Page 78 - 2019_12-Haematologica-web

A. Ferrari et al.
ribonucleotide reductase inhibitor considered non-muta- genic, or interferon-alfa (IFN) are appropriate first-line drugs to prevent vascular complications in high-risk patients (age >60 years and/or prior thrombosis).1
Hydroxyurea was recommended in the treatment of high-risk PV based on the results of the Polycythemia Vera Study Group (PVSG) protocol 08 in which this drug was found to be effective in reducing the rate of thrombotic events in 51 patients compared to historical controls treat- ed with PHL alone.2 Very few studies were designed to confirm these conclusions. Recently, a propensity score analysis of patients enrolled in the European Collaboration on Low-dose Aspirin in Polycythaemia Vera (ECLAP) trial documented superiority of HU in reducing thrombosis compared with well-matched control patients treated with PHL only.3 In three recent randomized con- trolled trials (RCT) in PV,4-6 HU was compared to IFN; unfortunately, the primary end point was not the reduc- tion of vascular complications but included only hemato- logic response that cannot be considered a surrogate of vascular events.7 The only demonstration of an antithrom- botic efficacy results from two RCT in essential thrombo- cythemia (ET) in which the drug was superior to chemotherapy-free and to anagrelide control arms.8,9 Therefore, the lack of a solid demonstration of thrombosis prevention or survival advantage in PV, and the concern that HU may increase the risk of leukemia led to this drug being under-used in clinical practice10 and to suggest that the first-line cytoreductive therapy in PV should be PHL only, irrespective of patient risk category.11
However, even in the absence of a clear demonstration of benefit, there is a consensus among European LeukemiaNet (ELN) and National Comprehensive Cancer Network (NCCN) experts of HU use in high-risk cases and the drug is currently the first-line therapy in clinical prac- tice. We have now several observational studies reporting single or multicenter experience regarding the risk-esti- mates of clinical events associated with HU. We, there- fore, considered it useful to provide a summary of these results in order to help clinical decision-making and to offer estimates for a more realistic sample calculation in future comparative clinical trials. Responding to the unmet need for such knowledge requires a huge input of energy and expertise in order to retrieve and analyze data. Based on these premises, we carried out a literature review aimed at systematically assessing and performing a meta-analysis of the incidence rate and absolute risk of events in patients treated with HU.
Methods
Inclusion criteria
The protocol of the original review was registered in PROS- PERO (n. CRD4201811781412).
Inclusion criteria were:
tional studies, editorials, and narrative reviews. Studies aimed specifically at HU-resistant patients were excluded.
In the case of duplicate studies on the same sample, the most numerous, or most informative, or most recent study was taken into consideration. Studies not reporting follow-up duration were excluded.
Search strategy
We searched for articles or abstracts published between 2008 and 2018 in the following databases: Medline, EMBASE, clinical- trials.gov, WHO International Clinical Trials Registry (for unpub- lished or ongoing trials), LILACS.
Terms used in research for primary end points were poly- cythemia vera and hydroxyurea/hydroxycarbamide and thrombo- sis and myelofibrosis. Research was focused on primary out- comes, although we also collected data on secondary outcomes (survival, leukemia, bleeding). Whenever possible, specific filters were used to exclude case reports, reviews, animal studies and studies on very young patients (aged < 18 years) or pregnant women. Conference abstracts and posters reporting relevant data were not excluded from consideration. Duplicate records were individually checked and merged using reference managing soft- ware.
Data extraction
The following data were extracted from selected studies: type of study, mean (or median) follow-up duration, number of HU treated patients in the study, incidence of myelofibrotic and/or leukemic transformations, number of patients with at least one incident or recurrent episode of thrombosis or one bleeding, mor- tality, median/mean age, gender of patients, number of patients with cardiovascular risk factors, number of patients with history of thrombosis, number of patients undergoing antiplatelet or anti- coagulant therapy. Whenever possible, the number of patients with major arterial or venous thrombosis was also extracted.
Quality assessment
Quality assessment of eligible studies was performed independ- ently by two reviewers (TB and AF) according to the Joanna Briggs Institute (JBI) critical appraisal tool for studies reporting prevalence data.13 The tool evaluates methodological quality of studies according to a 9-object scale accounting for representativeness of the sample, accuracy of reporting, adequacy of diagnostic criteria, and statistical analysis.
Statistical analysis
Incidence of each outcome was calculated and is reported as number of events per 100 persons/year. Forest plots show punctu- al estimates with exact binomial 95% confidence intervals for each study and globally. Persons/year were estimated by multiply- ing mean follow-up duration by number of HU-treated patients; when mean follow-up duration was not available, median dura- tion was deemed to be a reasonable approximation.
In order to obtain global adjusted incidence estimates, a logistic Generalized Linear Mixed Model (GLMM) was used for meta- regression of outcomes on study-specific confounders. The model included follow-up duration and known risk factors for the out- come as fixed effects; the random component of the model includ- ed a random slope for follow-up duration in studies. The method assumes that probability of displaying the event at time zero is the same across the studies, but it increases as a function of follow-up duration at a study-specific rate under the effect of selected co- variates. The advantage of this model is that it uses an exact bino- mial likelihood and error structure, and naturally accounts for het- erogeneity in sample sizes.14-16 For meta-regression, missing data
1) studies in English language published in the period 2008-2018 using WHO diagnostic criteria for PV;
2) studies on adult (aged ≥18 years) non-pregnant patients;
3) RCT, prospective and retrospective cohort studies reporting frequency of outcomes of interests (thrombotic and/or hemor- rhagic events and/or hematologic transformations in adult patients) stratified by HU therapy, as reported by authors;
4) studies with at least 20 participants.
The following studies were excluded: case reports, cross-sec-
2392
haematologica | 2019; 104(12)