Late Cytomegalovirus Research Articles

Challenges for the improvement of valganciclovir prophylaxis in solid organ transplantation and the possible role of therapeutic drug monitoring in adults.

Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring.

#1731 Clinico-epidemiological characteristics of early versus late onset cytomegalovirus disease among renal transplant recipients: two decade experience

Abstract Background and Aims The epidemiology of the Cytomegalo virus (CMV) disease among renal transplant recipients has changed with the advent of effective antiviral prophylaxis usually occurs in the later part of the post transplant period. To study the difference between CMV infections occurring in early versus late post renal transplant period with respect to nature of immunosuppressive medications (induction agents, maintenance agents and heightening of immunosuppression), type of CMV infection and occurrence of biopsy proven rejection post CMV infection. Method A single centre retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between 1st January, 2002 and 31st December, 2021. CMV disease was classified as early or late depending on detection before or after 90 days post transplant. The differences in clinical presentation between early and late onset CMV disease, use of immunosuppression, and the impact on graft outcomes were studied. Results Total number of recipients with CMV disease was 156 (7.2%) out of total 2164 renal transplant recipients. Twenty-five (16%) patients had early CMV while one hundred and thirty one (84%) had late CMV. The two groups did not differ with respect to induction or use of maintenance immunosuppressive agents. Proportion of CMV syndrome was more among early CMV group (56.0% vs 26.7%, p = 0.01) while tissue invasive disease was more frequent among late CMV group (44.0% vs. 73.3%, p = 0.01). Diarrhoea was more frequent in late (63.4%) versus early CMV (36%) (p = 0.01). Graft loss occurred in 4.0% of early and 25.2% of late CMV cases (p = 0.03). However, both groups did not differ with respect to occurrence of biopsy proven rejection post infection. Conclusion Early CMV presents more frequently as CMV syndrome while late CMV usually manifests as tissue invasive disease. Graft loss is more common in patients with late onset disease.

Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques

AbstractPreemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.

Clinico-epidemiological characteristics of early- versus late-onset cytomegalovirus disease among renal transplant recipients: A two-decade experience

BackgroundReactivation of cytomegalovirus (CMV) infection in transplant patients is high because of immunosuppression. We have evaluated the clinical and epidemiological characteristics of early versus late onset of CMV infection among renal transplant recipients. MethodsA single center retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between January 2002 and December 2021. CMV disease was classified as early or late depending on its detection prior to or after 90 days post-transplantation. Herein, we reported the differences between early and late onset of CMV disease with respect to clinical symptoms, the use of immunosuppression and the impact on graft outcomes. ResultsOut of total 2164 renal transplant recipients, 156 patients (7.2%) were diagnosed with CMV disease. Among these 156 patients, 25 patients (16%) had early CMV while 131 patients (84%) had late CMV. Overall, the two groups did not differ with respect to the induction or maintenance of immunosuppressive agents. However, the proportion of CMV syndrome was greater among early (56.0%) than late (26.7%) CMV groups (p = 0.01). In contrast, tissue invasive disease was more frequent among late (73.3%) in comparison to early (44.0%) CMV groups (p = 0.01). Among clinical symptoms, diarrhea was more frequent in late (63.4%) vs. early (36%) CMV-affected patients (p = 0.01). Graft loss occurred in 4.0% of early CMV group vs. 25.2% of late CMV group (p = 0.03). Neither of the clinical groups differed with respect to occurrence of biopsy-proven allograft rejection post-infection. ConclusionsEarly CMV disease presents more frequently as CMV syndrome while late CMV disease usually manifests itself as tissue invasive disease. Graft loss is more common in patients with late onset of CMV disease.

