On August 22–23, 2025, the 13th Lu Daopei Hematology Conference was held in Beijing, jointly organized by the Beijing Health Promotion Association and the Guangzhou Kapok Oncology and Rare Disease Foundation, and hosted by the Beijing Lu Daopei Hematology Institute. The conference brought together leading hematology experts from around the world, focusing on core topics such as hematopoietic stem cell transplantation, cellular therapy, and precision treatment of hematologic malignancies. With over a thousand attendees, the meeting provided a high-level and in-depth academic exchange. During the conference, Professor Jiong Hu from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, delivered an insightful lecture on “Cytomegalovirus (CMV) Infection Following Allogeneic Hematopoietic Stem Cell Transplantation.” Oncology Frontier – Hematology News has compiled and summarized the academic highlights of his presentation to provide practical guidance and theoretical reference for optimizing transplant management.I. Overview of Post-Transplant Viral Infections
Viral infections are among the most common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remain a major cause of infection-related mortality. Frequently encountered viral infections include members of the herpesvirus family such as cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpesvirus-6/8 (HHV6/HHV8), herpes simplex virus (HSV), and varicella-zoster virus (VZV). Other pathogens include adenovirus, respiratory viruses, polyomaviruses (e.g., JC virus, BK virus), and hepatitis viruses. Among these, CMV infection, due to its high incidence and potentially severe consequences, is a major clinical concern.
The occurrence of viral infections is closely linked to impaired immune function. Key risk factors include immunoablation during conditioning and delayed immune reconstitution, the use of immunosuppressants for graft-versus-host disease (GVHD) prevention or treatment, and patients’ preexisting viral infection status.
Infections also follow a time-dependent pattern: before engraftment, bacterial and fungal infections predominate; during engraftment, Pneumocystis, fungal, and viral infections are common; after engraftment, chronic GVHD, viral reactivation (such as CMV or respiratory viruses), and acute GVHD are more frequent. This evolving infection profile can be clearly illustrated along the “days post-HSCT” timeline.
II. Clinical Features and Risk Factors of Cytomegalovirus Infection
01 Definition and Incidence
CMV reactivation refers to detectable viral DNA replication in blood samples, with an incidence of 30%–80%. CMV disease refers to tissue-invasive infection involving organs such as the lungs, gastrointestinal tract, retina, or central nervous system, with an incidence of 10%–40%. Both reactivation and overt CMV disease significantly increase non-relapse mortality (NRM) and adversely affect post-transplant survival.
Patients’ immune status after transplantation undergoes dynamic changes, including neutropenia, lymphopenia, and hypogammaglobulinemia. These states, combined with additional risk factors such as mucositis, hepatic veno-occlusive disease (VOD), central venous catheterization, idiopathic pneumonia, acute or chronic GVHD, and co-infections with pathogens like HSV, VZV, EBV, Candida, adenovirus, Aspergillus, Gram-positive/negative bacteria, encapsulated bacteria, or Pneumocystis, collectively elevate the risk of CMV infection.
Risk levels vary across populations. Among allo-HSCT recipients, CMV-seropositive patients face higher risks than seronegative patients. Autologous transplant recipients with seropositivity are at relatively lower risk. Additional high-risk groups include solid organ transplant recipients, patients with immunodeficiencies, individuals with active HIV infection (though those on antiretroviral therapy have lower risk), ICU patients, dialysis patients, neonates, very low birth-weight infants, patients with hematologic malignancies, and those with congenital CMV infection.
02 Immune-Related Risk Factors
Immune status is the central determinant of CMV infection risk. Umbilical cord blood transplant recipients face markedly delayed immune reconstitution, which substantially increases infection risk. In GVHD prophylaxis, unrelated or haploidentical donor transplantation or the use of anti-thymocyte globulin (ATG) increases the likelihood of infection. During GVHD treatment, the use of high-dose corticosteroids or potent immunosuppressants further compromises host defense. Donor–recipient mismatch also plays a critical role: in donor-negative/recipient-positive (D–/R+) cases, delayed CMV-specific immune reconstitution increases both reactivation rates and viral loads, thereby raising the risk of CMV disease.
