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Prognosis and treatment of primary myelofibrosis

INTRODUCTION

Primary myelofibrosis (PMF), known in the past as agnogenic myeloid metaplasia or chronic idiopathic myelofibrosis, is one of the myeloproliferative neoplasms (figure 1). In addition to PMF, the group includes essential thrombocythemia (ET), and polycythemia vera (PV), both of which may undergo delayed disease transformation into a fibrotic state called post-ET myelofibrosis (post-ET MF) or post-PV MF, respectively. The conversion rates after 10 to 20 years of disease are less than 5 percent for ET and approximately 10 to 20 percent for PV. PMF, post-ET MF, and post-PV MF are all referred to as myelofibrosis (MF).

The prognosis and treatment of PMF will be reviewed here [1-4]. An overview of the myeloproliferative neoplasms, as well as discussions of pathogenetic mechanisms, clinical manifestations, and diagnosis of PMF, are presented separately. (See "Overview of the myeloproliferative neoplasms" and "Clinical manifestations and diagnosis of primary myelofibrosis" and "Pathogenetic mechanisms in primary myelofibrosis".)

CLINICAL FEATURES

Most patients with primary myelofibrosis (PMF) present with anemia, marked splenomegaly, early satiety, and hypercatabolic symptoms including severe fatigue, low grade fever, night sweats, and weight loss [5]. During their clinical course, most patients experience massive hepatosplenomegaly along with progressive anemia requiring frequent red blood cell transfusions. Portal hypertension might accompany marked splenomegaly and could contribute to variceal bleeding or ascites. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

Hepatosplenomegaly in PMF results from extramedullary hematopoiesis (EMH), which might also involve other organ sites, including around the spinal column, causing cord compression, or in the pleural and peritoneal cavity, causing pleural effusion or ascites, respectively.

PROGNOSIS

In an epidemiologic study of patients within Olmsted county, the three-year survival rate was 52 percent [6]. Longer survival times have been reported in several non-population-based studies, including the series used for constructing the International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF), in which the median survival was reported to be 69 months [7].

                                            

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Literature review current through: Oct 2014. | This topic last updated: Nov 10, 2014.
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References
Top
  1. Tefferi A. How I treat myelofibrosis. Blood 2011; 117:3494.
  2. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29:761.
  3. Reilly JT, McMullin MF, Beer PA, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol 2012; 158:453.
  4. Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013; 88:141.
  5. Tefferi A, Silverstein MN, Noël P. Agnogenic myeloid metaplasia. Semin Oncol 1995; 22:327.
  6. Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol 1999; 61:10.
  7. Cervantes F, Dupriez B, Pereira A, 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.
  8. Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996; 88:1013.
  9. Cervantes F, Barosi G, Demory JL, et al. Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. Br J Haematol 1998; 102:684.
  10. Dingli D, Schwager SM, Mesa RA, et al. Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer 2006; 106:623.
  11. Elliott MA, Verstovsek S, Dingli D, et al. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leuk Res 2007; 31:1503.
  12. Tefferi A, Huang J, Schwager S, et al. Validation and comparison of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients from a single institution. Cancer 2007; 109:2083.
  13. Vener C, Fracchiolla NS, Gianelli U, et al. Prognostic implications of the European consensus for grading of bone marrow fibrosis in chronic idiopathic myelofibrosis. Blood 2008; 111:1862.
  14. Tam CS, Kantarjian H, Cortes J, et al. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol 2009; 27:5587.
  15. Morel P, Duhamel A, Hivert B, et al. Identification during the follow-up of time-dependent prognostic factors for the competing risks of death and blast phase in primary myelofibrosis: a study of 172 patients. Blood 2010; 115:4350.
  16. Passamonti F, Cervantes F, Vannucchi AM, 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.
  17. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood 2010; 116:2857.
  18. Hussein K, Huang J, Lasho T, et al. Karyotype complements the International Prognostic Scoring System for primary myelofibrosis. Eur J Haematol 2009; 82:255.