Risk Factors for CMV Infection, Including HLA Disparity and Ptcy Transplant in the Era of Letermovir Prophylaxis

Reports suggest that post-transplant cyclophosphamide (PTCy) for haploidentical and HLA-matched sibling donor allogeneic stem cell transplant (allo-SCT) is associated with a higher incidence of cytomegalovirus (CMV) infection than calcineurin inhibitor (CNI) for HLA-matched sibling donor allo-SCT. Prophylactic letermovir has been shown effective for CMV seropositive patients, based on the data mostly before the FDA approval of letermovir (2017). We reevaluated the risk of CMV infection in PTCy transplants. We retrospectively analyzed 175 patients after allo-SCT between May 2019-May 2022). CMV infection was monitored at least for the first year by serostatus, viral load over 500 IU/mL, and/or evidence of CMV end-organ disease. Univariate and multivariate Cox regression analyses were used for the factors, including CMV serostatus, use of letermovir, GVHD prophylaxis, and HLA disparities, to affect the risk of CMV infection and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS). Cumulative incidence curves were used to visualize the incidence of CMV infection stratified by HLA match and PTCY use. A landmark analysis at Day +100 was used for GRFS, where patients who had CMV infection beyond Day +100 (N=13) were assigned to the no-infection group. Of the 175 patients, 108 received HLA-matched donors with GVHD prophylaxis, either CNI (N=70) or PTCy (N=38), while 67 received HLA mismatched donors with either CNI (n=6) or PTCy (N=66) ( Table). Letermovir was given to 137 patients (CMV IgG positive N=130, negative N=7) but not to 38 patients (CMV IgG positive N=12, negative N=26). CMV infection occurred in 28 patients (CMV IgG positive N= 28, CMV IgG negative N=0) before or after Day +100 (N=15 or N=13, respectively). CMV IgG positive recipients not receiving letermovir demonstrated a higher risk of infection by Day +100 than those receiving letermovir (Hazard ratio (HR) 10.1 (95% confidence interval (CI) 3.6-28.6), p&amp;lt;0.01). All 13 infections after Day +100 occurred after the cessation of letermovir (median: 82.9 days after cessation). On univariate analysis, PTCy and HLA mismatch donors increased the risk of CMV infection. The risk of infection by Day +100 increased with PTCy (p=0.07). The risk of infection after Day +100 increased with HLA mismatch donors (p=0.05). In addition, it was confirmed that HLA mismatch allo-SCT with PTCy increased the risk of CMV infection over matched allo-SCT with CNI ( Figure, HR 4.6 (95% CI 1.6-11.9), p&amp;lt;0.01), while HLA match allo-SCT with PTCy did not (p=0.3) (Figure 1). The trend was similar when analyzed only in the case of CMV infection by Day +100 (p&amp;lt;0.05) and after Day +100 (p=0.1). In the 130 CMV IgG seropositive patients who received letermovir, multivariate analysis showed that HLA mismatch donors with PTCy increased the risk of CMV infection over HLA match allo-SCT with CNI. When analyzed only for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome with letermovir (N=91), HLA mismatch transplant with PTCy increased the risk of CMV infection over HLA match transplant with CNI (p=0.05), but not for HLA match transplant with PTCy. Landmark analysis demonstrated better GRFS in the PTCy group than the CNI group and in patients who received PTCy with CMV infection than those who received CNI without CMV infection (p&amp;lt;0.01). PTCy increased the incidence of CMV infection in HLA mismatch allo-SCT by D+100 but not HLA match allo-SCT in the era of letermovir prophylaxis. Patients with PTCy transplant who overcome CMV infection have improved GRFS, possibly due to the increased graft-versus-leukemia effect. Further analysis is required to confirm the difference in the incidence of CMV infection between HLA match and mismatch transplant with PTCy and to assess the significance of late CMV (after Day +100) infection on GRFS.

Clinical significance of late CMV disease in adult patients who underwent allogeneic stem cell transplant

