Recently, a multi-center research team led by Professor Xiaoxia Hu (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine), Professor Yang Cao (Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), and Professor Yanmin Zhao (The First Affiliated Hospital, Zhejiang University School of Medicine) jointly published an article titled “Epstein-Barr virus infection following allogeneic hematopoietic stem cell transplantation in the era of letermovir for cytomegalovirus prophylaxis” in Experimental Hematology & Oncology. The study found that although letermovir significantly reduces CMV infection incidence, its use is closely associated with increased risk of PTLD post-transplant. This may be due to impaired early immune reconstitution of CD8+ T cells, thereby affecting the host’s ability to control EBV reactivation.Background
EBV reactivation occurs in 19.6%–65.0% of allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients and is closely related to post-transplant lymphoproliferative disease (PTLD). Letermovir is effective in reducing CMV reactivation, but its impact on EBV infection remains unclear. To address this, the team conducted a multi-center retrospective study to evaluate the relationship between letermovir prophylaxis and EBV reactivation.
Study Findings
Among 706 allo-HCT recipients, 565 met the inclusion criteria. Patients were divided into a letermovir group (n=284) and a control group (n=281) based on whether they received letermovir. The median duration of letermovir use was 100 days (range: 54–327 days). Compared with the control group, letermovir significantly reduced the 1-year cumulative incidence of clinically significant CMV infection (cs-CMVi) (25.5% vs. 69.0%, P<0.0001), and delayed its onset (median time [range]: 104 [14–336] vs. 39 [13–330] days, P<0.0001). However, there was no significant difference between the two groups in the 1-year cumulative incidence of EBV DNAemia (58.1% vs. 52.7%, P=0.3) or EBV disease (6.29% vs. 5.46%, P=0.96). All patients with EBV disease (n=21) or PTLD (14 confirmed, 15 suspected) had prior EBV DNAemia. Notably, the 1-year cumulative incidence of PTLD was significantly higher in the letermovir group than in the control group (7.39% vs. 1.80%, P=0.00059). Multivariate Cox regression analysis identified an HCT-CI score ≥3, prior EBV DNAemia, and letermovir use as significant risk factors for PTLD.
To explore whether letermovir affects post-transplant immune reconstitution (IR), the study measured IFN-γ release from peripheral blood mononuclear cells (PBMCs) in 83 patients from the letermovir group to assess antiviral capacity. Results showed that IFN-γ peaks occurred earlier in patients with EBV DNAemia or EBV disease, but remained impaired in PTLD patients. Partial least squares discriminant analysis (PLS-DA) revealed that PTLD patients had distinct lymphocyte reconstitution patterns, especially marked delay in CD8+ T cell recovery. IR dynamics were similar between patients with EBV DNAemia and those with EBV disease; due to the small number of EBV disease cases (n=4), the two groups were analyzed together.
PTLD patients lacked early recovery of naïve CD8+ T cells (TN) within the first 3 months post-transplant. By month 2, frequencies of central memory (TCM) and effector memory (TEM) CD8+ T cells were similar across groups, but PTLD patients had significantly fewer terminally differentiated effector memory T cells (TEMRA). The study speculates that letermovir may hinder CD8+ T cell recovery in patients with poor immune reconstitution capacity, leading to severe EBV infection (i.e., EBV-PTLD).
As expected, letermovir prophylaxis significantly altered immune reconstitution profiles. The impact on immune reconstitution increased with EBV infection severity: No EBV infection < EBV DNAemia/disease < PTLD. Multiple CD8+ T cell subsets also showed delayed recovery. While CD8+ T cell frequencies were similar in the first month post-transplant, marked recovery impairment was observed in months 2 and 3 in the letermovir group.
