Chronic Myeloproliferative Disorders

A group of disorders characterized by abnormal proliferation of one or more hematopoietic cell lines or connective tissue elements.

The classic chronic myeloproliferative disorders are primary thrombocythemia, polycythemia vera, and myelofibrosis; the atypical ones are atypical chronic myelocytic leukemia (which is bcr/abl-negative), chronic neutrophilic leukemia, hypereosinophilic syndrome (chronic eosinophilic leukemia), and mast cell disease.

Primary Thrombocythemia

(Essential Thrombocythemia; Essential Thrombocytosis; Thrombocythemia Vera)

A disease characterized by an increased platelet count, megakaryocytic hyperplasia, and a tendency toward hemorrhage or thrombosis.

Primary thrombocythemia is the most common of the chronic myeloproliferative disorders, with an approximate incidence of 2.5/100,000 per year. The median age at presentation is 60 years (female:male ratio = 1.6:1); only 20% of patients present before age 40. Primary thrombocythemia is usually discovered incidentally during routine blood testing.

The pathogenetic basis of vasomotor symptoms is believed to be platelet-mediated endothelial injury of small vessels. However, the risk of thrombosis and hemorrhage has not been correlated with quantitative or qualitative platelet abnormalities.

Symptoms, Signs, and Complications

Most patients are asymptomatic. Vasomotor symptoms occur in one third of patients and include headache, erythromelalgia (burning pain and erythema of the hands or feet), paresthesias, and visual disturbances.

Major hemorrhagic complications are infrequent (5%) and usually result from the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Thrombotic complications occur in 15% of patients at presentation and in 11% during follow-up. They can be life threatening, although they occur less frequently and are less likely to be fatal than in polycythemia vera. They can be arterial or venous and include ischemic stroke, transient ischemic attacks, myocardial infarction, deep vein thrombosis, digital ischemia, and superficial thrombophlebitis. Characteristic thrombotic syndromes include Budd-Chiari syndrome, portal vein thrombosis, superior sagittal vein thrombosis, and skin necrosis. Acquired von Willebrand's disease is a rare complication associated with extreme thrombocytosis and is related to abnormal platelet adsorption of circulating von Willebrand's multimers.

Diagnosis

The first step in diagnosis is to rule out secondary (reactive) thrombocythemia (see Table 71-2). Shorter duration of thrombocytosis, low levels of serum ferritin (which is diagnostic of iron depletion), and an increase in C-reactive protein suggest secondary thrombocythemia. The presence of Howell-Jolly bodies in the peripheral blood smear indicates functional or anatomic asplenia.

If the initial evaluation does not suggest secondary thrombocythemia, a bone marrow examination with cytogenetic studies and a reticulin stain is recommended. Bone marrow examination in primary thrombocythemia shows megakaryocyte clusters in most cases, mild reticulin fibrosis in about 15% of cases, and cytogenetic abnormalities in < 5% of cases.

The following disorders associated with thrombocytosis can be distinguished from primary thrombocythemia by their diagnostic features:

• Chronic myelocytic leukemia is diagnosed through karyotypic analysis revealing the Philadelphia chromosome [t(9;22)]. Cases undetectable by karyotypic analysis may be diagnosed by a fluorescence in situ hybridization study of peripheral blood.
• Polycythemia vera is diagnosed by demonstrating an increase in red blood cell (RBC) mass, although this finding does not always indicate polycythemia vera.
• Myelodysplastic syndrome is diagnosed by demonstrating dyserythropoiesis and other bone marrow morphologic and cytogenetic features.

Prognosis

Elderly persons with primary thrombocythemia are at significantly increased risk of thrombosis compared with younger persons (1.7 thrombotic events/100 person-years in patients < 40; 15.1 thrombotic events/100 person-years in patients > 60). A history of thrombosis raises the risk even further, to almost 20% per year. Primary thrombocythemia may transform into leukemia (<= 5%); postthrombocythemic myeloid metaplasia (< 5%), which is a fibrotic stage; or polycythemia vera (< 5%).

Treatment

Hydroxyurea (starting dose, 500 mg po bid) decreases the significant risk of thrombotic complications in high-risk patients and may be given to most elderly patients with primary thrombocythemia. The goal of therapy is to keep the platelet count below 400,000/µL. Because of concern about potential leukemogenicity that may be associated with long-term use of hydroxyurea, alternative agents, including anagrelide and interferon-, may be considered for patients < 60 and for some elderly patients.