IntroductionLate cytomegalovirus (CMV) disease, which was defined as CMV disease occurring >100 days post-transplant, remains an important complication among allogeneic stem cell transplant recipients, even now that the prophylactic strategy using ganciclovir preemptive therapy has been established. Due to the recent expansion of donor sources and conditioning regimens, it is therefore appropriate to reevaluate the incidence, risk factors, and clinical impacts of late CMV disease. MethodsThis study included the 1295 adult patients, who underwent transplant for the first time from 2008 to 2015, without underlying disease relapse or CMV disease within 100 days post-transplant. There were no restrictions on underlying diseases or transplant procedures. ResultsDuring the median follow-up period of 48.4 months, 21 patients developed late CMV disease and the 5-year cumulative incidence of late CMV disease was 1.6%. By multivariate analysis, haploidentical related donor, adult T-cell leukemia lymphoma, and preemptive therapy before 100 days post-transplant were extracted as independent risk factors. Late CMV disease negatively affected transplant outcomes, and was identified as an independent risk factor for the non-relapse mortality rate (hazard ratio 3.83, p < 0.001) and overall survival rate (hazard ratio 4.01, p < 0.001). Although 17 of 21 patients with late CMV disease died, the main causes of death were not related to CMV, except in three patients with CMV pneumonia. ConclusionsAlthough the incidence of late CMV disease is low in transplant recipients, this complication negatively affects clinical courses. Therefore, transplant recipients with these risk factors should be more carefully managed.

The Best Method for CMV Prevention in High-risk Kidney Transplant Recipients? Either, per National Norwegian Transplant Database: Commentary on Blom et al, Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

The Best Method for CMV Prevention in High-risk Kidney Transplant Recipients? Either, per National Norwegian Transplant Database: Commentary on Blom et al, Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation.

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n= 44), mycophenolate mofetil (MMF; n= 414), or methotrexate (MTX; n= 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference= 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference= 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Clinical Value of Serial Quantitative Analysis of Cytomegalovirus DNA in Blood and Saliva Over the First 24Months of Life in Congenital Infection: The French Cymepedia Cohort.

To evaluate cytomegalovirus (CMV) viral load dynamics in blood and saliva during the first 2years of life in symptomatic and asymptomatic infected infants and to identify whether these kinetics could have practical clinical implications. The Cymepedia cohort prospectively included 256 congenitally infected neonates followed for 2years. Whole blood and saliva were collected at inclusion and months 4 and 12, and saliva at months 18 and 24. Real-time CMV polymerase chain reaction (PCR) was performed, results expressed as log10 IU/mL in blood and in copies per milliliter in saliva. Viral load in saliva progressively decreased from 7.5 log10 at birth to 3.3 log10 at month 24. CMV PCR in saliva was positive in 100% and 96% of infants at 6 and 12months, respectively. In the first month of life, neonatal saliva viral load of less than 5 log10 was related to a late CMV transplacental passage. Detection in blood was positive in 92% of neonates (147/159) in the first month of life. No viral load threshold values in blood or saliva could be associated with a high risk of sequelae. Neonatal blood viral load of less than 3 log10 IU/mL had a 100% negative predictive value for long-term sequelae. Viral loads in blood and saliva by CMV PCR testing in congenital infection fall over the first 24months. In this study of infants affected mainly after primary maternal infection during pregnancy, all salivary samples were positive in the first 6months of life and sequelae were not seen in infants with neonatal blood viral load of less than 3 log10 IU/mL.

Prognostic outcomes of cytomegalovirus reactivation after autologous stem cell transplantation.

Background: Cytomegalovirus (CMV) reactivation is a common complication in patients undergoing allogeneic stem cell transplantation. However, the incidence of CMV reactivation is low after autologous stem cell transplantation (auto-SCT), and the prognostic value of CMV reactivation remains controversial. Moreover, reports on late CMV reactivation after auto-SCT are limited. We aimed to analyze the association between CMV reactivation and survival outcomes and develop a predictive model for late CMV reactivation in patients undergoing auto-SCT. Methods: Data of 201 patients who underwent SCT at the Korea University Medical Center from 2007 to 2018 were collected. We analyzed prognostic factors for survival outcomes after auto-SCT and risk factors for late CMV reactivation using a receiver operating characteristic curve. Then, we developed a predictive risk model for late CMV reactivation based on results of the risk factor analysis. Results: Early CMV reactivation was significantly associated with better overall survival (OS) (hazard ratio [HR], 0.329; P = 0.045) in patients with multiple myeloma; however, no significant differences were observed in patients with lymphoma. For late CMV reactivation, a serum lactate dehydrogenase level greater than the upper limit of normal (HR, 2.251; P = 0.027) and late CMV reactivation (HR, 2.964; P = 0.047) were independent risk factors for poor OS, while lymphoma diagnosis (vs. multiple myeloma; HR, 0.389; P = 0.016) was an independent risk factor for good OS. In risk factor analysis for late CMV reactivation, T-cell lymphoma diagnosis (odds ratio [OR], 8.499; P = 0.029), ≥ two prior chemotherapies (OR, 8.995; P = 0.027), failure to achieve complete response (CR) after transplantation (OR, 7.124; P = 0.031), and early CMV reactivation (OR, 12.853; P = 0.007) were significantly associated with late CMV reactivation. To develop the predictive risk model for late CMV reactivation, a score (1 to 1.5) was assigned for each of the above-mentioned variables. The optimal cutoff value (1.75 points) was calculated using the receiver operating characteristic curve. The predictive risk model showed good discrimination, with an area under the curve of 0.872 (standard error, 0.062; P < 0.001). Conclusions: Late CMV reactivation was an independent risk factor for inferior OS, whereas early CMV reactivation was associated with better survival in patients with multiple myeloma. This risk prediction model could be helpful in identifying high-risk patients who require monitoring for late CMV reactivation and potentially benefit from prophylactic or preemptive therapy.

