Use Of Letermovir Research Articles

Management of cytomegalovirus infection after liver transplantation.

Cytomegalovirus (CMV) infection is one of the primary causes of morbidity and mortality following liver transplantation (LT). Based on current worldwide guidelines, the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive treatment. CMV- IgG serology is the established technique for pretransplant screening of both donors and recipients. The clinical presentation of CMV infection and disease exhibits variability, prompting clinicians to consistently consider this possibility, particularly within the first year post-transplantation or subsequent to heightened immunosuppression. At annual symposia to discuss CMV prevention and how treatment outcomes can be improved, evidence on the incorporation of immune functional tests into clinical practice is presented, and the results of studies with new antiviral treatments are evaluated. Although there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation, a consensus reflected in the guidelines has not been formed. Determining the most appropriate strategy at the individual level appears to be the key to enhancing outcomes. Although prevention strategies reduce the risk of CMV disease, the disease can still occur in up to 50% of high-risk patients. A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant recipients. The objective of this study was to establish a comprehensive framework for the management of CMV in patients who have had LT.

Letermovir use for cytomegalovirus prophylaxis following lung transplantation: A single-center review

Cytomegalovirus (CMV) remains a major cause of infection following solid organ transplant and valganciclovir prophylaxis is the standard of care. However, valganciclovir associated myelosuppression limits its tolerability and can require dose reduction in immunosuppression, particularly cell cycle inhibitors, or changes in antimicrobial prophylaxis. Letermovir, a viral terminase inhibitor, is approved by the FDA for use as CMV prophylaxis in kidney transplant recipients; data on its use in lung transplant recipients (LTRs) is limited. We performed a single-center retrospective cohort study of LTRs prescribed letermovir for prophylaxis between 1/1/18-9/1/23. Over the study period, 88 LTRs were prescribed letermovir with most (93%) switching due to myelosuppression while on valganciclovir. Of those prescribed letermovir, 67 (76%) actually started letermovir, with the primary barrier being insufficient insurance coverage or high copay cost. Among LTRs who started letermovir due to myelosuppression, 90% had improvement in their leukopenia or neutropenia, with a significant increase in white blood cell count one month after switching therapy (P<0.0001). Additionally, 46% of those who were not receiving a cell cycle inhibitor previously were able to restart this after switching to letermovir. CMV was detected in 14 LTRs following letermovir switch, with two discontinuing letermovir due to breakthrough CMV. Our findings support the use of letermovir for CMV prophylaxis in LTRs with possible benefits over valganciclovir, although a direct comparison is needed.

Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients.

Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV). Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0×109/L), severe leukopenia (WBC ≤ 2.0×109/L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection. 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3%vs. 58.6%, p = 0.008), severe leukopenia (57.1%vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9%vs. 51.7%, p = 0.048). Breakthrough (5.7%vs. 3.4%, p = 0.955) and post-PPX (24.6%vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance. In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX.

Phenotypes of cytomegalovirus genetic variants encountered in a letermovir clinical trial illustrate the importance of genotyping validation

Emergence of drug resistance is rare after use of letermovir (LMV) as prophylaxis for post-transplant cytomegalovirus (CMV) infection. In a recent study involving renal transplant recipients, no known LMV resistance mutations were detected in those receiving LMV prophylaxis. However, uncharacterized viral amino acid substitutions were detected in LMV recipients by deep sequencing in viral subpopulations of 5%–7%, at codons previously associated with drug resistance: UL56 S229Y (n = 1), UL56 M329I (n = 9) and UL89 D344Y (n = 5). Phenotypic analysis of these mutations in a cloned laboratory CMV strain showed that S229Y conferred a 2-fold increase in LMV EC50, M329I conferred no LMV resistance, and D344Y knocked out viral viability that was restored after the nonviable clone was reverted to wild type D344. As in previous CMV antiviral trials, the detection of nonviable mutations, even in multiple study subjects, raises strong suspicion of genotyping artifacts and encourages the use of replicate testing for authentication of atypical mutation readouts. The non-viability of UL89 D344Y also confirms the biologically important locus of the D344E substitution that confers resistance to benzimidazole CMV terminase complex inhibitors, but does not feature prominently in LMV resistance.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p=.370). The median (interquartile range) white blood cell (WBC) count was3.1 (2.1-5.6)at LET initiation which increased to5.1 (3.9-7.2)at the end of follow-up (p <.001). For VGCV controls, WBC was4.8 (3.4-7.2)at baseline and5.4 (3.6-7.2)at the end of follow-up; this difference was not statistically significant (p=.395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

