Professor Pilsoo Sung's Team at Seoul St. Mary’s Hospital Proposes Personalized Prevention Strategies for Patients Receiving CD38 Antibody Therapy

The team led by Professor Pilsoo Sung of the Department of Gastroenterology at Seoul St. Mary's Hospital, Catholic University of Korea, announced on March 10 that they have systematically analyzed the incidence and risk stratification of hepatitis B virus (HBV) reactivation in patients with hematologic malignancy multiple myeloma who received anti-CD38 antibody therapy. Through this, they identified the existence of clinically significant high-risk subgroups among patients receiving the same anti-CD38 therapy.

Hepatitis B is a major infectious disease with approximately 257 million people chronically infected worldwide. According to the World Health Organization (WHO), about 1.1 million people die each year from hepatitis B-related complications. Even in individuals who are hepatitis B negative but have a history of past infection, latent virus can reactivate under immunosuppressive treatment, potentially leading to severe complications such as acute hepatitis, liver failure, and death. Previous studies have reported that about 20% to 30% of patients who developed severe hepatitis due to viral reactivation experienced liver-related mortality.

Professor Pilsoo Sung (left) and Clinical Instructor Kwon-yong Tak (right), Department of Gastroenterology, Seoul St. Mary's Hospital. Seoul St. Mary's Hospital

Currently, anti-CD38 antibodies are widely used as a core drug in the treatment of multiple myeloma, spanning from first-line therapy to relapsed/refractory stages. This therapy has played a significant role in improving patient prognosis and survival rates by enhancing treatment outcomes through its powerful immunomodulatory effects.

However, because CD38 is broadly expressed not only on myeloma cells but also on normal plasma cells and immune-regulatory cells, anti-CD38 therapy may disrupt the immune defense system against hepatitis B virus while exerting its antitumor effects. Nevertheless, due to a lack of clear evidence regarding the risk of viral reactivation, guidelines have not uniformly recommended prophylactic antiviral therapy, leaving a "gray area." Although there have been reports in the academic community of viral reactivation cases caused by this mechanism, real-world data proving the actual incidence and the effect of prophylactic antiviral therapy have been insufficient.

To address this, the research team conducted a retrospective cohort study on 180 patients (anti-HBc positive, HBsAg negative) with a history of hepatitis B exposure among 709 multiple myeloma patients who received anti-CD38 therapy between January 2015 and December 2025. The median follow-up period was 14.5 months; among these patients, 14 (7.8%) received prophylactic antiviral therapy, while 166 (92.2%) underwent periodic monitoring of viral markers and liver function testing every 1 to 3 months without prophylactic treatment.

Among the 166 patients who did not receive prophylactic therapy, hepatitis B reactivation was confirmed in 13 (7.8%). This rate falls within the moderate-risk category (1-10%) as defined by the European Association for the Study of the Liver (EASL) clinical guidelines, under which current recommendations do not uniformly advocate prophylactic antiviral administration for this group.

However, the research team hypothesized that the risk of reactivation would not be uniform even among patients receiving the same treatment, and performed multivariate analysis to identify independent risk factors within the non-prophylaxis group. As a result, two key predictors of reactivation were identified: baseline anti-HBs (antibody to hepatitis B surface antigen) levels below 100 IU/L, and initiation of therapy in the relapsed/refractory stage. By combining these two factors, patients were stratified into four subgroups for analysis. Notably, in the low-risk group, there were no cases of reactivation during the entire follow-up period, whereas in the high-risk group, about 19.6% experienced reactivation during the median follow-up of 10.6 months, with the 24-month cumulative incidence estimated to reach approximately 40%.

Importantly, this high-risk group is still classified as "moderate risk (<10%)" under the current EASL criteria and is excluded from prophylactic antiviral therapy recommendations. While the overall incidence appears moderate, the study highlights that within this category exist subgroups at genuinely high risk, meaning that patients who require preventive treatment may fall through the cracks if only the conventional uniform risk classification is applied. This is the core finding of the study.

The effectiveness of prophylactic antiviral therapy was also clearly demonstrated. Among the 14 patients who received prophylactic therapy, no reactivation events occurred, and both severe hepatitis and liver-related deaths were observed only in the non-prophylaxis group. Severe hepatitis was concentrated in the high-risk subgroup, and all liver-related deaths occurred exclusively in the high-risk group, underscoring that risk group identification and preventive treatment can avert fatal outcomes.

Clinical Instructor Kwon Yongtak, the first author, stated, "As anti-CD38 therapy is increasingly being adopted in earlier stages of hematologic cancer treatment, the risk assessment of hepatitis B reactivation must also become more precise. The risk stratification based on anti-HBs levels and treatment history can be directly applied in real-world clinical practice."

Professor Pilsoo Sung, who led the study, emphasized, "This research is significant because it is the first to present a clearly defined high-risk group, moving beyond the conventional perception of anti-CD38 therapy as simply 'moderate risk.' It provides clinical evidence that a selective prophylactic antiviral strategy can prevent liver failure and death."

Meanwhile, the research team plans to pursue multicenter studies to establish standardized preventive strategies for patients receiving anti-CD38 therapy. In particular, for the moderate-risk group in which sporadic reactivation was observed in this study, determining whether prophylactic antiviral therapy or enhanced monitoring is more effective remains a future task.

This study, which provided additional clinical opinions for the "Hepatitis B Reactivation" section in the recently revised European guidelines for the management of liver diseases, has been published in the Journal of Hepatology (IF 33.0), the world's leading journal in the field of liver diseases.

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