2098. Cytomegalovirus (CMV) Infection Following Hematopoietic Cell Transplantation (HCT) with Post-transplant Cyclophosphamide (PTCy): Outcomes in Haploidentical versus Matched or Mismatched Unrelated Donor (MUD/MMURD) Allografts

Abstract Background PTCy is increasingly being used in MUD/MMURD, and haploidentical donor HCT for prevention of graft-versus-host disease (GVHD). PTCy has been associated with increased risk of infections including CMV viremia after HCT. It remains unclear if this observation is independent of graft type. This study aims to evaluate the incidence of clinically significant CMV infection (CS-CMVi) following PTCy in MUD/MMURD compared to haploidentical donor HCT. Methods We performed a single-center retrospective study of all adults undergoing HCT with PTCy between January 1, 2015 and July 1, 2021. CS-CMVi, defined as CMV viremia or disease requiring initiation of CMV therapy, was evaluated in two groups: haploidentical HCT (n=170) and MUD/MMURD HCT (n=137). We assessed the incidence of CMV viremia, CS-CMVi, and CMV disease, as well as incidence of letermovir breakthrough infections and late CMV events after cessation of prophylaxis. Cumulative Incidence Functions were calculated based on time to CS-CMVi using dates of infection-free death, disease relapse, and repeat HCT as competing risks. Results The one-year cumulative incidence of CS-CMVi accounting for competing risks was 25% (95% CI 19 – 32) in the haploidentical group and 18% (95% CI 12 – 25) in the MUD/MMURD group (HR 1.50; 95% CI 0.91 – 2.46; p=0.11). CMV disease was rare, (haploidentical n=1; MUD/MMURD n=1) and no patients died of CMV infection. CS-CMVi in CMV seropositive patients was more common in the haploidentical group (23% versus 9%; p=0.002). Notably, CMV D+/R- HCT patients had a significantly higher rate of CS-CMVi in the MUD/MMURD cohort than in the haploidentical cohort. Of the CS-CMVi, letermovir breakthrough constituted 26% in the haploidentical group and 29% in the MUD/MMURD group. Late infections after cessation of letermovir occurred in only 14% of cases in the haploidentical group and 25% of cases in the MUD/MMURD group. Conclusion Rates of CS-CMVi, CMV viremia, and CMV disease were similar following PTCy in haploidentical donor HCT and MUD/MMURD HCT. CS-CMVi in CMV seropositive patients was more common in the haploidentical donor HCT population and MUD/MMURD HCT recipients had a higher incidence of CS-CMVi in the D+/R- patients. Disclosures Roman M. Shapiro, M.D., Miltenyi Biotec: Honoraria Rizwan Romee, M.D., Crispr Therapeutics: Grant/Research Support|Glycostem Therapeutics: Advisor/Consultant|NK Therapeutics: Advisor/Consultant|Skyline Therapeutics: Grant/Research Support Robert J. Soiffer, M.D., CSL Behring: Advisor/Consultant|Gilead: Career Chair Development Award|Jasper Therapeutics: Advisor/Consultant|Jazz Pharmaceuticals: Advisor/Consultant|Juno (BMS): DSMB|Kiadis: Board Member|Vor: Advisor/Consultant Vincent T. T. Ho, M.D., Alexion Pharmaceuticals: Advisor/Consultant|Allovir: Advisor/Consultant|Allovir: DSMC|Jazz Pharmaceuticals: Grant/Research Support|Omeros: Advisor/Consultant Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support.

