Abstract

This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

    Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28:1804–10.

  4. 4.

    Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128–38.

  5. 5.

    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807.

  6. 6.

    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98.

  7. 7.

    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;372:426–35.

  8. 8.

    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;18:88–99.

  9. 9.

    Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013;121:1720–28.

  10. 10.

    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.

  11. 11.

    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;176:76–85.

  12. 12.

    Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31:1252.

  13. 13.

    Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1:643–51.

  14. 14.

    Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, et al. SIMPLIFY-1: A phase iii randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844–50 [epub ahead of print].

  15. 15.

    Mesa RA. NCCN debuts new guidelines for myeloproliferative neoplasms. J Natl Compr Canc Netw. 2017;15:720–22.

  16. 16.

    Choi CW, Bang SM, Jang S, Jung CW, Kim HJ, Kim HY, Choi CW, Bang SM, Jang S, et al. Guidelines for the management of myeloproliferative neoplasms. Korean J Intern Med. 2015;30:771–88.

  17. 17.

    Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe AS, et al. Use of JAK inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines for Investigation and Management of Myelofibrosis 2012. Br J Haematol. 2014;167:418–20.

  18. 18.

    Vannucchi AM, Barbui T, Cervantes F, Harrison C, Kiladjian JJ, Kröger N, et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v85–99.

  19. 19.

    Marchetti M, Barosi G, Cervantes F, Birgegård G, Griesshammer M, Harrison C, et al. Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Leukemia. 2017;31:882–88.

  20. 20.

    Sliwa T, Beham-Schmid C, Burgstaller S, Buxhofer-Ausch V, Gastl G, Geissler K, et al. Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement. Wien Klin Wochenschr. 2017;129:293–02.

  21. 21.

    Ho PJ, Marlton P, Tam C, Stevenson W, Ritchie D, Bird R, et al. Practical management of myelofibrosis with ruxolitinib. Intern Med J. 2015;45:1221–30.

  22. 22.

    Guglielmelli P, Pietra D, Pane F, Pancrazzi A, Cazzola M, Vannucchi AM, et al. Recommendations for molecular testing in classical Ph1-neg myeloproliferative disorders- A consensus project of the Italian Society of Hematology. Leuk Res. 2017;58:63–72.

  23. 23.

    Kröger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29:2126–33.

  24. 24.

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

  25. 25.

    Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.

  26. 26.

    Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

  27. 27.

    William PL, Webb C. The Delphi technique: a methodological discussion. J Adv Nurs. 1994;19:180–6.

  28. 28.

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

  29. 29.

    Kvasnicka HM, Orazi A, Thiele J, Barosi G, Bueso-Ramos CE, Vannucchi AM, et al. European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia. Am J Hematol. 2017;92:1062–67 [epub ahead of print].

  30. 30.

    Tefferi A, Pardanani A. Genetics: CALR mutations and a new diagnostic algorithm for MPN. Nat Rev Clin Oncol. 2014;11:125–26.

  31. 31.

    Kvasnicka HM, Thiele J. Prodromal myeloproliferative neoplasms: the 2008 WHO classification. Am J Hematol. 2010;85:62–9.

  32. 32.

    Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22:437–38.

  33. 33.

    Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28:1407–13.

  34. 34.

    Tefferi A, Finke CM, Lasho TL, Wassie EA, Knudson R, Ketterling RP, et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia. 2014;28:431–33.

  35. 35.

    Tefferi A, Barbui T. Essential thrombocythemia and polycythemia vera: Focus on clinical practice. Mayo Clin Proc. 2015;90:1283–93.

  36. 36.

    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;124:3021–23.

  37. 37.

    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;27:1874–81.

  38. 38.

    Barbui T, Carobbio A, Rambaldi A, Finazzi G, Barbui T, Carobbio A, et al. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009;114:759–63.

  39. 39.

    Barbui T, Masciulli A, Marfisi MR, Tognoni G, Finazzi G, Rambaldi A, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126:560–61.

  40. 40.

    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;120:5128–33.

  41. 41.

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

  42. 42.

    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;91:390–94.

  43. 43.

    Finazzi G, Carobbio A, Guglielmelli P, Cavalloni C, Salmoiraghi S, Vannucchi AM. Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood. 2014;124:2611–12.

  44. 44.

    Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895–901.

  45. 45.

    Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Cazzola M, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703–08.

  46. 46.

    Hussein K, Pardanani AD, Van Dyke DL, Hanson CA. Tefferi. International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood. 2010;115:496–99.

