ABSTRACT
Background
Limited data exists on the incidence of CMV infections after chimeric antigen receptor (CAR) T‐cell or bispecific antibody (BsAb) therapy for hematologic malignancies.
Methods
We reviewed medical records of patients with hematologic malignancies treated with CAR T‐cells or BsAbs between July 2018 and October 2024 in a tertiary hospital in Seoul, South Korea. CMV infections were detected using CMV DNA qPCR assays performed within 180 days after CAR T‐cell infusion or the last BsAb treatment. Secondary outcomes were the occurrence of clinically significant CMV infections (CS‐CMVi) and end‐organ diseases.
Results
Of 179 patients, 76 (42%) received CAR T‐cell therapy, and 103 (58%) received BsAb therapy. The incidence of CMV infection was 62% in BsAb recipients, and 43% in CAR T‐cell recipients. Two (6.1% of total CMV infections) CAR T‐cell recipients had CS‐CMVi, and 1 (3.0%) developed possible CMV pneumonia. In the BsAb group, 10 (16% of total CMV infections) patients received antiviral therapy, and 4 (6.3%) had end‐organ diseases. Receiving three or more previous systemic chemotherapy regimens in the CAR T‐cell group was associated with increased CMV infection risks (HR 4.7, 95% CI 1.88–11.8, p < 0.001), and older age in the BsAb group had a trend toward having more CMV infection (HR 1.02, 95% CI 1.00–1.05, p = 0.06).
Conclusion
Approximately 43% and 62% of patients receiving CAR T‐cell and BsAb therapy had CMV infection, with 1%–4% developing CMV diseases. Effective strategies for preventing CMV infections in these patients are warranted.
Keywords: bispecific antibodies, chimeric antigen receptor T‐cell therapy, cytomegalovirus
This retrospective study analyzed the incidence of CMV infections among 179 patients who received CAR T‐cell or BsAb therapy for hematologic malignancies. CMV infections occurred in 43% in CAR T‐cell and 62% in BsAb recipients, with 1–4% progressing to CMV diseases.
Abbreviations
- ALL
Acute lymphoblastic leukemia
- BCMA
B‐cell maturation antigen
- BsAb
Bispecific antibody
- CAR
Chimeric antigen receptor
- CI
Confidence interval
- CMV
Cytomegalovirus
- CRS
Cytokine release syndrome
- CS‐CMVi
Clinically significant CMV infection
- DLBCL
Diffuse large B‐cell lymphoma
- DNA
Deoxyribonucleic acid
- FL
Follicular lymphoma
- GPRC5D
g protein‐coupled receptor class C group 5 member D
- HSCT
Hematopoietic stem cell transplantation
- ICANS
Immune effector cell‐associated neurotoxicity syndrome
- IQR
Interquartile range
- MCL
Mantle cell lymphoma
- MM
Multiple myeloma
- MZBL
Marginal zone B‐cell lymphoma
- qPCR
Quantitative polymerase chain reaction
- SOT
Solid organ transplantation
1. Introduction
Chimeric antigen receptor (CAR) T‐cell therapy uses genetically engineered T‐cells to target cancer cells and is effective against hematologic malignancies, including B‐cell lymphoma, B‐cell acute lymphocytic leukemia (ALL), and multiple myeloma [1, 2]. Bispecific antibodies (BsAbs) recruit immune effector cells to tumor cells and induce cytolysis [3]. These treatments involve immune reconstitution and are associated with complications, including cytokine release syndrome (CRS), immune effector cell‐associated neurotoxicity syndrome (ICANS), hypogammaglobulinemia, and clinically significant immunosuppression after treatment with immunosuppressants (e.g., tocilizumab and corticosteroids) [3, 4].
Although immunosuppression in these patients is clinically significant, data on CMV infection and outcome in these patients are insufficient. In regards to CAR T‐cell therapy recipients, previous studies presented that CMV infection occurred in less than 30% of the patients post treatment and rarely developed into an CMV end‐organ disease [5, 6, 7], but the incidence of CMV infections after CAR T‐cell and BsAb therapy and the effect of CMV infections on the development of end‐organ diseases in a population with high seroprevalence is unclear. This single‐center retrospective study investigated the incidence of CMV infections after CAR T‐cell or BsAb treatment and explored potential risk factors for CMV infections after treatment.
