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Myeloproliferative disorders

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General Information
Stage Information
Treatment Option Overview
Polycythemia Vera
Agnogenic Myeloid Metaplasia
Essential Thrombocythemia

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Information from PDQ -- for Health Professionals

GENERAL INFORMATION

The myeloproliferative disorders consist of polycythemia vera, chronic myelogenous leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. All these disorders are thought to result from a hematopoietic stem cell lesion. (Refer to the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.)

Prognosis for polycythemia vera has been carefully studied by the Polycythemia Vera Study Group; 40% to 50% of all patients who are treated survive about 10 years.[1] Patients with agnogenic myeloid metaplasia have a median survival of 3.5 to 5.5 years,[2,3] while patients with essential thrombocythemia have a 5-year survival of greater than 50%.[4,5]

References:

  1. Berk PD, Goldberg JD, Silverstein MN, et al.: Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. New England Journal of Medicine 304(8): 441-447, 1981.
  2. Silverstein MN: Myeloproliferative disease. Current Hematology and Oncology 6: 163-184, 1988.
  3. Demory JL, Dupriez B, Fenaux P, et al.: Cytogenetic studies and their prognostic significance in agnogenic myeloid metaplasia: a report on 47 cases. Blood 72(3): 855-859, 1988.
  4. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. Journal of Clinical Oncology 17(9): 2954-2970, 1999.
  5. Tefferi A: Myelofibrosis with myeloid metaplasia. New England Journal of Medicine 342(17): 1255-1265, 2000.

STAGE INFORMATION

Polycythemia vera

In polycythemia vera (p. vera), formal staging as such is not done. Diagnosis depends on findings from the blood, bone marrow, physical examination, and the exclusion of other causes of erythrocytosis. Specific criteria have been established by the Polycythemia Vera Study Group for the diagnosis of p. vera. Major criteria include a red cell mass greater than 36 milliliters per kilogram in males and greater than 32 milliliters per kilogram in females, arterial oxygen saturation of greater than 92%, and splenomegaly. Minor criteria include thrombocytosis greater than 400,000 per cubic millimeter, leukocytes greater than 12,000 per cubic millimeter, and leukocyte alkaline phosphatase greater than 100 units (no fever or infection). The diagnosis is established if the patient fulfills all three major criteria or the first 2 major criteria and any 2 minor criteria. Serum erythropoietin is either absent or found in very low levels in patients with p. vera.[1,2]

Examination of the bone marrow reveals a panmyelosis and erythroid hyperplasia with a decrease in the ratio of adipose to hematopoietic tissue. In most patients there is no stainable iron found in the bone marrow.

There is no staging system for this disease.

Agnogenic myeloid metaplasia

Agnogenic myeloid metaplasia is characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red cells. Marrow fibrosis is often a prominent feature. As distinguished from chronic myelogenous leukemia, agnogenic myeloid metaplasia usually presents with a white blood cell count less than 30,000 per cubic millimeter, prominent teardrops on peripheral smear, normocellular or hypocellular marrow with moderate to marked fibrosis, and an absence of the Philadelphia (Ph') chromosome or the bcr-abl translocation. 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 over 60 years of age at diagnosis and one third 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, and weight loss. The median survival is 3.5 to 5.5 years and the major causes of death include progressive marrow failure, transformation to acute nonlymphoblastic leukemia, infection, thrombohemorrhagic events, heart failure, and portal hypertension.[3,4]

Bone marrow examination including cytogenetic testing may exclude other causes of myelophthisis such as chronic myelogenous leukemia, 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 age, anemia, leukopenia, leukocytosis, circulating blasts, karyotype abnormalities, or systemic "B" symptoms (fever, night sweats, weight loss).[5] Patients without any of these adverse features (excluding age) have a median survival of more than 10 years, while the presence of any 2 of these adverse features lowers the median survival to less than 3 years.[5]

Essential thrombocythemia [1]

Essential thrombocythemia is characterized by a platelet count of greater than 600,000 per cubic millimeter, profound megakaryocytic hyperplasia in the bone marrow, absence of increased red cell mass, and absence of a disorder associated with reactive thrombocytosis such as severe iron deficiency, cancer, surgery, or infection. Although the karyotype is usually normal, occasional otherwise typical patients exhibit the Ph' chromosome or the bcr-abl translocation.

Patients older than 60 years of age or those with a prior thrombotic episode have up to 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.[6] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (less than 10%) with long-term follow-up.

There is no staging system for this disease.

