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Chronic Myeloproliferative Disorders Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Chronic Myeloproliferative Disorders Treatment

General Information About Chronic Myeloproliferative Disorders

The chronic myeloproliferative disorders consist of chronic myelogenous leukemia, polycythemia vera (p. vera), primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. All of these disorders involve dysregulation at the multipotent hematopoietic stem cell (CD34), with one or more of the following shared features:

  • Overproduction of one or several blood elements with dominance of a transformed clone.
  • Hypercellular marrow/marrow fibrosis.
  • Cytogenetic abnormalities.
  • Thrombotic and/or hemorrhagic diatheses.
  • Extramedullary hematopoiesis (liver/spleen).
  • Transformation to acute leukemia.
  • Overlapping clinical features.

Patients with p. vera and essential thrombocythemia have marked increases of red blood cell and platelet production, respectively. Treatment is directed at reducing the excessive numbers of blood cells. Both p. vera and essential thrombocythemia can develop a spent phase late in their courses that resembles primary myelofibrosis with cytopenias and marrow hypoplasia and fibrosis.[1,2,3] A specific point mutation in one copy of the Janus kinase 2 gene (JAK2), a cytoplasmic tyrosine kinase, on chromosome 9, which causes increased proliferation and survival of hematopoietic precursors in vitro, has been identified in most patients with p. vera, essential thrombocythemia, and idiopathic myelofibrosis.[4,5,6,7,8,9] Researchers are pursuing specific targeting of this aberrant protein.

References:

1. Schafer AI: Bleeding and thrombosis in the myeloproliferative disorders. Blood 64 (1): 1-12, 1984.
2. 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.
3. Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med 342 (17): 1255-65, 2000.
4. Kralovics R, Passamonti F, Buser AS, et al.: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352 (17): 1779-90, 2005.
5. Baxter EJ, Scott LM, Campbell PJ, et al.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365 (9464): 1054-61, 2005 Mar 19-25.
6. James C, Ugo V, Le Couédic JP, et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434 (7037): 1144-8, 2005.
7. Levine RL, Wadleigh M, Cools J, et al.: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7 (4): 387-97, 2005.
8. Scott LM, Tong W, Levine RL, et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356 (5): 459-68, 2007.
9. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.

Chronic Myelogenous Leukemia

Refer to the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.

Polycythemia Vera

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.)

Disease Overview

The proposed revised World Health Organization criteria for the diagnosis of polycythemia vera (p. vera) requires two major criteria and one minor criterion or the first major criterion together with two minor criteria.[1]

Major Criteria

1. Hemoglobin of more than 18.5 g/dL in men, 16.5 g/dL in women, or elevated red cell mass greater than 25% above mean normal predicted value.
2. Presence of JAK2 617V greater than F or other functionally similar mutations, such as the exon 12 mutation ofJAK2.

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
2. Serum erythropoietin level below normal range.
3. Endogenous erythroid colony formationin vitro.

Other confirmatory findings no longer required for diagnosis include:[2,3,4]

  • Oxygen saturation with arterial blood gas greater than 92%.
  • Splenomegaly.
  • Thrombocytosis (>400,000 platelets/mm3).
  • Leukocytosis (>12,000/mm3).
  • Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).

There is no staging system for this disease.

Patients have an increased risk of cardiovascular and thrombotic events and transformation to acute myelogenous leukemia or primary myelofibrosis.[5,6,7] Age older than 65 years and a history of vascular events are independent predictors of thrombosis.[5,8]

Treatment Overview

Therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45% in men.[9] The target level for women may need to be lower (e.g., hematocrit <40%), but there are no empiric data to confirm this recommendation.[10]

Complications of phlebotomy include:

  • Progressive and sometimes extreme thrombocytosis and symptomatology related to chronic iron deficiency, including pica, angular stomatitis, and glossitis.
  • Dysphagia that is the result of esophageal webs (very rare).
  • Possibly muscle weakness.

(Refer to the Oral Complications of Chemotherapy and Head/Neck Radiation summary for more information.)

In addition, progressive splenomegaly or pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. (Refer to the Pruritus summary for more information.) If phlebotomy becomes impractical, hydroxyurea or interferon-alpha can be added to control the disease.

