Do All Patients With Polycythemia Vera or Essential Thrombocythemia Need Cytoreduction?

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Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia chromosome–negative chronic myeloproliferative neoplasms (MPNs), characterized by expansion of normal blood counts, bleeding, thrombosis, and the potential for transformation to myelofibrosis (MF) or acute myeloid leukemia (AML). The primary goals of treatment for MPNs are to reduce the risk of thrombosis, alleviate systemic symptom burden (eg, fatigue, pruritus, microvascular symptoms, and symptomatic splenomegaly), and to prevent transformation to MF/AML. Preventing transformation is clearly important, but not expected with current therapies. Currently, cytoreduction is advised based on vascular risk assessments, which include age and thrombosis history, as well as molecular profile in ET. Traditionally, cytoreduction has been advised only in patients with high vascular risk. Recently, a large prospective study evaluated the safety and efficacy of cytoreduction in patients with ET with less-than-high-risk vascular profiles. A larger question in the MPN field is whether cytoreduction is advisable for all patients with ET and PV, regardless of risk. This article reviews existing data on cytoreduction, evaluating hydroxyurea, interferons, and ruxolitinib in ET and PV. This review evaluates whether evidence supports a more liberal strategy of cytoreduction for all patients with ET and PV.

Correspondence: Brady L. Stein, MD, MHS, Department of Medicine, Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 1020, Chicago, IL 60611. Email: bstein@nm.org
  • 1.

    BaxterEJScottLMCampbellPJ. Acquired mutation of the tyrosine kinase Jak2 in human myeloproliferative disorders. Lancet2005;365:10541061.

    • Search Google Scholar
    • Export Citation
  • 2.

    PassamontiFRumiEPietraD. 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. Leukemia2010;24:15741579.

    • Search Google Scholar
    • Export Citation
  • 3.

    PassamontiFElenaCSchnittgerS. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood2011;117:28132816.

    • Search Google Scholar
    • Export Citation
  • 4.

    VannucchiAMGuglielmelliPTefferiA. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin2009;59:171191.

    • Search Google Scholar
    • Export Citation
  • 5.

    CampbellPJGreenAR. The myeloproliferative disorders. N Engl J Med2006;355:24522466.

  • 6.

    KlampflTGisslingerHHarutyunyanAS. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med2013;369:23702390.

  • 7.

    VannucchiAMAntonioliEGuglielmelliP. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood2008;112:844847.

    • Search Google Scholar
    • Export Citation
  • 8.

    SteinBLOhSTBerenzonD. Polycythemia vera: an appraisal of the biology and management 10 years after discovery of JAK2 V617F. J Clin Oncol2015;33:39533960.

    • Search Google Scholar
    • Export Citation
  • 9.

    BarbuiTBarosiGBirgegardG. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol2011;29:761769.

    • Search Google Scholar
    • Export Citation
  • 10.

    EttingerDEWoodDEAisnerDL. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 2.2018. Accessed May 3 2018. To view the most recent version of these guidelines visit NCCN.org.

    • Search Google Scholar
    • Export Citation
  • 11.

    KanderEMMoliternoARRademakerA. Practice patterns in the diagnosis and treatment of polycythemia vera in the post-JAK2 V617F discovery era. J Natl Compr Canc Netw2016;14:12381245.

    • Search Google Scholar
    • Export Citation
  • 12.

    GodfreyALCampbellPJMacLeanC. Hydroxycarbamide plus aspirin vs aspirin alone in intermediate risk essential thrombocythemia: results of the PT-1 international, prospective, randomized clinical trial [abstract]. Blood2017;130:Abstract 319.

    • Search Google Scholar
    • Export Citation
  • 13.

    CrisaEVenturinoEPasseraR. A retrospective study of 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs. Ann Hematology2010;89:691699.

    • Search Google Scholar
    • Export Citation
  • 14.

    TefferiA. Mutant molecules of interest in myeloproliferative neoplasms: introduction. Acta Haematol2008;119:192193.

  • 15.

    MesaRAMillerCBThyneM. Differences in treatment goals and perception on symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: findings from the MPN Landmark survey. Cancer2017;123:449458.

    • Search Google Scholar
    • Export Citation
  • 16.

    MartinK. Risk factors for and management of MPN-associated bleeding and thrombosis. Curr Hematol Malig Rep2017;12:389396.

  • 17.

    TefferiARumiEGinazziG. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia2013;27:18741881.

    • Search Google Scholar
    • Export Citation
  • 18.

    HaiderMGangatNLashoT. Validation of the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in 585 Mayo Clinic patients. Am J Hematol2016;91:390394.

    • Search Google Scholar
    • Export Citation
  • 19.

    LandolfiRMarchioliRKuttiJ. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med2004;350:114124.

  • 20.

    MarchioliRFinazziGSpecchiaG. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med2013;368:2232.

  • 21.

    Alvarez-LarranACervantesFPereiraA. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood2010;116:12051210.

    • Search Google Scholar
    • Export Citation
  • 22.