The starting dose of anagrelide is 0.5 mg po qid. Adverse effects, occurring in one third of patients, include headache, fluid retention, dizziness, palpitations, tachycardia, diarrhea, and, rarely, heart failure. The response rate is > 90%, and response occurs at a median of 3 weeks. Anagrelide does not affect the leukocyte count or the Hb level.

Interferon- controls thrombocytosis, splenomegaly, and disease-associated symptoms in about 80% of patients. The starting dose is 3 to 5 million U sc daily, and the average response time is 12 weeks. Short-term adverse effects include a transient influenza-like syndrome of fever and chills, myalgias, headache, and arthralgias. Long-term adverse effects include fatigue, nausea, anorexia, weight loss, diarrhea, increased liver transaminase, altered mental status, and depression.

For patients with vasomotor symptoms, a low dose of aspirin (81 mg daily) is effective, presumably by reducing thromboxane production. For high-risk patients > 60, hydroxyurea plus a low dose of aspirin is usually appropriate.

Polycythemia Vera

An idiopathic chronic myeloproliferative disorder characterized by an increase in Hb concentration and RBC mass (erythrocytosis).

Polycythemia vera (PV) is almost as common as primary thrombocythemia, with an incidence of 2.3/100,000 per year. The median age at presentation is 60 years (male:female = 1.2:1), with only 7% of patients presenting before age 40.

Symptoms, Signs, and Complications

Presenting symptoms may include headache, dizziness, visual disturbances, paresthesias, fatigue, abdominal discomfort, weight loss, and night sweats. Postbathing pruritus is a poorly understood, common complaint. Clinical examination may reveal plethora (facial fullness and erythema), retinal vein distention, and palpable splenomegaly. Erythromelalgia may occur.

Three major complications of PV are early thrombotic events, development of myelofibrosis, and leukemic conversion (transformation into acute leukemia), the latter two occurring after 10 to 20 years of disease.

Thrombotic events are common (20% of cases) and include ischemic stroke, transient ischemic attacks, retinal vein thrombosis, central retinal artery occlusion, myocardial infarction, angina, pulmonary embolism, hepatic and portal vein thrombosis, deep vein thrombosis, and peripheral arterial occlusion. The risk of fatal or debilitating thrombotic events is much greater than with primary thrombocythemia. Patients receiving high doses of NSAIDs may have severe gastrointestinal (GI) hemorrhage. The risk of bleeding and thrombosis is significantly increased during periods of stress, including trauma and surgery.

The risk of thrombotic complications during the first 3 years in patients who have received adequate phlebotomy treatment (Hct <= 45% in men, <= 42% in women) ranges from 3% in low-risk patients to 15% in high-risk patients. Risk factors for thrombosis in PV include age > 60, history of thrombosis, and a need for phlebotomy more than 4 times/year. About 20% of all patients with PV present with thrombosis, and <= 25% subsequently develop thrombosis. The rate is higher in the elderly.

The cumulative risk of transformation to myelofibrosis increases with time and is estimated to be about 10% in the first 10 years and 20% in the first 20 years.

Risk of leukemic conversion depends on the type of treatment. Studies have shown risks of 1.5% for phlebotomy alone, 9.6% for phlebotomy plus chlorambucil, and 13.2% for phlebotomy plus radiophosphorus. The risk of transformation into a fibrotic state ("spent phase," or postpolycythemic myeloid metaplasia) is 10% over 10 years and 20% over 25 years and does not appear to be influenced by treatment.

Diagnosis

Unlike all other causes of erythrocytosis, the erythroid proliferation in PV is erythropoietin-independent and down-regulates erythropoietin production. Consequently, serum levels of erythropoietin are usually low, occasionally normal, but never increased. Similarly, endogenous erythroid colony growth is suggestive of PV rather than of secondary erythrocytosis.

Diagnostic criteria according to the Polycythemia Vera Study Group are shown in Table 71-3. These criteria require increased RBC mass as a diagnostic prerequisite. However, increased RBC mass does not always indicate PV and may be due to an erythropoietin-mediated secondary erythrocytosis (see Table 71-4).

Leukocytosis or thrombocytosis occurs in > 50% of patients. Microcytosis is common and indicates iron deficiency, usually from repeated phlebotomy for treatment or occult GI blood loss. Nonspecific additional laboratory abnormalities include increases in leukocyte alkaline phosphatase score, serum level of vitamin B₁₂, and uric acid.