2. Methods
2.1. Study Design and Patients
Patients who received CAR T‐cell therapy or started BsAb treatment for non‐Hodgkin lymphoma, B‐cell ALL, or multiple myeloma between July 2018 and October 2024 in a tertiary hospital in Seoul, South Korea, were screened for inclusion. The exclusion criteria were patients younger than 18 years and patients diagnosed with CMV end‐organ disease before therapy. Data on demographic characteristics and primary and secondary outcomes were obtained from electronic medical records. All patients treated with CAR T‐cell therapy received prophylactic acyclovir, trimethoprim‐sulfamethoxazole, and levofloxacin according to the institutional protocol unless contraindicated. Patients with anti‐HBc IgG‐positive were treated with prophylactic tenofovir disoproxil fumarate or entecavir under the guidance of hepatologists, and patients with interferon‐γ release assay‐positive results consulted pulmonologists for active pulmonary tuberculosis prevention. None of the patients received CMV prophylaxis.
2.2. Primary and Secondary Outcomes
The primary outcome was CMV infection, which were defined as any detection of CMV DNA even below the limit of quantification (1.49 log IU/mL) using CMV DNA qPCR (quantitative polymerase chain reaction) assays performed within 180 days after CAR T‐cell or the last BsAb treatment [8]. The decision to perform CMV DNA qPCR assays and testing intervals were determined by the attending physicians. Secondary outcomes were clinically significant CMV infections (CS‐CMVi) requiring antiviral therapy either preemptive or therapeutic, and the occurrence of CMV disease, meaning CMV infections with end‐organ involvements (e.g., enteritis, retinitis, and pneumonia) as defined by Ljungman et al. [8]. CMV enteritis was defined as gastrointestinal symptoms with macroscopic mucosal lesions, and CMV was confirmed using histopathology and immunohistochemistry [8]. CMV retinitis was defined as typical ophthalmologic findings identified by an ophthalmologist and the presence of CMV DNA in the vitreous fluid [8]. CMV pneumonia was defined as the presence of CMV and the absence of other opportunistic pathogens in lung tissues, but patients with a high viral load (titers ≥ 5.0 log IU/mL) in the bronchoalveolar lavage fluid were considered to have possible CMV pneumonia, even in the presence of other pathogens [8]. In the CAR T‐cell therapy group, the maximum duration of observation was 180 days after CAR T‐cell infusion. In the BsAb group, the patients were monitored from the first treatment until 180 days after the last treatment. All patients who were lost to follow‐up or died in this observation period were included as censored data. Preemptive ganciclovir therapy was initiated at the attending physician's discretion, as no specific CMV DNA level for preemptive therapy is not yet designated for CAR T‐cell or BsAb recipients. Physicians made their decisions referring to the center's protocol for autologous HSCT patients, which recommends initiating preemptive therapy at 4.0 log IU DNA/mL plasma, although not all patients were treated at this level.
2.3. Statistical Analysis
Demographic and clinical characteristics were compared using Pearson's chi‐square test, Wilcoxon rank sum test, or Fisher's exact test. The crude incidences of CMV infection, CS‐CMVi, and CMV disease in CAR T‐cell therapy and BsAb therapy recipients were presented. Subgroup analysis based on the diagnosis (lymphoma and multiple myeloma) and the treatment targets (CAR T‐cell therapy targeting CD19 and BsAb therapy targeting CD20 for lymphomas, and BsAb therapy targeting B‐cell maturation antigen [BCMA] and G protein‐coupled receptor, class C, group 5, member D [GPRC5D] for multiple myeloma) was performed additionally. The cumulative incidence of CMV infection in the CAR T‐cell and BsAb groups was analyzed using Kaplan–Meier curves, and potential risk factors were investigated using univariate and multivariate Cox proportional hazards regression models. The multivariate Cox proportional hazards model was built based on the backward stepwise elimination of the variables, while the variables of clinical relevance were also included. Certain baseline characteristics, including CMV DNA levels before treatment, were missing because data were collected retrospectively, and were handled by multiple imputations. All tests were two‐sided with a significance level of 0.05. Statistical analysis was performed using R version 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria) and the packages survival, ggplot2, dplyr, survminer, and gtsummary.
2.4. Ethics Statement
This study was reviewed and approved by the institutional review board of our hospital and the requirement for informed consent was waived because of the retrospective nature of the study. ChatGPT 5 (OpenAI, San Francisco, CA, USA) was used to correct grammatical errors and refine sentence structures.
3. Results
A total of 179 patients were included in the study; of these, 76 (42%) received CAR T‐cell therapy and 103 (58%) received BsAbs. The demographic and clinical characteristics of the cohort are shown in Table 1. The median age was 65 years (Interquartile range [IQR]: 55, 71), and diffuse large B‐cell lymphoma accounted for 65% of the sample (Table 1). Most of the patients treated with CAR T‐cell therapy received CD19‐targeting CAR T‐cell therapy, while only 3 patients with multiple myeloma received BCMA‐targeting CAR T‐cell therapy. In the BsAb group, 19 (18%) patients received BsAbs as the first‐line treatment, and all patients in the CAR T‐cell group received at least one chemotherapy regimen before CAR T‐cell therapy. CRS, ICANS, tocilizumab use, and corticosteroid use were more frequent in the CAR T‐cell group.