Patients are stratified into high- or low-risk categories for monitoring. High-risk populations include cord blood transplant recipients, haploidentical transplant recipients, HLA-mismatched transplants, T-cell-depleted transplants, and patients receiving ≥1 mg/kg corticosteroids. Low-risk populations include all transplant recipients who do not meet these criteria.
III. Strategies for Diagnosis and Management of CMV Infection
01 Diagnosis and Treatment Principles
Diagnosis relies primarily on quantitative polymerase chain reaction (PCR) monitoring of CMV DNA in peripheral blood, enabling early detection and viral load assessment.
Therapeutic approaches include preemptive therapy, definitive therapy, and options for drug-resistant CMV. Preemptive therapy is the most common strategy, initiated based on PCR or antigen testing results. First-line antivirals include ganciclovir (GCV) and foscarnet. While effective, these agents carry notable toxicities—myelosuppression for GCV and nephrotoxicity for foscarnet. Definitive therapy is reserved for confirmed CMV disease, which already involves organ damage and carries higher mortality. For drug-resistant CMV infections, maribavir or CMV-specific cytotoxic T lymphocyte (CTL) therapy provide effective alternatives.
02 Prophylaxis and Clinical Evidence
Letermovir is a novel, non-nucleoside CMV inhibitor belonging to the 3,4-dihydroquinazoline class. Its mechanism of action involves targeting the viral terminase complex, thereby blocking viral replication. This unique activity profile avoids cross-resistance with traditional nucleoside antivirals. Letermovir is approved for CMV prophylaxis after allo-HSCT, typically initiated between day 0 and day 28 post-transplant, at doses of 240 mg or 480 mg daily. Its key advantage lies in minimal myelotoxicity, offering good tolerability compared to conventional prophylactic agents.
Clinical evidence strongly supports its efficacy. A Phase III randomized controlled trial (2:1 randomization, n=565) used the incidence of clinically significant CMV (csCMV) infection by week 24 as the primary endpoint. Results showed a significantly lower incidence of csCMV in the letermovir group, with no difference in all-cause mortality by week 48, confirming both efficacy and safety. Another Phase III randomized controlled trial (2:1 randomization, n=255) extended prophylaxis to 200 days in 145 patients compared with 100 days in 75 patients. Between weeks 14 and 28, the incidence of csCMV was only 3% in the extended treatment group versus 19% in controls (P=0.0005). No drug-related deaths were reported during the study.
IV. Key Issues in Letermovir Prophylaxis
01 Immune-Related Risk Factors for csCMV Infection After Discontinuing Letermovir
The risk of CMV infection after discontinuing letermovir is closely associated with the status of immune reconstitution. A study of 24 allo-HSCT patients showed that 13 developed csCMV infection after stopping letermovir, while 11 did not. Immune monitoring during days 90–270 post-transplant revealed that patients in the infection group experienced significantly delayed reconstitution of CMV-specific CD4+ and CD8+ T cells, both in terms of quantity and functional recovery, compared with the non-infected group. Moreover, reconstitution of natural killer (NK) cells and memory NK cells was also markedly delayed in the infection group. These findings indicate that impaired immune recovery of these key cell subsets is a critical factor leading to csCMV infection after letermovir discontinuation, underscoring the need for close immune monitoring and timely identification of high-risk patients.
02 Association Between Letermovir Prophylaxis and EBV Infection Risk
Whether letermovir prophylaxis increases the risk of Epstein–Barr virus (EBV) infection remains controversial. A single-center retrospective study from the First Affiliated Hospital of Soochow University compared 133 patients receiving letermovir prophylaxis with 97 controls, all of whom underwent haploidentical donor transplantation with ATG-based GVHD prophylaxis. Results showed that letermovir significantly reduced CMV infection but was associated with a trend toward increased EBV infection. In contrast, a multicenter retrospective study including 284 patients receiving letermovir prophylaxis and 281 controls found that letermovir reduced the incidence of csCMV infection from 69% to 25.5%, but the incidence of post-transplant lymphoproliferative disorder (PTLD) associated with EBV increased significantly (1.8% vs. 7.39%).
