Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies

26

Chronic Myeloproliferative Diseases

Manish Monga*

Marcel P. Devetten^†

*Department of Oncology, Wheeling Hospital, Wheeling, West Virginia

^†Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska

The World Health Organization (WHO) designates seven conditions as myeloproliferative disorders (MPDs): BCR-ABL–positive chronic myeloid leukemia (CML); chronic neutrophilic leukemia; chronic eosinophilic leukemia/hypereosinophilic syndrome; idiopathic myelofibrosis (MF, also known as agnogenic myeloid metaplasia); polycythemia vera (PV); essential thrombocythemia (ET); and myeloproliferative disease, unclassifiable (see Fig. 26.1). CML is discussed in Chapter 25 because of its specific association with the Philadelphia chromosome translocation (bcr-abl tyrosine kinase), and because of its unique treatment paradigm of imatinib mesylate and interferon-α (INF-α). This chapter is limited to a discussion of the three major clinical entities: PV, ET, and MF. Although these are distinct clinical entities, they all share some of the same clinical and laboratory features: increased numbers of one or more circulating cell lines, hepatosplenomegaly, and clonal marrow hyperplasia without dysplasia. Diagnosis depends on exclusion of secondary causes of increased blood counts and on distinguishing between the various MPDs (prompted by the particular blood cell lineage that appears to be in excess, followed by identifying characteristic biochemical or cytogenetic abnormalities) (see Table 26.1). Treatment for PV, ET, and MF is generally directed toward minimizing morbidity and prolonging survival by preventing complications such as hemorrhage and thrombosis, in the case of PV and ET, and alleviating anemia and symptoms associated with the splenomegaly of MF. Because these are clonal disorders, there is a risk of transformation of PV, ET, and MF to acute leukemia. This risk is highest for MF; therefore, bone marrow transplantation is a potentially curative option that should be considered for this disease.

TABLE 26.1. Distinguishing Features of the Myeloproliferative Disorders

CML PV ET MF CML, chronic myeloid leukemia; PV, polycythemia vera; ET, essential thrombocytopenia; MF, myelofibrosis; N, normal; WBC, white blood cell; LAP, leukocyte alkaline phosphatase (see Chapter 25); MPD, myeloproliferative disease. Hematocrit N or ↓ ↑↑ N ↓ WBC count ↑↑↑ ↑ N ↑ or ↓ Platelet count ↑ or ↓ ↑ ↑↑↑ ↑ or Splenomegaly +++ + + +++ Cytogenetic abnormality Ph chromosome ± - ± LAP score ↓ ↑↑ N or ↑ N or ↑ Marrow fibrosis ± ± or ↓ ± +++ (Dry tap) Marrow cellularity ↑↑↑ myeloid ↑↑ ↑↑ megakaryocytes N or ↓ Basophils ≥2% + ± ± Usually +

FIG. 26.1. Classification of the chronic myeloid disorders. *Atypical chronic myeloid diorders include chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic neutrophilic leukemia, juvenile myelomonocytic leukmia, systemic cell disease, and a chronic myeloid process that shows characteristics of myelodysplastic syndrome and chronic myeloproliferative disorder.

EPIDEMIOLOGY AND RISK FACTORS

Annual incidence per 100,000 population:

• 0.5 to 1.7 cases of PV
• Approximately 2.5 cases of ET
• Approximately 1.4 cases of MF.

Median age at diagnosis:

• 50 to 60 years for all three disorders.

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RISK FACTORS

Some studies have suggested radiation exposure or occupational exposure to solvents and glues as risk factors, but these have not been confirmed.

ETIOLOGY AND PATHOPHYSIOLOGY

Clonal Hematopoiesis

The etiology of these disorders remains unclear. PV and MF are disorders of an early stem cell or progenitor because blood lineages of all three disorders are derived from the same clone; however, careful clonal studies in patients with clinically diagnosed ET demonstrate clonal hematopoiesis in only about 50% of the cases. The detection of a clonal population has been shown to be associated with an increased risk for thrombotic complications. The marrow

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fibroblasts in MF are not derived from an abnormal clone. Because of clonal hematopoiesis, all the MPDs have a tendency to transform to acute leukemia, although the probability of this occurrence differs considerably among the disorders.