  19. Tefferi A, Meyer RG, Wyatt WA, Dewald GW. Comparison of peripheral blood interphase cytogenetics with bone marrow karyotype analysis in myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 115:316.
  20. Tam CS, Abruzzo LV, Lin KI, et al. The role of cytogenetic abnormalities as a prognostic marker in primary myelofibrosis: applicability at the time of diagnosis and later during disease course. Blood 2009; 113:4171.
  21. Hussein K, Pardanani AD, Van Dyke DL, et al. International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood 2010; 115:496.
  22. Caramazza D, Begna KH, Gangat N, 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.
  23. Tefferi A, Siragusa S, Hussein K, 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.
  24. Patnaik MM, Caramazza D, Gangat N, et al. 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.
  25. Gangat N, Caramazza D, Vaidya R, 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.
  26. Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc 2012; 87:25.
  27. Tefferi A, Vaidya R, Caramazza D, et al. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol 2011; 29:1356.
  28. Barbui T, Carobbio A, Finazzi G, et al. Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis. Leukemia 2013; 27:2084.
  29. Tefferi A, Lasho TL, Huang J, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia 2008; 22:756.
  30. Guglielmelli P, Barosi G, Specchia G, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood 2009; 114:1477.
  31. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124:2507.
  32. Rumi E, Harutyunyan AS, Pietra D, et al. CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis. Blood 2014.
  33. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27:1861.
  34. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014; 28:1804.
  35. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014; 28:1472.
  36. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 2014; 123:2220.
  37. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood 2013; 122:1395.
  38. Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 2012; 119:2657.
  39. Taylor UB, Bardeguez AD, Iglesias N, Gascon P. Idiopathic myelofibrosis in pregnancy: a case report and review of the literature. Am J Obstet Gynecol 1992; 167:38.
  40. Gotić M, Cvetković M, Bozanović T, Cemerikić V. [Successful treatment of primary myelofibrosis with thrombocytosis during pregnancy with alfa-interferon]. Srp Arh Celok Lek 2001; 129:304.
  41. Tulpule S, Bewley S, Robinson SE, et al. The management and outcome of four pregnancies in women with idiopathic myelofibrosis. Br J Haematol 2008; 142:480.
  42. Cervantes F. Modern management of myelofibrosis. Br J Haematol 2005; 128:583.
  43. Arana-Yi C, Quintás-Cardama A, Giles F, et al. Advances in the therapy of chronic idiopathic myelofibrosis. Oncologist 2006; 11:929.
  44. Kröger N, Mesa RA. Choosing between stem cell therapy and drugs in myelofibrosis. Leukemia 2008; 22:474.
  45. Guardiola P, Esperou H, Cazals-Hatem D, et al. Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation. Br J Haematol 1997; 98:1004.
  46. Deeg HJ, Gooley TA, Flowers ME, et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102:3912.
  47. Przepiorka D, Giralt S, Khouri I, et al. Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: review of forty cases. Am J Hematol 1998; 57:24.
  48. Singhal S, Powles R, Treleaven J, et al. Allogeneic bone marrow transplantation for primary myelofibrosis. Bone Marrow Transplant 1995; 16:743.
  49. Creemers GJ, Löwenberg B, Hagenbeek A. Allogeneic bone marrow transplantation for primary myelofibrosis. Br J Haematol 1992; 82:772.
  50. Benesch M, Deeg HJ. Hematopoietic cell transplantation for adult patients with myelodysplastic syndromes and myeloproliferative disorders. Mayo Clin Proc 2003; 78:981.
  51. Guardiola P, Anderson JE, Bandini G, et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 1999; 93:2831.
  52. Lissandre S, Bay JO, Cahn JY, et al. Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis. Bone Marrow Transplant 2011; 46:557.
  53. Visani G, Finelli C, Castelli U, et al. Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 1990; 75:4.
  54. Merup M, Lazarevic V, Nahi H, et al. Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens. Br J Haematol 2006; 135:367.
