Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis

Abstract

Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.

Figure 1.

Study flowchart.

Figure 2.

Forest plot of outcomes incidences. The incidence is not graphed for Mesa et al. since its very large Confidence Interval could not fit in the plot, but is accounted for in global estimates. Size of markers annotates study sample size. MF: myelofibrosis; AML: acute myeloid leukemia.

Figure 3.

Outcomes incidence during follow up according to logistic Generalized Linear Mixed Model (GLMM) and comparison with negative-binomial model. Dashed lines are 95% Confidence Interval (CI), observed frequencies are plotted in hollow circles of size proportional to sample size in person/years. ICC (Intracluster Correlation Coefficients) and P-values of Likelihood Ratio Tests of random slopes are reported. Thrombosis (A). Mortality (B). Myelofibrosis (C). Acute myeloid leukemia (D).