The Polycythemia Vera Study Group randomly assigned more than 400 patients to phlebotomy (target hematocrit <45), radioisotope phosphorous-32 (2.7 mg/m2 administered intravenously every 12 weeks as needed), or chlorambucil (10 mg administered by mouth daily for 6 weeks, then given daily on alternate months).[11] The median survival for the phlebotomy group (13.9 years) and the radioisotope phosphorous-32 group (11.8 years) was significantly better than that of the chlorambucil group (8.9 years), primarily because of excessive late deaths from leukemia or other hematologic malignancies.[11][Level of evidence: 1iiA] Because of these concerns, many clinicians use hydroxyurea for patients who require cytoreductive therapy that is caused by massive splenomegaly, a high phlebotomy requirement, or excessive thrombocytosis.[11]

In a pooled analysis of 16 different trials, interferon-alpha therapy resulted in avoidance of phlebotomy in 50% of patients, with 80% of patients experiencing marked reduction of splenomegaly.[12][Level of evidence: 3iiiDiv] Interferon posed problems of cost, side effects, and parenteral route of administration, but no cases of acute leukemia were seen in this analysis. When patients are poorly compliant with phlebotomy or issues of massive splenomegaly, leukocytosis, or thrombocytosis supervene, treatment with interferon or pegylated interferon is considered for patients younger than 50 years (who are more likely to tolerate the side effects and benefit from a lack of transformation to leukemia), while hydroxyurea is considered for patients older than 50 years.[2,13]

A phase II study (PVN1) provided evidence that V617F JAK2 mutation is a reliable molecular marker of p. vera and is potentially useful in monitoring treatment effect.

In a Cochrane review of two randomized studies of 630 patients with no clear indication or contraindication for aspirin, those receiving 100 mg of aspirin versus placebo had reduction of fatal thrombotic events, but this benefit was not statistically significant (OR = 0.20; 95% CI, .03–1.14).[14] A retrospective review of 105 patients who underwent surgery documented 8% thromboembolism and 7% major hemorrhage with prior cytoreduction by phlebotomy and postoperative subcutaneous heparin in one half of the patients.[15]

Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.[3]

Treatment options:

1. Phlebotomy.[9]
2. Hydroxyurea (alone or with phlebotomy).[10,11]
3. Interferon-alpha[12,16,17]and pegylated interferon-alpha.[18]
4. Rarely, chlorambucil or busulfan may be required, especially if interferon or hydroxyurea are not tolerated, as is often seen in patients older than 70 years.[2]
5. Low-dose aspirin (≤100 mg) daily, unless contraindicated by major bleeding or gastric intolerance.[8,14]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with polycythemia vera. 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. 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.
2. Streiff MB, Smith B, Spivak JL: The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood 99 (4): 1144-9, 2002.
3. McMullin MF, Bareford D, Campbell P, et al.: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130 (2): 174-95, 2005.
4. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
5. Marchioli R, Finazzi G, Landolfi R, et al.: Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23 (10): 2224-32, 2005.
6. Elliott MA, Tefferi A: Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 128 (3): 275-90, 2005.
7. Chait Y, Condat B, Cazals-Hatem D, et al.: Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol 129 (4): 553-60, 2005.
8. Finazzi G, Barbui T: How I treat patients with polycythemia vera. Blood 109 (12): 5104-11, 2007.
9. Berk PD, Goldberg JD, Donovan PB, et al.: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 23 (2): 132-43, 1986.
10. Lamy T, Devillers A, Bernard M, et al.: Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 102 (1): 14-20, 1997.
11. Kaplan ME, Mack K, Goldberg JD, et al.: Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 23 (3): 167-71, 1986.
12. Lengfelder E, Berger U, Hehlmann R: Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79 (3): 103-9, 2000.
13. Kiladjian JJ, Cassinat B, Chevret S, et al.: Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 112 (8): 3065-72, 2008.
14. Squizzato A, Romualdi E, Middeldorp S: Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev (2): CD006503, 2008.
15. 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.
16. Silver RT: Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107 (3): 451-8, 2006.
17. Quintás-Cardama A, Kantarjian HM, Giles F, et al.: Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders. Semin Thromb Hemost 32 (4 Pt 2): 409-16, 2006.
18. Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009.

Primary Myelofibrosis

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.)