  55. Kröger N, Alchalby H, Klyuchnikov E, et al. JAK2-V617F-triggered preemptive and salvage adoptive immunotherapy with donor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation. Blood 2009; 113:1866.
  56. Klyuchnikov E, Holler E, Bornhäuser M, et al. Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting. Br J Haematol 2012; 159:172.
  57. Jovanovic JV, Ivey A, Vannucchi AM, et al. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study. Leukemia 2013; 27:2032.
  58. Robin M, Tabrizi R, Mohty M, et al. Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Br J Haematol 2011; 152:331.
  59. Guardiola P, Anderson JE, Gluckman E. Myelofibrosis with myeloid metaplasia. N Engl J Med 2000; 343:659; author reply 659.
  60. Deeg HJ, Appelbaum FR. Stem-cell transplantation for myelofibrosis. N Engl J Med 2001; 344:775.
  61. Lussana F, Rambaldi A, Finazzi MC, et al. Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2014; 99:916.
  62. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012; 120:1367.
  63. Maziarz RT, Mesa RA, Tefferi A. Allogeneic stem cell transplantation for chronic myeloproliferative disorders and myelodysplastic syndromes: the question is "when?". Mayo Clin Proc 2003; 78:941.
  64. Babushok D, Hexner E. Allogeneic transplantation for myelofibrosis: for whom, when, and what are the true benefits? Curr Opin Hematol 2014; 21:114.
  65. Soll E, Massumoto C, Clift RA, et al. Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment. Blood 1995; 86:4667.
  66. Li Z, Gooley T, Applebaum FR, Deeg HJ. Splenectomy and hemopoietic stem cell transplantation for myelofibrosis. Blood 2001; 97:2180.
  67. Ciurea SO, Sadegi B, Wilbur A, et al. Effects of extensive splenomegaly in patients with myelofibrosis undergoing a reduced intensity allogeneic stem cell transplantation. Br J Haematol 2008; 141:80.
  68. Devine SM, Hoffman R, Verma A, et al. Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia. Blood 2002; 99:2255.
  69. Hessling J, Kröger N, Werner M, et al. Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 119:769.
  70. Kröger N, Zabelina T, Schieder H, et al. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol 2005; 128:690.
  71. Rondelli D, Barosi G, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 2005; 105:4115.
  72. Kröger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114:5264.
  73. Bacigalupo A, Soraru M, Dominietto A, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant 2010; 45:458.
  74. Alchalby H, Badbaran A, Zabelina T, et al. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood 2010; 116:3572.
  75. Abelsson J, Merup M, Birgegård G, et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012; 47:380.
  76. Alchalby H, Yunus DR, Zabelina T, et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol 2012; 157:75.
  77. Rondelli D, Goldberg JD, Isola L, et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood 2014; 124:1183.
  78. Samuelson S, Sandmaier BM, Heslop HE, et al. Allogeneic haematopoietic cell transplantation for myelofibrosis in 30 patients 60-78 years of age. Br J Haematol 2011; 153:76.
  79. Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Núñez V, et al. Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia. Am J Hematol 2007; 82:400.
  80. Benjamini O, Koren-Michowitz M, Amariglio N, et al. Relapse of postpolycythemia myelofibrosis after allogeneic stem cell transplantation in a polycythemic phase: successful treatment with donor lymphocyte infusion directed by quantitative PCR test for V617F-JAK2 mutation. Leukemia 2008; 22:1961.
  81. Silverstein MN. Agnogenic Myeloid Metaplasia. Publishing Sciences Group, Acton, MA 1975.
  82. Petti MC, Latagliata R, Spadea T, et al. Melphalan treatment in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 116:576.
  83. Löfvenberg E, Wahlin A. Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol 1988; 41:375.
  84. Löfvenberg E, Wahlin A, Roos G, Ost A. Reversal of myelofibrosis by hydroxyurea. Eur J Haematol 1990; 44:33.
  85. Manoharan A. Management of myelofibrosis with intermittent hydroxyurea. Br J Haematol 1991; 77:252.
  86. Wagner H Jr, McKeough PG, Desforges J, Madoc-Jones H. Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea. Cancer 1986; 58:1204.