Prognosis and Treatment

Median survival without therapy is < 2 years and is about 12 years for patients treated with phlebotomy alone.

Phlebotomy significantly reduces the risk of thrombosis. Therefore, all patients should undergo regular phlebotomy. About 500 mL of blood may be removed daily (in symptomatic patients) or weekly (in asymptomatic patients) until the Hct is < 45% in men and < 42% in women. Thereafter, the frequency is adjusted to maintain the Hct at this level.

Hydroxyurea has been shown to decrease the risk of early thrombosis without significantly increasing the risk of leukemic conversion. Thus, hydroxyurea (starting dose, 500 mg po bid) is recommended as a supplement to phlebotomy in elderly patients, particularly those who have a history of thrombosis.

Interferon- (3 million U sc 3 times weekly) may be used for patients who cannot tolerate hydroxyurea because of adverse effects or neutropenia.

Radiophosphorus (2.3 mCi/m² given IV q 3 months) may be considered if the life expectancy of the patient is < 10 years and when compliance with drug treatment is poor.

A low dose of aspirin (81 mg daily) alleviates vasomotor symptoms and should be used if there are other reasons for giving aspirin. Whether aspirin is safe and effective for preventing early thrombosis associated with PV is being evaluated.

Pruritus associated with PV is often difficult to alleviate. In patients with adequate phlebotomy treatment, the addition of hydroxyurea or the alternative use of interferon- may control refractory pruritus. Some patients may benefit from starch baths and the avoidance of brisk rubbing with a towel and showering. Although some medications, including cimetidine (900 mg daily), cyproheptadine (12 mg daily), and aspirin (81 mg daily) may be used, they have not shown consistent effectiveness and have major adverse effects in the elderly. Low doses of antidepressants (doxepin, 50 mg daily; paroxetine, 20 mg daily) are sometimes beneficial. In refractory cases, phototherapy or cholestyramine (20 g daily) may be tried.

Myelofibrosis

(Agnogenic Myeloid Metaplasia)

A chronic, usually idiopathic disease characterized by bone marrow fibrosis, splenomegaly, and leukoerythroblastic anemia with teardrop-shaped RBCs.

Myelofibrosis is the least common of the chronic myeloproliferative diseases, with an incidence of 1.3/100,000 per year. The median age at presentation is 60 years (male:female = 1.2:1). Only about 5% of patients present with myelofibrosis before age 40.

The cause is unknown. Myelofibrosis may complicate the course of chronic myelocytic leukemia, primary thrombocythemia, and polycythemia vera. Fewer than 5% of patients with primary thrombocythemia and about 20% of those with polycythemia vera develop myelofibrosis after 10 to 20 years of disease. Such transformations are called postthrombocythemic myeloid metaplasia and postpolycythemic myeloid metaplasia, respectively, and their clinical course is similar to that of myelofibrosis. Together, all three are called myelofibrosis with myeloid metaplasia.

The spleen and liver are sites of extramedullary hematopoiesis, which is largely responsible for the enlargement of these organs.

Symptoms, Signs, and Complications

Most patients present with anemia and marked splenomegaly, the latter usually causing early satiety. Progressive anemia and massive hepatosplenomegaly usually develop during the course of the disease. Hypercatabolic symptoms include severe fatigue, low-grade fever, night sweats, and weight loss. Occasionally, severe left upper quadrant pain results from splenic infarction. Thrombotic complications are less common than in polycythemia vera.

Hemorrhagic complications are usually due to thrombocytopenia, esophageal varices, the use of NSAIDs, or acquired deficiency of factor V. Marked splenomegaly or intrahepatic obstruction may lead to portal hypertension. In some patients, extramedullary hematopoiesis develops in the spinal cord (causing cord compression), in the pleural or peritoneal cavity (causing pleural effusion or ascites), in the lymph nodes (causing lymphadenopathy), or in other organs.

Diagnosis

Diagnosis is suggested by examination of the peripheral blood smear and confirmed by bone marrow biopsy. In addition to normocytic (sometimes microcytic) anemia, laboratory findings often include an increased or decreased number of granulocytes and platelets. The peripheral blood smear demonstrates characteristic features of myelophthisis (bone marrow infiltration), including teardrop-shaped RBCs (dacryocytes), and of leukoerythroblastosis (the presence of nucleated RBCs and granulocyte precursors). In addition, the peripheral blood smear may show giant platelets and polychromasia (indicative of reticulocytosis). The latter finding is consistent with a component of hemolytic anemia that may occur in a small proportion of patients.

