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

Abstract

H ydroxyurea 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 followup 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.

Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications

“…Treatments no longer in general use such as 32 P and pipobroman induce a well-established increased risk of AML [ 17 , 31 ]. The same applies to busulfan and other alkylating drugs, whereas there is ongoing controversy over whether hydroxyurea may also contribute to this increased risk [ 15 , 21 , 32 ]. Recent studies also suggest that risks of solid cancer or lymphoid malignancies may be associated with MPN treatment.…”

From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms

“…Although surrogates for thrombosis may be helpful, prior landmark studies 12,31,74 have proved that thrombosis reduction is a feasible endpoint, and a recent meta-analysis provides risk estimates that will be useful for sample size calculation. 5 Future treatment strategies targeting inflammation and abnormal adhesion may reduce recurrent thrombosis, which remains a problem, especially for those with SVT and MF. Management of SVT and other special situations remains largely empirical and consensus based.…”

“…The former was highlighted in a metaanalysis of 3236 patients treated with hydroxyurea (HU) in which thrombosis rates were 1.9%, 3.6%, and 6.8% at median ages of 60, 70, and 80, respectively. 5 Statistical associations between cardiovascular (CV) risk factors and MPN thrombosis have been inconsistent in ET. [6][7][8][9] Although CV factors are not included in PV risk classification, low-risk patients with PV with hypertension had a thrombosis-free survival of 34% compared with 66% of those without hypertension (P 5 .025).…”

Impact of platelets on major thrombosis in patients with a normal white blood cell count in essential thrombocythemia

“…Pathogenesis of thrombosis in myeloproliferative neoplasms is considered very complex and not fully elucidated 3 . In addition to the traditional risk factors, advanced age and past history of thrombosis, 4 the mutational profile, 5 inflammation, 3 novel mechanisms including abnormal cell adhesion and formation of neutrophil extracellular traps, 6 blood cell counts are also supposed to contribute significantly to the thrombotic risk in MPNs 3 . A recent meta‐analysis including more than 30 000 patients reported an association between leukocytosis and thrombosis in ET 7 .…”