  87. Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol 2010; 89:1233.
  88. Sirhan S, Lasho TL, Hanson CA, et al. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol 2008; 83:363.
  89. Verstovsek S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res 2010; 16:1988.
  90. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011; 29:789.
  91. Verstovsek S. Janus-activated kinase 2 inhibitors: a new era of targeted therapies providing significant clinical benefit for Philadelphia chromosome-negative myeloproliferative neoplasms. J Clin Oncol 2011; 29:781.
  92. Pardanani A, Tefferi A. Targeting myeloproliferative neoplasms with JAK inhibitors. Curr Opin Hematol 2011; 18:105.
  93. Quintás-Cardama A, Verstovsek S. Spleen deflation and beyond: the pros and cons of Janus kinase 2 inhibitor therapy for patients with myeloproliferative neoplasms. Cancer 2012; 118:870.
  94. Cervantes F, Mesa R, Harrison C. JAK inhibitors: beyond spleen and symptoms? Haematologica 2013; 98:160.
  95. Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 2013; 27:1322.
  96. Vainchenker W, Favale F. Myelofibrosis, JAK2 inhibitors and erythropoiesis. Leukemia 2013; 27:1219.
  97. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366:787.
  98. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799.
  99. Passamonti F, Caramazza D, Maffioli M. JAK inhibitor in CALR-mutant myelofibrosis. N Engl J Med 2014; 370:1168.
  100. Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood 2014; 123:2157.
  101. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2013; 31:1285.
  102. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363:1117.
  103. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013; 122:4047.
  104. Wilkins BS, Radia D, Woodley C, et al. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica 2013; 98:1872.
  105. Tefferi A. Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms. N Engl J Med 2012; 366:844.
  106. Tefferi A. JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Blood 2012; 119:2721.
  107. Verstovsek S, Mesa RA, Gotlib J, et al. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis. Br J Haematol 2013; 161:508.
  108. Harrison CN, Mesa RA, Kiladjian JJ, et al. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol 2013; 162:229.
  109. Mascarenhas J, Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood 2013; 121:4832.
  110. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202192s006lbl.pdf (Accessed on August 04, 2014).
  111. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 2011; 365:1455.
  112. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012; 120:1202.
  113. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86:1188.
  114. Dai T, Friedman EW, Barta SK. Ruxolitinib withdrawal syndrome leading to tumor lysis. J Clin Oncol 2013; 31:e430.
  115. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122:1192.
  116. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest 2013; 143:1478.
  117. Caocci G, Murgia F, Podda L, et al. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia 2014; 28:225.
  118. Colomba C, Rubino R, Siracusa L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes 2012; 5:552.
  119. Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med 2013; 369:681.
  120. Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med 2013; 369:197.
  121. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood 2013; 122:3843.
  122. Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood 2014; 123:1833.
  123. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica 2013; 98:1865.
  124. Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood 2014.
  125. Verstovsek S, Passamonti F, Rambaldi A, et al. Durable responses with the JAK1/JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea (HU) (abstract 313). Blood 2010; 116:142.
  126. Benbassat J, Penchas S, Ligumski M. Splenectomy in patients with agnogenic myeloid metaplasia: an analysis of 321 published cases. Br J Haematol 1979; 42:207.
  127. Mesa RA, Nagorney DS, Schwager S, et al. 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.
  128. Barosi G, Ambrosetti A, Buratti A, et al. Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction. Leukemia 1993; 7:200.
  129. Lafaye F, Rain JD, Clot P, Najean Y. Risks and benefits of splenectomy in myelofibrosis: an analysis of 39 cases. Nouv Rev Fr Hematol 1994; 36:359.
  130. Petroianu A. Subtotal splenectomy for treatment of patients with myelofibrosis and myeloid metaplasia. Int Surg 1996; 81:177.
