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.)

Chronic idiopathic myelofibrosis (also known as agnogenic myeloid metaplasia, primary 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), chronic idiopathic myelofibrosis usually presents with 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, and frequent positivity for the JAK2 mutation.[2] 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.

The median survival is 3.5 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 progressive marrow failure, transformation to acute nonlymphoblastic leukemia, infection, thrombohemorrhagic events, heart failure, and portal hypertension.[5]

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:[6-8]

• Age.



• Anemia.



• Leukopenia.



• Leukocytosis.



• Circulating blasts.



• Karyotype abnormalities. In a retrospective series of 81 patients, 13q and 20q lesions correlated with improved survival and no leukemia transformation in comparison to the trisomy 8 or 12p lesions.[9]



• Systemic B symptoms (i.e., fever, night sweats, and weight loss).

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.[6]

For asymptomatic patients, no treatment is necessary.[3,10]

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 erythropoietin, hydroxyurea, cladribine, thalidomide, lenalidomide, or interferon.[4,11-13]

Painful splenomegaly can be treated temporarily with chemotherapy (hydroxyurea), interferon, thalidomide, lenalidomide, or radiation therapy, but often requires splenectomy.[13,14] 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).[4,14] 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.[15] 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.[16,17] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[11-13,18,19][Level of evidence: 3iiiDiv] A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable sibling donor is available.[20-22] 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.[23]

Treatment options:

1. Interferon-alpha.[16,17]
2. Splenectomy.[14,24]
3. Splenic radiation therapy.[4]
4. Hydroxyurea.[3,4]
5. Allogeneic peripheral stem cell or bone marrow transplantation.[12,21,22,25]
6. Thalidomide.[11,18-20]
7. Lenalidomide.[13]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with chronic idiopathic 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. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. Tefferi A: Survivorship and prognosis in myelofibrosis with myeloid metaplasia. Leuk Lymphoma 47 (3): 379-80, 2006.  [PUBMED Abstract]
   
   
9. Tefferi A, Dingli D, Li CY, et al.: Prognostic diversity among cytogenetic abnormalities in myelofibrosis with myeloid metaplasia. Cancer 104 (8): 1656-60, 2005.  [PUBMED Abstract]
   
   
10. 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 88 (3): 1013-8, 1996.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. Tefferi A, Cortes J, Verstovsek S, et al.: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 108 (4): 1158-64, 2006.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.  [PUBMED Abstract]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102 (12): 3912-8, 2003.  [PUBMED Abstract]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. Deeg HJ, Appelbaum FR: Stem-cell transplantation for myelofibrosis. N Engl J Med 344 (10): 775-6, 2001.  [PUBMED Abstract]
    
    

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