TABLE 1.
Demographic and clinical characteristics of the cohort.
| CAR T‐cell therapy a (N = 76) | BsAb therapy b (N = 103) | ||||||
|---|---|---|---|---|---|---|---|
| Characteristics |
Total (N = 179) |
CMVi— (N = 43) |
CMVi + (N = 33) |
p‐value c |
CMVi— (N = 39) |
CMVi + (N = 64) [1] |
p‐value c |
| Age, median (IQR), years | 65 (55, 71) | 68 (52, 71) | 66 (54, 71) | 0.78 | 60 (50, 71) | 65 (59, 72) | 0.12 |
| Sex | 0.72 | 0.79 | |||||
| Female | 70 (39) | 20 (47) | 14 (42) | 13 (33) | 23 (36) | ||
| Male | 109 (61) | 23 (53) | 19 (58) | 26 (67) | 41 (64) | ||
| Diagnosis | 0.95 | 0.42 | |||||
| DLBCL | 117 (65) | 38 (88) | 29 (88) | 18 (46) | 32 (50) | ||
| ALL | 2 (1.1) | 1 (2.3) | 1 (3.0) | 0 (0) | 0 (0) | ||
| MM | 35 (20) | 2 (4.7) | 1 (3.0) | 11 (28) | 21 (33) | ||
| FL | 19 (11) | 1 (2.3) | 2 (6.1) | 9 (23) | 7 (11) | ||
| MZBL | 1 (0.6) | 1 (2.3) | 0 (0) | 0 (0) | 0 (0) | ||
| MCL | 5 (2.8) | 0 (0) | 0 (0) | 1 (2.6) | 4 (6.3) | ||
| Prior HCT (both allogeneic and autologous) | 43 (24) | 13 (30) | 4 (12) | 0.05 | 9 (23) | 17 (27) | 0.69 |
| Autologous HCT | 41 (23) | 12 (28) | 3 (8.8) | 9 (23) | 17 (27) | ||
| Allogeneic HCT | 2 (1) | 1 (2.3) | 1 (2.9) | 0 (0) | 0 (0) | ||
| Time between the treatment and HCT, median (IQR), days | 1,154 (329, 2565) | 256 (233, 600) | 1,241 (356, 2997) | 0.35 | 1,362 (862, 1740) | 1,154 (329, 2565) | 0.63 |
| Number of previous systemic antitumor therapy regimens | 0.002 | 0.83 | |||||
| 0 | 19 (11) | 0 (0) | 0 (0) | 7 (18) | 12 (19) | ||
| 1 or 2 | 64 (36) | 23 (53) | 6 (18) | 12 (31) | 23 (36) | ||
| ≥3 | 96 (54) | 20 (47) | 27 (82) | 20 (51) | 29 (45) | ||
| Post‐treatment neutropenia d , days | 1 (0, 7) | 6 (1, 21) | 9 (2, 15) | 0.97 | 0 (0, 1) | 0 (0, 2) | 0.16 |
| Initial hypogammaglobulinemia e , median (IQR) |
779 (540, 1079) |
724 (464, 924) |
661 (513, 903) |
0.69 |
824 (597, 1391) |
899 (604, 1180) |
0.86 |
| Comorbidities | |||||||
| Diabetes mellitus | 27 (15) | 8 (19) | 5 (15) | 0.38 | 5 (13) | 9 (14) | 0.92 |
| Hypertension | 65 (36) | 16 (37) | 16 (48) | 0.32 | 11 (28) | 22 (34) | 0.52 |
| HBV infection f | 75 (42) | 15 (35) | 18 (55) | 0.087 | 11 (28) | 31 (48) | 0.043 |
| LTBI | 13 (7.3) | 6 (14) | 5 (15) | >0.99 | 1 (2.6) | 1 (1.6) | >0.99 |
| Malignancy g | 13 (7.3) | 5 (12) | 5 (15) | 0.74 | 0 (0) | 3 (4.7) | 0.29 |
| Pre‐treatment CMV viremia h | 63 (35) | 13 (30) | 13 (39) | 0.40 | 12 (31) | 25 (39) | 0.39 |
| Post‐treatment adverse events | |||||||
| CRS, any grade | 101 (56) | 30 (70) | 23 (70) | >0.99 | 14 (36) | 34 (53) | 0.089 |
| ICANS, any grade | 17 (9.5) | 12 (28) | 5 (15) | 0.19 | 0 (0) | 0 (0) | >0.99 |
| Corticosteroid use, days | 0.41 | 0.52 | |||||
| 0 | 152 (85) | 26 (60) | 25 (76) | 39 (100) | 62 (97) | ||
| 1 or 2 | 10 (5.6) | 7 (16) | 3 (9.1) | 0 (0) | 0 (0) | ||
| ≥3 | 17 (9.5) | 10 (23) | 5 (15) | 0 (0) | 2 (3.1) | ||
| Tocilizumab use, doses | 0.41 | 0.33 | |||||
| 0 | 106 (59) | 14 (33) | 13 (39) | 33 (85) | 46 (72) | ||
| 1 or 2 | 54 (30) | 17 (40) | 15 (45) | 6 (15) | 16 (25) | ||
| ≥3 | 19 (11) | 12 (28) | 5 (15) | 0 (0) | 2 (3.1) | ||
| Disease Outcome | 0.33 | 0.77 | |||||
| Relapse | 74 (41) | 23 (53) | 21 (64) | 13 (33) | 17 (27) | ||
| Not evaluated i | 11 (6.1) | 3 (7.0) | 0 (0) | 3 (7.7) | 5 (7.8) | ||
