Abstract
Purpose of Review
Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET.
Recent Findings
International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis.
Summary
International collaborations (“big data”) with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.
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References
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599–613.
Geyer HL, Dueck AC, Scherber RM, Mesa RA. Impact of inflammation on myeloproliferative neoplasm symptom development. Mediators Inflamm. 2015;2015: 284706.
Mesa R, Palmer J, Eckert R, Huberty J. Quality of life in myeloproliferative neoplasms: symptoms and management implications. Hematol Oncol Clin North Am. 2021;35(2):375–90.
Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U, Mesa RA. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92(4):289–97.
• Verstovsek S, Yu J, Scherber RM, Verma S, Dieyi C, Chen CC, Parasuraman S. Changes in the incidence and overall survival of patients with myeloproliferative neoplasms between 2002 and 2016 in the United States. Leuk Lymphoma. 2022;63(3):694–702. This most recent study examined incidences, thrombotic risk, and survival outcomes among US adults with MPNs.
Shallis RM, Wang R, Davidoff A, Ma X, Podoltsev NA, Zeidan AM. Epidemiology of the classical myeloproliferative neoplasms: the four corners of an expansive and complex map. Blood Rev. 2020;42: 100706.
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.
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.
Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost. 2007;33(4):313–20.
Pemmaraju N, Gerds AT, Yu J, Parasuraman S, Shah A, Xi A, Kumar S, Scherber RM, Verstovsek S. Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia. Leuk Res. 2022;115: 106809.
Lucijanic M, Krecak I, Soric E, Sabljic A, Galusic D, Holik H, Perisa V, Moric Peric M, Zekanovic I, Kusec R. Patients with post polycythemia vera myelofibrosis might experience increased thrombotic risk in comparison to primary and post essential thrombocythemia myelofibrosis. Leuk Res. 2022;119: 106905.
Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, Hoffman R, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057–69.
Haider M, Gangat N, Lasho T, Abou Hussein AK, Elala YC, Hanson C, et al. Validation of the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in 585 Mayo Clinic patients. Am J Hematol. 2016;91(4):390–4.
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.
Guglielmelli P, Carobbio A, Rumi E, De Stefano V, Mannelli L, Mannelli F, et al. Validation of the IPSET score for thrombosis in patients with prefibrotic myelofibrosis. Blood Cancer J. 2020;10(2):21.
Cerquozzi S, Barraco D, Lasho T, Finke C, Hanson CA, Ketterling RP, et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J. 2017;7(12):662.
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.
Mancuso S, Santoro M, Accurso V, Agliastro G, Raso S, Di Piazza F, et al. Cardiovascular risk in polycythemia vera: thrombotic risk and survival: can cytoreductive therapy be useful in patients with low-risk polycythemia vera with cardiovascular risk factors? Oncol Res Treat. 2020;43(10):526–30.
Krečak I, Morić Perić M, Zekanović I, Holik H, Coha B, Gverić-Krečak V, et al. No impact of the increased number of cardiovascular risk factors on thrombosis and survival in polycythemia vera. Oncol Res Treat. 2021;44(4):201–3.
• Lucijanic M, Krecak I, Kusec R. Renal disease associated with chronic myeloproliferative neoplasms. Expert Rev Hematol. 2022;9:1–4. This is the first paper reviewing currently available evidence on the clinical presentation, evolution, and treatment outcomes of MPN-associated renal disease, which recently emerged as a potentially clinically relevant and treatable cardiovascular risk factor in PV and ET patients.
• Krečak I, Holik H, Martina MP, Zekanović I, Coha B, Gverić-Krečak V. Chronic kidney disease could be a risk factor for thrombosis in essential thrombocythemia and polycythemia vera. Int J Hematol. 2020;112(3):377–84. This is the first retrospective multicenter study which has suggested that chronic kidney disease in PV and ET patients may be associated with an increased thrombotic risk.
Sørensen AL, Knudsen TA, Skov V, Kjaer L, Holm N, Ellervik C, et al. Smoking impairs molecular response, and reduces overall survival in patients with chronic myeloproliferative neoplasms: a retrospective cohort study. Br J Haematol. 2021;193(1):83–92.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88.
Krečak I, Holik H, Coha B, Perić MM, Zekanović I, Krečak MV, et al. Low-density lipoprotein (LDL) and the risk of thrombotic events in essential thrombocythemia and polycythemia vera. Ann Hematol. 2021;100(5):1335–6.
Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit JAK2-V617F-dependent cell growth. Br J Haematol. 2013;160(2):177–87.
Krečak I, Holik H, Morić-Perić M, Zekanović I, Coha B, Gverić-Krečak V. The impact of statins on the intensity of phlebotomies in polycythemia vera. Ann Hematol. 2020;99(4):911–2.
Hasselbalch HC, Riley CH. Statins in the treatment of polycythaemia vera and allied disorders: an antithrombotic and cytoreductive potential? Leuk Res. 2006;30(10):1217–25.
Marchetti M, Vannucchi AM, Griesshammer M, Harrison C, Koschmieder S, Gisslinger H, et al. Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol. 2022;9(4):e301–11.
Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood. 2007;109(6):2310–3.
De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, GIMEMA Chronic Myeloproliferative Neoplasms Working Party, et al. Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia. Am J Hematol. 2010;85(2):97–100.
Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R, European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP), et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446–52.
• Carobbio A, Ferrari A, Masciulli A, Ghirardi A, Barosi G, Barbui T. Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2019;3(11):1729–37. This paper is the most recent meta-analysis of published articles in the last 15 years evaluating the potential impact of leukocytosis on thrombotic risk in PV and ET.
Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778–81.
• Ronner L, Podoltsev N, Gotlib J, Heaney ML, Kuykendall AT, O’Connell C, et al. Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis. Blood. 2020;135(19):1696–703. This paper has used a novel statistical technique which measures an evolution of an outcome over time, and has suggested that leukocytosis in patients with PV may be associated with disease evolution but not with thrombotic risk.
Alvarez-Larrán A, Pereira A, Cervantes F, Arellano-Rodrigo E, Hernández-Boluda JC, Ferrer-Marín 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(6):1363–9.
Tremblay D, Srisuwananukorn A, Ronner L, Podoltsev N, Gotlib J, Heaney ML, et al. European LeukemiaNet response predicts disease progression but not thrombosis in polycythemia vera response predicts disease progression but not thrombosis in polycythemia vera. HemaSphere. 2022;6: e721.
Hernández-Boluda JC, Alvarez-Larrán A, Gómez M, Angona A, Amat P, Bellosillo B, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol. 2011;152(1):81–8.
Hernández-Boluda JC, Pereira A, Cervantes F, Gómez M, Arellano-Rodrigo E, Alvarez-Larrán A, et al. Clinical evaluation of the European LeukemiaNet response criteria in patients with essential thrombocythemia treated with anagrelide. Ann Hematol. 2013;92(6):771–5.
•• Verstovsek S, De Stefano V, Heidel FH, Zuurman M, Zaiac M, Bigan E, et al. US OPTUM database study in polycythemia vera patients: thromboembolic events (TEs) with hydroxyurea (HU) vs ruxolitinib switch therapy and machine-learning model to predict incidence of TEs and HU failure. Blood. 2019;134(Supplement_1):1659. This large retrospective study was the first to use artificial intelligence and machine learning techniques in order to identify novel biomarkers associated with an increased risk of thrombosis in patients with PV.
Krečak I, Holik H, Morić Perić M, Zekanović I, Coha B, Gverić-Krečak V, Lucijanić M. High platelet-to-lymphocyte ratio may differentiate polycythemia vera from secondary polycythemia. Wien Klin Wochenschr. 2022.
• Krečak I, Holik H, Morić Perić M, Zekanović I, Coha B, Valovičić-Krečak M, et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as prognostic biomarkers in polycythemia vera. Int J Lab Hematol. 2021. https://doi.org/10.1111/ijlh.137863. This multicenter retrospective study has identified platelet-to-lymphocyte ratio as a cheap and an easily obtainable biomarker to be associated with an increased risk of thrombosis and death in patients with PV.
• Carobbio A, Vannucchi AM, De Stefano V, Masciulli A, Guglielmelli P, Loscocco GG, Ramundo F, Rossi E, Kanthi Y, Tefferi A, Barbui T. Neutrophil-to-lymphocyte ratio is a novel predictor of venous thrombosis in polycythemia vera. Blood Cancer J. 2022;12(2):28. This multicenter retrospective study has also shown that a high neutrophil-to-lymphocyte ratio may be predictive of future thrombotic events in patients with PV.
Zhou D, Chen W, Cheng H, Qiao JL, Zhu LL, Li ZY, et al. Clinico-hematological profile and thrombotic/hemorrhagic events in 150 Chinese patients with essential thrombocythemia. Leuk Res. 2018;69:1–6.
