New generation small-molecule inhibitors in myeloproliferative neoplasms

Current Opinion in Hematology

Volumn 19, Issue 2, 2012, Pages 117-123

  Passamonti, Francesco ^a   Maffioli, Margherita ^a   Caramazza, Domenica ^a  

^a OSPEDALE DI CIRCOLO   (Italy)

Author keywords

JAK2; JAK2 inhibitor; myelofibrosis; polycythemia; thrombocythemia

Indexed keywords

CYT 387; EVEROLIMUS; GIVINOSTAT; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; LESTAURTINIB; LY 2784544; MAMMALIAN TARGET OF RAPAMYCIN; PANOBINOSTAT; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RUXOLITINIB; SAR 302503; SB 1518; TG 101348; UNCLASSIFIED DRUG; VORINOSTAT;

CHROMATIN ASSEMBLY AND DISASSEMBLY; EPIGENETICS; ERYTHROCYTE TRANSFUSION; HEMOGLOBIN BLOOD LEVEL; HUMAN; MYELOPROLIFERATIVE DISORDER; PRIORITY JOURNAL; REVIEW; SPLENOMEGALY; SYMPTOM;

ANIMALS; BENZAMIDES; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; HUMANS; JANUS KINASE 2; JANUS KINASES; MICE; MYELOPROLIFERATIVE DISORDERS; PROTEIN KINASE INHIBITORS; PYRAZOLES; PYRIMIDINES; PYRROLIDINES; SULFONAMIDES;

EID: 84857048507     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e32834ff575     Document Type: Review

References (60)

1. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 2007; 110:1092-1097. (Pubitemid 47281402)
2. Barbui T, Carobbio A, Cervantes F, et al. Thrombosis in primary myelofibrosis: Incidence and risk factors. Blood 2010; 115:778-782.
3. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350:114-124. (Pubitemid 38056222)
4. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004; 117:755-761. (Pubitemid 39482529)
5. Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of postpolycythemia vera and postessential thrombocythemia myelofibrosis: A consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 2008; 22:437-438. (Pubitemid 351250553)
6. Passamonti F, Rumi E, Arcaini L, et al. Leukemic transformation of polycythemia vera: A single center study of 23 patients. Cancer 2005; 104:1032-1036. (Pubitemid 41170231)
7. Passamonti F, Rumi E, Arcaini L, et al. Blast phase of essential thrombocythemia: A single center study. Am J Hematol 2009; 84:641-644.
8. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: A single-institution experience with 91 cases. Blood 2005; 105:973-977. (Pubitemid 40170863)
9. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352:1779-1790. (Pubitemid 40570926)
10. 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; 7:387-397. (Pubitemid 40544655)
11. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3:e270.
12. Grand FH, Hidalgo-Curtis CE, Ernst T, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009; 113:6182-6192.
13. Pardanani A, Lasho T, Finke C, et al. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia 2010; 10:1713-1718.
14. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360:2289-2301.
15. Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23:2183-2186.
16. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42:722-726.
17. Tefferi A, Jimma T, Sulai NH, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: Clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 2011; doi:10.1038/ leu.2011.253. [Epub ahead of print].
18. 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; 113:2895-2901.
19. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia 2008; 22:905-914. (Pubitemid 351698623)
20. Passamonti F, Cervantes F, Vannucchi AM, et al. 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 2010; 115:1703-1708. This study reports the current risk stratification of patients with myelofibrosis, which should be use at any timepoint of the follow-up.
21. Gangat N, Caramazza D, Vaidya R, et al. 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 2011; 29:392-397.
22. Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol 2009; 27:4563-4569.
23. Passamonti F, Maffioli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: From JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget 2011; 2:485-490.
24. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007; 7:673-683. (Pubitemid 47327415)
25. 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; 363:1117-1127. This study reports efficacy and safety data of ruxolitinib in primary and secondary myelofibrosis
26. Pardanani A, Hood J, Lasho T, et al. TG101209, a small molecule JAK2-selective kinase inhibitor, potently inhibits myeloproliferative disorder-Associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21:1658-1668. (Pubitemid 47086756)
27. Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009; 23:905-911.
28. Cho YS, Kim EJ, Park UH, et al. Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor. J Biol Chem 2006; 281:17588-17598.
29. Quintas-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; 115:3109-3117.
30. Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008; 13:311-320. (Pubitemid 351446195)
31. Mullally A, Lane SW, Ball B, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 2010; 17:584-596.
32. Quintas-Cardama A, Manshouri T, Estrov Z, et al. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Invest New Drugs 2011; 29:818-826.
33. 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; 115:5232-5240.
34. Geron I, Abrahamsson AE, Barroga CF, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell 2008; 13:321-330. (Pubitemid 351446196)
35. 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; 25:1751-1759.
36. 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; 54:4638-4658.
37. Ma L, Zhao B, Walgren R, et al. Efficacy of LY2784544, a small molecule inhibitor selective for mutant JAK2 kinase, in JAK2 V617F-induced hematologic malignancy models. Blood (ASH Annual Meeting Abstracts) 2010; 116:4087.
38. Florensa L, Bellosillo B, Arenillas L, Ma L, et al. LY2784544, a novel JAK2 inhibitor, decreases in vitro growth of hematopoietic human progenitors from JAK2 V617F positive polycythemia vera patients. Blood (ASH Annual Meeting Abstracts) 2010; 116:5054.
39. Ugo V, Marzac C, Teyssandier I, et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol 2004; 32:179-187. (Pubitemid 38177643)
40. Grimwade LF, Happerfield L, Tristram C, et al. Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. Br J Haematol 2009; 147:495-506.
41. 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; 115:3589-3597.
42. Leoni F, Fossati G, Lewis EC, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 2005; 11:1-15.
43. Guerini V, Barbui V, Spinelli O, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia 2008; 22:740-747. (Pubitemid 351552623)
44. Smith BD, Levis M, Beran M, et al. Single-Agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004; 103:3669-3676. (Pubitemid 38596280)
45. 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; 111:5663-5671.
46. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the histonedeacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010; 150:446-455.
47. Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWGMRT). Blood 2006; 108:1497-1503. (Pubitemid 44316114)
48. Verstovsek S, Mesa RA, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF). 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (suppl. May 20):6500.
49. Harrison CN, Kiladjian J, Al-Ali KH, et al. Results of a randomized study of the JAK inhibitor INC424 compared with best available therapy (BAT) in primary myelofibrosis (PMF), postpolycythemia vera-myelofibrosis (PPV-MF) or postessential thrombocythemia myelofibrosis (PET-MF). 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (suppl. May 20):6501.
50. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): International prospective validation and reliability trial in 402 patients. Blood 2011; 118:401-408.
51. Verstovsek S, Mesa RA, Gotlib J, et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: Results from COMFORT-I. Blood (ASH Annual Meeting Abstracts) 2011; 118:278.
52. Verstovsek S, Kantarjian HM, Estrov Z, et al. Comparison of outcomes of advanced myelofibrosis patients treated with ruxolitinib (INCB018424) to those of a historical control group: Survival advantage of ruxolitinib therapy. Blood (ASH Annual Meeting Abstracts) 2011; 118:793.
53. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 2011; 365:1455-1457.
54. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011; 29:789-796. This study reports efficacy and safety data of SAR302503 in primary and secondary myelofibrosis.
55. Pardanani AD, Caramazza D, George G, et al. Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (suppl. May 20):6514.
56. Verstovsek S, Deeg HJ, Odenike O, Zhu J, et al. Phase 1/2 study of SB1518, a novel JAK2/FLT3 inhibitor, in the treatment of primary myelofibrosis. Blood 2010; 116:3082.
57. Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood 2011; 118:2069-2076.
58. Moliterno A, Roboz GJ, Carroll M, Luger S, et al. An open-label study of CEP-701 in patients with JAK2 V617F-positive polycythemia vera and essential thrombocytosis. Blood (ASH Annual Meeting Abstracts) 2008; 112:99.
59. Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or postpolycythemia vera/ essential thrombocythemia myelofibrosis. Blood 2010; 115:1131-1136.
60. Barosi G, Bordessoule D, Briere J, et al. Response criteria for myelofibrosis with myeloid metaplasia: Results of an initiative of the European Myelofibrosis Network (EUMNET). Blood 2005; 106:2849-2853. (Pubitemid 41510763)