Development and Validation of Pretreatment Serum Total Bilirubin as a Biomarker to Predict the Clinical Outcomes in Primary Central Nervous System Lymphoma: A Multicenter Cohort Study

SIMPLE SUMMARY: The prognosis of patients with primary central nervous system lymphoma (PCNSL) is poor due to the high recurrence rate and lack of consensus on the optimal treatment for refractory or relapsed diseases. Despite having good prognostic scores, such as an MSKCC score or IELSG score, none of them are able to fully explain the clinical outcomes of patients with PCNSL, and they are complicated at the same time. Thus, there is an urgent need to develop simple and readily available parameters that help to stratify the prognosis of patients, especially those at high risk, and provide them with appropriate treatment measures. For the first time, this study identified that pretreatment serum total bilirubin (STB) could predict the prognosis of patients with PCNSL receiving high-dose methotrexate-based combination immunochemotherapy. The results from this study demonstrate that STB is a simple, cost-effective prognostic biomarker that clinicians can apply easily and quickly into routine practice. ABSTRACT: Primary central nervous system lymphoma (PCNSL) is a predominantly aggressive neoplasm isolated to the central nervous system or vitreoretinal space. Bilirubin is an important biomarker reflecting hepatic function and oxidative stress status that is associated with the occurrence and development of various tumors. However, its prognostic role in PCNSL has yet to be evaluated. Therefore, we conducted a prospective–retrospective study to analyze the predictive value of serum total bilirubin (STB) in PCNSL patients. The association between the pretreatment STB and clinical outcomes in PCNSL was developed in the discovery cohort (retrospective [n = 44] and prospective [n = 45]) and validated in an independent retrospective cohort (n = 69). A generalized additive model, Kaplan–Meier curve, and Cox analysis were applied. In the discovery cohort, the STB showed a linear relationship with overall survival (OS, p = 0.011) and progression-free survival (PFS, p = 0.0476). The median STB level of 12.0 µmol/L was determined as the cutoff value to predict the clinical outcomes with area under the receiver operating characteristic curve (AUROC) values of 0.9205 and 0.8464 for OS and PFS, respectively. The median STB level resulted in similar accuracy for predicting the clinical outcomes in the validation cohort with AUROC values of 0.8857 and 0.8589 for OS and PFS, respectively. In both the discovery and validation cohorts, the Kaplan–Meier survival curve and Cox regression analysis showed that the upper median STB groups showed significantly worse OS than the lower median STB groups. In conclusion, the pretreatment STB could be considered a novel biomarker to predict the clinical outcomes in patients with PCNSL receiving high-dose methotrexate-based combination immunochemotherapy.