The 2020 revision of the guidelines for the management of myeloproliferative neoplasms

In 2016, the World Health Organization revised the diagnostic criteria for myeloproliferative neoplasms (MPNs) based on the discovery of disease-driving genetic aberrations and extensive analysis of the clinical characteristics of patients with MPNs. Recent studies have suggested that additional somatic mutations have a clinical impact on the prognosis of patients harboring these genetic abnormalities. Treatment strategies have also advanced with the introduction of JAK inhibitors, one of which has been approved for the treatment of patients with myelofibrosis and those with hydroxyurea-resistant or intolerant polycythemia vera. Recently developed drugs aim to elicit hematologic responses, as well as symptomatic and molecular responses, and the response criteria were refined accordingly. Based on these changes, we have revised the guidelines and present the diagnosis, treatment, and risk stratification of MPNs encountered in Korea.

[1]  M. Griesshammer,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. , 2020, The Lancet. Haematology.

[2]  H. Hasselbalch,et al.  Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study , 2019, Haematologica.

[3]  Junshik Hong,et al.  Risk of disease transformation and second primary solid tumors in patients with myeloproliferative neoplasms. , 2019, Blood advances.

[4]  P. Shah,et al.  Association of Treatments for Myeloproliferative Neoplasms During Pregnancy With Birth Rates and Maternal Outcomes , 2019, JAMA network open.

[5]  E. Papaemmanuil,et al.  Pegylated Interferon Alfa-2a for Polycythemia Vera or Essential Thrombocythemia Resistant or Intolerant to Hydroxyurea. , 2019, Blood.

[6]  S. Verstovsek,et al.  Updates in the management of polycythemia vera and essential thrombocythemia , 2019, Therapeutic advances in hematology.

[7]  M. Heuser,et al.  Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. , 2019, Blood.

[8]  Emily A. Stevens,et al.  Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis , 2019, Bone Marrow Transplantation.

[9]  A. Tefferi Primary myelofibrosis. , 2008, Cancer treatment and research.

[10]  M. Griesshammer,et al.  Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet , 2018, Leukemia.

[11]  S. Verstovsek,et al.  Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial , 2018, JAMA oncology.

[12]  P. Guglielmelli,et al.  MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  P. Guglielmelli,et al.  GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis , 2018, Leukemia.

[14]  B. Bellosillo,et al.  Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up , 2018, Annals of Hematology.

[15]  P. Dickman,et al.  Second malignancies in patients with myeloproliferative neoplasms: a population-based cohort study of 9379 patients , 2018, Leukemia.

[16]  M. Cazzola,et al.  MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  P. Cony-Makhoul,et al.  Benefits and pitfalls of pegylated interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis: a French Intergroup of Myeloproliferative neoplasms (FIM) study , 2017, Haematologica.

[18]  J. Rowe,et al.  Allogeneic stem-cell transplantation for myelofibrosis , 2017, Current opinion in hematology.

[19]  A. Mead,et al.  Ruxolitinib versus best available therapy for ET intolerant or resistant to hydroxycarbamide in a randomized trial. , 2017, Blood.

[20]  S. Swerdlow WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , 2017 .

[21]  Z. Shun,et al.  Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. , 2017, The Lancet. Haematology.

[22]  M. Cazzola,et al.  Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. , 2017, Blood.

[23]  M. Konopleva,et al.  Efficacy and safety of pegylated interferon alpha-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV): results of a phase 2 study after a 7-year median follow-up , 2017, The Lancet. Haematology.

[24]  J. Yang,et al.  Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004–2013 , 2017, Annals of Hematology.

[25]  W. Ghanima,et al.  Myeloproliferative neoplasms: trends in incidence, prevalence and survival in Norway , 2017, European journal of haematology.

[26]  A. Tefferi,et al.  Prefibrotic versus overtly fibrotic primary myelofibrosis: clinical, cytogenetic, molecular and prognostic comparisons , 2016, British journal of haematology.

[27]  M. Rodger,et al.  Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. , 2016, Blood.

[28]  M. Griesshammer,et al.  Symptom Burden As Primary Driver for Therapy in Patients with Myelofibrosis: An Analysis By MPN International Quality of Life Study Group , 2016 .

[29]  P. Guglielmelli,et al.  Targeted deep sequencing in polycythemia vera and essential thrombocythemia. , 2016, Blood advances.

[30]  S. Bewley,et al.  Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study , 2016, British journal of haematology.

[31]  S. Bang,et al.  Incidence, Survival and Prevalence Statistics of Classical Myeloproliferative Neoplasm in Korea , 2016, Journal of Korean medical science.

