Thrombotic Events and Overall Survival in BCR-ABL1 Negative Myeloproliferative Neoplasms: A Single-Center Analysis

Abstract

Aim: BCR-ABL1–negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders characterized by increased myeloid proliferation. This study retrospectively evaluated the clinical, demographic, molecular, and survival characteristics of patients with classical MPNs treated at the Hematology Outpatient Clinic, Dokuz Eylül University.

Material and Methods: In this single-center retrospective analysis, data from 363 patients diagnosed between January 2012 and May 2021 were reviewed according to the 2016 WHO criteria: ET (n=230), PV (n=104), and PMF (n=29).

Results: JAK2 mutations were identified in 85.1% of PV, 65.4% of ET, and 60% of PMF cases. Thrombosis at diagnosis occurred in 18% of PV, 19.1% of ET, and 10.3% of PMF patients. Cytoreductive therapy was administered to 88.2% of patients, predominantly hydroxyurea (85.7%). Leukemic and fibrotic transformations developed in 1.6% and 14.5% of cases, respectively. Among 126 patients with thrombotic events, JAK2 positivity was significantly associated with increased thrombotic risk (p=0.0025). Thrombosis was more frequent in patients aged >65 years (p=0.0047). Ten-year overall survival (OS) rates were 81% in PV, 79% in ET, and 38% in PMF. In multivariable Cox regression, age >65 years independently predicted inferior OS (p<0.001), and leukocytosis was similarly associated with poorer outcomes (p=0.026).

Conclusion: Advanced age and JAK2 V617F mutation are key risk factors for thrombosis in classical MPNs. Hydroxyurea remains the most widely used cytoreductive therapy in clinical practice.

Keywords

• Myeloproliferative disorders
• thrombosis
• JAK2 protein
• human
• survival analysis
• myelofibrosis

References

1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372-5.
2. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-9. doi:10.1038/leu.2013.119.
3. Tefferi A, Lasho TL, Finke CM, Elala Y, Hanson CA, Ketterling RP, et al. Targeted deep sequencing in primary myelofibrosis. Blood Adv. 2016;1(2):105-11. doi:10.1182/bloodadvances.2016000208.
4. Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, Szuber N, et al. Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood Adv. 2018;2(4):370-80. doi:10.1182/bloodadvances.2018015875.
5. Tefferi A, Mudireddy M, Mannelli F, Begna KH, Patnaik MM, Hanson CA, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018;32(5):1200-10. doi:10.1038/s41375-018-0019-y.
6. Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021;96(1):145-62. doi:10.1002/ajh.26050.
7. Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24(9):1574-9. doi:10.1038/leu.2010.148.
8. Guglielmelli P, Loscocco GG, Mannarelli C, Rossi E, Mannelli F, Ramundo F, et al. JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis. Blood Cancer J. 2021;11(12):199. doi:10.1038/s41408-021-00581-6.

9. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342(17):1255-65. doi:10.1056/NEJM200004273421706.
10. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, et al. Development and validation of an international prognostic score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128-33; quiz 5252. doi:10.1182/blood-2012-07-444067
11. Barbui T, Vannucchi AM, Buxhofer-Ausch V, de Stefano V, Betti S, Rambaldi A, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 2015;5(11):e369. doi:10.1038/bcj.2015.94.
12. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405. doi:10.1182/blood-2016-03-643544.
13. Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, 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):2895-901. doi:10.1182/blood-2008-07-170449.
14. Finazzi G, Carobbio A, Guglielmelli P, Cavalloni C, Salmoiraghi S, Vannucchi AM, et al. Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood. 2014;124(16):2611-2. doi:10.1182/blood-2014-08-596676.
15. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905-14. doi:10.1038/leu.2008.72.
16. Shallis RM, Zeidan AM, Wang R, Podoltsev NA. Epidemiology of the Philadelphia chromosome-negative classical myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2021;35(2):177-89. doi:10.1016/j.hoc.2020.11.005.
17. Anía BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton 3rd LJ. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. Br J Haematol. 1994;47(2):89-93. doi:10.1002/ajh.2830470205.
18. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874-81. doi:10.1038/leu.2013.163.
19. Szuber N, Mudireddy M, Nicolosi M, Penna D, Vallapureddy RR, Lasho TL, et al. 3023 Mayo Clinic patients with myeloproliferative neoplasms: risk-stratified comparison of survival and outcomes data among disease subgroups. Mayo Clin Proc. 2019;94(4):599-610. doi:10.1016/j.mayocp.2018.08.022.
20. Barbui T, Carobbio A, Rumi E, Finazzi G, Gisslinger H, Rodeghiero F, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124(19):3021-3. doi:10.1182/blood-2014-07-591610.
21. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507-13; quiz 2615. doi:10.1182/blood-2014-05-579136.
22. Khanal N, Giri S, Upadhyay S, Shostrom VK, Pathak R, Bhatt VR. Risk of second primary malignancies and survival of adult patients with polycythemia vera: a United States population-based retrospective study. Leuk Lymphoma. 2016;57(1):129-33. doi:10.3109/10428194.2015.1071492.