  47. 47.

    Caramazza D, Begna KH, Gangat N, Vaidya R, Siragusa S, Van Dyke DL, et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia. 2011;25:82–8.

  48. 48.

    Tefferi A, Siragusa S, Hussein K, Schwager SM, Hanson CA, Pardanani A, et al. Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis--prognostic relevance is independent of IPSS or karyotype. Am J Hematol. 2010;85:14–7.

  49. 49.

    Elena C, Passamonti F, Rumi E, Malcovati L, Arcaini L, Boveri E, et al. Red blood cell transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS and DIPSS. Haematologica. 2011;96:167–70.

  50. 50.

    Patnaik MM, Caramazza D, Gangat N, Hanson CA, Pardanani A, Tefferi A. Age and platelet count are IPSS-independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival. Eur J Haematol. 2010;84:105–8.

  51. 51.

    Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, 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. J Clin Oncol. 2011;29:392–7.

  52. 52.

    Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28:1494–1500.

  53. 53.

    Tefferi A, Lasho TL, Tischer A, Wassie EA, Finke CM, Belachew AA, et al. The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants. Blood. 2014;124:2465–66.

  54. 54.

    Guglielmelli P, Rotunno G, Fanelli T, Pacilli A, Brogi G, Calabresi L, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood. Cancer J. 2015;5:e360.

  55. 55.

    Tefferi A, Jimma T, Sulai NH, Lasho TL, Finke CM, Knudson RA, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia. 2012;26:475–80.

  56. 56.

    Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP, et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood. 2012;120:4168–71.

  57. 57.

    Tefferi A, Vannucchi AM. Genetic risk assessment in myeloproliferative neoplasms. Mayo Clin Proc. 2017;92:1283–90.

  58. 58.

    Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36:310–8.

  59. 59.

    Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol. 2011;64:1283–93.

  60. 60.

    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;112:3065–72.

  61. 61.

    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;122:893–901.

  62. 62.

    Gowin K, Jain T, Kosiorek H, Tibes R, Camoriano J, Palmer J, et al. Pegylated interferon alpha-2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial. Leuk Res. 2017;54:73–7.

  63. 63.

    Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, 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.

  64. 64.

    Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, et al. Primary thrombocythemia 1 study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33–45.

  65. 65.

    Cassinat B, Verger E, Kiladjian JJ. Interferon alfa therapy in CALR-mutated essential thrombocythemia. N Engl J Med. 2014;371:188–9.

  66. 66.

    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;161:865–71.

  67. 67.

    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;101:926–31.

  68. 68.

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

  69. 69.

    Barosi G, Besses C, Birgegard G, Briere J, Cervantes F, Finazzi G, et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia. 2007;21:277–80.

  70. 70.

    Komrokji RS, Seymour JF, Roberts AW, Wadleigh M, To LB, Scherber R, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2 (V617F) inhibitor, in patients with myelofibrosis. Blood. 2015;125:2649–56.

  71. 71.

    Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27:1322–27.

  72. 72.

    Mascarenhas JO, Talpaz M, Gupta V, Foltz LM, Savona MR, Paquette R, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017;102:327–35.

  73. 73.

    Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908–19.

  74. 74.

    Duffield JS, Lupher ML Jr. PRM-151 (recombinant human serum amyloid P/pentraxin 2) for the treatment of fibrosis. Drug News Perspect. 2010;23:305–15.

  75. 75.

    Barosi G, Rosti V, Gale RP. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis. Onco Targets Ther. 2015;8:1091–102.

  76. 76.

    Martí-Carvajal AJ, Anand V, Solà I. Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis. Cochrane Database Syst Rev. 2015;4:CD010298.

  77. 77.

    Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood. 2017;129:832–37.

  78. 78.

    Ross DM. Responses to pomalidomide and placebo in myelofibrosis-related anaemia. Leukemia. 2017;31:532–33.

  79. 79.

    Schlenk RF, Stegelmann F, Reiter A, Jost E, Gattermann N, Hebart H, et al. Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2017;31:889–95.

  80. 80.

    Daver N, Shastri A, Kadia T, Newberry K, Pemmaraju N, Jabbour E, et al. Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia. Leuk Res. 2014;38:1126–29.

  81. 81.

    Daver N, Shastri A, Kadia T, Newberry K, Pemmaraju N, Jabbour E, et al. Modest activity of pomalidomide in patients with myelofibrosis and significant anemia. Leuk Res. 2013;37:1440–44.