(968) - Use of Letermovir as Secondary Prophylaxis in Cardiac Transplant Patient, Mismatch for CMV (d+/r-), Resistant to Ganciclovir and Foscarnet

(968) - Use of Letermovir as Secondary Prophylaxis in Cardiac Transplant Patient, Mismatch for CMV (d+/r-), Resistant to Ganciclovir and Foscarnet

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience

ObjectivesAllogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. MethodsWe conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D−/R−, R+/LTV−, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D−/R− group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. ResultsThe analysis included 1071 consecutive allo-HCT recipients: 131 D−/R−, 557 R+/LTV−, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D−/R− group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV− and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV−, R+/LTV+, and D−/R− groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12–2.99, p 0.017) for R+/LTV− compared with D−/R− and 1.05 (95% CI 0.62–1.77, p 0.85) for R+/LTV + compared with D−/R−. DiscussionCMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.

Current Perspectives on Letermovir and Maribavir for the Management of Cytomegalovirus Infection in Solid Organ Transplant Recipients.

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.

Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity.

The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.

PP105 Efficacy, Effectiveness And Safety Of Letermovir For Prophylaxis Of Cytomegalovirus Infection And Disease Post-Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionClinically significant cytomegalovirus infection (CSI-CMV) is an important factor associated with mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). It is estimated that the incidence of CSI-CMV in the post-HSCT period is 30 percent to 70 percent in transplanted individuals. Therefore, CSI-CMV is considered a complication in allogeneic HSCT, which can trigger Cytomegalovirus disease (CMVD). Letermovir is an antiviral agent indicated especially for the prophylaxis of CMVD post-HSCT. The objective of this work was to evaluate the efficacy, effectiveness and safety of letermovir, comparing it with placebo or other existing prophylactic treatments.MethodsA systematic review was carried out according to PRISMA 2020. A strategy was developed for searching electronic bibliographic databases. Retrieved publications were selected by a pair of reviewers. The same pair performed the data extraction. A qualitative assessment of the efficacy, effectiveness and safety of letermovir was performed.ResultsEighteen studies were included, being experimental and observational. Overall, the pivotal RCT demonstrates the efficacy of letermovir in reducing the incidence of CSI-CMV. However, there was no statistically significant difference in all-cause mortality and letermovir-related overall survival, events of graft versus host disease, neutropenia, acute kidney disease and 48-week mortality. Observational studies, in general, present results similar to those found in the pivotal RCT. The main adverse events associated with letermovir were peripheral edema (14.5%), vomiting (18.5%), headache (13.9%), cough (14.2%), abdominal pain (11.8%) and fatigue (13.4%).ConclusionsThe prophylactic use of letermovir in CMV-R+ patients after allogeneic HSCT demonstrates beneficial results in the prevention of CSI-CMV. However, there were no identified improvements for other outcomes. As for safety, it was observed that there is still little information about adverse events related to the drug, and studies assessing this aspect are needed for better comprehension.

