofibrosis. PLoS ONE 2013; 8(3):e59791
33. Guglielmelli P, Barosi G, Specchia G, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood 2009;114(8):1477-83
34. Vannucchi AM, Passamonti F, Al-Ali HK, et al. Reductions in JAK2 V617F allele burden with ruxolitinib treatment in COMFORT-II, a Phase 3 Study comparing the safety and efficacy of ruxolitinib with Best Available Therapy (BAT). ASH Annual Meeting Abstracts 2012. 120(21):802
35. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011;86(12): 1188-91
36. Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 2013;27(6):1322-7
37. 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):789-96
38. Chu SH, Heiser D, Li L, et al. FLT3-ITD knockin impairs hematopoietic stem cell quiescence/homeostasis, leading to myeloproliferative neoplasm. Cell Stem Cell 2012;11(3):346-58
39. Li L, Piloto O, Nguyen HB, et al. Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model. Blood 2008;111(7):3849-58
40. Kelly LM, Liu Q, Kutok JL, et al. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002;99(1):310-18
41. Abu-Duhier FM, Goodeve AC, Wilson GA, et al. FLT3 internal tandem duplication mutations are rare in agnogenic myeloid metaplasia. Blood 2002;100(1): 364
42. Lin P, Jones D, Medeiros LJ, et al. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol 2006;126(4):530-3
43. Abu-Duhier FM, Goodeve AC, Care RS, et al. Mutational analysis of class III receptor tyrosine kinases (C-KIT, C-FMS, FLT3) in idiopathic myelofibrosis. Br J Haematol 2003;120(3):464-70
44. Deangelo DJ, Mesa RA, Fiskus W, et al. 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
45. Mascarenhas J, Lu M, Li T, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post- PV/ET MF). Br J Haematol 2013;161(1): 68-75
46. Wang Y, Fiskus W, Chong DG, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009;114(24):5024-33
47. Baffert F, Evrot E, Ebel N, et al. Improved efficacy upon combined JAK1/2 and pan-deacetylase inhibition using ruxolitinib (INC424) and panobinostat (LBH589) in preclinical mouse models of JAK2V617F-driven disease. ASH Annual Meeting Abstracts 2011. 118(21): 798
48. Novotny-Diermayr V, Hart S, Goh KC, et al. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. Blood Cancer J 2012;2(5):e69
49. Weigert O, Lane AA, Bird L, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med 2012;209(2):259-73 D