  131. Tefferi A, Silverstein MN, Li CY. 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. Br J Haematol 1997; 99:352.
  132. Faoro LN, Tefferi A, Mesa RA. Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74:117.
  133. Barosi G, Ambrosetti A, Centra A, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood 1998; 91:3630.
  134. Mesa RA, Li CY, Schroeder G, Tefferi A. Clinical correlates of splenic histopathology and splenic karyotype in myelofibrosis with myeloid metaplasia. Blood 2001; 97:3665.
  135. Pardanani A, Brown P, Neben-Wittich M, et al. Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy. Am J Hematol 2010; 85:715.
  136. Elliott MA, Chen MG, Silverstein MN, Tefferi A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 1998; 103:505.
  137. Sciascia R, Mazza P, Tondi L. [Splenic irradiation in the treatment of idiopathic myelofibrosis. Retrospective study of 14 cases]. Radiol Med 1988; 76:87.
  138. Lavrenkov K, Krepel-Volsky S, Levi I, Ariad S. Low dose palliative radiotherapy for splenomegaly in hematologic disorders. Leuk Lymphoma 2012; 53:430.
  139. Steensma DP, Hook CC, Stafford SL, Tefferi A. Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 118:813.
  140. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003; 78:1223.
  141. Hoffman R. Agnogenic myeloid metaplasia (ch.63). In: Hematology: Basic Principles and Practice, 3rd ed, Hoffman R, Benz EJ Jr, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2000.
  142. Tefferi A, Jiménez T, Gray LA, et al. Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia. Eur J Haematol 2001; 66:37.
  143. Neben-Wittich MA, Brown PD, Tefferi A. Successful treatment of severe extremity pain in myelofibrosis with low-dose single-fraction radiation therapy. Am J Hematol 2010; 85:808.
  144. Tefferi A, Silverstein MN, Petitt RM, et al. Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of actin, efficacy, toxicity, current indications. Semin Thromb Hemost 1997; 23:379.
  145. Yoon SY, Li CY, Mesa RA, Tefferi A. Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1999; 106:682.
  146. Gilbert HS. Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 1998; 83:1205.
  147. Radin AI, Kim HT, Grant BW, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer 2003; 98:100.
  148. Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia 2008; 22:1990.
  149. Tefferi A, Elliot MA, Yoon SY, et al. Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia. Blood 2001; 97:1896.
  150. Ianotto JC, Kiladjian JJ, Demory JL, et al. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d'Etudes des Myelofibroses (GEM) and France Intergroupe des syndromes Myéloprolifératifs (FIM). Br J Haematol 2009; 146:223.
  151. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 2011; 117:4706.
  152. Silver RT, Vandris K, Goldman JJ. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. Blood 2011; 117:6669.
  153. Ianotto JC, Boyer-Perrard F, Gyan E, et al. Efficacy and safety of pegylated-interferon α-2a in myelofibrosis: a study by the FIM and GEM French cooperative groups. Br J Haematol 2013; 162:783.
  154. Barosi G, Elliott M, Canepa L, et al. Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 2002; 43:2301.
  155. Canepa L, Ballerini F, Varaldo R, et al. Thalidomide in agnogenic and secondary myelofibrosis. Br J Haematol 2001; 115:313.
  156. Elliott MA, Mesa RA, Li CY, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 117:288.
  157. Marchetti M, Barosi G, Balestri F, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol 2004; 22:424.
  158. Thomas DA, Giles FJ, Albitar M, et al. Thalidomide therapy for myelofibrosis with myeloid metaplasia. Cancer 2006; 106:1974.
  159. Merup M, Kutti J, Birgergård G, et al. Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia. Med Oncol 2002; 19:79.
  160. Mesa RA, Elliott MA, Schroeder G, Tefferi A. Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc 2004; 79:883.
  161. Berrebi A, Feldberg E, Spivak I, Shvidel L. Mini-dose of thalidomide for treatment of primary myelofibrosis. Report of a case with complete reversal of bone marrow fibrosis and splenomegaly. Haematologica 2007; 92:e15.
