The place of JAK2 inhibitors in the treatment of myelofibrosis. An amendment to the recommendations for diagnosis and treatment of Ph negative myeloproliferations of the Czech group for Ph- myeloproliferative disorders (CZEMP)

Česká verzia

Authors: Libor Červinek ¹; Michael Doubek ¹; Miroslav Penka ²; Jiří Schwarz (česká Pracovní Skupina Pro Ph Negativní Myeloproliferativní Onemocnění) ³
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc. ¹; Oddělení klinické hematologie FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Miroslav Penka, CSc. ²; Ústav hematologie a krevní transfuze, Praha, ředitel prof. MUDr. Petr Cetkovský, Ph. D., MBA ³
Published in the journal: Vnitř Lék 2014; 60(2): 158-163
Category: Guidelines

Summary

Primary myelofibrosis (PMF) belongs to Ph- myeloproliferative diseases. The only curative treatment is hematopoietic stem cell transplantation (HSCT). Conservative treatment options comprise supportive care, especially administration of red blood cell and platelet transfusions, and medication. Hydroxyurea, interferon α, anagrelide, corticosteroids, androgens, or inhibitors of angiogenesis (thalidomide, lenalidomide, pomalidomide) may be used for treatment of PMF, depending on the clinical stage and disease symptoms present. Also splenectomy or radiotherapy of enlarged spleen have palliative potential. JAK2 kinase inhibitors represent a novel class of drugs with a very dynamic development. Ruxolitinib, an oral selective inhibitor of JAK1 and JAK2 kinases, has shown high efficacy in patients with high-risk PMF (or with myelofibrosis following polycythemia vera or essential thrombocythemia) to ameliorate disease symptoms and to reduce splenomegaly in randomized trials COMFORT-I and COMFORT-II. Long-term monitoring of the enrolled patients demonstated prolongation of overall survival. The drug is well-tolerated, the most common side effects of treatment with ruxolitinib being deepening of thrombocytopenia and temporary worsening of anemia. The current review deals with the place of JAK2 inhibitors (and the only drug already approved for clinical use - ruxolitinib) in the management of PMF, as an addendum to the Summary of recommendations for the diagnosis and therapy of BCR/ABL-negative myeloproliferations of the Czech Hematological Society’s CZEMP.

Key words:
JAK2 inhibitors – ruxolitinib – Ph negative myeloproliferative diseases – myeloproliferative diseases/ myeloproliferative neoplasia – primary myelofibrosis – treatment recommendations

Zdroje

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(4): 1092–1097.

2. Schwarz J, Penka M, Campr V et al. Diagnostika a léčba BCR/ABL-negativních myeloproliferativních onemocnění – principy a východiska doporučení CZEMP. Vnitř Lék 2011; 57(2): 189–213.

3. Penka M, Schwarz J, Campr V et al. Shrnutí doporučení České pracovní skupiny pro Ph-negativní myeloproliferativní onemocnění (CZEMP) České hematologické společnosti ČLS JEP pro diagnózu a terapii BCR/ABL-negativních myeloproliferací. Vnitř Lék 2012; 58(2): 163–168.

4. 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(12): 1117–1127.

5. Georgii A, Buhr T, Buesche G et al. Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies. Leuk Lymphoma 1996; 22 (Suppl 1): S15-S29.

6. Thiele J, Kvasnicka HM, Facchetti F et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005; 90(8): 1128–1132.

7. Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 1999; 17(9): 2954–2970.

8. Vannucchi AM. Management of myelofibrosis. Hematology Am Soc Hematol Educ Program 2011. 2011: 222–230. Dostupné z DOI:<http://doi: 10.1182/asheducation-2011.1.222>.

9. Barosi G, Mesa RA, Thiele J et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 2008; 22(2): 437–438.

10. Harrison C, Mesa R, Ross D et al. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev Hematol 2013; 6(5): 511–523.

11. 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.

12. 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(9): 1703–1708.

13. 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(4): 392–397.

14. Pardanani A, Vannucchi AM, Passamonti F et al. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia 2011; 25(2): 218–225.

15. Kyttaris VC. Kinase inhibitors: a new class of antirheumatic drugs. Drug Des Devel Ther 2012; 6: 245–250. Dostupné z DOI: <http://doi: 10.2147/DDDT.S25426>.

16. Keohane C, Mesa R, Harrison C. The Role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms. Am Soc Clin Oncol Educ Book 2013; 33: 301–305. Dostupné z DOI: < http://doi: 10.1200/EdBook_AM.2013.33.301>.

17. 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.

18. 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): 787–798.

19. Verstovsek S, Mesa RA, Gotlib J et al. Efficacy, safety and survival with ruxolitinib treatment in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica 2013; 98(12):1865–1867.

20. Cervantes F, Vannucchi AM, Kiladjian JJ et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013; 122(25):4047–4053.

21. Cervantes F, Mesa R, Harrison C. JAK inhibitors: beyond spleen and symptoms? Haematologica 2013; 98(2): 160–162.

22. Červinek L, Doubek M. Ruxolitinib v léčbě primární myelofibrózy. Farmakoterapie 2013; 9(2): 120–123.

23. Wilkins BS, Radia D, Woodley C et al. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitortreatment with ruxolitinib. Haematologica 2013; 98(12):1872–1876.

24. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86(12): 1188–1191.