  82. 82.

    Begna KH, Pardanani A, Mesa R, Litzow MR, Hogan WJ, Hanson CA, et al. Long-term outcome of pomalidomide therapy in myelofibrosis. Am J Hematol. 2012;87:66–8.

  83. 83.

    Begna KH, Mesa RA, Pardanani A, Hogan WJ, Litzow MR, McClure RF, et al. A phase-2 trial of low-dose pomalidomide in myelofibrosis. Leukemia. 2011;25:301–4.

  84. 84.

    Mesa RA, Pardanani AD, Hussein K, Wu W, Schwager S, Litzow MR, et al. Phase1/-2 study of pomalidomide in myelofibrosis. Am J Hematol. 2010;85:129–30.

  85. 85.

    Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol. 2009;83:154–55.

  86. 86.

    Tefferi A, Lasho TL, Mesa RA, Pardanani A, Ketterling RP, Hanson CA. Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia. 2007;21:1827–28.

  87. 87.

    Mead AJ, Milojkovic D, Knapper S, Garg M, Chacko J, Farquharson M, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015;170:29–39.

  88. 88.

    Al-Ali HK, Griesshammer M, le Coutre P, Waller CF, Liberati AM, Schafhausen P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101:1065–73.

  89. 89.

    Rago A, Latagliata R, Montanaro M, Montefusco E, Andriani A, Crescenzi SL, et al. Hemoglobin levels and circulating blasts are two easily evaluable diagnostic parameters highly predictive of leukemic transformation in primary myelofibrosis. Leuk Res. 2015;39:314–17.

  90. 90.

    Kröger N, Panagiota V, Badbaran A, Zabelina T, Triviai I, Araujo Cruz MM, et al. Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017l;23:1095–101.

  91. 91.

    Barosi G, Vannucchi AM, De Stefano V, Pane F, Passamonti F, Rambaldi A, et al. Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper. Leuk Res. 2014;38:155–160.

  92. 92.

    Santos FP, Tam CS, Kantarjian H, Cortes J, Thomas D, Pollock R, et al. Splenectomy in patients with myeloproliferative neoplasms: efficacy, complications and impact on survival and transformation. Leuk Lymphoma. 2014;55:121–7.

  93. 93.

    Mesa RA, Nagorney DS, Schwager S, Allred J, Tefferi A. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006;107:361–70.

  94. 94.

    Barosi G, Ambrosetti A, Buratti A, Finelli C, Liberato NL, Quaglini S, et al. Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction. Leukemia. 1993;7:200–206.

  95. 95.

    Passamonti F, Giorgino T, Mora B, Guglielmelli P, Rumi E, Maffioli M, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31:2726–31 [epub ahead of print].

  96. 96.

    Hernández-Boluda JC, Correa JG, García-Delgado R, Martínez-López J, Alvarez-Larrán A, Fox ML, et al. Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. Eur J Haematol. 2017;98:407–14.

  97. 97.

    Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, et al. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126:1762–69.

  98. 98.

    Gisslinger H, Klade C, Georgiev P, Skotnicki A, Gercheva-Kyuchukova L, Egyed M, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients. Presented at the American Society of Hematology 58th Annual Meeting; December 3–6, San Diego, CA; Blood 2016; 128: Abstract 475.

  99. 99.

    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;130:1889–97.

Download references

Acknowledgements

AMV, FP, and G Ba were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC; Milan, Italy), Special Program Molecular Clinical Oncology 5 × 1000 to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) project #1005.

Author contributions

TB, AT, and GBa developed the study design. GBa did the critical appraisal of evidence of the randomized trials. TB and AT wrote the first draft of the recommendations. All the authors participated to the consensus meetings. GBa wrote the manuscript. All authors critically revised, reviewed, and approved the final version of this study.

