Targeted Therapy-Induced Erythrocytosis in Thyroid Cancers: An Underrecognized Safety Signal from a Retrospective Study

Background: Antiangiogenic and targeted therapies represent the most effective systemic options for advanced thyroid cancers. In this setting, toxicity management is essential to ensure treatment adherence. Among hematological toxicities, erythrocytosis has been rarely investigated, and its clinical pattern and management remain unclear. Materials and Methods: We conducted a retrospective cohort study including patients with any advanced thyroid cancer histology treated with antiangiogenic or targeted therapies between 2012 and 2023 at two Italian referral centers. Therapies included RET inhibitors ( RET i: selpercatinib, pralsetinib), cabozantinib, the BRAF / MEK inhibitor combination dabrafenib + trametinib, lenvatinib, sorafenib, and vandetanib. Erythrocytosis, defined according to 2022 World Health Organization criteria, was assessed through serial hemoglobin and hematocrit measurements up to 36 months from treatment start. Associations with clinical variables, event-free survival (EFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and acute vascular events were assessed using Fisher’s exact and regression models, as appropriate. Results: Among 173 screened patients, 135 were included in the final analysis (median follow-up 68.5 months). Erythrocytosis occurred in 24 patients (17.8%), with 16/24 (66.6%) experiencing recurrent events (total: 50). Median time to onset was 1.28 months (Q1–Q3: 0.76–5.14). RET i showed the highest incidence (46.7%), followed by vandetanib (20.7%). Among 14/24 tested patients, no JAK2 V617F or exon 12 alterations were detected. Management involved temporary treatment interruption in 60.0% (30/50) of events, with 53.3% (16/30) resuming at a reduced dose; in selected cases (4/9, 44.4%), hematology-guided phlebotomy was performed without drug discontinuation. Erythrocytosis was not associated with EFS, OS, or ORR, but was associated with higher DCR ( p = 0.031). Incidence of acute vascular events was comparable among patients with (8.3%) and without (14.4%) erythrocytosis. Conclusions: Erythrocytosis represents an underrecognized, early, recurrent, and indolent adverse event of antiangiogenic and targeted therapies, particularly RET i, in advanced thyroid cancer. Its biological mechanisms and optimal management strategies warrant further investigation.