Haploidentical Donor Transplants with Cytokine Release Syndrome Have Increased Risk of Clinically Significant Early CMV Reactivation Compared with Matched Donor Transplants Receiving Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) enables safe haploidentical stem cell transplantation by reducing graft-versus-host-disease (GVHD) but is associated with an increased risk of reactivation of Cytomegalovirus (CMV). PTCy has more recently been adopted for matched-donor transplants, where early CMV reactivation may also be more common. This suggests that CMV reactivation is a function of PTCy rather than donor source. However, other studies comparing the rates of CMV in transplants using PTCy-based prophylaxis suggested disparity in donor source may contribute to CMV reactivation. Aim: The goal of this single-centre, retrospective study was to determine if donor type had any impact on CMV reactivation in the setting of PTCy-based GVHD prophylaxis. Methods: The Alfred Hospital Bone Marrow Transplantation Unit has used PTCy for GVHD prophylaxis in both haploidentical and matched-donor allogeneic stem cell transplants (alloSCT) since 2015. A local database search identified 119 allogeneic peripheral blood alloSCT recipients receiving PTCy-based GVHD prophylaxis between February 2015 and December 2022. Matched-donor alloSCTs also received cyclosporin from Day +5 while haploidentical alloSCTs also received tacrolimus and mycophenolate from Day +5. One patient was excluded due to CMV viremia at the time of transplant. Recipients who were CMV seropositive received therapeutic dose valganciclovir 900 mg twice daily from the start of conditioning until the day prior to stem cell infusion. Prophylactic valganciclovir (900 mg daily) was planned upon engraftment for seropositive recipients and those receiving stem cells from a seropositive donor. CMV DNA PCR was performed weekly for the first 100 days post-transplant and beyond when clinically indicated. CMV viremia was defined as any positive CMV PCR (&amp;gt; 34.5 copies/mL) within the first 100 days post-transplant. Therapeutic valganciclovir was initiated for CMV viral loads (VL) &amp;gt; 1,000 copies/mL or earlier for rapidly rising VLs. Cytokine release syndrome (CRS) was defined as fever &amp;gt; 38 degrees Celsius between stem cell infusion and PTCy on Day +3 without an alternate explanation and graded according to CTCAE criteria. CMV donor and recipient negative transplants were excluded from the analysis of the impact of donor disparity on CMV reactivation. Statistical analyses included Fisher's Exact test, one-way ANOVA and Binomial Logistic Regression. Results: Transplant characteristics according to donor source were similar apart from conditioning intensity, where recipients of haploidentical stem cells were more likely to receive myeloablative conditioning (Table 1). The cumulative incidence of moderate-severe chronic GVHD was significantly higher in matched sibling transplants but overall, 12-month GVHD-free and relapse-free survival were similar. As previously reported, CRS (overall and grades II-IV) was significantly more common in haploidentical transplants. Day 100 CMV viremia rates were not statistically different between donor groups. However, haploidentical transplants trended for earlier CMV reactivation (p=0.08), and were significantly more likely to rise above 250 copies/mL (Table 1 and Figure 1). Consequently, haploidentical transplant recipients received significantly more anti-CMV therapy (p=0.009). Multivariable analysis identified haploidentical donor as a major risk factor for CMV &amp;gt; 250 (odds ratio, OR 1.24, p=0.011) and &amp;gt; 1,000 copies/mL (OR 1.41, p=0.032) while transplant for AML/MDS was negatively associated with CMV &amp;gt; 250 (OR 0.19, p=0.009) and CMV &amp;gt; 1,000 copies/mL (OR 0.16, p=0.003). CRS was significantly associated with CMV &amp;gt; 1,000 copies/mL (OR 3.33, p=0.032) but this was no longer significant in multivariable analysis due to the association with haploidentical donor transplantation. Conclusion: This single-center retrospective comparison of PTCy-based transplants shows that haploidentical transplants have increased risk of early and clinically significant reactivation of CMV. Potential explanations include increased immunosuppression with mycophenolate and the presence of CRS, where inflammatory cytokines may de-repress the CMV major immediate early promoter. Selecting this high-risk group (haploidentical transplants with CRS) may be a cost-effective use of letermovir, which can be initiated prior to engraftment.