Author information

Author notes

  1. These authors contributed equally: Tiziano Barbui, Ayalew Tefferi.

Affiliations

  1. Division of Hematology, Ospedale Giovanni XXIII, Bergamo, Italy

    • Tiziano Barbui
    •  & Guido Finazzi
  2. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    • Ayalew Tefferi
  3. CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy

    • Alessandro M. Vannucchi
  4. Division of Hematology, Department of Medicine and Surgery, Ospedale di Circolo, University of Insubria, ASST Sette Laghi, Varese, Italy

    • Francesco Passamonti
  5. Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA

    • Richard T. Silver
  6. Tisch Cancer Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA

    • Ronald Hoffman
  7. Department of Leukemia, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA

    • Srdan Verstovsek
  8. UT Health San Antonio Cancer Center, San Antonio, TX, USA

    • Ruben Mesa
  9. Centre d’Investigations Cliniques (CIC 1427), Assistance Publique—Hôpitaux de Paris, Hôpital Saint-Louis, INSERM, Université Paris 7, Paris, France

    • Jean-Jacques Kiladjian
  10. Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany

    • Rȕdiger Hehlmann
    •  & Andreas Reiter
  11. Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain

    • Francisco Cervantes
  12. Department of Hematology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

    • Claire Harrison
  13. Centre for Medical Education, Queen’s University, Belfast, UK

    • Mary Frances Mc Mullin
  14. Department of Hematology, Zealand University Hospital, Roskilde, Denmark

    • Hans Carl Hasselbalch
  15. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    • Steffen Koschmieder
  16. Hematology Day Service, Oncology SOC, Hospital Cardinal Massaia, Asti, Italy

    • Monia Marchetti
  17. Istituto di Ematologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Gemelli, Rome, Italy

    • Andrea Bacigalupo
  18. Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    • Nicolaus Kroeger
  19. Department of Hematology and Oncology, Johannes Wesling Medical Centre Minden, Academic Hospital of the University of Hannover, Minden, Germany

    • Martin Griesshammer
  20. Department of Hematology, Uppsala University, Uppsala, Sweden

    • Gunnar Birgegard
  21. Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

    • Giovanni Barosi

Authors

  1. Search for Tiziano Barbui in:

  2. Search for Ayalew Tefferi in:

  3. Search for Alessandro M. Vannucchi in:

  4. Search for Francesco Passamonti in:

  5. Search for Richard T. Silver in:

  6. Search for Ronald Hoffman in:

  7. Search for Srdan Verstovsek in:

  8. Search for Ruben Mesa in:

  9. Search for Jean-Jacques Kiladjian in:

  10. Search for Rȕdiger Hehlmann in:

  11. Search for Andreas Reiter in:

  12. Search for Francisco Cervantes in:

  13. Search for Claire Harrison in:

  14. Search for Mary Frances Mc Mullin in:

  15. Search for Hans Carl Hasselbalch in:

  16. Search for Steffen Koschmieder in:

  17. Search for Monia Marchetti in:

  18. Search for Andrea Bacigalupo in:

  19. Search for Guido Finazzi in:

  20. Search for Nicolaus Kroeger in:

  21. Search for Martin Griesshammer in:

  22. Search for Gunnar Birgegard in:

  23. Search for Giovanni Barosi in:

Conflict of interest

TB received advisory board fee from Novartis; FC received advisory board fee from Novartis, honoraria from Novartis, AOP Orphan Disease and Shire, and speaker bureau fee from Novartis, AOP and Shire; AMV received advisory board fee from Novartis, and Speaker bureau fee from Novartis and Shire; MM received speaker bureau fee from Gilead and Amgen; SK received research funding from Novartis, Bristol-Myers Squibb, and Janssen, honoraria and advisory board fees from Novartis, Incyte/Ariad, Pfizer, Bristol-Myers Squibb, Janssen, AOP, CTI, and travel support from Shire; AR received advisory board fee and honoraria from Novartis; MG received honoraria from Shire, Novartis, Baxalta, AOP Orphan Disease, Gilead and Janssen; JJK received advisory board fee and funding from Novartis and AOP Orphan; AB received honoraria form Novartis, Therakos, Sanofi and Adienne, and advisory board fee from Novartis; MFMM received honoraria and consulting fee from Novartis and Gilead; SV received support for research from: Incyte Corporation, Roche, Astra Zeneca, Lilly Oncology, NS Pharma, Bristol Mayers Squibb, Celgene, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corp., Galena BioPharma, Pfizer, Genentech, Blueprint Medicines Corp.; RM received consulting fee from Novartis, AOP, Shire, and research funding from Incyte, Gilead, Pharmessential, Celgene and Promedior; R Ho received research funding from Incyte and Janssen; FP served on advisory boards for Sanofi, Gilead, Janssen Pharmaceutical, Celgene, Novartis, Bristol-Myers Squibb and Roche; GB received advisory board fee from Novartis. GF and G Bi have no conflict of interest.

Corresponding author

Correspondence to Giovanni Barosi.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41375-018-0077-1

Further reading