Necessity of neutrophil-to-lymphocyte ratio monitoring for hypothyroidism using nivolumab in patients with cancer

BACKGROUND: Low neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a favorable therapeutic response to nivolumab. The activation of immunocompetent cells such as lymphocytes exhibits an antitumor effect; however, the development of excessive immune responses in autologous organs along with the breakdown of self-tolerance causes immune-related adverse events, including hypothyroidism. Therefore, the possibility that NLR is associated with immune response shows that NLR can be not only a predictive factor for good response to nivolumab but also a predictive factor for the development of hypothyroidism. AIM: To evaluate whether continuous NLR monitoring during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism. METHODS: This retrospective study comprised patients who received nivolumab for treating all types of cancer at our hospital between January 2015 and December 2019. The NLRs of patients were measured before each administration, and the patients were followed up till the administration of 12 doses. NLR at treatment initiation was compared between patients with and without hypothyroidism. Patients who developed hypothyroidism were categorized into three groups: those with NLR < 3.5, 3.5 to < 5, and ≥ 5 according to their maximum NLR from treatment initiation to hypothyroidism development. Further, the onset periods of hypothyroidism were compared between the groups. RESULTS: Overall, 104 patients were included in the analysis. Twenty-one patients developed hypothyroidism throughout the observation period. NLR at treatment initiation was significantly lower (2.54 ± 1.21 vs 4.58 ± 4.03; P = 0.017) in patients with hypothyroidism than in those without hypothyroidism, and patients with NLR < 5 had a significantly higher incidence of hypothyroidism than those with NLR ≥ 5 (26%: 20 of 78 patients vs 4%: 1 of 26 patients; P = 0.022). Additionally, treatment continuity in patients with hypothyroidism was significantly longer than in those without hypothyroidism (median not reached vs 7 times administration, P = 0.010). Patients with maximum NLR < 3.5 until the development of hypothyroidism had a significantly earlier onset of hypothyroidism than those with maximum NLR ≥ 5 (hazard ratio for low tertile [NLR < 3.5] vs high tertile [NLR ≥ 5]: 5.33, P = 0.011). CONCLUSION: Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.