Abstract 1971: Lymphocyte kinetics, frailty and survival outcomes in HNSCC
Authors: Kut Carmen , McNutt Todd , Fakhry Carole , DeWeese Theodore , Quon Harry 
Published: June 2022

Abstract
Lymphopenia is associated with decreased survival outcomes in head and neck squamous cell carcinoma (HNSCC). This is a significant concern especially for frail individuals who are more vulnerable to immunological dysregulations. A robust analysis is needed to understand whether we should expend efforts to limit treatment-related hematological toxicities in HNSCC.
First, we would like to understand the prognostic significance for baseline (BL) vs. treatment-related lymphopenia (TRL). We want to know if lymphopenia is merely a reflection of the patient’s frailty at baseline, or if this is iatrogenic and therefore can be a target for treatment modifications in a bid to improve survival. Here, we identified 222 newly diagnosed M0 HNSCC patients treated with radiation ± systemic therapy in 2015-2018 at our institution. Clinical frailty is defined by age ≥ 65 or KPS ≤ 70. Using Kaplan Meier estimates and Cox regression with dichotomous variables, we performed multivariate analysis for both overall survival (OS) and progression-free survival (PFS). Important predictors included frailty (p ≤ 0.002) and ≥ 2K/mm3 decrease in absolute lymphocyte counts (ALC) (p ≤ 0.006). BL did not significantly impact OS or PFS (p ≤ 0.37). For TRL, ALC decrease had greater prognostic significance compared with ALC nadirs (p ≤ 0.45).
Next, we simplified our survival model to include only frailty and TRL. Overall, fit patients with modest ALC decline (&lt; 2K/mm3) achieved excellent survival outcomes while frail patients with severe ALC decline (≥ 2K/mm3) had inferior outcomes (3-year OS 95% vs. 56%, p &lt; 0.0001; 3-year PFS 84% vs. 42%, p = 0.002). On subgroup analyses, similar outcomes were also identified for HPV+ HNSCC (n = 172, 3-year OS 96% vs. 71%, p = 0.002; 3-year PFS 89% vs. 54% p = 0.03).
Finally, we want to know if ALC decline is determined primarily by treatment intensity, or if frail patients are naturally predisposed to greater ALC decline during treatment. In our data, frail patients had more modest ALC decline when compared to fit patients (1.26 ± 0.57 vs. 1.54 ± 0.58 K/mm3 p = 0.0006). In our survival model, we did not observe any first-order interactions between frailty and ALC decline (p = 0.54). The extent of ALC decline was also higher for patients with concurrent administrations of cisplatin (as opposed to radiation alone, p &lt; 0.0001). Thus, we postulate that the extent of ALC decline is determined primarily by treatment intensity. It is possible that frail patients with severe ALC decline have inferior survival outcomes because they cannot maintain immunological balance and respond poorly when there is significant TRL. This opens opportunities to re-evaluate if the risk of TRL is modifiable by limiting the number of concurrent cycles of chemotherapy administered, and by considering radiation dose de-intensification especially for HPV-associated HNSCC. Lastly, TRL becomes an important consideration when immunotherapeutics are grafted onto existing CRT treatment paradigms.
Citation Format: Carmen Kut, Todd McNutt, Carole Fakhry, Theodore DeWeese, Harry Quon. Lymphocyte kinetics, frailty and survival outcomes in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1971.