Breakthrough CMV Viremia Outcomes of Letermovir Prophylaxis in Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide

Background Cytomegalovirus (CMV) causes significant morbidity and mortality in patients who have undergone allogeneic transplant with 45-60% mortality rates or end-organ failure related to CMV disease secondary to immunosuppression. The use of post-transplant Cyclophosphamide (PT-Cy), commonly used in haploidentical transplants (haplo-SCT), has been associated with high rates of CMV infection, reported to be 42% based on a CIBMTR analysis performed in 2021. Letermovir is FDA approved for prevention of CMV infection and disease in adult CMV-seropositive recipients [R+] undergoing allogeneic hematopoietic stem cell transplant (SCT). Despite the use of letermovir to decrease incidence of CMV, there has been limited literature on the incidence of CMV breakthrough infections in haplo-SCT patients receiving letermovir. We set out to quantify the incidence of breakthrough CMV infections in patients undergoing haplo-SCT with PT-Cy receiving letermovir prophylaxis. Endpoints The primary endpoint was to determine the incidence of breakthrough CMV reactivation (single quantifiable viral load of >200 CMV IU/mL of plasma, 2 detectable viral loads of <200 CMV IU/mL of plasma tested 3-4 days apart) both early <100 days post-transplant and late >100 days. Key secondary end points were mortality due to CMV infection, incidence of disease, end organ involvement, duration of CMV treatment, risk factors associated with CMV reactivation (based on age, sex, and seropositive status), and timing of CMV infections after haploidentical transplant. Methods This single-center, retrospective, cohort study was performed at OHSU under an IRB approved protocol. Electronic health records of patients from January 2017 to September 2021 were retrospectively reviewed to assess incidence of breakthrough CMV infection. Eligible patients were at least 18 years of age, received a haploidentical hematopoietic stem cell transplant, and received PT-Cy for graft vs host disease (GVHD) prophylaxis. Those discovered to have active CMV infections (defined as..) during conditioning who were later put on letermovir or foscarnet for treatment of their CMV reactivation were excluded. These data have been previously reported. A posthoc analysis was then performed comparing patients who received letermovir prophylaxis with a historical treatment group that underwent haplo-SCT and receive an identical treatment protocol, but did not received letermovir prophylaxis. Patients were matched by age and CMV seropositive status in a 2:1 ratio (letermovir: no letermovir), and analyzed for comparative CMV related outcomes. Results: A total of 14 eligible study subjects received letermovir prophylaxis (LP) and 7 patients did not receive letermovir prophylaxis (NLP). Overall, median age was 45 years in both groups with LP group being more male (63%) and the NLP being more female (70%) (Table 1). Thirteen of the 21 subjects received myeloablative conditioning. All subjects received PTCy, MMF until D+35 and tacrolimus goal 5-10 until D100. Letermovir was started 5 days post-transplant and stopped 100 days post-transplant. The number of patients that experienced early CMV reactivation (<100 days) was 3/14 (21.4%) and 6/7 (85.7%) in the LP and NLP treatment groups, respectively. Late CMV reactivations were rare, the LP group had 1 patient reactivate past 100 days post-transplant while there were no patients who reactivated past 100 days in the no NLP group. Mean timing of CMV viremia for the LP was significantly longer at 62 days while the NLP group was at 36.5 days. No significant risk factors were associated with age, CMV recipient seropositivity, or sex. Duration of CMV treatment was 23 days for the LP group and 21 days for the NLP group. Importantly, no patients in either cohort died of CMV (Table 2). Discussion/Conclusion: Overall, we found the LP was associated with significantly less CMV reactivations, indicating that letermovir provides effective CMV prophylaxis for patients undergoing haplo-SCT with PT-Cy. Interestingly, mean timing of CMV viremia was later for the LP group compared to the NLP group. In our cohort, we did observe 1 patient who reactivated CMV late post-transplant. This observation and the results of a study published by L.W.Liu et al. (doi: 10.1016/j.jtct.2022.05.020.) may suggest that letermovir prophylaxis past day 100 post-transplant may be indicated for haplo-SCT patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