Untreated essential thrombocythemia

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

References:

  1. Silverstein MN: Myeloproliferative disease. Current Hematology and Oncology 6: 163-184, 1988.
  2. Erslev AJ, Caro J: Pure erythrocytosis classified according to erythropoietin titers. American Journal of Medicine 76(1): 57-61, 1984.
  3. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. Journal of Clinical Oncology 17(9): 2954-2970, 1999.
  4. Tefferi A: Myelofibrosis with myeloid metaplasia. New England Journal of Medicine 342(17): 1255-1265, 2000.
  5. Cervantes F, Barosi G, Demory JL, et al.: Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. British Journal of Haematology 102(3): 684-690, 1998.
  6. Cortelazzo S, Finazzi G, Ruggeri M, et al.: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New England Journal of Medicine 332(17): 1132-1136, 1995.

TREATMENT OPTION OVERVIEW

The myeloproliferative disorders, excluding chronic myelogenous leukemia, are chronic diseases with a variable propensity to convert into acute myelogenous leukemia. Patients with polycythemia vera and essential thrombocythemia have marked increases of red cell and platelet production, respectively. Treatment is directed at reducing the excessive numbers of blood cells. Both polycythemia vera and essential thrombocythemia can develop a "spent phase" late in their courses which resembles agnogenic myeloid metaplasia with cytopenias and marrow hypoplasia and fibrosis.[1-3]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

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. Journal of Clinical Oncology 17(9): 2954-2970, 1999.
  3. Tefferi A: Myelofibrosis with myeloid metaplasia. New England Journal of Medicine 342(17): 1255-1265, 2000.

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.)

Untreated polycythemia vera

Therapy for polycythemia vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45% and decrease blood viscosity in order to prevent the thrombotic and hemorrhagic complications of the untreated disorder.[1,2] Complications of phlebotomy include progressive and sometimes extreme thrombocytosis and symptomatology related to chronic iron deficiency, including pica, angular stomatitis and glossitis, dysphagia due to 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, therapy with the radioisotope phosphorous-32 or alkylating agents can be used to control the disease. However, radioisotope phosphorous-32 or alkylating agent therapy increases the risk of subsequent acute leukemia.[3] The Polycythemia Vera Study Group randomized over 400 patients to phlebotomy (target hematocrit less than 45), radioisotope phosphorous-32 (2.7 milligrams per meter squared intravenously every 12 weeks as needed), or chlorambucil (10 milligrams by mouth daily for 6 weeks, then daily on alternate months).[4] 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 due to excessive late deaths from leukemia or other hematologic malignancies.[4][Level of evidence: 1iiA] Because of these concerns, many clinicians use hydroxyurea for patients who require cytoreductive therapy.[4] Results from a series of 11 patients showed that red cell indices can be controlled with interferon alfa within 6 to 12 months, eliminating the need for phlebotomy.[5] No thrombohemorrhagic events occurred in this series, in contrast to the 40% incidence of significant thrombotic complications in the phlebotomy group during the first 3 years of therapy reported by the Polycythemia Vera Study Group.[1] Additional follow-up and other confirmatory trials are required.

Standard treatment options:

1. Phlebotomy.[1,2]

2. Radioisotope phosphorous-32, alkylating agent therapy, or
hydroxyurea.[1,3,4]

3. Interferon alfa.[5]

References:

  1. Berk PD, Goldberg JD, Donovan PB, et al.: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Seminars in Hematology 23(2): 132-143, 1986.
  2. Rector WG Jr, Fortuin JF, Conley CL: Non-hematologic effects of chronic iron deficiency: a study of patients with polycythemia vera treated solely with venesections. Medicine 61(6):382-389 1982.
  3. Berk PD, Goldberg JD, Silverstein MN, et al.: Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. New England Journal of Medicine 304(8): 441-447, 1981.
  4. Kaplan ME, Mack K, Goldberg JD, et al.: Long-term management of polycythemia vera with hydroxyurea: a progress report. Seminars in Hematology 23(3): 167-171, 1986.
  5. Silver RT: Interferon-alpha2b: a new treatment for polycythemia vera. Annals of Internal Medicine 119(11): 1091-1092, 1993.