Letermovir Prophylaxis for Cytomegalovirus Reactivation in β Thalassemia Major Children after Hematopoietic Cell Transplantation

Background: Cytomegalovirus(CMV) is one of the most important infections following allogeneic haematopoietic stem cell transplantation (HSCT). Although Letermovir is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV seropositive patients. There are limited data for letermovir as primary CMV prophylaxis in pediatric patients . The objective of the study was to analyze the the use of letermovir for prophylaxis from CMV infection in β thalassemia major children undergoing allo-HSCT in a single center. M ethods : This study was an retrospective, single-center evaluation of β thalassemia major pediatric recipients treated by allo-HSCT in the First Affiliated Hospital of Guangxi Medical University. 34 patients included in the study were CMV-seropositive, underwent allo-HSCT, and were started on letermovir for primary CMV prophylaxis between June 2022 and July 2023. CMV monitoring was performed 2 times a week until day +100 after HSCT. The primary end point was CMV reactivation on days +100. Results: 34 patients were analyzed. 20 patients were transplanted from haploidentical donor, 9 patients were transplanted from matched-related donor, 5 patients were transplanted from matched-unrelated donor. The median followed-up was 129 days (range, 50-405 days).The median age was 9 years (range, 2-16 years). The GVHD prophylaxis for matched-related donor group was cyclosporine-based , and the GVHD prophylaxisfor haploidentical and matched-unrelated donor groups were tacrolimus-based. Letermovir start at median 21 days (range 10-35 days) after HSCT. The median weight at the initiation of letermovir was 18.8 kg (range, 12-25 kg). The dose of letermovir was 240mg and 120mg orally once daily in tacrolimus co-administration and cyclosporine co-administration, respectively. During the follow-up period , CMV reactivation was observed in 8 patients totally (23.5%). Among them, 6 patients(17.6%) were in haploidentical donor group. 1 patient (2.9%) in matched-related group and 1 patient (2.9%) in matched-unrelated donor group was CMV reactivated, respectively. Throughout letermovir prophylaxis, the median CMV DNAemia level was 1945 copies (range,526-3800 copies), and the CMV DNAemia lasting time were 17.5 days (range,15-59 days). No patients developed clinically significant CMV infection. 1 patient died because of pulmonary infection of mucor. No serious hepatotoxicity, nephrotoxicity or letermovir intolerance was described. Conclusion: Our data support letermovir prophylaxis efficacy and safety in β thalassemia major children after allo-HSCT.

928. Concordance with Institutional Guidelines for Letermovir Cytomegalovirus Infection Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract Background Cytomegalovirus (CMV) is an opportunistic infection in immunocompromised patients associated with significant morbidity and mortality. Letermovir (LET) is used for prophylaxis for CMV-seropositive allogeneic hematopoietic stem cell transplant (HSCT) recipients. An institutional guideline was developed to provide guidance on the appropriate use of letermovir. The purpose of this study was to determine overall concordance with letermovir institutional guidelines and to identify areas for quality improvement. Methods Our evaluation included adult hospitalized patients admitted from November 2019 to July 2022 for allogeneic HSCT who received LET, identified via medication administration records. The primary outcome was concordance with the institutional guideline criteria for use, as outlined in Figure 1. Secondary outcomes included incidence of breakthrough CMV viremia, use of concomitant HSV prophylaxis, and appropriate management of drug interactions (Figure 1). Results We identified 41 patients who received LET during the study period. After excluding patients who received a solid organ transplant, 32 patients were included in the study. The median time to LET initiation post-transplant was 7 days and the median time to discontinuation was 105 days post-transplant. Overall, 9 patients (28%) were fully concordant with our guidelines. Of the remaining patients, reasons for discordance are summarized in Table 1, mainly driven by continuation of LET &amp;gt;110 days post-transplant (n=12, 37%). Three (9%) patients received LET despite CMV recipient negative serostatus (CMV R-). Breakthrough CMV viremia occurred in 3 patients (9%). All patients received concomitant HSV prophylaxis and had drug interactions managed appropriately. Conclusion Our evaluation identified a lower than expected rate of letermovir guideline concordance, primarily related to the recommended duration of drug therapy. We found that our guideline has supported providers to ensure that concomitant HSV prophylaxis is given and drug interactions are managed appropriately. A further investigation into the use of letermovir in CMV R- subjects and a cost analysis is planned to guide future institutional guideline updates. Disclosures Carolyn D. Alonso, MD, Academy for Continued Healthcare Learning: Honoraria|AiCuris: Advisor/Consultant|American Society of Healthcare Pharmacists: Honoraria|Cidara Therapeutics: Advisor/Consultant|Clinical Care Options: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support

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.