Growth Factor or Growth Factor–Receptor Mutations

Studies that have sought to implicate the involvement of erythropoietin (EPO) levels or erythropoietin receptor (EPO-R) in PV have thus far demonstrated the EPO-R involvement only in some cases of familial polycythemias. EPO levels tend to be low in PV. In contrast, thrombopoietin (TPO) levels can be high in ET, and molecular abnormalities of the TPO gene have been identified in certain families with an autosomal dominant form of hereditary thrombocytosis. Mutations of the TPO receptor have not been demonstrated in ET, but posttranslational glycosylation impairment of the TPO receptor is common in PV. Increased levels of platelet-derived growth factor and other cytokines secreted by megakaryocytes and by platelets are believed to play a role in the marrow fibrosis of MF.

PROGNOSIS

Median Survivals

• Patients with PV have a median survival of 1.5 to 13 years. In a recent multicountry prospective study of 1,638 patients with PV, the 5-year event-free survival was 82%, with a relatively low risk of death from cardiovascular disease and a high risk of death from noncardiovascular causes (mainly hematologic transformations).
• The median survival is more than 10 years for patients with ET.
• For patients with MF, the median survival is 3 to 5 years.

Rate of Transformation to Acute Leukemia

• The rate of transformation of PV to acute leukemia is 1% to 5% [1.5% of patients treated with phlebotomy alone, 5.9% of patients treated with hydroxyurea (HU), 10% to 13.5% of those treated with chlorambucil or ³²P exhibit transformation of PV to acute leukemia].
• The rate of transformation for patients with ET is 3% to 5% (transformation to MF and acute leukemia).
• The rate of transformation for patients with MF is 10%.

The major cause of death in PV is thrombosis (i.e., cerebral, cardiac, pulmonary, and mesenteric), and the major causes of death in ET are thrombosis and hemorrhage.

Spent Phase

Both PV and ET may progress to a “spent phase,” which resembles MF and which is characterized by cytopenia, splenomegaly, and marrow fibrosis.

Risk Factors for Thrombosis

• In PV, a hematocrit equal to and greater than 45% is a risk factor. Surgery should be avoided in patients until a hematocrit less than 45% has been maintained for more than 2 months.
• In ET, being older than 60 years and the presence of other cardiovascular risk factors (e.g., smoking and previous thrombosis) increases the risk for thrombosis.

In ET, an association between platelet count and thrombosis has not been established, but platelet cytoreduction on treatment with HU has been associated with a reduced risk.

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Risk Factors for Hemorrhage

• In ET, a platelet count >2 × 10⁶per µL is a risk factor for hemorrhage.

DIAGNOSIS AND CLINICAL FEATURES

Excluding Secondary Causes of Polycythemia or Thrombocytosis

In the absence of a disease-specific positive marker for PV, the Polycythemia Vera Study Group (PVSG), an international study group, has published the diagnostic criteria that include demonstration of increased red cell mass in the presence of normal hemoglobin oxygen saturation, supported by other diagnostic criteria such as splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased serum vitamin B₁₂ levels. The application of these diagnostic criteria may exclude some cases of PV; therefore, an algorithmic approach using serum EPO and histologic characteristics of the bone marrow is useful in formulating a working diagnosis of PV (see Fig. 26.2). Karyotype abnormalities are infrequent and nonspecific in PV; they include trisomies of chromosomes 8 and 9 and deletions of long arms of chromosomes 13 and 20. PVSG has also established the diagnostic criteria for ET (see Table 26.2).

TABLE 26.2. Diagnostic Criteria for Essential Thrombocytopenia

Hct, hematocrit; MCV, mean corpuscular volume; Ph, Philadelphia; MDS, myelodysplastic syndrome. 1. Platelets >600 × 103/µL 2. Hct <40% or normal RBC mass 3. Stainable iron in marrow, or normal ferritin, or normal MCV 4. No Ph chromosome or bcr-abl rearrangement, or MDS-type cytogenetic abnormality 5. No marrow fibrosis or marrow fibrosis <1/3 of biopsy and no more than minimal splenomegaly and no leukoerythroblastic cells in the peripheral blood 6. No other cause for reactive thrombocytosis

FIG. 26.2. Algorithm for the diagnosis of polycythemia vera (PV).

Distinguishing between the Myeloproliferative Disorders

All the MPDs can present because of incidentally noted abnormal blood counts (Table 26.1). Otherwise, PV can demonstrate symptoms of increased red blood cell (RBC) mass, such as headaches, vertigo, tinnitus, and blurred vision. A distinctive symptom in PV is pruritus aggravated by hot water. Cerebrovascular ischemia, digital ischemia, erythromelalgia, and spontaneous abortions resulting from arterial thrombosis are more commonly seen in patients with ET. Patients with MF may have symptoms related to anemia or may experience abdominal fullness or early satiety because of splenomegaly. Hypermetabolic symptoms such as weight loss and sweating can be seen in all types of MPDs. ET is diagnosed after excluding PV; MF is diagnosed after excluding PV and ET because marrow fibrosis can be a sequela of the other MPDs. The thrombotic episodes seen in all the MPDs can occur in unusual locations such as the hepatic vein (Budd–Chiari syndrome) and portal vein. Platelet function tests or bleeding times are of little use in diagnosing or in guiding the management of MPDs.