    MichielsJJBernemanZSchroyensW. Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemia and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and Coumadin-resistant arterial thrombophilia. Platelets2006;17:528544.

    • Search Google Scholar
    • Export Citation
  • 23.

    Alvarez-LarranAPereiraAGuglielmelliP. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation. Haematologica2016;101:926931.

    • Search Google Scholar
    • Export Citation
  • 24.

    ChuDKHillisCMLeongDP. Benefits and risks of antithrombotic therapy in essential thrombocythemia: a systematic review. Ann Intern Med2017;167:170180.

    • Search Google Scholar
    • Export Citation
  • 25.

    FruchtmanSMMackKKaplanME. From efficacy to safety: a polycythemia vera study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol1997;34:1723.

    • Search Google Scholar
    • Export Citation
  • 26.

    KiladjianJJChevretSDosquetC. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol2011;29:39073913.

    • Search Google Scholar
    • Export Citation
  • 27.

    NajeanYRainJD. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood1997;90:33703377.

    • Search Google Scholar
    • Export Citation
  • 28.

    BarbuiTVannucchiAMFinazziG. A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study. Am J Hematol2017;92:11311136.

    • Search Google Scholar
    • Export Citation
  • 29.

    De StefanoVZaTRossiE. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica2008;93:372380.

    • Search Google Scholar
    • Export Citation
  • 30.

    PassamontiFRumiEPungolinoE. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med2004;117:755761.

    • Search Google Scholar
    • Export Citation
  • 31.

    FinazziGCarusoVMarchioliR. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood2005;105:26642670.

    • Search Google Scholar
    • Export Citation
  • 32.

    BjorkholmMDerolfARHultcrantzM. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol2011;29:24102415.

    • Search Google Scholar
    • Export Citation
  • 33.

    BarbuiTVannucchiAMFinazziG. A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study. Am J Hematol2017;92:11311136.

    • Search Google Scholar
    • Export Citation
  • 34.

    CortelazzoSFinazziGRuggeriM. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med1995;332:11321136.

    • Search Google Scholar
    • Export Citation
  • 35.

    HarrisonCNCampbellPJBuckG. Hydroxyurea compared with anagrelide in high-risk ET. N Engl J Med2005;353:3345.

  • 36.

    GisslingerHGoticMHolowieckiJ. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET study, a randomized controlled trial. Blood2013;121:17201728.

    • Search Google Scholar
    • Export Citation
  • 37.

    FoucarCSteinBL. Contemporary use of interferon therapy in the myeloproliferative neoplasms. Curr Hematol Malig Rep2017;12:406414.

  • 38.

    KiladijanJJCassinatBChevretS. Pegylated interferon-alfa-2a induces complete hematologic molecular responses with low toxicity in polycythemia vera. Blood2008;112:30653072.

    • Search Google Scholar
    • Export Citation
  • 39.

    Quintas-CardamaAKantarjianHManshouriT. Pegylated interferon alfa-2a yields high rates of hematologic and molecular responses in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol2009;27:54185424.

    • Search Google Scholar
    • Export Citation
  • 40.

    LarsenTSMollerMDde StrickerK. Minimal residual disease and normalization of the bone marrow after long-term treatment with alpha-interferon2b in polycythemia vera. A report on molecular response patterns in seven patients in sustained complete hematological remission. Hematology2009;14:331334.

    • Search Google Scholar
    • Export Citation
  • 41.

    MascarenhasJOPrchalJTRambaldiA. Interim analysis of the myeloproliferative disorders research consortium (MPD-RC) 112 global phase III trial of front line pegylated interferon alpha-2a vs. hydroxyurea in high risk polycythemia vera and essential thrombocythemia [abstract]. Blood2016;128:Abstract 479.

    • Search Google Scholar
    • Export Citation
  • 42.

    VannucchiAMKiladjianJJGriesshammerM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med2015;372:426435.

    • Search Google Scholar
    • Export Citation
  • 43.

    PassamontiFGriesshammerMPalandriF. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomized, open-label, phase 3b study. Lancet Oncol2017;18:8899.

    • Search Google Scholar
    • Export Citation
  • 44.

    HarrisonCNMeadAJPanchalA. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood2017;130:18891897.

    • Search Google Scholar
    • Export Citation
  • 45.

    VerstovsekSPassamontiFRambaldiA. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood2017;130:17681771.

    • Search Google Scholar
    • Export Citation
  • 46.

    GisslingerHKladeCGeorgievP. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in PV patients [abstract]. Blood2016;128:Abstract 475.

    • Search Google Scholar
    • Export Citation
  • 47.

    GisslingerHKladeCGeorgievP. Ropeginterferon Alfa-2b induces high rates of clinical hematological and molecular responses in polycythemia vera: two-year results from the first prospective randomized controlled trial [abstract]. Blood2017;130:Abstract 320.

    • Search Google Scholar
    • Export Citation
  • 48.

    GisslingerHZagrijtschukOBuxhofer-AuschV. Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood2015;126:17621769.

    • Search Google Scholar
    • Export Citation
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