Dynamics of Immune Reconstitution after Unrelated Allogeneic Transplantation with Post-Transplantation Cyclophosphamide Compared to Classical Immunosuppression with ATG

Introduction: Post-transplant cyclophosphamide (PTCY), in hematopoietic stem cell transplantation (HSCT), is responsible for the success of haploidentical stem cell transplantation and is also being used in matched transplants such as unrelated transplants, with promising outcomes in graft versus host disease (GVHD). However, we lack data on immune reconstitution with this type of immunosuppression, especially in unrelated transplantation. Immune reconstitution is directly involved with post-transplant morbidity and mortality, being related to GVHD, relapses and infections, such as cytomegalovirus (CMV). Objectives: To evaluate global and CMV-specific immune reconstitution after unrelated donor HSCT, comparing the use of thymoglobulin (ATG) or PTCY protocol. Methods: We prospectively included patients undergoing first unrelated donor HSCT with ATG, methotrexate and tacrolimus or PTCY (50mg/Kg D+3 and D+4), mycophenolate mofetil (MMF) and tacrolimus with patient and/or donor CMV IgG positive. Immune reconstitution analyzes were performed by flow cytometry and CMV-specific recovery by ELISPot technique on days +30, +60, +90 and +180 post HSCT. Results: Thirty-six patients were included in this study, 20 in the ATG group and 16 in the PTCY group (table 1). Only 2 patients were 9x10 match, and the others were 10x10 match. All patients were submitted to preemptive strategy of CMV treatment, without the use of letermovir. Regarding clinical outcomes, neutrophilic engraftment was earlier with ATG (median of 12 days), compared to PTCY (median of 16 days) (p=0.0001). There was no difference between the groups in terms of length of hospital stay (median 33 days in both groups), CMV reactivation (70% in ATG and 75% PTCY, p=0.98), acute GVHD grades II to IV (p=0.26) or grades III-IV (p=0.56), and chronic GVHD (p=0.45), as well as relapse (p=0.3), non relapse mortality (p=0.77) and overall survival (p=0.4). Regarding immune reconstitution we observed an initial expansion of monocytes and NK lymphocytes in both groups and a higher increase in CD8+ T lymphocytes was evidenced, with an inversion of the CD4/CD8 ratio (CD4 14.9% vs 15.5% p=0.9 and CD8 49.7% vs 54.5%p=0.5 in ATG and PTCY respectively). We identified a CD4+/CD8+ double-positive T cell (DP) population, which was higher in PTCY group compared to ATG on days +30 (3.5% vs 10.2%, p=0.009), +90 (3.1% vs 12% p= 0.01) and +180 (5.2% vs 13%, p=0.007, in ATG and PTCY respectively ). On day +30 there were higher proportion of T cells (19.9% vs 9.6% p=0.004), B cells (0.76% vs 0.2%, p=0.006) and NK cells (19.2% vs 8.6% p=0.006) in ATG group compared to PTCY and monocytes were higher in PTCY (31.7 vs 44.5%, p=0.02). On day +180 the proportion of B cell were higher in PTCY (6.1% vs 16.6% p=0.014) and the NK cells were higher in the ATG (22.4% vs 14.7% p=0.021) (Figure 1), with higher CD56dim population in ATG group (46% vs 33.6% p=0.0079), while in PTCY there were a higher NK population CD56high on day +60 (40.3% vs 61%, p=0.014). We identified a peripheral expansion of a CD56negCD16posNKG2Dpos NK cell population, which was higher in the PTCY group on day +180 (3.7% vs 13.2% p=0.017). Regarding CMV-specific immune response, we found no difference between the groups on days +30 (5 vs 5 spots/10 4 PBMC p=0.41), +60 (10 vs 6 spots/10 4 PBMC p=0.38), +90 (13 vs 4 spots/10 4PBMC p=0.33) or +180 (7 vs 6 spots/10 4 PBMC p=0.57). Conclusions: In the context of unrelated HSCT, we found no difference in CMV-specific immune response with the use of PTCY or ATG protocol. Post-transplant immunosuppression with PTCY compared to ATG protocol is related to lower levels of T cells, NK cells and B cells on day +30 and later neutrophil engraftment, but with a higher proportion of double positive T cells on days +30, +90 and +180 and a higher proportion of B cells on day +180. At 6 months after transplantation, a proportionately lower number of NK cells, but higher proportion of CD56negCd16posNKG2D NK population was observed in the PTCY group.