[32]  Mario Cazzola,et al.  The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. , 2016, Blood.

[33]  A. Tefferi,et al.  Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia , 2016, American journal of hematology.

[34]  M. Arcasoy,et al.  Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[35]  P. Hari,et al.  Safety of ruxolitinib therapy prior to allogeneic hematopoietic stem-cell transplantation for myeloproliferative neoplasms , 2016, Bone Marrow Transplantation.

[36]  M. Cazzola,et al.  Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients , 2015, American journal of hematology.

[37]  T. Barbui,et al.  Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia , 2015, Blood Cancer Journal.

[38]  Jinny Park,et al.  Guidelines for the management of myeloproliferative neoplasms , 2015, The Korean journal of internal medicine.

[39]  J. Radich,et al.  The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. , 2015, Blood.

[40]  J. Cortes,et al.  Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. , 2015, JAMA oncology.

[41]  T. Barbui,et al.  White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. , 2015, Blood.

[42]  D. Neuberg,et al.  A population-based analysis of second malignancies among patients with myeloproliferative neoplasms in the SEER database , 2015, Leukemia & lymphoma.

[43]  Arturo Pereira,et al.  Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results , 2015, Annals of Hematology.

[44]  M. Cazzola,et al.  Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. , 2015, Blood.

[45]  C. Chai-Adisaksopha,et al.  Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis , 2015, Journal of Thrombosis and Thrombolysis.

[46]  M. Griesshammer,et al.  Ruxolitinib versus standard therapy for the treatment of polycythemia vera. , 2015, The New England journal of medicine.

[47]  F. Cervantes How I treat myelofibrosis. , 2014, Blood.

[48]  M. Cazzola,et al.  Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. , 2014, Blood.

[49]  Mike Clarke,et al.  How common are myeloproliferative neoplasms? A systematic review and meta‐analysis , 2014, American journal of hematology.

[50]  M. Cazzola,et al.  JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. , 2014, Blood.

[51]  P. Guglielmelli,et al.  Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. , 2014, Blood.

[52]  Hongwei Wang,et al.  Epidemiology of myeloproliferative neoplasms in the United States , 2014, Leukemia & lymphoma.

[53]  A. Tefferi,et al.  Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact , 2014, Leukemia.

[54]  F. Passamonti,et al.  CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons , 2014, Leukemia.

[55]  G. Superti-Furga,et al.  Somatic mutations of calreticulin in myeloproliferative neoplasms. , 2013, The New England journal of medicine.

[56]  J. D. Fitzpatrick,et al.  Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. , 2013, The New England journal of medicine.

[57]  T. Barbui,et al.  Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. , 2013, Blood.

[58]  T. Barbui,et al.  Masked polycythemia Vera (mPV): Results of an international study , 2018, American journal of hematology.

[59]  M. Cazzola,et al.  Mutations and prognosis in primary myelofibrosis , 2013, Leukemia.

[60]  Francisco Cervantes,et al.  Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. , 2013, Blood.

[61]  O. Abdel-Wahab,et al.  Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. , 2013, Blood.

[62]  T. Barbui,et al.  Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. , 2013, Blood.

[63]  R. Kralovics,et al.  Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. , 2013, Blood.

[64]  A. Tefferi,et al.  Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management , 2013 .

[65]  T. Barbui,et al.  Cardiovascular events and intensity of treatment in polycythemia vera. , 2013, The New England journal of medicine.

[66]  T. Barbui,et al.  Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). , 2012, Blood.

[67]  M. Griesshammer,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. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  T. Barbui,et al.  Front-line therapy in polycythemia vera and essential thrombocythemia. , 2012, Blood reviews.

[69]  P. Hari,et al.  Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. , 2012, Blood.

[70]  Ruben A. Mesa,et al.  The evolving treatment paradigm in myelofibrosis , 2012, Leukemia & lymphoma.

[71]  A. Mead,et al.  Guideline for the diagnosis and management of myelofibrosis , 2012, British journal of haematology.

[72]  A. Mead,et al.  Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012 , 2012, British journal of haematology.

[73]  Jason Gotlib,et al.  A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. , 2012, The New England journal of medicine.

[74]  P. Johansson,et al.  The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries , 2012, Bone Marrow Transplantation.

[75]  Francisco Cervantes,et al.  JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. , 2012, The New England journal of medicine.

[76]  B. Bellosillo,et al.  Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. , 2012, Blood.

[77]  T. Barbui,et al.  Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  M. Cazzola,et al.  Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. , 2011, Blood.

[79]  M. Griesshammer,et al.  Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  F. Passamonti,et al.  DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  B. Bellosillo,et al.  Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia , 2011, British journal of haematology.