Abbreviations: ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CMV, cytomegalovirus; CMVi, CMV infection; CRS, cytokine release syndrome; DLBCL, diffuse large B‐cell lymphoma; FL, follicular lymphoma; HBV, hepatitis B virus; HCT, hematopoietic cell transplantation; ICANS, immune effector cell‐associated neurotoxicity syndrome; IQR, interquartile range; LTBI, latent tuberculosis infection; MCL, mantle cell lymphoma; MM, multiple myeloma; MZBL, marginal zone B‐cell lymphoma.
Data are absolute numbers and percentages unless otherwise specified.
Four patients were treated with more than one bispecific antibody, and the last treatment was considered in the study. Five patients had been treated with bispecific antibodies before CAR T‐cell therapy.
Fourteen patients had been treated with CAR T‐cells before BsAb therapy.
Pearson's chi‐square test, Wilcoxon rank sum test, or Fisher's exact test.
Number of consecutive days with absolute neutrophil count < 500/µL after treatment initiation.
Serum IgG < 400 mg/dL before treatment initiation.
Patients who tested positive for hepatitis B core antibody and received prophylactic treatment with either entecavir or tenofovir disoproxil fumarate.
History of other primary malignancies.
157 patients had been tested using CMV DNA qPCR before treatment
These patients did not undergo disease evaluation due to early mortality or follow‐up loss.
CMV infections occurred in 33 out of 76 patients (43%) in the CAR T‐cell group and 64 out of 103 patients (62%) in the BsAb group (Table 2). CS‐CMVi occurred in 2 patients (6.1% of total CMV infection) in the CAR T‐cell group and 10 patients (16%) in the BsAb group, while CMV diseases occurred in 1 patient (3.0%) in the CAR T‐cell group and 4 patients (6.3%) in the BsAb group. The brief clinical course and CMV DNA titer kinetics of the patients who experienced CMV infections that remained subclinical and CS‐CMVi are shown in Figure 1. Disease relapses occurred prior to CMV infections in 21% of the cases in the CAR T‐cell group, with 15% having received a new treatment line before infection. In the BsAb therapy group, disease relapses occurred in 4.1% of CMV infections and 3.1% initiating new treatment prior to CMV infection. Serially increasing viral loads were observed in 14 CAR T‐cell recipients and 25 BsAb recipients, and time to reach the peak viral loads were 74 days (IQR: 24–103 days) and 42 days (IQR: 28–80 days) respectively (Table 2). Kaplan–Meier curves revealed that the median time to CMV infection was non‐significantly longer in the CAR T‐cell group than in the BsAb group (174 days [95% confidence interval (CI): 114–NA] and 93 days [95% CI: 38–256], p = 0.23) (Figure 2). In a subgroup of patients who had CMV infections before having their primary malignancy relapse, the median time to CMV infections was 27 days (IQR: 3.25–30 days) in CAR T‐cell group and 30 days (IQR: 22–84 days) in BsAb group. Multivariable Cox regression analysis showed that receiving three or more previous systemic chemotherapy regimens was an independent risk factor for CMV infection in the CAR T‐cell group (Hazard ratio [HR]: 4.72, 95% CI: 1.88–11.8, p < 0.001) (Table 3a). Older age tended to increase the risk of CMV infections in the BsAb group (HR: 1.02, 95% CI: 1.00–1.05, p = 0.06) (Table 3b).
TABLE 2.