Real-life experience in two cases of secondary prophylaxis with letermovir for CMV infection in solid organ transplantation.

The use of valganciclovir as secondary prophylaxis for cytomegalovirus (CMV) infection in solid organ transplantation (SOT) is the most prevalent therapeutic choice, but it has been dismissed by the presence of resistance and toxicity. Letermovir (LMV) is indicated as primary prophylaxis in hematopoietic stem cell transplantation, but there is scarce clinical data on its use as secondary prophylaxis in SOT. We present two cases of SOT recipients (lung, liver) who underwent LMV secondary prophylaxis. One patient developed the L595S (UL97)-resistant mutation to ganciclovir/valganciclovir and experienced several CMV relapses under LMV therapy, but no LMV resistance mutations were detected. The second patient developed the C325F (UL56)-resistant mutation to LMV under secondary prophylaxis which was rescued by foscarnet. This observation reviews previously published clinical data on LMV secondary prophylaxis and recommends a cautious use of LMV in the clinical practice due to the early development of UL56 resistance mutations. IMPORTANCE This observation provides comprehensive data on the clinical correlates of both cytomegalovirus (CMV) genotypic follow-up and clinical monitoring and outcomes for two different solid organ transplantation recipients that received letermovir as secondary prophylaxis. Our study emphasizes that monitoring of CMV disease in the patient and early genotypic detection of resistance mutations are essential when using new antiviral drugs for off-label indication in patients experiencing CMV relapses or not responding to standard antiviral therapy. These cases and the bibliography reviewed can be helpful for other researchers and clinicians working in the field to optimize the use of new treatments for transplant recipients since drug-resistant CMV infection is an important emerging problem even with new developments in antiviral treatment.

Letermovir for Cytomegalovirus prophylaxis in pediatric hematopoietic stem cell transplantation.

Letermovir (LTV), an antiviral with exclusive activity against Cytomegalovirus (CMV), is approved for prophylaxis of CMV infection and disease in adult hematopoietic cell transplant (HCT) patients. The use of LTV in the pediatric HCT population is off-label, and has limited literature to support its use. This was a single-center, retrospective, matched (1:1 LTV:non-LTV) cohort study of allogeneic HCT recipients transplanted at Children's Hospital Colorado from 2015 to 2022. The primary endpoint was clinically significant CMV DNAemia (defined as a CMV viral load >1000copies/mL or any CMV DNAemia leading to preemptive treatment) through 6months post transplant. Secondary outcomes included time to clinically significant CMV DNAemia, drug adverse effects, and dose adjustments of concomitant cyclosporine and voriconazole (known drug interactions). We compared 41 patients who received LTV prophylaxis to 41 patients who received no CMV prophylaxis. There was less clinically significant CMV DNAemia through D+180 in the LTV group (9.8% vs. 17.0%, p=.33). Overall, LTV was well tolerated, and 87.8% of patients experienced no adverse effects related to the drug. There was no observed pattern in LTV effect on cyclosporine serum concentrations, but LTV was associated with decreased voriconazole trough levels. In this retrospective study, the use of LTV prophylaxis in pediatric stem cell patients was associated with reduced clinically significant CMV DNAemia through D+180.

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

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.

