Erythrocytosis in Advanced Thyroid Cancer Therapy: Emerging Safety Concerns with Targeted Agents

Highlight

• Erythrocytosis, an increase in red blood cell mass, occurs in approximately 17.8% of patients with advanced thyroid cancer treated with antiangiogenic and targeted therapies.
• RET inhibitors show the highest incidence of therapy-induced erythrocytosis, signaling a specific safety concern with these agents.
• The hematologic abnormality is typically early in onset, recurrent, and manageable without significantly affecting survival or increasing vascular complications.
• Current management includes dose adjustments and occasionally phlebotomy, but standardized guidelines are lacking.

Study Background

Thyroid cancers, especially in advanced stages, often require systemic treatments that target tumor angiogenesis and oncogenic pathways, including RET, BRAF, and VEGF pathways. Antiangiogenic and targeted therapies have transformed the management of progressive thyroid cancers. However, their associated toxicities can compromise treatment adherence and patient safety. While hematological toxicities like anemia and thrombocytopenia are commonly monitored, erythrocytosis remains underrecognized. Understanding this adverse event’s clinical behavior and implications is critical for optimizing patient outcomes and avoiding complications like thrombosis.

Study Design

This retrospective cohort study reviewed 173 patients treated for advanced thyroid cancers at two Italian referral centers between 2012 and 2023, with 135 patients meeting inclusion criteria. Histologies spanned differentiated, poorly differentiated, and medullary thyroid cancers. Treatments included RET inhibitors (selpercatinib, pralsetinib), multi-target tyrosine kinase inhibitors (cabozantinib, vandetanib, sorafenib, lenvatinib), and BRAF/MEK inhibitor combination (dabrafenib + trametinib). Patients were monitored with serial hemoglobin and hematocrit measurements up to 36 months to detect erythrocytosis, defined by 2022 WHO criteria. Clinical correlations examined event frequency, timing, genetic mutations (JAK2), treatment modifications, response rates, survival outcomes, and vascular events using appropriate statistical models.

Key Findings

Erythrocytosis occurred in 24/135 patients (17.8%) and was recurrent in 66.6% of cases. It typically emerged early with a median onset of 1.28 months post-therapy initiation. RET inhibitors demonstrated the highest erythrocytosis incidence at 46.7%, followed by vandetanib at 20.7%; other agents showed lower rates. In mutation testing of 14 patients, no JAK2 V617F or exon 12 mutations were found, excluding clonal myeloproliferative causes. Management mainly consisted of temporary treatment interruptions (60%) and dose reductions upon reintroduction (53.3%). In selective cases, phlebotomy guided by hematology was applied without discontinuing drugs. Importantly, erythrocytosis was not associated with decreased event-free or overall survival, nor with objective tumor response. It correlated with a significantly higher disease control rate (p=0.031). The incidence of acute vascular events was not increased among erythrocytosis patients (8.3% vs 14.4%), suggesting a benign clinical course in terms of thrombotic risk.

Expert Commentary

This study highlights erythrocytosis as an underrecognized yet clinically relevant adverse event during targeted thyroid cancer therapy, particularly with RET inhibitors. The early onset and recurrent nature suggest a direct pharmacologic or tumor microenvironment effect rather than secondary polycythemia vera-like clonal disorders, supported by the absence of JAK2 mutations. While it does not appear to compromise survival or increase thrombotic risk substantially, its association with higher disease control might imply a complex link with treatment efficacy or tumor biology, warranting mechanistic investigations. Current management strategies are empirical; standardized guidelines incorporating hematology consultation and individualized monitoring are needed. Limitations include the retrospective design and lack of prospective biomarker evaluation, underscoring the need for future prospective studies to clarify pathophysiology, optimize management, and confirm safety profiles.

Conclusion

Erythrocytosis induced by antiangiogenic and targeted therapies in advanced thyroid cancers is a noteworthy and frequent safety signal, especially related to RET inhibitors. Despite its indolent course and manageable nature, awareness among clinicians is essential for prompt recognition and appropriate intervention to maintain optimal therapy adherence and patient safety. Further research is required to unravel the biological underpinnings and establish evidence-based management protocols.

Funding and Clinical Trials

The retrospective nature of this study and data from institutional databases did not involve direct funding disclosures. Clinical trials assessing novel targeted agents in advanced thyroid cancers continue to monitor safety profiles including hematological adverse events in prospective settings.

References

1. Marchesi S, et al. Targeted Therapy-Induced Erythrocytosis in Thyroid Cancers: An Underrecognized Safety Signal from a Retrospective Study. Thyroid. 2026 Jun 24; PMID: 42342601.
2. Yu YA, Baek K, et al. Hematologic side effects of tyrosine kinase inhibitors in thyroid cancer. J Clin Endocrinol Metab. 2022;107(4):1020-1032.
3. World Health Organization. Hematology: Erythrocytosis and Polycythemia diagnosis criteria. 2022.
4. Fallah M, Sundquist K, et al. Risk of vascular events in polycythemia vera and primary myelofibrosis. Blood Cancer J. 2020;10(6):55.
5. Patel UD, Rixe O. Review of vascular toxicities of targeted therapies for solid tumors. Future Oncol. 2018;14(3):235-247.