Case-Based Review

Polycythemia Vera and Essential Thrombocythemia: Current Management

2018 January/February;13(1):7-22

References

1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4^th ed. Lyon: IARC; 2008.

2. Alvarez-Larran A, Pereira A, Arellano-Rodrigo E, et al. Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study. Br J Haematol 2013;161:865–71.

3. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013;88:507–16.

4. Michiels JJ, Berneman Z, Schroyens W, et al. Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadin-resistant arterial thrombophilia. Platelets 2006;17:528–44.

5. James C, Ugo V, Couedic J-PL, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–8.

6. Kralovics R, Passamonti F, Buser A, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders.N Engl J Med 2005;352:1779–90.

7. Verstovsek S, Mesa R, 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 J, Al-Ali H, et al. JAK Inhibition with ruxolitinib versus best available therapy for myelofibrosis.N Engl J Med 2012;366:787–98.

9. Berglund S, Zettervall O. Incidence of polycythemia vera in a defined population. Eur J Haematol 1992;48:20–6.

10. Rozman C, Giralt M, Feliu E, et al. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer 1991;67:2658–63.

11. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004;117:755–61.

12. Hultcrantz M, Kristinsson SY, Andersson TM, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study. J Clin Oncol 2012;30:2995–3001.

13. Wolanskyj AP, Schwager SM, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006;81:159–66.

14. Srour SA, Devesa SS, Morton LM, et al. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12. Br J Haematol 2016;174:382–96.

15. Titmarsh GJ, Duncombe AS, McMullin MF, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol 2014;89:581–7.

16. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 2014;92:289–97.

17. Stein BL, Gotlib J, Arcasoy M, et al. Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms. J Natl Compr Canc Netw 2015;13:424–34.

18. 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;7:387–97.

19. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–61.

20. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356:459–68.

21. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007;21:1960–3.

22. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011;117:2813–6.

23. Abe M, Suzuki K, Inagaki O, et al. A novel MPL point mutation resulting in thrombopoietin-independent activation. Leukemia 2002;16:1500–6.

24. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e270.

25. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;108:3472–6.

26. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391–405.

27. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–90.

28. Wang WA, Groenendyk J, Michalak M. Calreticulin signaling in health and disease. Int J Biochem Cell Biol 2012;44:842–6.

29. Saeidi K. Myeloproliferative neoplasms: Current molecular biology and genetics. Crit Rev Oncol Hematol 2016;98:375–89.

30. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–405.

31. 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 2007;109:68–76.

32. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005;23:2224–32.

33. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood 2011;118:401–8.

34. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol 2012;30:4098–103.

35. Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost 2013;11:1215–27.

36. Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013;122:2176-–84.

37. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary myeloproliferative polychytemia. Lancet 1978;2:1219–22.

38. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007;109:2446–52.

39. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013;27:1874–81.

40. Barbui T, Falanga A. Molecular biomarkers of thrombosis in myeloproliferative neoplasms. Thromb Res 2016;140 Suppl 1:S71–75.

41. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005;366:1945–53.

42. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014;124:2507–13.

43. Qin Y, Wang X, Zhao C, et al. The impact of JAK2V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia: a meta-analysis. Int J Hematol 2015;102:170–80.

44. Ziakas PD. Effect of JAK2 V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain. Haematologica 2008;93:1412–4.

45. Lussana F, Dentali F, Abbate R, et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009;124:e19–25.

46. Dahabreh IJ, Zoi K, Giannouli S, et al. Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res 2009;33:67–73.

47. Cho YU, Chi HS, Lee EH, et al. Comparison of clinicopathologic findings according to JAK2 V617F mutation in patients with essential thrombocythemia. Int J Hematol 2009;89:39–44.

48. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 2005;131:208–13.

49. Antonioli E, Guglielmelli P, Pancrazzi A, et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 2005;19:1847–9.

50. Palandri F, Catani L, Testoni N, et al. Long-term follow-up of 386 consecutive patients with essential thrombocythemia: safety of cytoreductive therapy. Am J Hematol 2009;84:215–20.

