Ruxolitinib use in myelofibrosis patients: the single center experience and the relationship between JAK-2 allele burden and Ruxolitinib response

Purpose: Ruxolitinib is an oral JAK-1/2 inhibitor approved for the treatment of splenomegaly and/or constitutional symptoms in intermediate and high-risk myelofibrosis patients. The aim of our study is to evaluate the efficacy and safety of ruxolitinib in primary MF, post-ET MF and post-PV MF patients, to evaluate the relationship between response and JAK-2 allele burden and to compare them with literature data. Materials and methods: In our single centered and retrospective study, we investigated the data of 30 MF patients diagnosed in our clinic between May 2015 and December 2019. We reported demographic features, laboratory values, and spleen sizes. Results: 18 patients (60%) with a median age of 67.5 (45-78) had primary myelofibrosis. Spleen sizes decreased significantly 3 and 6 months after treatment. Constitutional symptoms have disappeared in 28 patients (93.3%). No association was found between JAK-2 allele burden and treatment response success. Conclusion: Ruxolitinib MF is very safe and effective to relieve constitutional symptoms and decrease spleen size. Despite JAK-2 inhibition, no linear relationship was found between JAK-2 allele burden and treatment efficacy.

Myelofibrozis hastalarında Ruxolitinib kullanımı: tek merkez deneyimi ve JAK-2 allel yükü ile Ruxolitinib yanıtı arasındaki ilişki

Amaç: Ruksolitinib, intermediate ve yüksek risk myelofibrozis hastalarında splenomegali ve/veya konstitusyonel semptomların tedavisi için onay almış oral olarak kullanılan bir JAK-1/2 inhibitörüdür. Bu çalışmamızda amacımız primer MF, post-ET MF ve post-PV MF hastalarında ruksolitinibin etkinlik ve güvenirliliğini değerlendirmek, JAK2 allel yüküyle yanıt ilişkisini değerlendirmek ve literatür verileriyle karşılaştırmaktır. Gereç ve yöntem: Tek merkezli ve retrospektif çalışmamızda kliniğimizde Mayıs 2015 ile Aralık 2019 tarihleri arasında tanı almış 30 MF hastasının verilerini dosyalarından inceledik. Demografik özelliklerini, laboratuvar değerlerini ve dalak boyutlarını kaydettik. Bulgular: Mediyan yaşları 67,5 (45-78) olan hastaların 18 tanesi (%60) primer myelofibrozis hastasıydı. Ruksolitinib tedavisi sonrası 3.ay ve 6.ayda hastaların dalak boyutlarında anlamlı azalma saptandı. Hastaların 28 tanesinin (%93,3) konstitusyonel semptomları kayboldu. JAK-2 allel yüküyle tedavi yanıt başarısı arasında ilişki saptanmadı. Tartışma: Ruxolitinib MF tedavisinde hem konstitusyonel semptomları ortadan kaldırmada hem de dalak boyutunda azalma sağlamada oldukça etkin ve güvenlidir. JAK-2 inhibisyonu yapmasına rağmen JAK-2 allel yükü ile tedavi etkinliği arasında ise lineer bir ilişki yoktur.

Kaynakça

1. Vannucchi AM, Guglielmelli P. Advances in understanding and management of polycythemia vera. Curr Opin Oncol 2010;22:636-641. https://doi. org/10.1097/CCO.0b013e32833ed81c

2. Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, Tefferi A. The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev 2016;30:453-459 http://dx.doi. org/10.1016/j.blre.2016.06.001

3. Mesa RA, Green A, Barosi G, Verstovsek S, Vardiman J, Gale RP. MPN-associated myelofibrosis (MPNMF). Leuk Res 2011;35:12-13. https://doi.org/10.1016/j. leukres.2010.07.019

4. 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;22:437-438. https://doi.org/10.1038/ sj.leu.2404914

5. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer 2006;109:68-76. https://doi. org/10.1002/cncr.22365

6. 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. https://doi.org/10.1182/ blood-2008-07-170449.

7. Vainchenker W, Constantinescu S. JAK/STAT signaling in hematological malignancies. Oncogene 2013;32:2601- 2613. https://doi.org/10.1038/onc.2012.347

8. Rampal R, Al Shahrour F, Abdel Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood 2014;123:123-133. https://doi.org/10.1182/blood-2014-02-554634

9. Tefferi A, Finke CM, Lasho TL, et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia 2014;28:431-433. https://doi.org/10.1038/leu.2013.286

10. Quintás 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. https://doi.org/10.1182/blood-2009-04-214957

11. Vannucchi AM, Verstovsek S, Guglielmelli P, et al. Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study. Ann Hematol 2017;96:1113-1120. https://doi.org/10.1007/s00277-017-2994-x

12. 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;10:55. https://doi.org/10.1186/ s13045-017-0417-z

13. Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORTII study. Blood 2014;123:2157-2160. https://doi. org/10.1182/blood-2013-11-536557

14. Al Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica 2016;101:1065-1073. https://doi.org/10.3324/haematol.2016.143677

15. Kröger N, Thiele J, Zander A, et al. Rapid regression of bone marrow fibrosis after dose-reduced allogeneic stem cell transplantation in patients with primary myelofibrosis. Exp Hematol 2007;35:1719-1722. https://doi.org/10.1016/j.exphem.2007.08.022

16. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012;120:1367-1379. https://doi. org/10.1182/blood-2012-05-399048

17. 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. https://doi.org/10.1200/JCO.2010.32.2446

18. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood 2013;122:1395-1398. https://doi.org/10.1182/blood-2013-03-488098

19. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807. https://doi.org/10.1056/ NEJMoa1110557

20. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 2016;30:1701-1707. https:// doi.org/10.1038/leu.2016.148

21. Verstovsek S. Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med 2013;125:128-135. https://doi.org/10.3810/pgm.2013.01.2628

22. Yang Y, Luo H, Zheng Y, et al. Low-dose ruxolitinib shows effective in treating myelofibrosis. Ann Hematol 2020. https://doi.org/10.1007/s00277-020-04311-z

23. Kvasnicka HM, Thiele J, Bueso Ramos CE, et al. Longterm effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol 2018;11:42. https://doi.org/10.1186/ s13045-018-0585-5

24. Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol 2013;6:79. https://doi.org/10.1186/1756-8722-6-79

25. Breccia M, Luciano L, Pugliese N, et al. Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Ann Hematol 2019;98:1933-1936. https://doi.org/10.1007/ s00277-019-03727-6

26. Griesshammer M, Saydam G, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial. Ann Hematol 2018;97:1591-1600. https://doi.org/10.1007/s00277- 018-3365-y

27. Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol 2020. https://doi.org/10.1002/ajh.26050

28. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 2015;100:1139-1145. https://doi.org/10.3324/ haematol.2014.119545

29. Gill H, Leung GMK, Yim R, et al. Myeloproliferative neoplasms treated with hydroxyurea, pegylated interferon alpha-2A or ruxolitinib: clinicohematologic responses, quality-of-life changes and safety in the real-world setting. Hematology 2020;25:247-257. https://doi.org/10.1080/16078454.2020.1780755

30. Wilkins BS, Radia D, Woodley C, Farhi SE, Keohane C, Harrison CN. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica 2013;98:1872-1876. https:// doi.org/10.3324/haematol.2013.095109

31.Gupta V, Griesshammer M, Martino B, et al. Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study. Leuk Lymphoma 2020;19:1-9. https://doi.org/10. 1080/10428194.2020.1845334

Kaynak Göster

  • ISSN: 1309-9833
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2008

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