Frequency and characteristics of CMV infection in CAR T‐cell and BsAb therapy groups.
|
CAR T‐cell therapy (N = 76) |
Bispecific antibodies (N = 103) |
|
|---|---|---|
| CMV infection (% total cohort) | 33 (43) | 64 (62) |
| Relapses before CMV infection | 7 (21) | 3 (4.7) |
| New treatment initiated before CMV infection | 5 (15) | 2 (3.1) |
| Serially increased viral load | 14 (18) | 25 (24) |
| CS‐CMVi | 2 (6.1) | 10 (16) |
| CMV disease | 1 (3.0) | 4 (6.3) |
| Enteritis | 0 | 1 a |
| Possible pneumonia b | 1 | 2 |
| Retinitis | 0 | 1 |
| Initial viral load, IU/mL, median (IQR) | 1.82 (1.49, 2.25) | 1.96 (1.49, 2.48) |
| > Lower quantification limit of viral load | 25 (76) | 49 (77) |
| Peak viral load, IU/mL, median (IQR) | 1.95 (1.65, 3.56) | 2.18 (1.56, 3.18) |
| ≥ 2 Positive qPCR assays | 22 (67) | 43 (67) |
| Days to reach peak viral load, median (IQR) | 74 (24, 103) | 42 (28, 80) |
Abbreviations: CAR, chimeric antigen receptor; CS‐CMVi, clinically significant CMV infection.
Data are absolute numbers and percentages of total CMVi unless otherwise specified.
One patient was diagnosed with CMV enteritis and then with retinitis. Only enteritis was considered in the analysis.
All cases had co‐pathogens, and CMV DNA qPCR titers in the bronchoalveolar lavage fluid were higher than 5.0 log IU/mL
FIGURE 1.
The brief clinical course of patients with CMV infections. Patients had (a) spontaneously resolving CMV infections. The patients were likely to have titers lower than 3.00 IU/mL and decreasing titers subsequently. Patients who had no follow‐up CMV DNA assay performed were not included in this graph. Patients with (b) CS‐CMVi tended to have initial DNA level over 3.00 IU/mL and had increasing or at least persisting DNA levels in serial follow‐up assays. BsAb3 in (b) were locally treated for CMV retinitis via vitreous injection of GCV. Abbreviations: CAR, chimeric antigen receptor; CMV, cytomegalovirus; GCV, ganciclovir.
FIGURE 2.
Cumulative incidence of CMV infection in patients treated with CAR T‐cell of BsAb therapy. Median time to event (CMV infection) was 174 days (95% CI: 114–NA) in the CAR T‐cell therapy group and 93 days (95% CI: 38–256) in the BsAb therapy group. Abbreviations: CAR, chimeric antigen receptor; BsAb, bispecific antibody; CMV, cytomegalovirus.
TABLE 3.
Univariate and multivariate Cox proportional hazard regression analyses of CMV infections.
| Characteristic | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p‐value | HR | 95% CI | p‐value | |
| (a) CAR T‐cell therapy group (N = 76) | ||||||
| Sex, male | 1.18 | 0.59, 2.36 | 0.64 | |||
| Age | 1.18 | 0.59, 2.36 | 0.64 | |||
| Prior HCT a | 1.18 | 0.59, 2.36 | 0.64 | 1.18 | 0.59, 2.36 | 0.64 |
| Three or more systemic chemotherapy regimens | 4.33 | 1.77, 10.6 | 0.001 | 4.72 | 1.88, 11.8 | <0.001 |
| Post‐treatment neutropenia, days | 76 | 0.99 | 0.96, 1.01 | |||
| Initial hypogammaglobulinemia | 1.09 | 0.42, 2.83 | 0.86 | |||
| Pre‐treatment CMV viremia | 1.09 | 0.42, 2.83 | 0.86 | 1.09 | 0.42, 2.83 | 0.86 |
| Comorbidities | ||||||
| Diabetes mellitus | 1.49 | 0.74, 2.98 | 0.26 | |||
| Hypertension | 1.36 | 0.69, 2.70 | 0.37 | |||
| HBV infection | 1.74 | 0.88, 3.45 | 0.11 | 1.57 | 0.73, 3.35 | 0.25 |
| LTBI | 1.09 | 0.42, 2.84 | 0.85 | |||
| Malignancy | 1.30 | 0.50, 3.36 | 0.59 | |||
| Post‐treatment adverse events | ||||||
| CRS, any grade | 1.31 | 0.62, 2.77 | 0.47 | |||
| ICANS, any grade | 0.70 | 0.27, 1.80 | 0.45 | |||
| Corticosteroid use, days | ||||||
| 1 or 2 | 0.56 | 0.17, 1.86 | 0.35 | |||
| ≥3 | 0.91 | 0.35, 2.38 | 0.85 | |||
| Tocilizumab use, doses | ||||||
| 1 or 2 | 1.15 | 0.55, 2.43 | 0.71 | |||
| ≥3 | 0.71 | 0.25, 1.99 | 0.51 | |||
| (b) BsAb treatment group (N = 103) | ||||||
| Sex, male | 0.87 | 0.52, 1.46 | 0.61 | |||
| Age | 1.03 | 1.01, 1.05 | 0.009 | 1.02 | 1.00, 1.05 | 0.060 |
| Autologous HCT | 1.01 | 0.58, 1.78 | 0.97 | |||
| Number of previous systemic chemotherapy regimens | ||||||
| 1 or 2 | 0.83 | 0.41, 1.68 | 0.61 | |||
| ≥3 | 0.74 | 0.37, 1.46 | 0.38 | |||
| Post‐treatment neutropenia, days | 1.01 | 0.97, 1.04 | 0.69 | |||
| Initial hypogammaglobulinemia | 0.97 | 0.48, 1.97 | 0.93 | |||
| Pre‐treatment CMV viremia | 1.21 | 0.67, 2.17 | 0.53 | 1.15 | 0.63, 2.08 | 0.65 |
| Comorbidities | ||||||
