Abstract
Introduction
Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are widely used in the treatment of renal cell carcinoma (RCC). While both therapies have demonstrated efficacy, emerging case reports suggest an association between TKI use and secondary polycythemia. However, large-scale, real-world data on the incidence of TKI-associated polycythemia and its potential impact on survival remain limited. This study aims to evaluate the risk of polycythemia in RCC patients treated with TKIs (alone or in combination with ICIs) compared to ICIs alone and to assess how baseline hemoglobin (Hb) levels influence survival outcomes.
Methods
A retrospective cohort study was conducted using the TriNetX database, including patients aged ≥18 years diagnosed with RCC between 2010 and 2024. A total of 8,049 patients treated with TKIs (alone or in combination with ICIs) were compared to 5,377 patients treated with ICIs alone. Propensity score matching was used to control for sex, baseline Hb and hematocrit (Hct), and major comorbidities. Patients were stratified based on sex for the diagnosis of polycythemia, defined by ICD-10 code or a Hb ≥ 16 g/dL for females and ≥ 16.5 for males. For survival, patients were stratified into four baseline Hb categories: <10, 10–12, 12–15, and ≥15 g/dL. Polycythemia development within 3 months of TKI treatment was assessed using risk differences, chi-square tests, and Kaplan-Meier analysis. Overall survival was evaluated using Kaplan-Meier curves and hazard ratios with 95% CIs, while baseline and post-treatment Hb and Hct were compared using t-tests.
Results
Among females, there was a significantly higher risk of developing polycythemia in the TKI group (6.3% vs. 0.74%, p < 0.0001, RD = 5.5%, 95% CI: 4.1%–6.9%). The risk of developing polycythemia among males was also higher in the TKI group (2.6% vs. 0.82%, p < 0.0001, RD = 1.8%, 95% CI: 1.04%–2.5%). These results represent a hazard ratio (HR) for polycythemia of 9.6 in women (95% CI: 4.6-19.1, p < 0.0001) and 3.1 in men (95% CI: 1.9-5.1, p < 0.0001). There was a small but statistically significant increase in Hb (12 to 12.4 g/dL, p < 0.0001) and Hct (36.6 to 37.6, p < 0.0001) in the TKI group, regardless of sex. Among patients with baseline Hb < 10 g/dL, there was no significant difference in overall survival between those treated with TKI and those treated with ICI alone (9% survival vs. 20.4%, median survival: 189 days vs. 152 days, p = 0.9507, HR = 1.01, 95% CI: 0.85 –1.2). In patients with baseline Hb between 10–12 g/dL, TKI treatment was associated with a modest but statistically significant reduction in overall survival based on Kaplan-Meier analysis, but lower median survival time (30.8% vs 26.4%, 535 days vs. 921 days, p = 0.0383, HR = 1.3, 95% CI: 1.01–1.6). However, in patients with baseline Hb between 12–15 g/dL, TKI treatment was associated with significantly worse survival compared to ICI alone (29% vs 44%, 1576 days vs. 2528 days, p < 0.0001, HR = 1.7, 95% CI: 1.5–2.0). Among patients with baseline Hb ≥ 15 g/dL, survival appeared lower in the TKI group, but this difference was not statistically significant (34.3% vs 73.4%, 3144 days vs. NR, p = 0.1163, HR = 1.5, 95% CI: 0.90–2.5).
Conclusions
Treatment with TKIs in patients with RCC is associated with a significantly increased risk of developing secondary polycythemia. Patients with a normal to elevated baseline hemoglobin (≥ 12 g/dL) experienced worse survival with TKI therapy compared to ICI treatment alone. The most pronounced difference was seen in the 12-15 g/dL group. While the ≥ 15 g/dL group did not reach statistical significance, the trend was also towards reduced survival. These findings suggest that higher baseline hemoglobin may indicate increase vulnerability to adverse outcomes with TKI use. Further research is needed to confirm these results and guide safer treatment selection.