Letermovir Discontinuation at Day 100 After Allogeneic Stem Cell Transplant Is Associated With Increased CMV-Related Mortality

Letermovir is approved by the Food and Drug Administration for cytomegalovirus (CMV) prophylaxis in CMV seropositive recipients of allogeneic stem cell transplantation (alloSCT) up to day 100. Letermovir use up to day 100 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) at 24 weeks and an overall mortality benefit as far as 48 weeks after transplantation. We report data on csCMVi incidence beyond 24 weeks and overall survival (OS) beyond 48 weeks and outcomes for patients who had a prior alloSCT, are CMV seronegative with seropositive donor (D+/R−), or are high risk (defined as those receiving haploidentical transplants, mismatched transplants, T-cell–depleted grafts, umbilical cord blood transplants, prednisone ≥1 mg/kg or equivalent steroid use, or the use of 2 or more immunosuppressants). Additionally, risk factors for CMV-related mortality and possible extended duration of letermovir are reported. This is a single-center, retrospective cohort study of 333 alloSCTs with CMV seropositive donors or recipients performed at Siteman Cancer Center and Barnes-Jewish Hospital from January 2016 to June 2019. The primary endpoint of csCMVi at day 180 was 19.46% with letermovir and 39.13% without letermovir (P < .0001). The secondary endpoints are as follows: day 100 csCMVi was 8.1% with letermovir and 34.8% without (P < .0001), day 365 csCMVi was 24.8% with letermovir and 41.3% without (P = .001). Our multivariate analyses demonstrated that exposure to letermovir was associated with improved OS (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.25-0.77), nonrelapse mortality (HR 0.50; 95% CI 0.27-0.94) and CMV-related mortality (HR 0.40; 95% CI 0.16-0.95) during day 0 to day 99 but worse CMV-related mortality during day 180 to day 364 (HR 3.19; 95% CI 1.29-7.92). Patients with serum IgG levels <400 mg/dL at day 100, high-risk transplants (P = .004), post-transplantation cyclophosphamide (PTCy; P = .001), and mismatched-unrelated donors (MMUD; P = .02) experienced increased CMV reactivation. The CMV D+/R− cohort demonstrated no difference in CMV reactivation overall (P = .19), but the subset receiving PTCy showed decreased reactivation with letermovir (P = .03). Discontinuation of letermovir at day 100 leads to increased incidence of late CMV reactivation and CMV-related mortality. Letermovir use in CMV recipient seropositive alloSCT may need to be extended. Serum IgG levels <400 mg/dL at day 100 was associated with increased CMV reactivation. Patients with subclinical CMV viremia before transplantation, high-risk transplants, PTCy, or MMUD had decreased CMV reactivation with letermovir. Although there was no difference in CMV reactivation in the CMV D+/R− cohort, the subset treated with PTCy for acute graft-versus-host disease prophylaxis had decreased CMV reactivation with letermovir.

Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis.

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131days after transplantation and 30days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with "high-risk" donors.

Late Cytomegalovirus Primoinfection in a Heart Transplant Recipient After COVID-19 Vaccine

