Page 99 - 2019_05-HaematologicaMondo-web

Ruxolitinib, nilotinib and prednisone for myelofibrosis
Our results indicate that the combination ruxolitinib, nilotinib and prednisone would eliminate more efficiently pathological cells, stopping and/or reverting MF. It must be remembered, however, that this evidence was obtained in vitro and the impact on the clinical situation still needs to be proved. With this is mind, and given that all the drugs are approved for clinical practice, we have recently initiat- ed a clinical trial (the RuNic Trial; clinicaltrials.gov identifier: 02973711) which does not require an in vivo analysis in animal models.
In summary, MF is a complex disease in which alter- ations in tyrosine kinase-related signaling participates in the amplification of hematopoietic clones and in the increased production of cytokines and growth factors by pathological cell clones, which stimulates MF.38 It is often advantageous to use combinations of drugs that target dif- ferent pathways involved in the pathophysiology of a dis- ease, shown here with the objective of decreasing fibrosis of the BM, and not only eradicating the tumor clone, as previously attempted.15,30,39,40 Our results lead us to hypoth- esize that the combination therapy ruxolitinib and pred- nisone might provide a dampened proinflammatory envi- ronment and nilotinib would block fibrosis. Accordingly,
the combination ruxolitinib/nilotinib/prednisone is con- figured as a therapeutic strategy against MF that aims to enhance the effect of ruxolitinib, and promote the reduc- tion of fibrosis in the BM and reduce inflammation. As mentioned above, this combination will be studied in a phase Ib/II clinical trial in MF (the RuNic Trial; clinicaltri- als.gov identifier: 02973711).
Further information is available in the Online Supplementary Appendix.
Funding
This study was supported by the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI13/02387 and PI16/01530, and the CRIS against Cancer foundation grant 2014/0120. M.L. holds a postdoc- toral fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI- 2013-16409).
Acknowledgments
The authors would like to thank to Carmen Delgado, from H12O Hematology Department for the support with the sam- ples, Kenneth McCreath for language support, and to all patients who participated in the study.
References
1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization crite- ria and point-of-care diagnostic algorithms. Leukemia. 2008;22(1):14-22.
2. TefferiA.HowItreatmyelofibrosis.Blood. 2011;117(13):3494-3504.
3. James C, Ugo V, Le Couédic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes poly-
cythaemia vera. Nature. 2005; 434(7037):1144-1148.
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):387-397.
5. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disor- ders. Lancet. 2005;365(9464):1054-1061.
6. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in poly- cythemia vera. J Biol Chem. 2005;280(24):22788-22792.
7. KralovicsR,PassamontiF,BuserAS,etal.A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790.
8. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679.
9. Ma W, Zhang X, Wang X, et al. MPL muta- tion profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagn Mol Pathol. 2011;20(1):34-39.
10. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.
11. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloprolifer- ative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405.
12. Ha J-S, Kim Y-K. Calreticulin exon 9 muta- tions in myeloproliferative neoplasms. Ann Lab Med. 2015;35(1):22-27.
13. Marty C, Pecquet C, Nivarthi H, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with fre- quent progression to myelofibrosis. Blood. 2016;127(10):1317-1324.
14. Chachoua I, Pecquet C, El-Khoury M, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016; 127(10):1325-1335.
15. 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.
16. Verstovsek S, Savona MR, Mesa RA, et al. A phase 2 study of simtuzumab in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia myelofi- brosis. Br J Haematol. 2017;176(6):939-949.
17. 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.
18. Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leuk Res 2017;6031-6035.
19. Mascarenhas J, Hoffman R. A comprehen- sive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood. 2013; 121(24):4832-4837.
20. Akhmetshina A, Dees C, Pileckyte M, et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J. 2008;22(7):2214-2222.
21. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neo- plasms and acute leukemia. Blood. 2016; 127(20):2391-2405.
22. Chou T-C. Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacol Rev. 2006;58(3):621-681.
23. Cervantes F, Isola IM, Alvarez-Larrán A, Hernández-Boluda J-C, Correa J-G, Pereira A. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results. Ann Hematol. 2015;94(11):1791- 1796.
24. Yu W, Guo F, Song X. Effects and mecha- nisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. Pharm Biol. 2017;55(1):450-455.
25. Vainchenker W, Leroy E, Gilles L, Marty C, Plo I, Constantinescu SN. JAK inhibitors for the treatment of myeloproliferative neo- plasms and other disorders. F1000Res. 2018;7:82.
26. Vannucchi AM, Kantarjian HM, Kiladjian J- J, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 ran- domized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139-1145.
27. Bennett TA, Montesinos P, Moscardo F, et al. Pharmacological Profiles of Acute Myeloid Leukemia Treatments in Patient Samples by Automated Flow Cytometry: A Bridge to Individualized Medicine. Clin Lymphoma Myeloma Leuk. 2014; 14(4):305-318.
28. Wagner-Ballon O, Pisani DF, Gastinne T, et al. Proteasome inhibitor bortezomib impairs both myelofibrosis and osteoscle- rosis induced by high thrombopoietin lev- els in mice. Blood. 2007;110(1):345-353.
29. Evrot E, Ebel N, Romanet V, et al. JAK1/2 and Pan-deacetylase inhibitor combination therapy yields improved efficacy in preclin- ical mouse models of JAK2V617F-driven disease. Clin Cancer Res. 2013; 19(22):6230-6241.
30. Marubayashi S, Koppikar P, Taldone T, et al. HSP90 is a therapeutic target in JAK2-
haematologica | 2019; 104(5)
945