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Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 Years

Gruppo Italiano Studio Policitemia*
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Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(9):656-664. doi:10.7326/0003-4819-123-9-199511010-00003
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Objective: To reassess the natural history of polycythemia vera and to obtain reliable estimates of both incidence of thrombosis and survival for use in defining the sample size for therapeutic clinical trials.

Study Design: Retrospective cohort study of patients with polycythemia who had been followed for 20 years.

Setting: 11 Italian hematology institutions.

Patients: 1213 patients with polycythemia vera, which was diagnosed according to criteria established by the Polycythemia Vera Study Group and commonly used in clinical practice.

Main Outcome Measures: All-cause mortality, venous and arterial thrombosis, and hematologic and nonhematologic neoplastic disease. Myocardial infarction and stroke were classified as major thrombotic events, and venous and peripheral arterial thrombosis were considered minor thrombotic events. The number of patients who died and the number of those who had major thrombotic events (combined end point) were used as a comprehensive measure of the benefit-risk ratio associated with the use of myelosuppressive agents.

Results: 634 fatal and nonfatal arterial and venous thromboses were recorded in 485 patients (41%); 36% of these episodes occurred during follow-up in 230 patients (19%), and 64% occurred either at presentation or before diagnosis. Thrombotic events occurred more frequently in the 2 years preceding diagnosis, suggesting a causal relation between the latent myeloproliferative disorder and the vascular event. The incidence of thrombosis during follow-up was 3.4%/y; older patients or those with a history of thrombosis had a higher risk for thrombosis. Overall mortality was 2.9/100 patients per year; thrombotic events and hematologic or nonhematologic cancers had similar effects on mortality. Patients receiving chemotherapy died three to four times more frequently than those not receiving chemotherapy. The increased risk for cancer in patients receiving myelosuppressive agents was seen approximately 6 years after diagnosis. In addition, the combined end point, computed as the sum of the hardest available events (death, nonfatal myocardial infarction, or stroke), suggests that myelosuppressive agents have an overall unfavorable effect.

Conclusions: Cytoreduction favorably affects the incidence of thrombotic events, but aggressive treatment seems to be associated with increased risk for neoplasm. These results provide a basis for reevaluating the therapeutic strategy in patients with polycythemia vera and for estimating the size of clinical trials aimed at testing new therapeutic approaches.

*For members of the Gruppo Italiano Studio Policitemia, see the Appendix.

Figures

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Figure 1.
Frequencies of diagnosis of polycythemia vera according to age and sex.

Age at diagnosis of polycythemia vera for 671 men (55%) and 542 women (45%). M/W equals ratio of men to women for diagnosis of polycythemia vera in each 5-year age group.

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Figure 2.
Thrombotic events in the years before the diagnosis of polycythemia vera.

The y-axis represents the percentage of patients who had at least one thrombotic event each year before the diagnosis of polycythemia vera.

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Figure 3.
Thrombosis-free survival by age group for 1213 patients with polycythemia vera.P

Patients at risk in the four age groups at the beginning of each 3-year period and the number of thrombotic events (in parentheses) during each 3-year period are shown below the x-axis. For patients younger than 40 years, median follow-up was 7.5 years and the maximum was 32.9 years; for patients aged 40 to 60 years, the median follow-up was 6.1 years and the maximum was 26.4 years; for patients aged 60 to 70 years, the median follow-up was 3.9 years and the maximum was 17.1 years; for patients older than 70 years, the median follow-up was 3.3 years and the maximum was 17.1 years ( = 0.0001).

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Figure 4.
Thrombosis-free survival by history of thrombosis at or before diagnosis of polycythemia vera.P

Patients at risk in the two groups at the beginning of each 3-year period and the number of thrombotic events (in parentheses) during each 3-year period are shown below the x-axis. For patients with no history of thrombosis, the median follow-up was 5.0 years and the maximum was 32.9 years. For patients with a history of thrombosis, the median follow-up was 3.5 years and the maximum was 17.3 years ( = 0.0001). No information was available for 28 patients.

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Figure 5.
Cancer-free survival by treatment for 1213 patients with polycythemia vera.P

Patients at risk in the two groups at the beginning of each 3-year period and the number of neoplastic deaths (in parentheses) during each 3-year period are shown below the x-axis ( = 0.05).

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Figure 6.
Kaplan-Meier survival analysis for death or major thrombosis, by type of treatment, for 1213 patients with polycythemia vera.P

Major nonfatal thrombosis and death from any cause are shown as a combined end point (event) according to treatment. Patients at risk in the four groups at the beginning of each 3-year period and the number of events (in parentheses) during each 3-year period are shown below the x-axis. For patients who did not receive chemotherapy, the median follow-up was 2.5 years and the maximum was 23.0 years. For patients who received alkylating myelosuppressive agents, the median follow-up was 6.5 years and the maximum was 27.7 years. For patients who received nonalkylating myelosuppressive agents, the median follow-up was 3.7 years and the maximum was 25.3 years. For patients who received both treatments, the median follow-up was 8.3 years and the maximum was 32.9 years ( = 0.10).

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