Key Findings
Letermovir suppresses early recovery of CD8+ T cells. PTLD patients showed a marked reduction in CD8+ TEMRA cells, a subset with limited proliferative capacity but potent cytotoxic and pro-inflammatory activity. Previous studies have indicated that CD27⁺ EBV-specific cytotoxic CD8+ T cells play a critical role in controlling EBV. This study also observed impaired recovery of two CD27-expressing T cell subsets (CD8⁺ TN and TCM) prior to disease onset in letermovir-associated PTLD patients. Normally, exposure to viral antigens can trigger the activation of TN cells into effector T cells through both TCR-dependent and TCR-independent mechanisms. Therefore, letermovir may impair EBV DNAemia control and increase PTLD risk by inhibiting early reconstruction and differentiation of CD8+ TN cells.
Conclusion
Letermovir prophylaxis is closely associated with a higher incidence of PTLD after allo-HCT. This study highlights the importance of early CD8+ T cell recovery, which may serve as a predictive marker for EBV-related clinical outcomes in the letermovir era. Although this was a retrospective study and did not fully clarify the underlying mechanisms, it underscores the need for future prospective cohort and translational studies to further investigate the relationship between letermovir and EBV infection.
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- Chief Physician, PhD, Doctoral Supervisor, Translational Medicine Center, Ruijin Hospital
- Specializes in basic and clinical research on hematopoietic stem cell transplantation
- Member, 6th Hematologic Oncology Committee, Chinese Anti-Cancer Association
- Member, Hematological Physiology Committee, Chinese Society for Physiology
- Recognized as Outstanding Young Medical Talent of Shanghai
- Named Excellent Academic Leader in the Shanghai Health System
- Honored as Outstanding Young Talent in the Shanghai Health System
- First or corresponding author of over 40 publications in journals such as Blood, JCI, Leukemia, BCJ, JCI Insight, and AJH
- Second contributor to a project awarded the First Prize of Shanghai Science and Technology Progress Award
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Associate Professor and Chief Physician, Department of Hematology, Tongji Hospital
- Member, Leukemia and Lymphoma Group, Hematology Branch, Chinese Medical Association
- Secretary, T-cell Transplantation and Cellular Immunotherapy Group, Hematology Committee, Chinese Anti-Cancer Association
- Deputy Chair, Youth Committee of Hematologic Oncology, Hubei Anti-Cancer Association
- Secretary, T-cell Transplantation and Cellular Immunotherapy Group, Hubei Anti-Cancer Association
- Specializes in basic and clinical research on hematopoietic stem cell transplantation and cellular immunotherapy
- Principal investigator of projects funded by the National Natural Science Foundation of China (NSFC), including general and youth programs, as well as the Ministry of Education’s fund for new faculty in key disciplines
- Participant in multiple national research programs, including the 973 Program, 863 Program, and key NSFC projects
- Published over 20 research articles in the field, including numerous first-author and corresponding-author papers in international SCI journals such as The Journal of Experimental Medicine (JEM)
The First Affiliated Hospital, Zhejiang University School of Medicine
- MD, Chief Physician, Doctoral Supervisor, and Distinguished Research Fellow
- Deputy Director, Hematology and Bone Marrow Transplantation Center
- Youth Member, Hematologic Oncology Committee, Chinese Anti-Cancer Association
- Member, Hematopoietic Stem Cell Transplantation and Cellular Therapy Committee, Chinese Association of Medical Education
- Deputy Chair, Youth Committee of the Hematology Branch, Zhejiang Medical Association
- Outstanding Young Scholar, Zhejiang Immunological Society
- Secretary, Clinical Trial Hematology Group, The First Affiliated Hospital of Zhejiang University
- Recognized Talent under Zhejiang Province’s “551 Talent Program” for high-level healthcare professionals
- Principal investigator of one Youth Project and three General Projects funded by the National Natural Science Foundation of China (NSFC); key contributor to China’s National Key R&D Program
- Editorial board member of Cell Transplantation
- Published over 40 SCI papers as first or corresponding author in Journal of Hematology & Oncology, JAMA Network Open, and American Journal of Hematology
- Frequent invited speaker at international conferences such as ASH, EHA, EBMT, and APBMT
- Recipient of Zhejiang Provincial Science and Technology Progress First Prize (1st Class) and National Science and Technology Progress Award (2nd Class) as a core contributor
