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

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Chronic Myeloproliferative Disorders Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myeloproliferative disorders. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Molecular diagnostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options for different types of cancer disorders.

This summary 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.

Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

The chronic myeloproliferative disorders consist of chronic myelogenous leukemia, polycythemia vera (p. vera), chronic idiopathic 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 chronic idiopathic 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] 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.

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

Persistent elevation of the hematocrit (>52% in men and >48% in women) should prompt investigation of polycythemia vera (p. vera).[1] In p. vera, formal staging is not done. Tests that are used to diagnose p. vera include:[2,3]

  • Red blood cell volume (>36 mL/kg in men and >32 mL/kg in women).
  • Oxygen saturation with arterial blood gas (>92%).
  • Serum erythropoietin levels (very low or absent).
  • JAK2 mutation in the presence of a high hematocrit (>52% in men and >48% in women).

Other confirmatory tests include:[2]

  • Splenomegaly.
  • Thrombocytosis (>400,000 platelets/mm3).
  • Leukocytosis (>12,000/mm3).
  • Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).

Erythroid progenitor cell assays are available at some academic centers.[2]

There is no staging system for this disease.

Patients older than 65 years have an increased risk of cardiovascular and thrombotic events and transformation to acute myelogenous leukemia or chronic idiopathic myelofibrosis.[4]

Treatment Overview

Therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45% in men.[5] The target level for women may need to be lower (e.g., hematocrit <40%), but there are no empiric data to confirm this recommendation.[6] 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), and possibly muscle weakness. In addition, progressive splenomegaly or pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. If phlebotomy becomes impractical, hydroxyurea or interferon-alpha can be added to control the disease.

The Polycythemia Vera Study Group randomized 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).[7] 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.[7][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.[7]

Interferon-alpha therapy resulted in avoidance of phlebotomy in 50% of patients, with 80% of patients experiencing marked reduction of splenomegaly, in a pooled analysis of 16 different trials.[8][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.[2,9] In a randomized study of 518 patients with no clear indication or contraindication for aspirin, those receiving 100 mg of aspirin versus placebo had reduction of the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk = 0.41; 95% confidence interval, 0.18–0.91, P = .03).[10][Level of evidence: 1iA]

Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.[1]

TREATMENT OPTIONS:

1. Phlebotomy.[5]
2. Hydroxyurea (alone or with phlebotomy).[6,7]
3. Interferon-alpha.[8]
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]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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. 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.
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. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
4. 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.
5. 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.
6. Lamy T, Devillers A, Bernard M, et al.: Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 102 (1): 14-20, 1997.
7. 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.
8. Lengfelder E, Berger U, Hehlmann R: Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79 (3): 103-9, 2000.
9. Kiladjian JJ, Cassinat B, Turlure P, et al.: High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood 108 (6): 2037-40, 2006.
10. Landolfi R, Marchioli R, Kutti J, et al.: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350 (2): 114-24, 2004.

Chronic Idiopathic 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

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:[6,7,8]

  • 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]

Treatment Overview

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.[4,11,12,13]

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.[11,12,13,18,19][Level of evidence: 3iiiDiv] A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable sibling donor is available.[20,21,22] 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.[11,18,19,20]
7. Lenalidomide.[13]

Current Clinical Trials

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

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

Essential thrombocythemia is characterized by:

  • A platelet count of more than 600,000/mm3.
  • Profound megakaryocytic hyperplasia in the bone marrow.
  • Absence of increased red blood cell mass (polycythemia), myelodysplasia, or chronic myelogenous leukemia (absence of BCR/ABL fusion gene).
  • Absence of a disorder associated with reactive thrombocytosis, such as severe iron deficiency, cancer, surgery, or infection (normal ferritin).
  • JAK2 mutation in the presence of a high platelet count (>450,000/mm3).[1]

Although the karyotype is usually normal, 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.[2] 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%).[2][Level of evidence: 1iiDiv] A retrospective analysis of this trial found that antiplatelet drugs had no significant influence on the outcome.

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.[3] A prospective randomized trial of 809 patients compared hydroxyurea ± aspirin versus anagrelide ± aspirin.[4] 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.[5][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.

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.[2]
3. Interferon-alpha.[6,7]
4. Anagrelide.[5,8]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
2. 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.
3. 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.
4. 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.
5. Green A, Campbell P, Buck G: The Medical Research Council PT1 trial in essential thrombocythemia. [Abstract] Blood 104 (11): A-6, 2004.
6. 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.
7. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
8. 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 PDQ Cancer Clinical Trials Registry 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, constitutional symptoms, such as fever, fatigue, cough, angioedema, muscle pains, pruritus, and diarrhea are found.[1,2] No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.

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 corticosteroids; chemotherapeutic agents such as hydroxyurea, cyclophosphamide, and vincristine; and interferon-alpha.[5,6] 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 PDQ Cancer Clinical Trials Registry 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.

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Changes to This Summary (05 / 08 / 2008)

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.

Editorial changes were made to this summary.

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Date Last Modified: 2008-05-08

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