TREATMENT

Polycythemia Vera

Maintaining a hematocrit less than 45% dramatically decreases the incidence of thrombotic complications (in PV, 35% of initial thrombotic events are fatal). This is preferably achieved through phlebotomy; alternatives are myelosuppressive oral chemotherapy or IFN-α. Selection among these options is guided by data from the PVSG studies. A randomized study of 518 patients with PV has shown that treatment with low-dose aspirin (100 mg per day) lowers the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Polycythemia Vera Study Group Studies (Phlebotomy and Chemotherapy)

PVSG-01 randomized more than 400 patients to phlebotomy, chlorambucil, or ³²P. The thrombosis rate in patients treated with phlebotomy alone was significantly higher than that for those patients receiving myelosuppressive therapy with chlorambucil or ³²P. Median survival was more than 10 years in the groups treated with ³²P and phlebotomy, and was 9 years in the group treated with chlorambucil, with an excess of leukemic deaths in the group of patients treated with chlorambucil and ³²P. In PVSG-05, when aspirin, 325 mg three times a day, was given in addition to phlebotomy, the risk of life-threatening thrombosis did not decrease, but

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hemorrhagic complications increased. PVSG-08 studied the nonalkylating myelosuppressive agent, HU, in the hope that this agent would not be associated with leukemic transformation, which was noted for ³²P and chlorambucil in PVSG-01. HU, with supplemental phlebotomy as needed, was found to have a significantly lower risk of thrombosis compared with phlebotomy alone. However, a statistically nonsignificant higher risk of transformation of PV to acute leukemia was observed in patients who were treated with HU alone.

A reasonable treatment strategy for PV is based on risk stratification:

• Low risk: Patients younger than 60 years, with no history of thrombocytosis and with platelet count <1,500 × 10⁹per L, are at low risk. Phlebotomy alone with or without low-dose aspirin should be recommended.
• Indeterminate risk: Patients younger than 60 years, with no history of thrombocytosis and with either a platelet count >1,500 × 10⁹per L or cardiovascular risk factors, are at intermediate risk. Phlebotomy alone is adequate therapy; use of low-dose aspirin is encouraged.
• High risk: Patients who are 60 years or older or with a positive history of thrombosis are at high risk. HU and low-dose aspirin are recommended therapies.
• Spent phase: Options to alleviate cytopenia associated with massive splenomegaly include HU, IFN-α, and EPO. Analgesia may be required for splenic infarct pain. It is difficult to treat cytopenia associated with marrow fibrosis and massive splenomegaly. Splenectomy can be followed by progressive hepatomegaly and can eventually transform to acute leukemia. In selected patients, allogeneic transplantation can be curative.
• Pruritus: Intractable pruritus responds to IFN-α in up to 81% of patients. In low-risk patients in whom IFN-α is not indicated, paroxetine, a selective serotonin reuptake inhibitor, can alleviate symptoms in most cases.
• Hyperuricemia: Allopurinol should be started before chemotherapy to decrease the risk of urate nephropathy (300 mg per day given orally; dose reduction needed in renal insufficiency).

Essential Thrombocythemia

Treatment in ET must be provided on the basis of the fact that life expectancy in this condition is nearly normal and that platelet reduction with HU may be associated with an increased risk for transformation to leukemia. Treatment is directed at preventing thrombosis and hemorrhage in those patients deemed to be at risk for these complications. These patients have a history of thrombosis, with associated cardiovascular risk factors such as smoking and age older than 60 years, and have a platelet count >2 × 10⁶ per µL

For platelet cytoreduction, see Table 26.3.

