Background: Hyperbilirubinemia, particularly severe hyperbilirubinemia, is uncommon in classical Hodgkin lymphoma (cHL) and is not incorporated into conventional prognostic scoring systems. Delivery of first-line chemotherapy is challenging because of concerns regarding altered hepatic metabolism and drug toxicity. These patients are under-represented in clinical trials, and evidence to guide management remains limited. We evaluated treatment approaches, hepatic recovery, and outcomes in patients with cHL presenting with baseline hyperbilirubinemia.
Methods: We retrospectively analysed patients with newly diagnosed cHL treated between January 2010 - December 2025 with baseline hyperbilirubinemia (total bilirubin >2 mg/dL), further stratified into mild (2–5 mg/dL), moderate (5.1–10 mg/dL), and severe (>10 mg/dL) hyperbilirubinemia. Clinical outcomes included normalization of liver function and event-free survival (EFS).
Results: Of 1541 patients treated during the study period, 50 (3.2%) had hyperbilirubinemia at presentation, of whom 28 (56%), 10 (20%), and 12 (24%) patients had mild, moderate, and severe hyperbilirubinemia, respectively. Corticosteroid bridging was used in 23 patients, predominantly in moderate/severe hyperbilirubinemia (p<0.001), only 3 patients achieved sufficient hepatic recovery to receive standard ABVD.
Following chemotherapy, liver function normalized in 67.9% and 80% of patients with mild and moderate hyperbilirubinemia, respectively. Median time to normalization was 12 and 100 days; only one patient with severe hyperbilirubinemia achieved normalization. The 2-year EFS was 78.4%, 75.0%, and 9.5% in patients with mild, moderate, and severe hyperbilirubinemia, respectively (log-rank p<0.001). On univariable analysis, severe hyperbilirubinemia (HR 8.4, p<0.001), non-cholestatic liver injury (HR 2.7, p=0.037) and persistent liver dysfunction (HR 23.4, p<0.001) were associated with inferior EFS. On multivariable analysis, only persistent liver dysfunction remained independently associated with inferior EFS (HR 30.5, 95% CI 4.6–204.8; p<0.001).
Conclusions: Severe hyperbilirubinemia identifies an ultra-high-risk subgroup of patients with cHL characterized by poor hepatic recovery and markedly inferior EFS. Persistent liver dysfunction following treatment initiation was the strongest predictor of adverse outcome. Prospective studies evaluating alternative therapeutic strategies for this rare and vulnerable population.
Yash Patel, Kavitha Lakshmi, Anu Korula, Vikram Mathews