Disease Overview

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 theBCR/ABLtranslocation.
  • 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:[9,10,11,12,13]

  • 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]

Treatment Overview

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:[4,15,16,17]

  • 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.[15,16,17,22,23][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.[25,26,27] 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-Itrial [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]

Current Clinical Trials

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.
2. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
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.
4. Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med 342 (17): 1255-65, 2000.
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.
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.
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.
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.
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.
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.
11. Tefferi A: Survivorship and prognosis in myelofibrosis with myeloid metaplasia. Leuk Lymphoma 47 (3): 379-80, 2006.
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.
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.
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.
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.
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.
17. Tefferi A, Cortes J, Verstovsek S, et al.: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 108 (4): 1158-64, 2006.
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.
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.
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.
21. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
22. Strupp C, Germing U, Scherer A, et al.: Thalidomide for the treatment of idiopathic myelofibrosis. Eur J Haematol 72 (1): 52-7, 2004.
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.
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.
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.
26. Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102 (12): 3912-8, 2003.
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.
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.
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.
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.
31. Deeg HJ, Appelbaum FR: Stem-cell transplantation for myelofibrosis. N Engl J Med 344 (10): 775-6, 2001.
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.
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.

Essential Thrombocythemia

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.)

Disease Overview

The proposed revised World Health Organization criteria for the diagnosis of essential thrombocythemia requires all four criteria.[1]

Criteria

1. Sustained platelet count of at least 450 × 109 /L.
2. Bone marrow biopsy showing predominant proliferation of enlarged mature megakaryocytes; no significant increase of granulocytic or erythroid precursors.
3. Not meeting criteria for polycythemia vera (p. vera), primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
4. Demonstration of JAK2 617V greater than F or other clonal marker.[2]In the absence of a clonal marker, there must be no evidence for reactive thrombocytosis. In particular, with a decreased serum ferritin, there must be no increase in hemoglobin level to p. vera range with iron replacement therapy.

Patients older than 60 years or those with a prior thrombotic episode have as much as a 25% chance of developing cerebral, cardiac, or peripheral arterial thromboses and, less often, a chance of developing a pulmonary embolism or deep venous thrombosis.[3] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up.

There is no staging system for this disease.

Untreated essential thrombocythemia means that a patient is newly diagnosed and has had no prior treatment except supportive care.

Treatment Overview

Controversy is considerable regarding whether asymptomatic patients with essential thrombocythemia require treatment. A randomized trial of patients with essential thrombocythemia and a high risk of thrombosis compared treatment with hydroxyurea titrated to attain a platelet count below 600,000/mm3 with a control group that received no therapy. Hydroxyurea was found to be effective in preventing thrombotic episodes (4% vs. 24%).[3][Level of evidence: 1iiDiv] A retrospective analysis of this trial found that antiplatelet drugs had no significant influence on the outcome. Resistance to hydroxyurea is defined as a platelet count of greater than 600,000/mcL after 3 months of at least 2 g per day of hydroxyurea or a platelet count greater than 400,000/µL and a white blood count of less than 2,500/µL or a hemoglobin less than 10 g/dL at any dose of hydroxyurea.[4]

In a case-controlled observational study of 65 low-risk patients (<60 years of age, platelet count <1,500 × 109 /L, and no history of thrombosis or hemorrhage) with a median follow-up of 4.1 years, the thrombotic risk of 1.91 cases per 100 patient years and hemorrhagic risk of 1.12 cases per 100 patient years was not increased over the normal controls.[5] A prospective randomized trial of 809 patients compared hydroxyurea plus aspirin versus anagrelide plus aspirin.[6] Although the platelet-lowering effect was equivalent, the anagrelide group had significantly more thrombotic and hemorrhagic events (hazard ratio [HR] = 1.57; P = .03) and more myelofibrosis (HR = 2.92; P = .01). No differences were seen for myelodysplasia or acute leukemia.[7][Level of evidence: 1iiA] Many clinicians use hydroxyurea or platelet apheresis prior to elective surgery to reduce the platelet count and to prevent postoperative thromboembolism. No prospective or randomized trials document the value of this approach.

Among low-risk patients (defined as age 60 years or younger with no prior thrombotic episodes), a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis in patients with cardiovascular risk factors.[8]

Treatment options:

1. No treatment, unless complications develop, if patients are asymptomatic, younger than 60 years, and have a platelet count of less than 1,500 × 109 /L.
2. Hydroxyurea.[3]
3. Interferon-alpha[9,10]or pegylated interferon-alpha.[11]
4. Anagrelide.[7,12]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with essential thrombocythemia. 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. 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.
2. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
3. Cortelazzo S, Finazzi G, Ruggeri M, et al.: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332 (17): 1132-6, 1995.
4. Barosi G, Besses C, Birgegard 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 21 (2): 277-80, 2007.
5. Ruggeri M, Finazzi G, Tosetto A, et al.: No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 103 (3): 772-7, 1998.
6. Harrison CN, Campbell PJ, Buck G, et al.: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353 (1): 33-45, 2005.
7. Green A, Campbell P, Buck G: The Medical Research Council PT1 trial in essential thrombocythemia. [Abstract] Blood 104 (11): A-6, 2004.
8. Alvarez-Larrán A, Cervantes F, Pereira A, et al.: Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 116 (8): 1205-10; quiz 1387, 2010.
9. 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.
10. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
11. Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009.
12. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 92 (1): 69-76, 1992.