Chinese clinical data therefore suggest that while letermovir effectively reduces CMV infection, it may increase the risk of EBV viremia or EBV-PTLD. Proposed mechanisms include reduced CMV antigen exposure delaying both CMV-specific and broader antiviral immune reconstitution, and decreased use of antivirals such as ganciclovir or foscarnet, which have incidental anti-EBV activity, thereby indirectly allowing EBV reactivation. However, international studies have not observed the same association, which may be explained by differences in population susceptibility to EBV, racial or genetic background, or varying immunosuppressive strategies in terms of depth and duration. The central clinical challenge lies in balancing the intensity of immunosuppression to control both CMV and EBV risk.
03 Relationship Between Letermovir Prophylaxis and Risk of Acute Leukemia Relapse
Another important question is whether letermovir prophylaxis affects the risk of relapse in acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) after transplantation. A single-center retrospective analysis of 687 AML transplant patients using calcineurin inhibitor (CNI)-based GVHD prophylaxis (with donor types of 31% matched related donors, 62% 10/10 matched unrelated donors, and 7% 9/10 mismatched unrelated donors) found that in patients who did not receive ATG prophylaxis, CMV reactivation was associated with reduced relapse risk, whereas in those receiving ATG, CMV reactivation showed no significant relationship with relapse.
Further evidence from the Japan Society for Hematopoietic Cell Transplantation and Cellular Therapy database used landmark analysis of 3,793 AML and 2,213 ALL patients who survived disease-free beyond day 65 post-transplant. Results demonstrated that patients with CMV reactivation (CMVR+) had a significantly lower cumulative relapse rate compared with those without CMV reactivation (CMVR−).
V. Single-Center Study at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
01 Study Design and Inclusion Criteria
The Department of Hematology at Ruijin Hospital conducted a single-center retrospective study to evaluate the incidence, risk factors, and outcomes of viral infections following allo-HSCT, with a particular focus on the impact of letermovir within a post-transplant cyclophosphamide (PTCy)-based prophylaxis system on CMV, EBV infection, and disease relapse.
Patients included were those undergoing allo-HSCT for hematologic malignancies between 2019 and June 2024, using matched sibling donors (MSD), unrelated donors (URD), or haploidentical donors (Haplo). All received myeloablative conditioning and peripheral blood stem cell (PBSC) grafts. GVHD prophylaxis consisted of PTCy combined with tacrolimus, with URD/Haplo recipients additionally receiving low-dose ATG (total 2.5 mg/kg) after neutrophil engraftment. The letermovir group received oral letermovir (480 mg/day) beginning after engraftment and continued through day 100 (D100).
Viral screening consisted of weekly CMV/EBV DNA monitoring. HSV-1/2, VZV, HHV-4/6/7/8, BK virus, adenovirus, parvovirus B19, and HBV were tested only when unexplained infection-related symptoms or signs appeared.
02 Baseline Characteristics
A total of 300 patients were included: 206 in the non-letermovir group (No LTV) and 94 in the letermovir group (LTV). Baseline characteristics were well balanced between groups.
03 Incidence of Viral Infections and Impact of Letermovir
Overall, 160 cases of CMV infection were observed (53.3%), with a median detection time of 40 days post-transplant (range 3–745 days). Thirteen cases (4.3%) progressed to CMV disease. EBV infection occurred in 35 patients (11.7%), with a median detection time of 117 days (range 24–535 days). Four patients (1.3%) developed EBV disease (PTLD).
In terms of letermovir’s effect, the incidence of CMV viremia was 61.7% in the No LTV group versus 35.1% in the LTV group (P<0.001). The incidence of csCMV was 49.0% versus 20.2% (P<0.001), and CMV disease occurred in 6.3% versus 0% (P=0.02). For EBV, the incidence of EBV viremia was 14.6% in the No LTV group compared to 5.3% in the LTV group (P=0.02).
04 Risk Factor Analysis
Univariate analysis indicated that donor type (haploidentical vs. others) and letermovir prophylaxis were key factors influencing CMV infection risk (both HR<0.001). For EBV infection, age ≥55 years (HR=0.03), higher PTCy dose (50 mg/kg vs. 40 mg/kg, HR<0.001), and letermovir prophylaxis (HR=0.02) were significant factors. For HHV6 infection, possible risk factors included PTCy dose (50 mg/kg vs. 40 mg/kg, HR=0.05) and donor age ≤37 years (HR=0.09). Other factors showed no statistical significance.