| Diabetes mellitus | 0.92 | 0.52, 1.61 | 0.76 | |||
| Hypertension | 1.03 | 0.61, 1.74 | 0.91 | |||
| HBV infection | 1.72 | 1.05, 2.84 | 0.033 | 1.25 | 0.65, 2.41 | 0.50 |
| LTBI | 0.67 | 0.09, 4.82 | 0.69 | |||
| Malignancy | 3.14 | 0.97, 10.2 | 0.057 | 2.32 | 0.67, 8.03 | 0.18 |
| Post‐treatment adverse events | ||||||
| CRS, any grade | 1.28 | 0.78, 2.11 | 0.33 | |||
| Corticosteroid use, days, 3 or more | 2.38 | 0.57, 9.90 | 0.23 | |||
| Tocilizumab use, doses | ||||||
| 1 or 2 | 1.53 | 0.86, 2.73 | 0.15 | |||
| ≥3 | 2.67 | 0.63, 11.3 | 0.18 | |||
Abbreviations: BsAb, bispecific antibodies; CAR, chimeric antigen receptor; CI, confidence interval; CMV, cytomegalovirus; CRS, cytokine release syndrome; HBV, hepatitis B virus; HCT, hematopoietic cell transplantation; HR, hazard ratio; ICANS, immune effector cell‐associated neurotoxicity syndrome; LTBI, latent tuberculosis infection.
All patients received autologous HCT except for two ALL patients.
In a subgroup of 19 patients who received both therapies, CMV infection was detected in 10 patients treated with CAR T‐cells followed by BsAbs and three patients treated with BsAbs followed by CAR T‐cells (Table S1). Two patients who were initially treated with CAR T‐cells developed CS‐CMVi, while none of the patients initially treated with BsAbs did. Among 25 patients diagnosed with multiple myeloma, the incidence of CMV infection was higher in those treated with BsAb targeting GPRC5D compared to those treated with BsAb targeting BCMA (86 % vs. 56 %, p = 0.355), but there was no statistical significance.
4. Discussion
In both CAR T‐cell therapy and BsAb therapy, CMV infections frequently occurred after treatment, including some cases with CS‐CMVi with or without end‐organ involvements. These data provide significant insight into the need for surveillance and preemptive therapy after these treatments.
T‐cells play essential roles in CMV reactivation from latency. Therefore, T‐cell dysfunction can increase the risk of CMV reactivation and progression to CMV infections requiring antiviral therapy and end‐organ diseases. CAR T‐cell and BsAb therapies involve immune reconstitution, potentially leading to immune suppression due to cytopenia, B‐cell aplasia, hypogammaglobulinemia, and the use of immunosuppressants (e.g., corticosteroid and tocilizumab) to treat CRS and ICANS [4, 9]. Previous studies suggested that some patients have prolonged CD4+ T‐cell lymphopenia after lymphodepleting chemotherapy, which is performed before CAR T‐cell infusion and lasts more than 1 year, and prolonged CD4+ T‐cell lymphopenia is associated with an increased risk of infections [10, 11, 12]. A comprehensive review of studies on BsAb treatments for multiple myeloma observed that lymphopenia (Grade 3 or higher) occurred in 10%–51% of patients [13], and T‐cell exhaustion induced by continued BsAb administration increased the risk of opportunistic infections [14], thus increasing the risk of CMV infections. Moreover, CS‐CMVi is known to be associated with increased non‐relapse mortality in CAR T‐cell therapy recipients, although causal relationships are not evident [15, 16]
Despite this concern, only some studies evaluated CMV reactivation after CAR T‐cell therapy, especially because of the low frequency of CMV testing for surveillance purposes [6]. Previous studies reported CMV infections after CAR T‐cell therapy commonly occur (7.5%–56%), but the incidence of CS‐CMVi with or without end‐organ involvements remain relatively low (3%–15%) [16]. The varying incidence rates in these studies are considered to be because CMV surveillance strategies were largely variable and many studies were retrospective [16]. The incidence of CS‐CMVi including end‐organ diseases in our study was comparable to that reported in previous studies, further supporting the need for active surveillance and preemptive antiviral therapy at a specific threshold level considering the potential progression to CS‐CMVi. Moreover, the patients who received three or more systemic chemotherapy, including bridging chemotherapy, were at a higher risk of developing CMV infections, suggesting that the repeated administration of different chemotherapy regimens combined with lymphodepletion for CAR T‐cell infusion increases the risk of infection [17]. Interestingly, prior