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Polycythemia Vera

The chronic myeloproliferative diseases (CMPD) are currently organized to include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). Among the CMPDs, a clonal increase in red cell mass (RCM) defines PV. While bone marrow fibrosis characterizes myelofibrosis with myeloid metaplasia, ET remains a diagnosis of exclusion. The incidence of PV is estimated to be 2.3/100,000 per year. Median age at diagnosis is approximately 60 years. Median survival exceeds 10 years and the main causes of death are thrombosis and disease transformation into myelofibrosis with myeloid metaplasia (MMM) and acute myeloid leukemia (AML).

Diagnosis

Approximately 25 years ago, the PV study group (PVSG) published a set of diagnostic criteria to ensure accrual of a uniform group of patients to treatment protocols (table 1). Over the years, it has become clear that these criteria lacked sensitivity for detecting early or occult disease. The presence of disease-specific alterations in biological parameters.

Prognosis

The most reproducible risk factors for thrombosis in PV are advanced age and a previous history of thrombosis. In one of the largest retrospective studies in PV, the annual incidence of thrombosis ranged from 1.8% in patients below age 40 years to 5.1% in those over 70 years of age. Similarly, recurrent thrombosis, over a median follow-up of 5.3 years.

Treatment

Before the practice of aggressive phlebotomy, survival in PV was severely compromised (a median of less than 2 years) by fatal thrombotic complications. With adequate phlebotomy alone (hematocrit levels below 45% in males and 42% in females), the median survival in PV has been extended to over 12 years.

In order to reduce the aforementioned risks associated with treatment with phlebotomy alone, several clinical trials have evaluated the supplementary role of various myelosuppressive and antiplatelet agents. In one of the earlier trials, when either chlorambucil or ³²P was added to phlebotomy, survival was significantly compromised because of an increased incidence of acute leukemia. The incidence of acute leukemia over 13-19 years was 1.5, 9.6, 13.2 percent.

Based on the above observations, the cornerstone of current therapy in PV remains phlebotomy for all patients to keep hematocrit below 45 percent in men and 42 percent in women. In addition, balancing, on one hand, the risk of thrombosis associated with phlebotomy, and on the other hand, the potential risk of acute leukemia with myelosuppressive drug therapy.

Controversial Treatment Issues

The use of high doses of ASA (300 mg TID) in combination with dipyridamole (75 mg TID) did not alter the risk of thrombosis in PV and was shown, instead, to increase the risk of gastrointestinal bleeding. On the other hand, lower doses of ASA (75-325 mg/day) have been shown to be as effective as higher doses in preventing recurrent vascular events among various high-risk population groups. Furthermore, thromboxane biosynthesis is elevated in both PV and ET and the in vivo activity is suppressible, in PV, with low-dose ASA (50 mg/day).

One of the concerns in the long-term use of HU in PV is its potential to increase leukemia risk. However, current evidence is not conclusive in implicating HU, when used as a single agent, as being leukemogenic in the treatment of PV. On the other hand, most studies have suggested a further increase in leukemia risk when HU is combined with other agents. Alpha interferon has been considered as an alternative to HU in the treatment of PV. In general, control of erythrocytosis occurs in approximately 76% of the patients receiving subcutaneous drug in doses ranging from 4.5 to 27 million units per week.

The ability of alpha interferon to suppress clonal hematopoiesis in CML and rare reports of cytogenetic remissions in PV suggest a potentially exploitable biological effect. However, a prospective evaluation of the drug is necessary to determine its place in the treatment of both low-risk and high-risk patients.