Multivariate analysis confirmed that donor type (haploidentical vs. others, HR=2.54, 95% CI 1.57–4.13, P<0.001) and letermovir prophylaxis (HR=0.41, 95% CI 0.27–0.62, P<0.001) were independent factors for CMV infection. No independent associations were found for EBV or HHV6 infections.
05 Outcomes Before and After Day 100 Post-Transplant
Cumulative incidence of CMV infection before day 100 was 23.4%±4.4% in the LTV group compared with 57.8%±3.5% in the No LTV group (P<0.001). After day 100, cumulative incidence was 12.7%±4.0% versus 8.0%±3.2% (P=0.2).
Letermovir prophylaxis significantly improved transplant outcomes. One-year overall survival (OS) was 94.5% in the LTV group versus 84.5% in the No LTV group. Two-year OS was 94.5% versus 79.9%. One-year GVHD-free relapse-free survival (GRFS) was 78.6% versus 66.4%, and two-year GRFS was 68.5% versus 59.8%. Non-relapse mortality (NRM) at one year was 4.3% in the LTV group versus 14.2% in the No LTV group (P=0.01). These findings clearly demonstrate that letermovir prophylaxis improves GRFS, reduces NRM, and does not adversely affect relapse, thereby enhancing both survival quality and long-term prognosis.
VI. Summary
The PTCy–tacrolimus plus low-dose ATG GVHD prophylaxis regimen (the “Ruijin protocol”) has shown excellent clinical performance in controlling GVHD. The incidence of grade II–IV acute GVHD is approximately 15%, grade III–IV acute GVHD about 3.5%, and steroid-refractory acute GVHD as low as 3.5%. Moderate chronic GVHD occurs in roughly 11% of cases and severe chronic GVHD in about 5%–6%. This regimen achieves an effective balance between GVHD prevention and the degree of immunosuppression, thereby laying the foundation for infection control.
Post-transplant viral infections follow a distinct pattern: CMV, HHV6, and EBV are the three most common, each with an incidence exceeding 10%, predominantly presenting as viremia rather than organ-invasive disease. Other viruses such as BK virus, adenovirus, or VZV are less common but often manifest as organ infections when they occur, requiring close monitoring.
The role of letermovir within this prophylaxis system is clear. First, it significantly reduces the incidence of csCMV without a rebound effect after day 100. Second, it does not significantly increase EBV infection or EBV-PTLD, with lower rates than those reported by other centers in China. Multivariate analysis further confirmed no significant association between letermovir and EBV infection. Third, it does not increase the risk of relapse, while markedly reducing NRM, thereby improving survival outcomes.
In summary, the combination of PTCy–tacrolimus plus low-dose ATG with letermovir achieves the clinical goal of “low CMV risk + low EBV risk + no increased relapse risk.” This regimen successfully balances GVHD prevention, the depth and duration of immunosuppression, and viral infection control, providing a reliable clinical strategy for the safe management of allo-HSCT patients.
Expert Profile
Professor Jiong Hu Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Deputy Director of the Department of Hematology, Director of the Bone Marrow Transplantation Ward, Chief Physician, and Master’s Supervisor.
Professional Experience: April–October 1996, Department of Adult Hematology, Saint-Louis Hospital, Paris; October 1996–March 1997, Bone Marrow Transplantation, Queen Mary Hospital, University of Hong Kong; March 2000–December 2013, Postdoctoral Researcher, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), USA.
Research Focus: Optimization of clinical systems for hematopoietic stem cell transplantation, mechanisms of drug resistance in refractory leukemia and strategies for reversal, and induction of immune tolerance in GVHD.
Academic Roles: Full member of the American Society of Hematology (ASH); Committee member, ASH Myeloid Malignancies Group; International Committee member, European Society for Blood and Marrow Transplantation (EBMT); Vice President, Hematology Branch of the Chinese Medical Doctor Association, Shanghai; Vice Chair, Shanghai Society of Transplant Immunology.
Awards: Second Prize, National Natural Science Award (2016, 4th contributor); Special Prize, Shanghai Natural Science Award (2015, 4th contributor).
Grants and Publications: Principal investigator of four national research projects and one Shanghai Young Physician Excellence Program project; author of more than 90 SCI-indexed papers.