Lucijanic M, Cicic D, Stoos-Veic T, Pejsa V, Lucijanic J, Fazlic Dzankic A, et al. Elevated neutrophil-to-lymphocyte-ratio and platelet-to-lymphocyte ratio in myelofibrosis: inflammatory biomarkers or representatives of myeloproliferation itself? Anticancer Res. 2018;38(5):3157–63.
Tefferi A, Loscocco GG, Farrukh F, Szuber N, Mannelli F, Pardanani AD, et al. A globally applicable “triple AAA” risk model for essential thrombocythemia based on age, absolute neutrophil count, and absolute lymphocyte count. Blood. 2021;138(Supplement_1):238.
Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21–32.
Pasca S, Chifotides HT, Verstovsek S, Bose P. Mutational landscape of blast phase myeloproliferative neoplasms (BP-MPN) and antecedent MPN. In: Cellular and molecular aspects of MPNs - part B, Volume 366, Bartalucci N, Ed., In International Review of Cell and Molecular Biology, Bartalucci N, Galuzzi L, Serial Eds., Academic Press. 1st edition. 2022, pp. 83–124
•• Tefferi A, Guglielmelli P, Lasho TL, Coltro G, Finke CM, Loscocco GG, et al. Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera. Br J Haematol. 2020;189(2):291–302. This international, multicenter retrospective study has identified novel molecular biomarkers which may help to identify patients under an increased risk of inferior outcomes and additionally proposed a novel, molecularly based, prognostic model in PV and ET.
Guglielmelli P, Gangat N, Coltro G, Lasho TL, Loscocco GG, Finke CM, et al. Mutations and thrombosis in essential thrombocythemia. Blood Cancer J. 2021;11(4):77.
• Alvarez-Larrán A, Díaz-González A, Such E, Mora E, Andrade-Campos M, García-Hernández C, MPN Spanish Group (GEMFIN), et al. Genomic characterization of patients with polycythemia vera developing resistance to hydroxyurea. Leukemia. 2021;35(2):623–7. This study was to first to analyze molecular profiles of patients with PV, before and at the time of hydroxyurea resistance, identifying potentially high-risk mutations for developing hydroxyurea resistance.
Knudsen TA, Skov V, Stevenson K, Werner L, Duke W, Laurore C, et al. Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses. Blood Adv. 2022;6(7):2107–19.
Quintás-Cardama A, Abdel-Wahab O, Manshouri T, Kilpivaara O, Cortes J, Roupie AL, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893–901.
Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368:22–33.
Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350(2):114–24.
Michiels JJ, Berneman Z, Schroyens W, Koudstaal PJ, Lindemans J, Neumann HA, 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(8):528–44.
Alvarez-Larrán A, Pereira A, Arellano-Rodrigo E, Hernández-Boluda JC, Cervantes F, Besses C. 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(6):865–71.
• Alvarez-Larrán A, Pereira A, Guglielmelli P, Hernández-Boluda JC, Arellano-Rodrigo E, Ferrer-Marín F, et al. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation. Haematologica. 2016;101(8):926–31. This observational retrospective study has shown that CALR-mutated low-risk patients with ET may not benefit from aspirin.
•• Rocca B, Tosetto A, Betti S, Soldati D, Petrucci G, Rossi E, et al. A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia. Blood. 2020;136(2):171–82. This study was the first to show that twice-daily aspirin regimen in patients with ET may have the optimal safety and efficacy when compared to once-daily and thrice-daily regimens.
Tosetto A, Rocca B, Petrucci G, Betti S, Soldati D, Rossi E, Aspirin Regimens in EsSentialthrombocythemia (ARES) Investigators, et al. Association of platelet thromboxane inhibition by low-dose aspirin with platelet count and cytoreductive therapy in essential thrombocythemia. Clin Pharmacol Ther. 2022;111(4):939–49.
De Stefano V, Ruggeri M, Cervantes F, Alvarez-Larrán A, Iurlo A, Randi ML, et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia. 2016;30:2032–8.
De Stefano V, Vannucchi AM, Ruggeri M, Cervantes F, Alvarez-Larrán A, Iurlo A, et al. Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients. Blood Cancer J. 2016;6(11): e493.
Ianotto JC, Couturier MA, Galinat H, Mottier D, Berthou C, Guillerm G, et al. Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms. Int J Hematol. 2017;106(4):517–21.