Absolute lymphocyte counts (ALC) recovery and risk of viral reactivation in the setting of haploidentical hematopoietic stem cell transplant.

e19065 Background: The impact of early absolute lymphocyte repopulation after allogeneic hematopoietic stem cell transplant has historically been shown to predict the risk of post-transplant infection, and subsequently, non-relapse mortality (NRM). Previous studies have shown that ALC recovery after allogeneic stem cell transplant is associated with risk of viral reactivation and survival. In this study we aim to investigate the role of ALC recovery in the contemporary era with myeloablative haploidentical hematopoietic stem cell transplant (HI-HSCT). Methods: We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received myeloablative conditioning haplo-HSCT (Fludarabine with 12 Gy of radiation) from 2014 to 2020. The primary endpoint was correlation between ALC recovery day 21 and risk of viral reactivation including cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and BK virus. ALC recovery cut off was chosen to be 175/uL on day +21 and 500/uL on day +60 based on prior reports. Results: 58 patients were identified as recipients of MAC haploidentical-HSCT. 17 had ALC recovery at day +21. Mean age was 49 years, 31 (53.4%) were males and 27 (46.6%) were females. 41 (70%) patients were Hispanic, 12 (20%) were non-Hispanic White, and the majority had AML (51%). 76% received &gt; 5*106/kg CD34+ cell dose and 78% received CD3 + cell dose &lt; 3*108/kg. Serum CMV, EBV and urine BK virus were detected in 38 (65.5%), 8 (15.7%) and 11 (32.4%) respectively. Clinically significant CMV reactivation (required treatment with antiviral therapy) was detected in 26 (44.8%) patients. Lack of ALC recovery on day +21 did not show correlation with CMV, EBV and BK virus reactivation. Also, the risk of CMV reactivation was not related to day +60 ALC recovery (p-value = 0.469). On univariate analysis, ALC recovery day +21, day +60, and CMV reactivation did not show correlation with overall survival. In multivariate analysis when adjusted for age and pre-transplant CMV status, higher CD 3+ cell dose of &gt; 3*108/kg was associated with reduced risk of CMV reactivation HR = 0.35 (0.15-0.85) p-value = 0.02. Conclusions: Previous studies have established ALC recovery as a predictor of better outcome. This has not been established in patients undertaking myeloablative HI-HSCT. Our study shows that lack of ALC recovery on day +21 does not affect CMV, EBV and BK virus reactivation and risk of CMV reactivation does not correlate with day +60 ALC recovery. Also, ALC recovery and CMV reactivation does not impact overall survival. The use of Letermovir, effective CMV therapies and close viral surveillance in contemporary practice is likely responsible for mitigating poor outcomes with CMV reactivation. Graft composition needs to be studied prospectively, as higher CD3+ cell dose may present an opportunity to reduce CMV reactivation in HI-HSCT.

Effectiveness of letermovir for cytomegalovirus prophylaxis in allogeneic hematopoietic stem cell transplant recipients: A global systematic review

Objective(s)Letermovir (LET), a novel antiviral, has largely supplanted more traditional preemptive therapy (PET) for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HCT) patients. Use of LET demonstrated efficacy against placebo in phase III randomized controlled trials, but is considerably more expensive than PET. This review aimed to evaluate the real-world effectiveness of LET in preventing clinically significant CMV infection (csCMVi) for allo-HCT recipients and related outcomes. DesignA systematic literature review was performed using an a priori protocol using PubMed, Scopus, and ClinicalTrials.gov from January 2010 to October 2021. Setting and ParticipantsStudies were included if they met the following criteria: LET compared with PET, CMV-related outcomes, patients aged 18 years or older, and English language-only articles. Descriptive statistics were used to summarize study characteristics and outcomes. Outcome MeasuresCMV viremia, csCMVi, CMV end-organ disease, graft-versus-host-disease, all-cause mortality. ResultsA total of 233 abstracts were screened, with 30 included in this review. Randomized trials demonstrated efficacy of LET prophylaxis in preventing csCMVi. Observational studies demonstrated varying degrees of effectiveness of LET prophylaxis compared with use of PET alone. All studies with a comparator group resulted in lower rates of csCMVi for patients using LET. Included studies varied widely by CMV viral load threshold cutoff and CMV test units, limiting synthesis of results owing to high heterogeneity. ConclusionLET reduces risk of csCMVi, but lack of standardized clinical definitions on how to evaluate csCMVi and related outcomes largely prevent synthesis of results. Clinicians must consider this limitation in the context of evaluating the effectiveness of LET to other antiviral therapies, especially for patients at risk of late-onset CMV. Future studies should focus on prospective data collection through registries and concordance of diagnostic definitions to mitigate study heterogeneity.