TABLE 26.3. Chemotherapeutic Agents used in the Therapy of the Chronic Myeloproliferative Disorders

Agent Treatment plan Indications Toxicity Hct, hematocrit; PV, polycythemia vera; ET, essential thrombocytopenia; MF, myelofibrosis; plt, platelets; pts, patients; PO, oral administration; s.c., subcutaneous administration. Hydroxyurea Start with hydroxyurea, 1,000–2,000 mg PO daily All PV pts >69 yr of age; younger patients with thrombosis, hemorrhage, severe pruritus, painful splenomegaly, or B symptoms. Increased risk of acute leukemic transformation or myelodysplastic syndrome with a chromosome 17p deletion; leg ulceration In PV, adjust to keep Hct <45% without producing thrombocytopenia or neutropenia Augment with phlebotomy if necessary In ET, adjust dose to maintain plt counts <600 × 103/µL; long-term therapy is necessary ET pts who require therapy (see text). MF pts requiring cytoreduction after splenectomy. Anagrelide Anagrelide, 0.5–1 mg PO four times daily. Prolonged treatment is necessary Generally used as a second-line agent for decreasing plt counts. Consider using as primary therapy for young pts with ET requiring therapy. Fluid retention, congestive heart failure symptoms, postural hypotension, headaches, dizziness, nausea, and diarrhea Interferon-α 2a/b Start with interferon-α 2a/b 3 × 106 Units s.c. three times/wk. Adjust the dose against response and adverse effects. Long-term treatment is necessary Experimental therapy in PV (refer for clinical trials). Consider for young pts as an alternative to phlebotomy. A second-line plt-lowering agent in ET Flu-like symptoms, altered mental status, and depression

• A randomized trial of HU in 114 high-risk patients showed a significant reduction of thrombotic events in the treatment arm (3.6% versus 24%). The HU dose was adjusted to achieve a platelet count of <600 × 10³per µL. Anagrelide is a nonmutagenic orally active agent that produces selective platelet cytoreduction by interfering with megakaryocyte maturation. IFN-α can also effectively cause platelet cytoreduction. The study on HU has provided the precedent for a platelet count of 600 × 10³ per µL as the therapeutic target with anagrelide or IFN-α therapy. Plateletpheresis is used as an emergency therapy when ongoing thrombosis cannot be adequately managed with chemotherapy and antithrombotic agents.
• Antiplatelet agents: Aspirin can exacerbate the bleeding tendency in patients with ET and other MPDs and should be used selectively. Low-dose aspirin (81 mg per day orally) may benefit patients with ET who have cerebral or digital ischemia. Erythromelalgia (painful nonischemic fingers and toes) responds to aspirin.

Myelofibrosis

• Palliative therapy: Palliative therapy for MF is directed toward alleviating anemia and painful splenomegaly. For anemia, androgens (oxymethalone, 1 to 5 mg/kg/day orally, may

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take 3 to 6 months to produce a response) produce responses in about 30% of patients. Transfusion support (with iron chelation when indicated) may be necessary. Splenectomy, as performed in experienced centers, is associated with an operative mortality of less than 10%, and in addition to alleviating pain, discomfort, and early satiety, it can improve anemia. Increasing white blood cell counts and platelet counts after splenectomy may necessitate HU therapy. IFN-α is an experimental therapy for MF.

• Curative therapy: Allogeneic transplantation should be considered for patients younger than 55 years who have MF; 5-year survivals with a related or an unrelated matched transplant are 54% and 48%, respectively, as determined by the European Group for Blood and Marrow Transplantation (EBMT). A recommendation for transplantation is not clear-cut in asymptomatic patients without cytogenetic abnormalities and no cytopenia because the median survival in this group is greater than 14 years with palliative therapy alone. Although the outcome with transplantation also is adversely affected by these features, poor prognostic features such as hemoglobin level <10 g per dL; white blood cell count <4 × 10³per µL or >30 × 10³ per µL; more than 10% of circulating blasts, promyelocytes, or myelocytes; or abnormal cytogenetics should prompt consideration for transplantation. Pretransplantation splenectomy, although not necessary in every patient, is associated with faster engraftment and can be considered in those with massive splenomegaly. Marrow fibrosis is reversible with transplantation.

SUGGESTED READINGS

Berk PD, Goldberg JD, Donovoun PB, et al. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986;23:132–143.

Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk for thrombosis. N Engl J Med 1995;332:1132–1136.

Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a polycythemia vera study group report on hydroxyurea in patient with polycythemia vera. Semin Hematol 1997;34:17–23.

Guardiola P, Anderson JE, Bandini G, et al. 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 1999;93:2831–2838.

Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–3849.

Kaplan ME, Mack K, Goldberg JD, et al. Long term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 1986;23:167–171.

Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera (ECLAP study). Blood 2003;102:5a.

Silver RT. Interferon-alpha: effects of long-term treatment for polycythemia vera. Semin Hematol 1997;34:40–50.

Spivak J. Polycythemia vera: myths, mechanisms, and management. Blood 2002;100:4272–4290.