Elevated serum KL-6 concentration as an early detection biomarker of rituximab-related interstitial lung disease

Background: The rituximab-related interstitial lung disease (RTX-ILD) is a serious adverse event in rituximab treatment patients. Krebs Von den Lungen-6 (KL-6) is a glycoprotein, which was suggested to be associated with lung injury and repair. Studies have shown that KL-6 can be used as a diagnostic biomarker for a variety of interstitial lung diseases, while relevant researches are absent in RTX-ILD. Objectives: The purpose of this study was to evaluate the diagnostic value of serum KL-6 levels in detecting patients with RTX-ILD. Methods: 120 patients with non-Hodgkin's lymphoma treated with rituximab were enrolled from a single study center. The serum KL-6 was measured respectively before the 1st to 5th chemotherapy by the enzyme-linked immunosorbent assay (ELISA). Patients were divided into the non-ILD group (69 cases) and the RTX-ILD group (51 cases) according to follow-up results. The RTX-ILD group was further divided into four grades based on severity. Statistical analysis was performed using SPSS v26 and GraphPad Prism v9. Results: The serum KL-6 was similar between the non-ILD [176 (70–280) U/mL] and the RTX-ILD group [152 (73–280) U/mL] before chemotherapy, while it had dynamic change during the treatment regardless of the RTX-ILD occurrence. The serum KL-6 in the RTX-ILD group was significantly higher than that in the non-ILD group after chemotherapy. KL-6 was an effective means to identify RTX-ILD patients even after the first chemotherapy cycle [area under the curve (AUC) = 0.973, 95%CI 0.951–0.995, P  < 0.001]. Analysis of the serum KL-6 among different severity grades suggests that KL-6 may be inadequate as a marker for patient grading. Conclusions: Serum KL-6 can be an indicator of RTX-ILD occurrence and effectively identify patients at risk of RTX-ILD at the early stage of chemotherapy. The measurement of serum KL-6 during RTX treatment is beneficial to the early detection and active intervention of RTX-ILD. Strengths and limitations of this study This study comprehensively evaluated serum KL-6 as a marker for RTX-ILD, specifically demonstrating its potential for early risk stratification during chemotherapy. Due to limited sample size, this study was unable to establish an accurate threshold or confirm the correlation between KL-6 level and RTX-ILD severity.