[82]  M. Tallman,et al.  Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. , 2010, Blood.

[83]  M. Cazzola,et al.  Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. , 2010, Blood.

[84]  T. Barbui,et al.  Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria. , 2010, Blood.

[85]  M. Cazzola,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 , 2010, Leukemia.

[86]  A. Martínez-Trillos,et al.  Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients , 2010, Annals of Hematology.

[87]  N. Kröger,et al.  Outcome of transplantation for myelofibrosis. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[88]  M. Boccadoro,et al.  A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs , 2010, Annals of Hematology.

[89]  J. Sloan,et al.  The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. , 2009, Leukemia research.

[90]  Juergen Thiele,et al.  The 2008 World Health Organization classification system for myeloproliferative neoplasms , 2009, Cancer.

[91]  A. Tefferi,et al.  Erythropoiesis stimulating agents have limited therapeutic activity in transfusion‐dependent patients with primary myelofibrosis regardless of serum erythropoietin level , 2009, European journal of haematology.

[92]  R. Mesa,et al.  New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. , 2008, Blood.

[93]  P. Campbell,et al.  MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. , 2008, Blood.

[94]  G. Barosi,et al.  Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders , 2008, Leukemia.

[95]  M. Cazzola,et al.  Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. , 2008, Blood.

[96]  M. Cazzola,et al.  Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. , 2007, Blood.

[97]  T. Barbui,et al.  Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. , 2007, Blood.

[98]  M. Stratton,et al.  JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. , 2007, The New England journal of medicine.

[99]  J. Sloan,et al.  The Burden of Fatigue and Quality of Life in Myeloproliferative Disorders (MPDs): An International Internet Based Survey of 1179 MPD Patients. , 2006 .

[100]  D. Gilliland,et al.  MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. , 2006, Blood.

[101]  A. Tefferi,et al.  Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? , 2006, Blood.

[102]  E. Montserrat,et al.  Darbepoetin‐alpha for the anaemia of myelofibrosis with myeloid metaplasia , 2006, British journal of haematology.

[103]  Sandra A. Moore,et al.  MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia , 2006, PLoS medicine.

[104]  A. Tefferi,et al.  Conventional and new treatment options for myelofibrosis with myeloid metaplasia. , 2005, Seminars in oncology.

[105]  J. D. van der Walt,et al.  Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. , 2005, The New England journal of medicine.

[106]  E. Montserrat,et al.  Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long‐term results in 30 patients , 2005, British journal of haematology.

[107]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[108]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[109]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[110]  T. Barbui,et al.  Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[112]  V. Martinelli,et al.  Interferon alfa treatment for pregnant women affected by essential thrombocythemia: case reports and a review. , 2004, American journal of obstetrics and gynecology.

[113]  E. Montserrat,et al.  Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature , 2004, British journal of haematology.

[114]  T. Barbui,et al.  Efficacy and safety of low-dose aspirin in polycythemia vera. , 2004, The New England journal of medicine.

[115]  D. Steensma,et al.  A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. , 2003, Blood.

[116]  Riva,et al.  No treatment for low‐risk thrombocythaemia:results from a prospective study , 1998, British journal of haematology.

[117]  C. Demers,et al.  TREATMENT OF ESSENTIAL THROMBOCYTHEMIA DURING PREGNANCY WITH INTERFERON‐α , 1996, Obstetrics and gynecology.

[118]  P. Fenaux,et al.  Clinical course of essential thrombocythemia in 147 cases , 1990, Cancer.

[119]  R. Berger,et al.  Essential thrombocythemias. Clinical evolutionary and biological data , 1986, Cancer.

[120]  S. Verstovsek,et al.  Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. , 2018, The Lancet. Haematology.

[121]  M. Griesshammer,et al.  Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. , 2017, The Lancet. Oncology.

[122]  M. Cazzola,et al.  The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients , 2014, Leukemia.

[123]  N. Komatsu [Myeloproliferative neoplasms]. , 2013, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[124]  Ayalew Tefferi,et al.  Primary myelofibrosis. , 2008, Cancer treatment and research.

[125]  R. Silver Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. , 2006, Cancer.

[126]  M. Griesshammer,et al.  Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. , 2005, Haematologica.

[127]  F. Serrano,et al.  [Essential thrombocythemia and pregnancy]. , 2003, Acta medica portuguesa.

[128]  Z. Ruggeri,et al.  Acquired von Willebrand's disease in the myeloproliferative syndrome. , 1985, Blood.

[129]  T. Pearson,et al.  Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. , 1978, Lancet.