Background: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) driven primarily by JAK2V617F and is associated with an excess risk of thrombosis and progression to myelofibrosis (MF) and acute leukemia (AML). Advances in treatment of PV and earlier diagnosis has reduced fatal thrombotic events, but with longer thrombosis-free survival, the natural progression to MF is an increasingly common cause of morbidity. More than 50% of PV patients (pts) have MF after 30 years from diagnosis, independent of age, making this a particularly important issue for young pts1. Because of disease chronicity, short-term monitoring biomarkers are needed to dynamically predict risk of disease progression on the long-term and allow appropriate implementation and modification of therapy. Whole blood (WB) JAK2V617F allele frequency (MAF) is frequently measured in clinical trials to assess molecular response to treatment, yet no study has established whether serial changes in MAF are predictive of progression. Despite limitations of WB MAF monitoring 2, the readily accessible WB samples and feasibility of testing, along with the need for a clinical biomarker in PV, merits a study to determine whether MAF change correlates with disease progression.

Objective & Methods: We conducted a systematic review and meta-analysis to examine the correlation of molecular response with thrombosis or progression to MF and AML in PV pts. We searched the main scholarly engines: Pubmed, Scopus and Embase for "Polycythemia vera" and terms including "JAK2V617F" and "molecular response". Title and abstracts were screened by 2 reviewers independently based on predefined criteria and selected for full-text review if criteria are met or further information was required. Studies were included if they reported serial MAF measurements in PV patients, and excluded for other JAK2V617F MPNs or lack of serial MAF assessment. Pearson correlation analysis was conducted on the subset of studies that reported rates of thrombosis, MF and or AML to determine the correlation of MAF reduction with clinical outcomes.

Results: The search resulted in 563 abstracts to screen. A total of 59 studies were selected for full-text review and ultimately only 20 studies met inclusion criteria where MAF was serially assessed in PV patients. In all studies, MAF was monitored on cytoreductive therapy, and these included 12 on interferon (IFN), 8 on hydroxyurea (HU), and 2 on ruxolitinib (RUX). The median follow-up times were between 16-116 months. In most studies (n=18, 90%), there was an overall decrease in MAF on cytoreductive treatment (Figure 1). There was a poor correlation between molecular response rates and hematological response rates (n=11 studies, r2=0.20). Of the 20 studies, only 7 reported clinical outcomes of thrombosis and/or progression: 2 were prospective and 5 were retrospective. In our analysis, MAF reduction correlated with decreased rates of MF (n = 7 studies, r2=0.69) (Figure 2), irrespective of treatment (IFN: r2 =0.83, HU: r2 =0.72), but results were not statistically significant (p=0.08). On the other hand, there was no correlation between MAF reduction and progression to AML (n= 3 studies, r2=0.17), or the incidence of thrombotic events (n = 6 studies, r2=0.15), but fewer studies reported these outcomes.

Discussion: This systematic review highlights the lack of high-level evidence available to determine if molecular response in PV is associated with reduced risk of progression. The correlation observed between MAF reduction and MF rates requires validation in larger, ideally prospective studies. Until then, reduction in WB MAF should not be the determinant of a treatment's long-term likelihood of success. Alternative biomarkers are needed to capture the biology of malignant MPN stem cells and better predict the long-term outcomes of patients with PV.

References: 1. Abu-Zeinah G, et al. Leukemia 2021

2. Abu-Zeinah G, et al. Blood Advances. 2022.

3. Senín A, et al. Annals of Hematology. 2018.

Scandura:European Leukemia net: Honoraria, Other: Travel fees; CR&T: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MPN-RF: Research Funding; Sumitomo Pharma Oncology, Inc: Consultancy; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Research Funding.

Author notes

Asterisk with author names denotes non-ASH members.

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