hematopoietic stem cell transplantation (HCT) was not found to increase the risk of CMV infections, while previous studies showed strong association between the history of HCT and increased risk of CMV infections after CAR T‐cell therapy [5, 18]. Also, CRS and corticosteroid use, known to increase the risk of CMV infections [5], were not clinically relevant in our cohort, which was also unexpected because treatment of CRS or ICANS with steroids were found to be significantly associated with increased risk of CS‐CMVi in multiple studies, possibly due to reduced cellular immunity after steroid use [5, 15]. On the other hand, patients with multiple myeloma who received BMCA‐targeting CAR T‐cell therapy were found to have a two times higher risk of developing CMV infections than those receiving CD19‐targeting CAR T‐cell therapy (46% vs. 23%) [5], while it was not comparable in our study because only three patients receiving BCMA‐targeting CAR‐T cell therapy were included in our study.
Regarding the timing of CMV infections following CAR T‐cell infusion, our Kaplan–Meier analysis estimated a median time to infection of 174 days (95% CI 114‐NA). This finding initially appeared discordant with previous reports suggesting earlier onset. Kampouri et al. demonstrated in a prospective study of 72 CMV‐seropositive adults that CMV infections typically occurred within 2–6 weeks post‐infusion, coinciding with the nadir of CMV‐specific cell‐mediated immunity (CMV‐CMI) [5]. Similarly, other studies have reported median times of 60 days in a large database analysis of 2256 patients [18], and 17 days for CS‐CMVi in 230 CAR T‐cell recipients [15]. The longer median time observed in our analysis can be attributed to the inclusion of censored data, specifically patients who were lost to follow‐up, died before developing CMV infections, or experienced primary disease relapse requiring additional antitumor treatments that could independently influence CMV risk. When we performed a subgroup analysis restricted to patients who developed CMV infections prior to having disease relapse, the median time to infection was 26 days post‐CAR T‐cell infusion, which aligns closely with previously published data and supports the temporal relationship between CAR T‐cell therapy and early CMV reactivation.
Meanwhile, data on CMV infection after BsAb therapy are even scarcer. In our study, CMV infections occurred in more than half the patients who received BsAb therapy, and CMV diseases occurred in 4% of the total CMV infections. This rate is much higher than previously reported. For instance, a meta‐analysis of 21 studies on CMV infections in patients with lymphoma treated with CD20‐targeting BsAbs (epcoritamab, glofitamab, mosunetezumab, and odronextamab) reported that 44% (95% CI: 37%–50%) had CMV infections of any grade, and one patient died of CMV viremia [19]. Also, our analysis suggests that a greater proportion of patients with CS‐CMVi in patients treated with CD20‐targeting BsAbs (14%) than in those treated with BCMA‐targeting (6%) or GPRC5D‐targeting (0%) BsAbs, although the interpretation of these findings is limited due to small group sizes. Previous studies suggested that infection rates are known to vary depending on the target of BsAb therapy. For instance, BCMA‐targeting BsAb recipients had higher risk of infections than GPRC5D‐targeting BsAb recipients potentially due to more significant hypogammaglobulinemia after BCMA‐targeting BsAb therapy [20]. However, it is important to note that direct comparison of the incidence of CMV infections across different BsAb products based on absolute numbers alone may be misleading, because the indications for each BsAb and prior antitumor regimens can result in inherently different immunological risk levels. This warrants the need for further studies on the risk of CMV infections in different BsAb agents. Although there are some studies enhancing the necessity to monitor CMV infection after BsAb therapy based on the patients’ risk assessment [9, 21], little is known about the incidence of CMV infections after BsAb therapy in real‐world settings. CMV infections should be monitored in BsAb recipients because they may have clinical significance, and further studies on CMV infections depending on treatment targets are needed.
