Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis

Gabanti, Elisa; Borsani, Oscar; Colombo, Anna; Zavaglio, Federica; Binaschi, Luana; Caldera, Daniela; Sciarra, Roberta; Cassinelli, Gabriela; Alessandrino, Emilio Paolo; Bernasconi, Paolo; Lilleri, Daniele; Baldanti, Fausto

doi:10.1016/j.jtct.2022.01.008

Cited by 27 publications

(28 citation statements)

References 27 publications

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“…A seemingly detrimental impact of LMV prophylaxis on the reconstitution of polyfunctional 8 or monofunctional (IFN‐γ‐producing) 2 CMV‐specific T cells was previously reported. In a study published by Zamora et al., 8 decreased polyfunctional CMV IE1 and pp65‐specific T‐cell levels were noticed by day +90 after allo‐HSCT in patients treated prophylactically with LMV compared with patients managed with PET.…”

Section: Discussionmentioning

confidence: 83%

“…A seemingly detrimental impact of LMV prophylaxis on the reconstitution of polyfunctional 8 or monofunctional (IFN-γ-producing) 2 CMVspecific T cells was previously reported. In a study published by Zamora et al, 8 It must be stressed that SLM was not used in any patient from this series.…”

Section: We Next Compared Cmv-specific T-cell Countsmentioning

confidence: 82%

“…For example, in a rather heterogeneous series of allo‐HSCT, 8 the incidence of late CMV DNAemia at any level was around 50%, with only 15% reaching CMV DNA loads ≥500 IU/ml. In the study by Gabanti et al., 2 an exceedingly high number of patients (99%) developed late CMV DNAemia, of whom two thirds required PET. In‐line with these findings, four patients in our series (33.3%) developed CMV DNAemia after LMV cessation of which two required the administration of PET.…”

Section: Discussionmentioning

confidence: 94%

“…Unfortunately, the aforementioned study did not specify whether SLM was used. In turn, Gabanti et al 2 . reported that LMV appeared to eventually delay CMV‐specific T‐cell immunity reconstitution; however, blood counts of CMV‐specific CD4 + T and CD8 + T cells, regardless of whether or not the patients developed CMV DNAemia, were comparable at <120 and <90 days, respectively, after allo‐HSCT.…”

Section: Discussionmentioning

confidence: 99%

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Features of cytomegalovirus DNAemia and virus‐specific T‐cell responses in allogeneic hematopoietic stem‐cell transplant recipients during prophylaxis with letermovir

Giménez

Guerreiro

Torres

et al. 2023

Transplant Infectious Dis

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Background There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV‐specific T‐cell reconstitution in allogeneic hematopoietic transplant recipients (allo‐HSCT) undergoing letermovir (LMV) prophylaxis. Methods Twelve adult CMV‐seropositive high‐risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non‐LMV allo‐HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real‐time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500 IU/ml. CMV‐specific interferon‐gamma (IFN‐γ)‐producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo‐HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV‐specific T‐cell expansion in a single CMV‐seropositive donor were also conducted. Results Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non‐LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non‐LMV patients exhibiting detectable CMV‐specific T‐cell responses was comparable (7/10 vs. 10/13; p = .71). Nevertheless, median CMV‐specific CD4+ and CD8+ T‐cell counts were lower in LMV patients by days +60 (p = .006 and .02, respectively) and +90 (p = .08 and .02). Ex vivo, CMV‐specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%). Conclusions In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV‐specific T‐cell reconstitution in LMV patients compared to non‐LMV patients was observed.

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Section: Discussionmentioning

confidence: 83%

Section: We Next Compared Cmv-specific T-cell Countsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Features of cytomegalovirus DNAemia and virus‐specific T‐cell responses in allogeneic hematopoietic stem‐cell transplant recipients during prophylaxis with letermovir

Giménez

Guerreiro

Torres

et al. 2023

Transplant Infectious Dis

View full text Add to dashboard Cite

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“…Moreover, the monitoring of CMV-specific responses should probably be more widely adopted for its clinical value in the new era of letermovir prophylaxis [ 16 ]. Since letermovir use potentially delays the occurrence of CMV infection and CMV-specific immune reconstitution, immunological [ 17 ] and virologic monitoring should be implemented after discontinuation of its prophylaxis. More frequent HHV6 [ 10 ] and AdV [ 11 ] cases have been reported across different donor sources and also in an adult setting with PT-Cy approaches [ 2 , 3 ], potentially explaining this trend towards a more careful monitoring of viremia for many centers in recent years.…”

Section: To the Editormentioning

confidence: 99%

Monitoring for virus-specific T-cell responses and viremia in allogeneic HSCT recipients: a survey from the EBMT Cellular Therapy & Immunobiology Working Party

Greco

Hoogenboom

Bonneville

et al. 2023

Bone Marrow Transplant

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Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Solano

Giménez

Albert

et al. 2023

Journal of Medical Virology

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On November 7, 2017, the US Food and Drug Administration approved the use of letermovir (LMV) for prophylaxis of cytomegalovirus (CMV) infection in adult CMV‐seropositive allogeneic stem cell transplant recipients. After 6 years of use, a large body of real‐world experience has been accumulated that validates the Phase III clinical trial results, in which LMV was shown to significantly reduce the risk of clinically significant CMV infection—defined as CMV end‐organ disease or CMV DNAemia requiring pre‐emptive antiviral therapy (PET)—and increase survival up to Week 24 after treatment inception. Notwithstanding, several issues still need to be settled, thus further investigation is required. First, since viral DNA may accumulate as a result of LMV‐driven abortive CMV infection, what is the optimal viral load threshold in the blood that would prompt LMV prophylaxis interruption and PET inception? Should this be adapted to the patient's risk? Second, what is the impact of LMV prophylaxis on the reconstitution of functional CMV‐specific T‐cell responses? Would it be a wise approach to individually tailor the duration of LMV treatment according to the number of peripheral blood CMV‐specific T cells at the end of regular prophylaxis? Third, how frequently do LMV‐resistant strains arise while patients are on LMV prophylaxis and how could this be minimized? Here, we discuss the literature addressing these topics.

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Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis

Cited by 27 publications

References 27 publications

Features of cytomegalovirus DNAemia and virus‐specific T‐cell responses in allogeneic hematopoietic stem‐cell transplant recipients during prophylaxis with letermovir

Features of cytomegalovirus DNAemia and virus‐specific T‐cell responses in allogeneic hematopoietic stem‐cell transplant recipients during prophylaxis with letermovir

Monitoring for virus-specific T-cell responses and viremia in allogeneic HSCT recipients: a survey from the EBMT Cellular Therapy & Immunobiology Working Party

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

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