IntroductionCytomegalovirus [CMV] is a frequent infection in solid organ transplant recipients and the mRNA COVID-19 vaccine has been associated with transient lymphopenia, which could be a risk factor to consider for CMV replication.Case ReportA 51-year-old man with arterial hypertension and a history of repaired complex congenital heart disease, which required a heart transplant [HT] in 2019. He had a high risk CMV missmatch (D+/R-). Routine HT follow up tests after the first year were normal, with neither signs of rejection nor allograft vascular disease. His immunosuppressive treatment consisted in Tacrolimus 5 mg once a day, Mycophelonate 500 mg twice a day, and Prednisone 5 mg a day. 77 weeks after his heart transplant, two doses of mRNA COVID-19 vaccine were inoculated separated by 28 days. After 4 days of the second dose, he developed fever, diarrhea, and general malaise. The physical findings were abdominal pain, slight hepatomegaly and several painful gum lesions. Laboratory tests showed severe lymphopenia; and elevated C-reactive protein. CMV by polymerase chain reaction was tested positive with 228.356 copies/ml. The decision was to admit him and to initiate intravenous ganciclovir 5 mg/kg twice a day and to reduce the immunosuppressive treatment. He completed a course of 15 days with ganciclovir, and then continued with valganciclovir 900 mg twice a day. Early after ganciclovir start, clinical manifestations gradually disappeared. Due to persistent lymphopenia, mycophenolate was switched to everolimus. After 60 days of antiviral treatment, CMV loading was below detection range (Image 1).SummaryThe probability of favoring CMV replicability after mRNA COVID-19 vaccine has not been yet described. We here present a case of CMV primoinfection closely related in time with a full mRNA COVID-19 vaccine administration. We hypothesize that lymphopenia and a high risk CMV could be factors to consider at the time of mRNA COVID-19 vaccine administration. A close CMV monitoring should be advised in this scenario.

Assessment of Risk Factors and Outcome of Early Versus Late Cytomegalovirus Infection Infection in Living-related D+/R + Renal Allograft Recipients.

Introduction:Cytomegalovirus infection (CMV) in a kidney transplant recipient (KTR) is a serious complication resulting in increased morbidity, mortality and reduced graft survival. There is limited data on early (within 3 months posttransplant) CMV infection (ECMVI) vs. late CMV infection (LCMVI) in patients not receiving CMV prophylaxis. In India, majority of kidney transplants are D + R + combination. This study aimed to compare the risk factors and outcome of ECMVI vs. LCMVI in living related post-KTR.Methods:This was a single-center ambispective study of adult KTR from living donor between January 2001 and December 2015 who had CMV infection. This study had two cohorts: retrospective and prospective. Retrospective cohort included all KTR from January 2001 to September 2014. Prospective cohort included KTR who received transplants from October 2014 to December 2015. Of both cohorts, patients with early and late CMV infection were included. All patients received triple-drug immunosuppression. CMV infection was diagnosed when KTR had detectable CMV copies > 500/mL. In the prospective cohort, CMV PCR was done at 45 days, 3, 6, 9 and 12 months in all patients. Patients with CMV were treated on conventional lines. All patients were followed up till June 2016.Results:Of 2175 retrospective cohort, 97 and of the 155 prospective cohorts 75 had CMV infection, total being 172 CMV infections. Of these, 90 patients had ECNVI and 82 LCMVI. Induction was used in 48.8% in ECMVI group vs. 35.3% in LCMVI group (p = 0.02). CNI toxicity was present prior to CMV infection in 15 (17.4%) in ECMVI as compared to 14 (17.9%) in LCMVI (P = 0.93). In the ECMVI, 6 (6.6%) had acute rejection as compared to 13 (15.8%) in the LCMVI (P = 0.05). While asymptomatic CMV infection was more common in early (63.3% vs 37.8%, P = 0.001), symptomatic CMV without tissue diagnosis was more common in late (54.8% vs. 31.1%, P = 0.002). Total duration of post-transplant follow-up was 22.8 ± 22.1 months in ECMVI as compared to 49.7 + 40.9 months in the LCMVI (P < 0.001). The serum creatinine at last follow-up was 1.9 ± 1.6 mg/dL in ECMVI group and 2.4 ± 2.0 mg/dL in LCMVI (P = 0.02).Conclusion:In D+/R + living renal transplant recipients, without routine CMV prophylaxis, late CMV infection had more tissue invasive disease and is associated with inferior graft function on long-term follow-up.

Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation

AbstractDecreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

Late onset CMV disease presenting as a colonic stricture in a liver transplant recipient

Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant (SOT) recipients in the first 6months after transplant. Late onset CMV infection or disease outside the classical risk period is uncommon and can present with atypical signs and symptoms. Here, we report a case of late onset CMV presenting as a colonic stricture more than 10years after liver transplantation in the absence of traditional CMV risk factors. We also briefly review CMV colitis presenting as a mass or stricture in SOT recipients.