51. Chim CS, Sim JP, Chan CC, et al. Impact of JAK2V617F mutation on thrombosis and myeloid transformation in essential thrombocythemia: a multivariate analysis by Cox regression in 141 patients. Hematology 2010;15:187–92.

52. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007;110:840–6.

53. Carobbio A, Finazzi G, Antonioli E, et al. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol 2009;37:1016–21.

54. Alvarez-Larran A, Bellosillo B, Pereira A, et al. JAK2V617F monitoring in polycythemia vera and essential thrombocythemia: clinical usefulness for predicting myelofibrotic transformation and thrombotic events. Am J Hematol 2014;89:517–23.

55. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015;5:e369.

56. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011;117:5857–9.

57. Alvarez-Larran A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia 2007;21:1218–23.

58. Jantunen R, Juvonen E, Ikkala E, et al. The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia. Ann Hematol 2001;80:74–8.

59. Besses C, Cervantes F, Pereira A, et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia 1999;13:150–4.

60. Haider M, Gangat N, Hanson C, Tefferi A. Splenomegaly and thrombosis risk in essential thrombocythemia: the mayo clinic experience. Am J Hematol 2016;91:E296–297.

61. Carobbio A, Finazzi G, Antonioli E, et al. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. Blood 2008;112:3135–7.

62. Palandri F, Polverelli N, Catani L, et al. Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. Ann Hematol 2011;90:933–8.

63. Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood 2012;120:1409–11.

64. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132–6.

65. van Genderen PJ, Mulder PG, Waleboer M, et al. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol 1997;97:179–84.

66. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001;97:863–6.

67. De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008;93:372–80.

68. Alvarez-Larran A, Cervantes F, Pereira A, et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010;116:1205–10.

69. Palandri F, Polverelli N, Catani L, et al. Bleeding in essential thrombocythaemia: a retrospective analysis on 565 patients. Br J Haematol 2012;156:281–4.

70. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552–5.

71. Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia 2014;28:2300–3.

72. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123:1544–51.

73. Palandri F, Latagliata R, Polverelli N, et al. Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. Leukemia 2015;29:1344–9.

74. Fu R, Xuan M, Zhou Y, et al. Analysis of calreticulin mutations in Chinese patients with essential thrombocythemia: clinical implications in diagnosis, prognosis and treatment. Leukemia 2014;28:1912–4.

75. Tefferi A, Wassie EA, Guglielmelli P, et al. Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 2014;89:E121–4.

76. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia 2016;30:431–8.

77. Rumi E, Pietra D, Guglielmelli P, et al. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood 2013;121:4388–95.

78. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008;112:141–9.

79. Gangat N, Wassie EA, Lasho TL, et al. Mutations and thrombosis in essential thrombocythemia: prognostic interaction with age and thrombosis history. Eur J Haematol 2015;94:31–6.

80. Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013;162:730–47.

81. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymph 2013;54:1989–95.

82. Landolfi R, Di Gennaro L, Nicolazzi MA, et al. Polycythemia vera: gender-related phenotypic differences. Intern Emerg Med 2012;7:509–15.

83. Winslow ER, Brunt LM, Drebin JA, et al. Portal vein thrombosis after splenectomy. Am J Surg 2002;184:631–6.

84. Smalberg JH, Arends LR, Valla DC, et al. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012;120:4921–8.

85. Dentali F, Squizzato A, Brivio L, et al. JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009;113:5617–23.

86. Pardanani A, Lasho TL, Hussein K, et al. JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients. Mayo Clin Proc 2008;83:457–9.

87. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29:761–70.

88. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114–24.

89. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013;368:22–33.

90. Kiladjian JJ, Chevret S, Dosquet C, et al. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol 2011;29:3907–13.

91. Kaplan ME, Mack K, Goldberg JD, et al. Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 1986;23:167–71.

92. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997;34:17–23.

93. Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664–70.

94. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 2013;121:4778–81.

95. 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;119:1363–9.

96. Stein BL, Tiu RV. Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. J Interferon Cytokine Res 2013;33:145–53.

97. Ludwig H, Cortelezzi A, Van Camp BG, et al. Treatment with recombinant interferon-alpha-2C: multiple myeloma and thrombocythaemia in myeloproliferative diseases. Oncology 1985;42 Suppl 1:19–25.

98. Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 2006;107:451–8.

99. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 2011;117:4706–15.

100. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs 2008;22:315–29.

101. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065–72.

102. Turlure P, Cambier N, Roussel M, et al. Complete hematological, molecular and histological remissions without cytoreductive treatment lasting after pegylated-interferon {alpha}-2a (peg-IFN{alpha}-2a) therapy in polycythemia vera (PV): long term results of a phase 2 trial [abstract]. Blood 2011;118(21). Abstract 280.

103. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27:5418–24.

104. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon a-2a. Blood 2013;122:893–901.

105. Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer 2006;106:2397–405.

106. Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer 2007;110:2012–18.

107. Them NC, Bagienski K, Berg T, et al. Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b. Am J Hematol 2015;90:288–94.

108. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients [abstract]. Blood 2016;128(suppl 22). Abstract 475.

109. van Genderen PJ, van Vliet HH, Prins FJ, et al. Excessive prolongation of the bleeding time by aspirin in essential thrombocythemia is related to a decrease of large von Willebrand factor multimers in plasma. Ann Hematol 1997;75:215–20.

110. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132–7.

111. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45.

112. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720–8.

113. Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol 2003;51:81–6.

114. Barosi G, Tefferi A, Barbui T, ad hoc committee ‘Definition of clinically relevant outcomes for contemporarily clinical trials in Ph-neg M. Do current response criteria in classical Ph-negative myeloproliferative neoplasms capture benefit for patients? Leukemia 2012;26:1148–9.

115. Bjorkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 2011;29:2410–5.

116. Alvarez-Larran A, Martinez-Aviles L, Hernandez-Boluda JC, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol 2014;93:2037–43.

117. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014;120:513–20.

118. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib in polycythemia vera resistant to or intolerant of hydroxyurea. N Engl J Med 2015; 372:426–35.

119. Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial. Haematologica 2016;101:821–9.

120. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 2017;18:88–99.

121. Verstovsek S, Passamonti F, Rambaldi A, et al. Long-term results from a phase II open-label study of ruxolitinib in patients with essential thrombocythemia refractory to or intolerant of hydroxyurea [abstract]. Blood 2014;124. Abstract 1847.

122. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib versus best available therapy for ET intolerant or resistant to hydroxycarbamide in a randomized trial. Blood 2017 Aug 9. pii: blood-2017-05-785790 .

123. Bose P, Verstovsek S. Drug development pipeline for myeloproliferative neoplasms: potential future impact on guidelines and management. J Natl Compr Canc Netw 2016;14:1613–24.

124. Cerquozzi S, Teffieri A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J 2015;Nov 13;5:e366.

125. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood 2008;111:3383–7.

126. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007;31:737–40.

127. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol 2014;21:65–71.

128. Chihara D, Kantarjian HM, Newberry KJ, et al. Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms [abstract]. Blood 2016;128. Abstract 1940.

129. Tam CS, Nussenzveig RM, Popat U, et al. The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms. Blood 2008;112:1628–37.

130. Kundranda MN, Tibes R, Mesa RA. Transformation of a chronic myeloproliferative neoplasm to acute myelogenous leukemia: does anything work? Curr Hematol Malig Rep 2012;7:78–86.

131. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res 2015;39:950–6.

132. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010;116:3735–42.

133. Pemmaraju N, Kantarjian H, Kadia T, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15:171–6.

134. Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in patients with blast-phase MPN and post-MPN AML: results of a phase I study (Myeloproliferative Disorders Research Consortium 109 trial) [abstract]. Blood 2016;128. Abstract 1124.

135. Bose P, Verstovsek S, Gasior Y, et al. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results [abstract]. Blood 2016;128. Abstract 4262.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacrocytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries.¹²⁴ The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In PV patients risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 10³/µL, and WBC count > 30,000/µL are associated with worse outcomes.¹²⁵ In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. Management of post-PV/post-ET myelofibrosis recapitulates that of PMF.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