Primary Myelofibrosis

Disease Overview
Treatment Overview
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Primary myelofibrosis (also known as agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, myelosclerosis with myeloid metaplasia, and idiopathic myelofibrosis) is characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red blood cells.[1] In its early phase, the disease is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells.

As distinguished from chronic myelogenous leukemia (CML), primary myelofibrosis usually presents as follows:[2]

• A white blood cell count smaller than 30,000/mm³.
• Prominent teardrops on peripheral smear.
• Normocellular or hypocellular marrow with moderate to marked fibrosis.
• An absence of the Philadelphia chromosome or the BCR/ABL translocation.
• Frequent positivity for the JAK2 mutation.

In addition to the clonal proliferation of a multipotent hematopoietic progenitor cell, an event common to all chronic myeloproliferative disorders, myeloid metaplasia is characterized by colonization of extramedullary sites such as the spleen or liver.[3,4]

Most patients are older than 60 years at diagnosis, and 33% of patients are asymptomatic at presentation. Splenomegaly, sometimes massive, is a characteristic finding.

Symptoms include:

• Splenic pain.
• Early satiety.
• Anemia.
• Bone pain.
• Fatigue.
• Fever.
• Night sweats.
• Weight loss.

(Refer to the PDQ summaries on Pain; Fatigue; Fever, Sweats, and Hot Flashes; and Nutrition for information on many of the symptoms listed above.)

The proposed World Health Organization criteria for the diagnosis of primary myelofibrosis requires all three major criteria and two minor criteria.[5]

Major Criteria

1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis; or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (so-called prefibrotic cellular-phase disease).
2. Not meeting criteria for polycythemia vera, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
3. Demonstration of JAK2 617V greater than F or other clonal marker; or, in the absence of a clonal marker, no evidence of bone marrow fibrosis caused by an underlying inflammatory disease or another neoplastic disease.

Minor Criteria

1. Leukoerythroblastosis.
2. Increased serum level of lactate dehydrogenase.
3. Anemia.
4. Palpable splenomegaly.

Distinguishing prefibrotic myelofibrosis from essential thrombocythemia can be difficult because of substantial interobserver variability and because of no difference in clinical outcome.[6]

The median survival is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years.[3,4] The major causes of death include:[7]

• Progressive marrow failure.
• Transformation to acute nonlymphoblastic leukemia.
• Infection.
• Thrombohemorrhagic events.
• Heart failure.
• Portal hypertension.

Fatal and nonfatal thrombosis was associated with age more than 60 years and JAK2 positivity in a multivariable analysis of 707 patients followed from 1973 to 2008.[8] Bone marrow examination including cytogenetic testing may exclude other causes of myelophthisis, such as CML, myelodysplastic syndrome, metastatic cancer, lymphomas, and plasma cell disorders.[4] In acute myelofibrosis, patients present with pancytopenia but no splenomegaly or peripheral blood myelophthisis. Peripheral blood or marrow monocytosis is suggestive for myelodysplasia in this setting.

There is no staging system for this disease.

Prognostic factors include:[9-13]

• Age 65 years or older.

• Anemia (hemoglobin <10 g/dL).

• Constitutional symptoms: fever, night sweats, or weight loss.

• Leukocytosis (WBC >25 × 10⁹/L).

• Circulating blasts of at least 1%.

Patients without any of these adverse features, excluding age, have a median survival of more than 10 years, while the presence of any two of these adverse features lowers the median survival to less than 3 years.[14] An international prognostic scoring system has been proposed by the Working Group for Myelofibrosis Research and Treatment.[14]

Karyotype abnormalities can also affect prognosis. In a retrospective series of 200 patients, 13q and 20q deletions and trisomy 9 correlated with improved survival and no leukemia transformation in comparison to the trisomy 8 or a complex karyotype.[8]

The profound anemia that develops in this disease usually requires red blood cell transfusion. Red blood cell survival is markedly decreased in some patients; this can sometimes be treated with glucocorticoids. Disease-associated anemia may occasionally respond to the following:[4,15-17]

• Erythropoietic growth factors.
• Hydroxyurea.
• Cladribine.
• Thalidomide.
• Lenalidomide.
• Interferon.

JAK2 inhibitors are being evaluated in randomized trials, and patients may be eligible even in the absence of a JAK2 mutation.(COMFORT-I trial [NCT00952289])

Painful splenomegaly can be treated temporarily with chemotherapy (hydroxyurea), interferon, thalidomide, lenalidomide, or radiation therapy, but often requires splenectomy.[17,18] The decision to perform splenectomy represents a weighing of the benefits (i.e., reduction of symptoms, decreased portal hypertension, and less need for red blood cell transfusions) versus the debits (i.e., postoperative mortality of 10% and morbidity of 30% caused by infection, bleeding, or thrombosis; no benefit for thrombocytopenia; and accelerated progression to blast crisis that was seen by some investigators but not others).[4,18]

Hydroxyurea is useful in patients with this disease but may have a potential leukemogenic effect.[4] In patients with thrombocytosis and hepatomegaly after splenectomy, cladribine has shown responses as an alternative to hydroxyurea.[19] The use of interferon-alpha can result in hematologic responses, including reduction in spleen size in 30% to 50% of patients, though many patients do not tolerate this medication.[20,21] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[15-17,22,23][Level of evidence: 3iiiDiv]

