Brandon Wood, Sri Tummala, Dharani Rohit Thota, Senthil Sambandam
Background/Objectives: Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, predominantly affects the aging population. With improved survival from modern targeted therapies, a growing number of CLL patients are living long enough to become candidates for quality-of-life-improving procedures such as elective total knee arthroplasty (TKA). However, the impact of CLL on postoperative outcomes remains poorly understood. Methods: A retrospective cohort analysis was performed using the TriNetX Research Network. Adult patients who underwent primary TKA were identified and divided into two cohorts. CLL and non-CLL control, and 1:1 propensity score matching was performed on demographics and comorbidities. Medical complications were assessed at 30 and 90 days, and implant-related complications at 1 and 3 years postoperatively. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Within the CLL cohort, a Cox proportional hazards model was used to identify preoperative laboratory values, medications, and comorbid diagnoses associated with complication development. Results: After matching, 2054 patients, 1027 per cohort, were analyzed. Patients with CLL demonstrated significantly higher risks of postoperative pain at both 30 days (p < 0.001) and 90 days (p < 0.001), as well as transfusion (p = 0.035) and acute kidney injury (p = 0.036) at 90 days. At 1 year, the CLL cohort had elevated risks of periprosthetic joint infection (PJI; p = 0.015) and arthrofibrosis (p = 0.036), and these differences persisted at 3 years (PJI p = 0.033; arthrofibrosis p = 0.006). In the hazards model, preoperative hemoglobin < 8 g/dL (HR: 1.75, 95% CI: 1.27-2.41, p < 0.001), long-term anticoagulant or antiplatelet use (HR: 1.43, 95% CI: 1.13-1.80, p = 0.003), chronic kidney disease (CKD; HR: 1.28, 95% CI: 1.04-1.58, p = 0.021), and overweight/obesity (HR: 1.23, 95% CI: 1.00-1.50, p = 0.047) were independently associated with short-term complications. Chronic opioid use was found to be associated with an increased risk of long-term complications (HR: 2.80, 95% CI: 1.49-5.24, p = 0.001). Conclusions: Patients with CLL undergoing TKA had higher observed risks of both early medical and late implant-related complications. These findings may reflect the combined effects of CLL-related immune dysfunction, cytopenias, and chronic systemic inflammation, which may impair wound healing, reduce physiologic reserve, and blunt infection clearance. Identification of associated, modifiable preoperative risk factors-anemia, anticoagulant exposure, CKD, obesity, and chronic opioid use-may provide actionable targets for optimization and risk stratification.