Serrao A, Breccia M, Napolitano M, Fiori L, Santoro M, Scalzulli E, et al. A multicenter real-life study on anticoagulant treatment with direct oral anticoagulants in patients with Ph-negative myeloproliferative neoplasms. Am J Hematol. 2020 Dec;95(12):E329–32.
•• Barbui T, De Stefano V, Carobbio A, Iurlo A, Alvarez-Larran A, Cuevas B, et al. Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients. Leukemia. 2021;35(10):2989–93. This is the largest international retrospective multicenter study to show that direct oral anticoagulants may be a safe alternative to warfarin in patients with PV and ET.
Hamulyák EN, Daams JG, Leebeek FWG, Biemond BJ, Te Boekhorst PAW, Middeldorp S, et al. A systematic review of antithrombotic treatment of venous thromboembolism in patients with myeloproliferative neoplasms. Blood Adv. 2021;5(1):113–21.
Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, et al. Hydroxyurea for patients with essential thrombocythemia and a high-risk of thrombosis. N Engl J Med. 1995;332:1132–6.
• Godfrey AL, Campbell PJ, MacLean C, Buck G, Cook J, Temple J, United Kingdom Medical Research Council Primary Thrombocythemia-1 Study; United Kingdom National Cancer Research Institute Myeloproliferative Neoplasms Subgroup; French Intergroup of Myeloproliferative Neoplasms; the Australasian Leukaemia and Lymphoma Group, et al. Hydroxycarbamide plus aspirin versus aspirin alone in patients with essential thrombocythemia age 40 to 59 years without high-risk features. J Clin Oncol. 2018;36(34):3361–9. This randomized clinical trial demonstrated no benefit from adding cytoreduction to ET patients aged 40–59 years without high-risk features.
Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, United Kingdom Medical Research Council Primary Thrombocythemia 1 Study, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33–45.
Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, ANAHYDRET Study Group, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET study, a randomized controlled trial. Blood. 2013;121(10):1720–8.
• Barbui T, Vannucchi AM, Finazzi G, Finazzi MC, Masciulli A, Carobbio A, et al. reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study. Am J Hematol. 2017;92(11):1131–6. This study is a propensity-matched analysis of the ECLAP clinical trials that further reinforced the use of hydroxyurea in high-risk patients with PV.
• Grunwald MR, Kuter DJ, Altomare I, Burke JM, Gerds AT, Walshauser MA, et al. Treatment patterns and blood counts in patients with polycythemia vera treated with hydroxyurea in the United States: an analysis from the REVEAL study. Clin Lymphoma Myeloma Leuk. 2020;20(4):219–25. This observational real-life study from the USA evaluated treatment patterns in PV patients treated with hydroxyurea and demonstrated that a significant proportion of patients has uncontrolled myeloproliferation and disease-related symptoms despite cytoreduction.
Alvarez-Larrán A, Kerguelen A, Hernández-Boluda JC, Pérez-Encinas M, Ferrer-Marín F, Bárez A, et al. Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera. Br J Haematol. 2016;172(5):786–93.
Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch H, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010;148(6):961–3.
Raman I, Pasricha SR, Prince HM, Yannakou CK. Management of hydroxyurea resistant or intolerant polycythemia vera. Leuk Lymphoma. 2021;62(10):2310–9.
Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–72.
Quintas-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, 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(32):5418–24.
Masarova L, Patel KP, Newberry KJ, Cortes J, Borthakur G, Konopleva M, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165–75.
Masarova L, Yin CC, Cortes JE, Konopleva M, Borthakur G, Newberry KJ, et al. Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Exp Hematol Oncol. 2017;6:30.
• Abu-Zeinah G, Krichevsky S, Cruz T, Hoberman G, Jaber D, Savage N, et al. Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival. Leukemia. 2021;35(9):2592–601. This large retrospective multicenter study with a long follow-up has shown that PV patients treated with interferons have improved clinical outcomes when compared to those treated with hydroxyurea or phlebotomy only.
Yacoub A, Mascarenhas J, Kosiorek H, Prchal JT, Berenzon D, Baer MR, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood. 2019;134(18):1498–509.
De Oliveira RD, Soret-Dulphy J, Zhao LP, Marcault C, Gauthier N, Verger E, et al. Interferon-alpha (IFN) therapy discontinuation is feasible in myeloproliferative neoplasm (MPN) patients with complete hematological remission. Blood. 2020;136(Supplement 1):35–6.