Chronic Neutrophilic Leukemia

Disease Overview

Chronic neutrophilic leukemia (CNL) is a rare chronic myeloproliferative disorder of unknown etiology, characterized by sustained peripheral blood neutrophilia (>25 × 109 /L) and hepatosplenomegaly.[1,2] The bone marrow is hypercellular. No significant dysplasia is in any of the cell lineages, and bone marrow fibrosis is uncommon.[1,2] Cytogenetic studies are normal in nearly 90% of the patients. In the remaining patients, clonal karyotypic abnormalities may include +8, +9, del (20q) and del (11q).[1,3,4,5] There is no Philadelphia chromosome or BCR/ABL fusion gene. CNL is a slowly progressive disorder, and the survival of patients is variable, ranging from 6 months to more than 20 years.

Treatment Overview

Until the last few years, the treatment of CNL focused on disease control rather than cure. Once the disease progressed to a more aggressive leukemia, there was typically little chance of obtaining a long-lasting remission because of the older age of most patients as well as the acquisition of multiple poor prognostic cytogenetic abnormalities. Allogeneic bone marrow transplantation represents a potentially curative treatment modality in the management of this disorder.[6,7,8] Varying success has been reported with the use of traditional chemotherapies including hydroxyurea and interferon.[9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic neutrophilic leukemia. 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. Imbert M, Bain B, Pierre R, et al.: Chronic neutrophilic leukemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 27-8.
2. Zittoun R, Réa D, Ngoc LH, et al.: Chronic neutrophilic leukemia. A study of four cases. Ann Hematol 68 (2): 55-60, 1994.
3. Froberg MK, Brunning RD, Dorion P, et al.: Demonstration of clonality in neutrophils using FISH in a case of chronic neutrophilic leukemia. Leukemia 12 (4): 623-6, 1998.
4. Yanagisawa K, Ohminami H, Sato M, et al.: Neoplastic involvement of granulocytic lineage, not granulocytic-monocytic, monocytic, or erythrocytic lineage, in a patient with chronic neutrophilic leukemia. Am J Hematol 57 (3): 221-4, 1998.
5. Matano S, Nakamura S, Kobayashi K, et al.: Deletion of the long arm of chromosome 20 in a patient with chronic neutrophilic leukemia: cytogenetic findings in chronic neutrophilic leukemia. Am J Hematol 54 (1): 72-5, 1997.
6. Piliotis E, Kutas G, Lipton JH: Allogeneic bone marrow transplantation in the management of chronic neutrophilic leukemia. Leuk Lymphoma 43 (10): 2051-4, 2002.
7. Hasle H, Olesen G, Kerndrup G, et al.: Chronic neutrophil leukaemia in adolescence and young adulthood. Br J Haematol 94 (4): 628-30, 1996.
8. Böhm J, Schaefer HE: Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease. J Clin Pathol 55 (11): 862-4, 2002.
9. Elliott MA, Dewald GW, Tefferi A, et al.: Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study. Leukemia 15 (1): 35-40, 2001.

Chronic Eosinophilic Leukemia

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.)

Disease Overview

Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative disorder of unknown etiology in which a clonal proliferation of eosinophilic precursors results in persistently increased numbers of eosinophils in the blood, bone marrow, and peripheral tissues. In CEL, the eosinophil count is greater than or equal to 1.5 × 109 /L in the blood.[1] To make a diagnosis of CEL, there should be evidence for clonality of the eosinophils or an increase in blasts in the blood or bone marrow. In many cases, however, it is impossible to prove clonality of the eosinophils, in which case, if there is no increase in blast cells, the diagnosis of idiopathic hypereosinophilic syndrome (HES) is preferred. Because of the difficulty in distinguishing CEL from HES, the true incidence of these diseases is unknown, though they are rare. In about 10% of patients, eosinophilia is detected incidentally. In others, the constitutional symptoms found include:[1,2]

  • Fever.
  • Fatigue.
  • Cough.
  • Angioedema.
  • Muscle pains.
  • Pruritus.
  • Diarrhea.