  162. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003; 101:2534.
  163. Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006; 108:1158.
  164. Quintás-Cardama A, Kantarjian HM, Manshouri T, et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 2009; 27:4760.
  165. Mesa RA, Yao X, Cripe LD, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 2010; 116:4436.
  166. Tefferi A, Lasho TL, Mesa RA, et al. Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia 2007; 21:1827.
  167. Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol 2009; 27:4563.
  168. Lacy MQ, Tefferi A. Pomalidomide therapy for multiple myeloma and myelofibrosis: an update. Leuk Lymphoma 2011; 52:560.
  169. Begna KH, Pardanani A, Mesa R, et al. Long-term outcome of pomalidomide therapy in myelofibrosis. Am J Hematol 2012; 87:66.
  170. Steensma DP, Mesa RA, Li CY, et al. Etanercept, a soluble tumor necrosis factor receptor, palliates constitutional symptoms in patients with myelofibrosis with myeloid metaplasia: results of a pilot study. Blood 2002; 99:2252.
  171. Mesa RA, Steensma DP, Li CY, et al. Phase II study of the combination of low-dose thalidomide, prednisone, and etanercept (PET regimen) in the treatment of anemia, splenomegaly, and constitutional symptoms associated with myelofibrosis with myeloid metaplasia (MMM) (abstract). Blood 2005; 106:724a.
  172. Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood 2011; 118:2069.
  173. Quintás-Cardama A, Kantarjian H, Estrov Z, et al. Therapy with the histone deacetylase inhibitor pracinostat for patients with myelofibrosis. Leuk Res 2012; 36:1124.
  174. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010; 150:446.
  175. Mascarenhas J, Lu M, Li T, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF). Br J Haematol 2013; 161:68.
  176. DeAngelo DJ, Mesa RA, Fiskus W, et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. Br J Haematol 2013; 162:326.
  177. Brubaker LH, Brière J, Laszlo J, et al. Treatment of anemia in myeloproliferative disorders: a randomized study of fluoxymesterone v transfusions only. Arch Intern Med 1982; 142:1533.
  178. Besa EC, Nowell PC, Geller NL, Gardner FH. Analysis of the androgen response of 23 patients with agnogenic myeloid metaplasia: the value of chromosomal studies in predicting response and survival. Cancer 1982; 49:308.
  179. Lévy V, Bourgarit A, Delmer A, et al. Treatment of agnogenic myeloid metaplasia with danazol: a report of four cases. Am J Hematol 1996; 53:239.
  180. Cervantes F, Alvarez-Larrán A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol 2005; 129:771.
  181. Tefferi A, Mesa RA, Gray LA, et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002; 99:3854.
  182. Cortes J, Giles F, O'Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003; 97:2760.
  183. Barosi G, Gattoni E, Barbui T, et al. A phase I study of the proteasome inhibitor bortezomib in patients with myelofibrosis (abstract). Blood 2007; 110:1036A.
  184. Mesa RA, Verstovsek S, Rivera C, et al. Bortezomib therapy in myelofibrosis: a phase II clinical trial. Leukemia 2008; 22:1636.
  185. Tefferi A, Silverstein MN. Recombinant human erythropoietin therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1994; 86:893.
  186. Rodríguez JN, Martino ML, Diéguez JC, Prados D. rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach. Haematologica 1998; 83:616.
  187. Mohr B, Herrmann R, Huhn D. Recombinant human erythropoietin in patients with myelodysplastic syndrome and myelofibrosis. Acta Haematol 1993; 90:65.
  188. Aloe Spiriti M, Latagliata R, Avvisati G, et al. Erythropoietin treatment of idiopathic myelofibrosis. Haematologica 1993; 78:371.
  189. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC, et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004; 127:399.
  190. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol 2006; 134:184.
  191. Mesa RA, Silver RT, Verstovsek S, et al. Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial. Haematologica 2013; 98:1421.