•• Mascarenhas J, Kosiorek HE, Prchal JT, Rambaldi A, Berenzon D, Yacoub A, Harrison CN, et al. A randomized, phase 3, trial of interferon-α versus hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022:blood.2021012743. This randomized phase 3 trial compared interferon with hydroxyurea for first-line treatment of PV and ET. The randomized trial demonstrated that both interferon and hydroxyurea comparably control the blood cell counts, suggesting that both agents could be offered as first-line treatment. Interestingly, although interferons resulted in a greater reduction of the JAK2 allele burden, histological response was more often seen in patients treated with hydroxyurea.
Gisslinger H, Buxhofer-Ausch V, Thaler J, Forjan W, Willenbacher E, Wolf D, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera — final phase I/II Peginvera study results. Blood. 2018;132(Supplement 1):3030.
•• Gisslinger GH, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, PROUD-PV Study Group, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196–208. This was a randomized study assessing ropeginterferon vs. hydroxyurea in PV patients who were either newly diagnosed or already on hydroxyurea but not optimally managed. After 1 year, non-inferiority of ropeginterferon with respect to hematological and spleen responses was not shown; however, after 24–36 months, more ropeginterferon-treated patients achieved complete hematological and molecular responses.
• Kiladjian JJ, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. PROUD-PV Study Group. Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia. 2022. https://doi.org/10.1038/s41375-022-01528-x. This study reports the 5-year follow-up of the PROUD-PV trial. Ropeginterferon continued to effectively control the hematocrit, achieve durable molecular responses, and minimize the occurrence of thromboembolic events in patients with PV.
Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. S196: ropeginterferon alfa-2B achieves patient-specific treatment goals in polycythemia vera: final results from the PROUD-PV/CONTINUATION-PV studies. HemaSphere. 2022;6:97–8.
•• Barbui T, Vannucchi AM, De Stefano V, Masciulli A, Carobbio A, Ferrari A, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021;8(3):e175–84. The results of this randomized trial indicated that the addition of ropeginterferon to phlebotomy is more efficacious than the current standard therapy of phlebotomy alone in low-risk PV patients with respect to hematocrit control and the number of phlebotomies needed to achieve this goal. These results challenge phlebotomy-only as a standard of care in low-risk PV patients.
Mesa RA, Komatsu N, Gill H, Jin J, Lee S-E, Hou H-A, et al. Surpass-ET trial: a phase 3, open-label, multicenter, randomized, active-controlled study to assess pharmacokinetics and compare the efficacy, safety, and tolerability of P1101 vs anagrelide as second line therapy for essential thrombocythemia. Blood. 2021;138(Supplement 1):1491.
•• Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35. This randomized clinical trial placed ruxolitinib as a first-line treatment option for PV patients with splenomegaly who are resistant or intolerant to hydroxyurea because it showed superiority of ruxolitinib over standard therapy in the achievement of composite endpoint of both hematocrit control and spleen volume reduction at 32 weeks.
Kiladjian JJ, Zachee P, Hino M, Pane F, Masszi T, Harrison CN, Mesa R, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226–37.
Verstovsek S, Harrison CN, Kiladjian JJ, Miller C, Naim AB, Paranagama DC, et al. Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy. Leuk Res. 2017;56:52–9.
•• Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, 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(1):88–99. This randomized trial was similarly designed to RESPONSE but included PV patients without splenomegaly. Similarly to the RESPONSE trial, it demonstrated superiority of ruxolitinib over standard therapy in terms of hematocrit control at 28 weeks.
Passamonti F, Palandri F, Saydam G, Callum J, Devos T, Guglielmelli P, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480–92.
Masciulli A, Ferrari A, Carobbio A, Ghirardi A, Barbui T. Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2020;4(2):380–6.
Alvarez-Larrán A, Garrote M, Ferrer-Marín F, Pérez-Encinas M, Mata-Vazquez MI, Bellosillo B, et al. Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea. Cancer. 2022;128(13):2441–8.
Wolach O, Sellar RS, Martinod K, Cherpokova D, McConkey M, Chappell RJ, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med. 2018;10(436):eaan8292.
Mesa R, Vannucchi AM, Yacoub A, Zachee P, Garg M, Lyons R, et al. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. 2017;176(1):76–85.
• Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889–97. This randomized trial suggested that ruxolitinib may not be superior to current second-line treatments for ET.