A possible explanation for a higher incidence of CMV infections in our cohort is higher CMV seropositivity. CMV serostatus is associated with the risk of CMV reactivation. Similar results were obtained for CMV‐seropositive non‐immunocompromised intensive care unit patients [22]. These data suggest that CMV serostatus can predict the risk of CMV infections [23, 24]. CMV seropositivity from 1995 to 2015 in South Korea was >94% [25], higher than in other populations [26]. This result can help explain the high incidence of CMV infections in our cohort. Further, the proportion of CMV infections progressing to end‐organ disease was higher in our cohort, advocating the need for developing guidelines for CMV surveillance in patients receiving these therapies. We previously showed that in a CMV‐seropositive population, 60% of kidney transplant recipients had CMV infection, and 4% developed tissue‐invasive CMV disease [27]. We obtained similar results, underscoring the need to perform CMV surveillance with preemptive therapy in patients receiving CAR T‐cells or BsAbs. The high incidence of CMV infections and consequent CMV diseases after CAR T‐cell and BsAb therapies may trigger the idea that CMV surveillance and potentially preemptive therapy at a certain CMV DNA threshold in at‐risk patients, may become an important strategy for at‐risk patients, as is in SOT and HSCT recipients. However, there is little data on how preemptive therapy or monitoring would successfully reduce CMV infection in these patients. Therefore, future studies are urgently needed to investigate the benefits of surveillance and preemptive therapy in these patients and to estimate appropriate CMV testing intervals and indications for prophylaxis and preemptive therapy if needed.
In our cohort, approximately one third of the patients with CMV infections had subsequent increases in CMV DNA titers. Nevertheless, about 90% of the patients with CMV infections remained subclinical and their infections resolved spontaneously without antiviral therapy. These patterns raise important questions about the cost‐effectiveness of active surveillance in patients receiving CAR T‐cell therapy and/or BsAbs, and therefore further evaluations on its cost‐benefit must be followed. Also, it is important to note that once clinically apparent, CS‐CMVi was frequently difficult to manage: One patient with presumed CMV colitis with serum CMV DNA titer of 4.79 log IU/mL could not undergo confirmatory endoscopy due to hemodynamic instability, and other patients with suspected CMV pneumonia with CMV DNA titer from bronchoalveolar fluid over 5 log IU/mL had bacterial coinfections that made the treatment more challenging. These real‐world constraints underscore the potential value of early interventions enabled by active surveillance to potentially avoid resource‐intensive downstream complications.
Our study has some limitations. First, the single‐center, retrospective design inherently limits the generalizability of our findings and introduces potential selection bias. Second, as CMV PCR testing and antiviral treatment decisions were made at the discretion of individual physicians rather than following a standardized protocol, the process of monitoring and treatment for CMV infections was variable among the patients. This could have introduced confounding effects to the outcome of our analysis. Third, our study spans a long time period from 2018 to 2024, when the clinical indications for both CAR T‐cell and BsAb therapies have evolved substantially. The indications for these treatments have expanded, with both therapeutic modalities increasingly being adopted at earlier treatment lines. This temporal evolution in treatment paradigms may have influenced patient characteristics, disease burden, and subsequent CMV infection risks, potentially affecting the comparability of patients treated at different time points within our study period. Fourth, data on CMV serostatus were not collected, and imputations were based on reported seroprevalence data [25].
In conclusion, we observed that the incidence of CMV infections after CAR T‐cell and BsAb therapies was considerably high (62% in BsAb therapy group and 43% in CAR T‐cell therapy group). The incidence of CS‐CMVi and CMV diseases was also notable in both groups indicating that careful monitoring of these patients is warranted. These findings highlight the need for developing systematic CMV surveillance strategies for patients receiving these immunotherapies, just like in SOT and HSCT recipients. Further research is needed to determine optimal testing intervals and indications for prophylaxis and preemptive therapy.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting File 1: tid70138‐sup‐0001‐TableS1.docx
Acknowledgments
This work was supported by the National Research Foundation of Korea from the Ministry of Science and ICT, South Korea (grant number RS‐2023‐00219002). The authors thank Dr. Jung Bok Lee from the Department of Biomedical statistics, University of Ulsan College of Medicine for aiding statistical analysis. ChatGPT 5 (OpenAI, San Francisco, CA, USA) was used to correct grammatical errors and refine sentence structures. The authors reviewed the final version of the manuscript, verified its factual accuracy, and take responsibility for its contents.
Han J., Lim S. Y., Hyung J., Cho H., Yoon D. H., and Kim S.‐H., “Cytomegalovirus Infection After Chimeric Antigen Receptor T‐Cell Therapy or Bispecific Antibody Treatment for Hematologic Malignancies.” Transplant Infectious Disease 27, no. 6 (2025): e70138. 10.1111/tid.70138
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Supplementary Materials
Supporting File 1: tid70138‐sup‐0001‐TableS1.docx