AGNOGENIC MYELOID METAPLASIA

For asymptomatic patients, no treatment is necessary.[1,2] The profound anemia which 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. Painful splenomegaly can be treated temporarily with chemotherapy (hydroxyurea), interferon, or radiation therapy, but often requires splenectomy.[3] The decision to perform splenectomy represents a weighing of the benefits (reduction of symptoms, decreased portal hypertension, and less need for red blood cell transfusions) versus the debits (postoperative mortality of 10% and morbidity of 30% due to infection, bleeding, or thrombosis; no benefit for thrombocytopenia; and accelerated progression to blast crisis, seen by some investigators but not others).[3,4] The use of interferon alfa can result in hematologic responses, including reduction in spleen size, in 30% to 50% of patients, although many patients do not tolerate this medication.[5,6] 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.[7] Disease-associated anemia does not usually respond to erythropoietin, hydroxyurea, cladribine, or interferon.[4] A potential curative approach for younger patients involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable sibling donor is available.[8] Eligible patients younger than 50 years of age may have prolonged event-free survival (39% +/- 7% at 5 years) after allogeneic bone marrow transplantation.[8][Level of evidence: 3iiiDi] Anecdotal reports of favorable responses to autologous peripheral stem cell transplantation and thalidomide have been reported.[4,9]

Standard treatment options:

1. Interferon alfa.[5,6]

2. Splenectomy.[3,10]

3. Splenic irradiation.[4]

4. Hydroxyurea.[2,4]

5. Allogeneic peripheral stem cell or bone marrow transplantation.[8]

6. Thalidomide and other new anti-angiogenesis agents are under clinical
evaluation.[4]

References:

  1. 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): 1013-1018, 1996.
  2. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. Journal of Clinical Oncology 17(9): 2954-2970, 1999.
  3. Barosi G, Ambrosetti A, et al., for the Italian Cooperative Study Group on Myelofibrosis With Myeloid Metaplasia: Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Blood 91(10): 3630-3636, 1998.
  4. Tefferi A: Myelofibrosis with myeloid metaplasia. New England Journal of Medicine 342(17): 1255-1265, 2000.
  5. Sacchi S: The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leukemia and Lymphoma 19(1-2): 13-20, 1995.
  6. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alfa-2b: feasibility and efficacy. Cancer 83(6): 1205-1213, 1998.
  7. Tefferi A, Mesa RA, Nagorney DM, et al.: Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 95(7): 2226-2233, 2000.
  8. Guardiola P, Anderson JE, et al. for the International Collaboration for Transplantation in Agnogenic Myeloid Metaplasia: Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Societe Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center collaborative study. Blood 93(9): 2831-2838, 1999.
  9. Deeg HJ, Appelbaum FR: Stem-cell transplantation for myelofibrosis. New England Journal of Medicine 344(10): 775-776, 2001.
  10. Tefferi A, Silverstein MN, Li CY: 2-chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. British Journal of Haematology 99(2): 352-357, 1997.

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.)

Untreated essential thrombocythemia

There is considerable controversy about 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 per cubic millimeter with a control group that received no therapy. Hydroxyurea was found to be effective in preventing thrombotic episodes (4% versus 24%).[1][Level of evidence: 1iiA] A retrospective analysis of this same 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 < 1500 X 10 9/l, 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.[2] Anagrelide is a non-cytotoxic inhibitor of platelet formation that can lower the platelet count below 600,000 per cubic millimeter with minimal toxicity.[3][Level of evidence: 3iiiD] The rationale for this level is not based on randomized studies with anagrelide but on the aforementioned study using hydroxyurea. A retrospective review of 35 patients under 50 years of age who received anagrelide for a median of 10.8 years showed 17 thrombotic or hemorrhagic events even though half the time the platelets were less than 650 X 10(9)/L.[4] The efficacy of anagrelide and the target platelet count cannot be confirmed without a prospective randomized trial. Many clinicians use anagrelide, hydroxyurea, or platelet apheresis prior to elective surgery to reduce the platelet count and prevent postoperative thromboembolism. Again, there are no prospective or randomized trials to document the value of this approach.

Standard treatment options:

1. Anagrelide.[3]

2. Hydroxyurea.[1]

3. Interferon alfa is under clinical evaluation.

References:

  1. Cortelazzo S, Finazzi G, Ruggeri M, et al.: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New England Journal of Medicine 332(17): 1132-1136, 1995.
  2. Ruggeri M, Finazzi G, Tosetto A, et al.: No treatment for low-risk thrombocythaemia: results from a prospective study. British Journal of Haematology 103(3): 772-777, 1998.
  3. Anagrelide Study Group: Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. American Journal of Medicine 92(1): 69-76, 1992.
  4. Storen EC, Tefferi A: Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 97(4): 863-866, 2001.
Date Last Modified: 07/2002

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