Experience with ruxolitinib in the treatment of myelofibrosis and polycythaemia vera at Czech haematological institutions

Česká verze

Authors: B. Weinbergerová ¹; P. Čičátková ¹; M. Palová ²; L. Stejskal ³; P. Bělohlávková ⁴; J. Kissová ⁵; L. Walterová ⁶; H. Fraňková ⁶; O. Černá ⁷; L. Lakomá ⁸; M. Brejcha ⁹; J. Pelková ¹⁰; M. Schutzova ¹¹; J. Obernauerová ¹²; D. Nechvílová ¹³; E. Bogoczová ¹⁴; A. Hluší ²; E. Faber ²; M. Penka ⁵; Y. Brychtová ¹; L. Červinek ¹; M. Doubek ¹; P. Žák ⁴; J. Mayer ¹; Z. Ráčil ¹
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; Hemato-onkologická klinika FN Olomouc ²; Klinika hematoonkologie FN Ostrava a LF OU ³; IV. Interní hematologická klinika FN a LF UK, Hradec Králové ⁴; Oddělení klinické hematologie FN Brno ⁵; Oddělení klinické hematologie Krajské nemocnice Liberec ⁶; Interní hematologická klinika FNKV a LF UK, Praha ⁷; Hematologická ambulance Nemocnice Havlíčkův Brod ⁸; Hematologická ambulance Nemocnice Nový Jičín ⁹; Hematologické a transfúzní oddělení Nemocnice Vsetín ¹⁰; Hematologicko-onkologické oddělení FN Plzeň ¹¹; Hematologicko-transfúzní oddělení Nemocnice Mladá Boleslav ¹²; Hematologicko-transfúzní oddělení Orlickoústecké nemocnice, Ústí nad Orlicí ¹³; Hematologická ambulance Vítkovické nemocnice, Ostrava-Vítkovice ¹⁴
Published in the journal: Transfuze Hematol. dnes,23, 2017, No. 1, p. 30-40.
Category: Souhrnné práce, původní práce, kazuistiky

Summary

Backgrounds:
Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated efficacy in patients with myelofibrosis and polycythaemia vera in the randomized COMFORT-I, COMFORT-II and RESPONSE studies. Ruxolitinib demonstrated superior durable reduction of splenomegaly and disease-associated symptoms, maintenance of haematocrit values, improvement in quality of life and overall survival compared to placebo or best available therapy.

Material and Methods:
A retrospective analysis evaluated efficacy and tolerability of ruxolitinib in a cohort of unselected myelofibrosis and polycythaemia vera patients treated in routine clinical practice at 14 Czech haematological centres from 2013 to 2016.

Results:
Myelofibrosis –⁠ a total of 62 patients with myelofibrosis treated with ruxolitinib were evaluated. The most frequent indication for treatment was concurrent splenomegaly and constitutional symptoms in 54 (87.1%) cases. Reduction ≥ 1/3 in palpable spleen length was achieved in 43 (72.9%) patients with baseline splenomegaly at a median of 4 weeks after starting therapy. Constitutional symptoms receded in 38 (92.7%) of 41 patients at a median of 4 weeks after starting therapy. While on ruxolitinib, eleven (18.0%) patients developed grade 3–4 anaemia and thirteen (21.3%) patients developed grade 3–4 thrombocytopenia. Forty six (74.2%) patients survived. Twenty five (40.3%) patients discontinued therapy, most frequently due to inefficacy (16.1% of patients) or haematological toxicity (8.1% of patients). Median duration of ruxolitinib therapy was 41 weeks.

Polycythaemia vera –⁠ a total of 8 patients with polycythaemia vera treated with ruxolitinib because of resistance or intolerance of previous treatment was analysed. Six (75.0%) patients achieved complete remission. All patients experienced resolution of disease-associated symptoms. No patient developed grade 3 to 4 toxicity. At evaluation, all patients remained on ruxolitinib with a median duration of 32.5 weeks.

Conclusion:
Our analysis confirmed the very good treatment efficacy of ruxolitinib in patients with myelofibrosis and polycythaemia vera on reduction of splenomegaly and alleviation of disease-associated symptoms. Ruxolitinib additionally led to the correction of haematocrit values in patients with polycythaemia vera. Haematological toxicity was generally low.

KEY WORDS:
ruxolitinib –⁠ myelofibrosis –⁠ polycythaemia vera –⁠ treatment outcome –⁠ drug toxicity

Zdroje

1. Abdel-Wahab O, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med 2009; 60 : 233–245.

2. 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): 1144–1148.

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): 1779–1790.

4. Mesa RA, Schwager S, Radia D, et al. The myelofibrosis symptom assessment form (MFSAF): an evidence-based brief inventory to mea-sure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009; 33 : 1199–1203.

5. 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.

6. 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.

7. 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.

8. 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 : 787–798.

9. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372(5): 426–435.

10. 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.

11. Evs.nci.nih.gov [internetová stránka]. Department of Health and Human Services, National Institutes of Health, National Cancer Institute: Common terminology criteria for adverse events v4.03. [aktualizováno 14. června 2010; citováno 12. prosince 2016]. Dostupné z: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

12. Verstovsek S, Mesa RA, Gotlib JR, et al. Long-term outcomes of ruxolitinib (RUX) therapy in patients (PTS) with myelofibrosis (MF): 5-year final efficacy and safety analysis from COMFORT-I. Abstract S452. Haematologica 2016; 101(S1): 162.

13. 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(8): 1701–1707.

14. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther 2013; 7 : 13–21.

15. Deininger M, Radich J, Burn TC, et al. The effect of long-term ruxolitinib treatment on JAK2 V617F allele burden in patients with myelofibrosis. Blood 2015; 126 : 1551-1554.

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

17. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Changes in bone marrow morphology in patients with myelofibrosis treated for up to 5 years with either ruxolitinib or best available therapy. Abstract P405. Haematologica 2014; 99(S1): 127.

18. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 2015; 100 : 1139–1145.

19. Giraldo P, Palandri F, Palumbo GA, et al Safety and efficacy of ruxolitinib (RUX) in patients with intermediate-1–risk myelofibrosis (MF) from an open-label, multicenter, single-arm expanded-access study. Abstract P675. Haematologica 2015; 100 : 265.

20. Mead AJ, Milojkovic D, Knapper S, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol 2015; 170 : 29–39.

21. Davis KL, Cote I, Kaye JA, et al. Real-world assessment of clinical outcomes in patients with lower-risk myelofibrosis receiving treatment with ruxolitinib. Adv Hematol 2015; 2015 : 848473.

22. Passamonti F, Kiladjian J-J, Vannucchi AM, et al. ReTHINK: a randomized, double-blind, placebo-controlled, multicenter, phase 3 study of ruxolitinib in early myelofibrosis patients with high molecular risk mutations. Abstract TPS7080. J Clin Oncol 2016; 34(S).

23. Polverelli N, Breccia M, Benevolo G, et al. Risk factors for infections in myelofibrosis: role of disease status and treatment. A study on 507 patients. Abstract. Blood 2015; 126 : 1606.

24. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification and management. Am J Hematol 2017; 92 : 95–108.

25. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012;119 : 1363–1369.