No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.

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

Treatment Overview

The optimal treatment of CEL remains uncertain, partially on account of the rare incidence of this chronic myeloproliferative disorder and the variable clinical course, which can range from cases with decades of stable disease to cases with rapid progression to acute leukemia. Case reports suggest that treatment options include bone marrow transplantation and interferon-alpha.[3,4]

Treatment of HES has included the following:[5,6]

  • Corticosteroids.
  • Chemotherapeutic agents such as hydroxyurea, cyclophosphamide, and vincristine.
  • Interferon-alpha.

Case reports suggest symptomatic responses to imatinib mesylate for patients with HES who have not responded to conventional options.[6,7,8][Level of evidence: 3iiiDiv] Imatinib mesylate acts as an inhibitor of a novel fusion tyrosine kinase, FIP1L1-PDGFR alpha fusion tyrosine kinase, which results as a consequence of interstitial chromosomal deletion.[6,9][Level of evidence: 3iiiDiv] HES with the FIP1L1-PDGFR alpha fusion tyrosine kinase translocation has been shown to respond to low-dose imatinib mesylate.[9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic eosinophilic leukemia. 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. Bain B, Pierre P, Imbert M, et al.: Chronic eosinophillic leukaemia and the hypereosinophillic syndrome. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 29-31.
2. Weller PF, Bubley GJ: The idiopathic hypereosinophilic syndrome. Blood 83 (10): 2759-79, 1994.
3. Basara N, Markova J, Schmetzer B, et al.: Chronic eosinophilic leukemia: successful treatment with an unrelated bone marrow transplantation. Leuk Lymphoma 32 (1-2): 189-93, 1998.
4. Yamada O, Kitahara K, Imamura K, et al.: Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation. Am J Hematol 58 (2): 137-41, 1998.
5. Butterfield JH, Gleich GJ: Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome. Ann Intern Med 121 (9): 648-53, 1994.
6. Gotlib J, Cools J, Malone JM 3rd, et al.: The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 103 (8): 2879-91, 2004.
7. Gleich GJ, Leiferman KM, Pardanani A, et al.: Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 359 (9317): 1577-8, 2002.
8. Ault P, Cortes J, Koller C, et al.: Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate. Leuk Res 26 (9): 881-4, 2002.
9. Cools J, DeAngelo DJ, Gotlib J, et al.: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348 (13): 1201-14, 2003.

Changes to This Summary (07 / 29 / 2011)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Polycythemia Vera

Added Tefferi et al. as reference 1.

Added text to include pegylated interferon-alpha with interferon alpha in the treatment options and cited Quintás-Cardama as reference 18.

Primary Myelofibrosis

Added Tefferi et al. as reference 5.

Added text to state that fatal and nonfatal thrombosis was associated with age 60 years or older and JAK2 positivity in a multivariable analysis of 707 patients followed from 1973 to 2008 (cited Hussein et al. as reference 8).

Added Tam et al. as reference 12.

Added Morel et al. as reference 13. Also added text to the list of prognostic factors to include: age of 65 years of older; constitutional symptoms: fever, night sweats, or weight loss; circulating blasts of at least 1%.

Added Cervantes et al. as reference 14. Also added that an international prognostic scoring system has been proposed by the Working Group for Myelofibrosis Research and Treatment.

Added text to state that karyotype abnormalities can also affect prognosis and that as seen 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.

Added text to state that JAK2 inhibitors are being evaluated in randomized trials, and patients may be eligible even in the absence of a JAK2 mutation.

Added text to include clinical trials involving JAK2 inhibitors to the treatment options. To the allogeneic peripheral stem cell or bone marrow transplantation treatment option was added Kröger et al. as reference 32.

Added Quintás-Cardama et al. as reference 33.

Essential Thrombocythemia

Added Tefferi et al. as reference 1.

Added text to state that among low-risk patients, a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis in patients with cardiovascular risk factors (cited Alvarez-Larrán et al. as reference 8).

Added text to include pegylated interferon-alpha or interferon-alpha as treatment options (cited Quintás-Cardama et al. as reference 11).

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myeloproliferative disorders. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Chronic Myeloproliferative Disorders Treatment are:

  • Steven D. Gore, MD (Johns Hopkins University)
  • Mark J. Levis, MD, PhD (Johns Hopkins University)
  • Eric J. Seifter, MD (Johns Hopkins University)
  • Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Chronic Myeloproliferative Disorders Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/myeloproliferative/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Last Revised: 2011-07-29

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