A response defined as 50% reduction of splenomegaly or development of transfusion independence was attained by one-third of 34 symptomatic patients using tipifarnib.[24][Level of evidence: 3iiiDiv] A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable sibling donor is available.[25-27] Detection of the JAK2 mutation after transplantation is feasible, but there are no data to confirm that a change in therapy based on persistence of this marker would have an effect on outcome.[28] A retrospective review of 150 patients who underwent surgery documented 8% thromboembolism and 7% major hemorrhage with prior cytoreduction and postoperative subcutaneous heparin in one-half of the patients.[29]

Treatment options:

1. Clinical trials involving JAK2 inhibitors.(COMFORT-I trial [NCT00952289])
2. Interferon-alpha.[20,21]
3. Splenectomy.[18,30]
4. Splenic radiation therapy.[4]
5. Hydroxyurea.[3,4]
6. Allogeneic peripheral stem cell or bone marrow transplantation.[26,27,31,32]
7. Thalidomide.[15,22,23,25]
8. Lenalidomide.[17,33]

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with primary myelofibrosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Hennessy BT, Thomas DA, Giles FJ, et al.: New approaches in the treatment of myelofibrosis. Cancer 103 (1): 32-43, 2005.  [PUBMED Abstract]
   
   
2. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.  [PUBMED Abstract]
   
   
3. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 17 (9): 2954-70, 1999.  [PUBMED Abstract]
   
   
4. Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med 342 (17): 1255-65, 2000.  [PUBMED Abstract]
   
   
5. Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009.  [PUBMED Abstract]
   
   
6. Wilkins BS, Erber WN, Bareford D, et al.: Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 111 (1): 60-70, 2008.  [PUBMED Abstract]
   
   
7. Chim CS, Kwong YL, Lie AK, et al.: Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia. Arch Intern Med 165 (22): 2651-8, 2005 Dec 12-26.  [PUBMED Abstract]
   
   
8. Hussein K, Pardanani AD, Van Dyke DL, et al.: International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood 115 (3): 496-9, 2010.  [PUBMED Abstract]
   
   
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 102 (3): 684-90, 1998.  [PUBMED Abstract]
   
   
10. Strasser-Weippl K, Steurer M, Kees M, et al.: Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score. Leuk Lymphoma 47 (3): 441-50, 2006.  [PUBMED Abstract]
    
    
11. Tefferi A: Survivorship and prognosis in myelofibrosis with myeloid metaplasia. Leuk Lymphoma 47 (3): 379-80, 2006.  [PUBMED Abstract]
    
    
12. 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 27 (33): 5587-93, 2009.  [PUBMED Abstract]
    
    
13. 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 115 (22): 4350-5, 2010.  [PUBMED Abstract]
    
    
14. 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 113 (13): 2895-901, 2009.  [PUBMED Abstract]
    
    
15. Giovanni B, Michelle E, Letizia C, et al.: Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 43 (12): 2301-7, 2002.  [PUBMED Abstract]
    
    
16. 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 22 (3): 424-31, 2004.  [PUBMED Abstract]
    
    
17. Tefferi A, Cortes J, Verstovsek S, et al.: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 108 (4): 1158-64, 2006.  [PUBMED Abstract]
    
    
18. 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 91 (10): 3630-6, 1998.  [PUBMED Abstract]
    
    
19. Tefferi A, Mesa RA, Nagorney DM, et al.: Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 95 (7): 2226-33, 2000.  [PUBMED Abstract]
    
    
20. Sacchi S: The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 19 (1-2): 13-20, 1995.  [PUBMED Abstract]
    
    
21. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.  [PUBMED Abstract]
    
    
22. Strupp C, Germing U, Scherer A, et al.: Thalidomide for the treatment of idiopathic myelofibrosis. Eur J Haematol 72 (1): 52-7, 2004.  [PUBMED Abstract]
    
    
23. Mesa RA, Elliott MA, Schroeder G, et al.: Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc 79 (7): 883-9, 2004.  [PUBMED Abstract]
    
    
24. Mesa RA, Camoriano JK, Geyer SM, et al.: A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia 21 (9): 1964-70, 2007.  [PUBMED Abstract]
    
    
25. 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 93 (9): 2831-8, 1999.  [PUBMED Abstract]
    
    
26. Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102 (12): 3912-8, 2003.  [PUBMED Abstract]
    
    
27. Daly A, Song K, Nevill T, et al.: Stem cell transplantation for myelofibrosis: a report from two Canadian centers. Bone Marrow Transplant 32 (1): 35-40, 2003.  [PUBMED Abstract]
    
    
28. Kröger N, Badbaran A, Holler E, et al.: Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis. Blood 109 (3): 1316-21, 2007.  [PUBMED Abstract]
    
    
29. Ruggeri M, Rodeghiero F, Tosetto A, et al.: Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 111 (2): 666-71, 2008.  [PUBMED Abstract]
    
    
30. Tefferi A, Silverstein MN, Li CY: 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. Br J Haematol 99 (2): 352-7, 1997.  [PUBMED Abstract]
    
    
31. Deeg HJ, Appelbaum FR: Stem-cell transplantation for myelofibrosis. N Engl J Med 344 (10): 775-6, 2001.  [PUBMED Abstract]
    
    
32. 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 114 (26): 5264-70, 2009.  [PUBMED Abstract]
    
    
33. 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 27 (28): 4760-6, 2009.  [PUBMED Abstract]