Nonspecific laboratory findings include increased blood levels of vitamin B₁₂, uric acid, and liver enzymes, including markedly increased levels of alkaline phosphatase. The bone marrow is often difficult to aspirate, and a bone marrow biopsy reveals extensive collagen fibrosis that is best seen with reticulin stain. Fibrosis often is associated with atypical megakaryocytic hyperplasia and thickening and distortion of the bony trabeculae (osteosclerosis). Cytogenetic studies of the bone marrow reveal clonal abnormalities in about 30% of patients.

The differential diagnosis of diseases associated with myelofibrosis is summarized in Table 71-5. Thorough morphologic and cytogenetic examinations are required for a diagnosis of myelofibrosis.

Prognosis

Median survival is estimated to be between 3 and 5 years. Risk factors for decreased survival are age > 60, hepatomegaly, weight loss, anemia (Hb < 10 g/dL), leukocytosis (white blood cell [WBC] count > 30,000/µL), leukopenia (WBC count < 4000/µL), circulating blasts >= 2%, male sex, thrombocytopenia (platelet count < 150,000/µL), and abnormal karyotype. Anemic patients with leukocytosis or leukopenia have a median survival of about 1 year. Patients with either anemia or leukocytosis/leukopenia have a median survival of about 2 years. Causes of death include leukemic conversion in about 10% of patients, heart failure, and infection. Splenomegaly and the degree of bone marrow fibrosis do not affect survival. Conversely, factors for longer survival include Hb >= 10 g/dL and a WBC count between 4,000 and 30,000/µL, forming the basis of a prognostic scoring system (Dupriez score).

Treatment

Allogeneic bone marrow transplantation (ABMT) may offer a possible "cure" to some patients. Five years after receiving ABMT, 50% of patients are alive and about 25% are disease-free. Generally, patients with a low Dupriez score fare better than those with a higher score.

Patients who are not candidates for ABMT receive palliative treatment. The combination of an androgen (fluoxymesterone, 10 mg po bid) and a corticosteroid (prednisone, 30 mg po daily) reduces anemia in one third of patients. If the patient responds after 1 month of treatment, fluoxymesterone is continued and the corticosteroid dosage is tapered. Before starting androgen therapy, men should be screened for prostate cancer (by digital rectal examination and measurement of prostate-specific antigen), because men with prostate cancer cannot receive androgen. All patients should have periodic monitoring of liver function. Women should be warned about virilizing adverse effects.

Erythropoietin does not usually alleviate anemia resulting from myelofibrosis. Patients who do not respond to androgen therapy receive supportive treatment with periodic RBC transfusions. Secondary hemosiderosis from long-term blood transfusion may be managed with desferoxamine (2 g daily by sc infusion pump), which may prevent complications of iron overload.

Hydroxyurea (starting at 500 mg po bid) may reduce spleen size and control thrombocytosis and leukocytosis in some patients but may worsen anemia.

Splenectomy is considered for patients who have symptomatic splenomegaly (mechanical discomfort, hypercatabolic symptoms, portal hypertension). Laboratory evidence of disseminated intravascular coagulation before splenectomy may increase the risk of perioperative hemorrhage; splenectomy should therefore be postponed until the abnormalities are corrected. At experienced centers, the mortality rate for splenectomy is generally < 10%. Postsurgical complications include intra-abdominal hemorrhage, subphrenic abscess, sepsis, large vessel thrombosis, extreme thrombocytosis, and accelerated hepatomegaly. The thrombocytosis and hepatomegaly may be controlled transiently with hydroxyurea (starting dosage, 500 mg po tid) or 2-chlorodeoxyadenosine (0.14 mg/kg given over 2 hours IV daily for 5 days).

After splenectomy, hypercatabolic symptoms and portal hypertension subside in almost all patients, and refractory anemia subsides in about 25% of the patients.

For patients unable to tolerate splenectomy, splenic irradiation (50 to 200 cGy delivered in 10 to 15 daily fractions) usually provides a transient (3 to 6 months) benefit. Irradiation is also useful in reducing extramedullary hematopoiesis at other sites, eg, spinal cord or pleural cavity.

As the factors that indicate a worsening prognosis increase, treatment is increasingly directed to end-of-life palliative care.