Verstovsek S, Amoloja T, Scherber RM, Yu J. Real-world patient characteristics and treatment patterns of ruxolitinib among patients with advanced essential thrombocythemia at community clinical practice. Leuk Res. 2021;110: 106711.
•• Sørensen AL, Mikkelsen SU, Knudsen TA, Bjørn ME, Andersen CL, Bjerrum OW, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica. 2020;105(9):2262–72. This “proof of concept” study of ruxolitinib and interferon combination has shown excellent efficacy and safety for the treatment of patients with PV who were resistant or refractory to pegylated interferon.
Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. Expert Opinion Investig Drugs. 2020;29(6):525–36.
Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, et al. A pilot study of the histone-deacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010;150(4):446–55.
Rambaldi A, Iurlo A, Vannucchi AM, Noble R, von Bubnoff N, Guarini A, et al. Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part phase Ib/II study. Leukemia. 2020;34(8):2234–7.
Rambaldi A, Iurlo A, Vannucchi AM, Martino B, Guarini A, Ruggeri M, et al. Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program. Blood Cancer J. 2021;11:53.
• Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br J Haematol. 2013;161(5):688–94. This phase 2 study demonstrated favorable efficacy and safety of a combination therapy with givinostat and hydroxyurea for the treatment of hydroxyurea-resistant PV.
Jutzi JS, Kleppe M, Dias J, Staehle HF, Shank K, Teruya-Feldstein J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3): e54.
Palandri F, Vianelli N, Ross DM, Cochrane T, Lane SW, Larsen SR, et al. A phase 2 study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). Blood. 2021;138(Supplement 1):38693.
•• Palandri F, Ross DM, Cochrane T, Tate C, Lane SW, Larsen SR, et al. P1033: a phase 2 study of the LSD1 inhibitor IMG-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). HemaSphere. 2022;6:923–4. This phase 2 study demonstrated the favorable efficacy and safety of bomedemstat for the treatment of hydroxyurea-resistant ET patients.
Nakatake M, Monte-Mor B, Debili N, Casadevall N, Ribrag V, Solary E, et al. JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene. 2012;31(10):1323–33.
Lu M, Wang X, Li Y, Tripodi J, Mosoyan G, Mascarenhas J, et al. Combination treatment in vitro with nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells. Blood. 2012;120(15):3098–105.
Mascarenhas J, Passamonti F, Burbury K, El-Galaly TC, Gerds A, Gupta V, et al. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022;6(4):1162–74.
Marcellino BK, Farnoud N, Cassinat B, Lu M, Verger E, McGovern E, et al. Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin. Blood Adv. 2020;4(22):5735–44.
Mosoyan G, Kraus T, Ye F, Eng K, Crispino JD, Hoffman R, et al. Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis. Leukemia. 2017;31(11):2458–67.
• Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med. 2015;373(10):920–8. This study demonstrated excellent and durable hematologic and molecular responses to imetelstat in ET patients refractory or intolerant to hydroxyurea.
Ginzburg YZ, Feola M, Zimran E, Varkonyi J, Ganz T, Hoffman R. Dysregulated iron metabolism in polycythemia vera: etiology and consequences. Leukemia. 2018;32(10):2105–16.
•• Hoffman R, Kremyanskaya M, Ginzburng Y, Kuykendall AT, Pemmarayu N, Yacoub A, et al. Rusfertide (PTG-300) controls hematocrit levels and essentially eliminates phlebotomy requirement in polycythemia vera patients. Abstract #388. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.This study demonstrated excellent safety and efficacy of rusfertide, a hepcidin mimetic, in controlling hematocrit <45% without the need for phlebotomies.
Yelena Ginzburg, Kamini Kirubamoorthy, Sinari Salleh, Lee S-E, Lee JH, Selvaratnam V, et al. Rusfertide (PTG-300) Induction therapy rapidly achieves hematocrit control in polycythemia vera patients without the need for therapeutic phlebotomy. Abstract #390. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.
Hoffman R, Ginzburg Y, Kremyanskaya M, Khanna S, Modi N, Valone FH, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(16_suppl):7003–7003.
Verstovsek S, Kuykendall AT, Hoffman R, Ginzburg Y, Pemmaraju N, Valone F, et al. A phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2021;138(Supplement 1):1504.
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Krecak, I., Lucijanic, M. & Verstovsek, S. Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia. Curr Hematol Malig Rep 17, 155–169 (2022). https://doi.org/10.1007/s11899-022-00670-8
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DOI: https://doi.org/10.1007/s11899-022-00670-8