595. Letermovir (LTV) for Secondary Cytomegalovirus (CMV) Prevention in High Risk Hematopoietic Cell Transplant (HCT) Recipients: Interim Results of a Single Center, Open Label Study
Ontology highlight
ABSTRACT:
SUBMITTER: Han G
PROVIDER: S-EPMC8644769 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundIn a phase 3 trial, letermovir reduced clinically significant cytomegalovirus infections (CS-CMVi) and all-cause mortality at week 24 versus placebo in CMV-seropositive allogeneic hematopoietic cell transplantation (HCT) recipients. This post hoc analysis of phase 3 data further investigated the effects of letermovir on all-cause mortality.MethodsKaplan-Meier survival curves were generated by treatment group for all-cause mortality. Observations were censored at trial discontinuation for reasons other than death or at trial completion. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox modeling, adjusting for risk factors associated with mortality.ResultsOf 495 patients with no detectable CMV DNA at randomization, 437 had vital-status data available through week 48 post-HCT at trial completion (101 deaths, 20.4%). Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35-0.98; P = .04) at week 24 and 0.74 (95% CI, 0.49-1.11; P = .14) at week 48 post-HCT versus placebo. Incidence of all-cause mortality through week 48 post-HCT in the letermovir group was similar in patients with or without CS-CMVi (15.8 vs 19.4%; P = .71). However, in the placebo group, all-cause mortality at week 48 post-HCT was higher in patients with versus those without CS-CMVi (31.0% vs 18.2%; P = .02). The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21-1.00; P = .05) at week 48 for letermovir versus placebo.ConclusionsLetermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients.Clinical trials registrationclinicaltrials.gov, NCT02137772.
| S-EPMC7146004 | biostudies-literature
Project description:Abstract Background LET prophylaxis through HCT Week 14 was highly effective in preventing clinically significant CMV infection (CS-CMVi), had a good safety profile, and was associated with lower all-cause mortality by HCT Week 24 compared with placebo (PBO). Patients with detectable CMV DNA at randomization were excluded from the trial’s efficacy analyses (NCT02137772). Here we report the outcomes of these patients. Methods We compared patients randomized 2:1 and treated with LET or PBO who had detectable CMV DNA at randomization (n = 70) to those with undetectable CMV DNA (n = 495; primary efficacy population, PEP). CS-CMVi was defined as CMV viremia requiring antiviral preemptive therapy (PET) or CMV disease; patients with missing data were imputed as events. PET was prescribed blinded to study drug. We analyzed CS-CMVi incidence, CMV viral load (VL) kinetics, and mortality using post study vital status. Detectable, nonquantifiable CMV VL (<151 c/mL) was imputed as 150 c/mL. Results Of 70 patients with detectable CMV DNA at randomization (48 LET, 22 PBO), CMV VL was 150 c/mL in 63 patients (range, 150–716). All patients had undetectable CMV VL ?5 days before randomization. Baseline characteristics were similar to the PEP, except for more patients with myeloablative conditioning (62.9% vs. 48.3%) and longer median days post-HCT to start of study drug (15 days vs. 8 days). Median study drug exposure was 70 days (range, 1–113) in LET group and 14 days (range, 7–99) in PBO group. By HCT Week 14, CS-CMVi occurred in 15 (31.3%) LET-treated patients and 17 (77.3%) PBO patients; CS-CMVi with imputed events were 22 (45.8%) in LET group and 20 (90.9%) in PBO group (difference –44.8%; 95% CI, –64.7% to –24.8%; P < 0.0001). Median CMV VL at time of PET was 413 c/mL (range, 150–31,847) and was similar between groups. Eight patients had quantifiable CMV VL (range, 171–1,728 c/mL) 1 week after starting study drug: 6 did not receive PET (5 LET [10.4%], 1 PBO [4.5%]). CMV VL was undetectable subsequently; other 2 withdrew from study. One (2.1%) LET-treated patient developed breakthrough CMV viremia with a UL56 C325W mutation. HCT Week 48 all-cause mortality was 26.5% in LET and 40.9% in PBO (figure). Conclusion LET prevented CS-CMVi compared with PBO among patients with detectable CMV DNA at randomization. Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. Cidara: Investigator, Research support. Ansun: Investigator, Research support. Gilead: Investigator, Research support. WHISCON: Investigator, Research support. P. Ljungman, Merck: Investigator, Research support. AiCuris: Consultant, Consulting fee. Astellas: Investigator, Research support. Oxford Immunotec: Consultant and Investigator, Consulting fee and Research support. R. F. Chemaly, Merck: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant, Consulting fee. Novartis: Investigator, Research support. Oxford Immunotec: Consultant, Consulting fee. H. Wan, Merck: Employee and Shareholder, Salary. V. L. Teal, Merck: Employee and Shareholder, Salary. J. Butterton, Merck: Employee and Shareholder, Salary. W. W. Yeh, Merck: Employee and Shareholder, Salary. R. Y. Leavitt, Merck: Employee and Shareholder, Salary. C. Badshah, Merck: Employee and Shareholder, Salary.
| S-EPMC6252851 | biostudies-literature
Project description:Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV-seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T-cell-depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 23%]). This was a retrospective, single-center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7 days (range, 7-40) after allo-HCT. The median duration of primary letermovir prophylaxis was 116 days (range, 12-221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty-nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real-world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis.
| S-EPMC8573720 | biostudies-literature
Project description:BackgroundLetermovir (LET), a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) terminase inhibitor, was recently approved for prophylaxis of CMV infection in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. Cytomegalovirus genotyping was performed to identify LET-resistance-associated variants (RAVs) among subjects in a Phase 3 trial.MethodsThe CMV UL56 and UL89 genes, encoding subunits of CMV DNA terminase, were sequenced from plasma collected from subjects with clinically significant CMV infection (CS-CMVi). Novel variants were evaluated by recombinant phenotyping to assess their potential to confer resistance to LET.ResultsGenotyping was successful for 50 of 79 LET subjects with CS-CMVi. Resistance-associated variants (encoding pUL56 V236M and C325W) were detected independently in subjects 1 and 3 who experienced CS-CMVi while receiving LET prophylaxis, and 2 other variants (encoding pUL56 E237G and R369T) were detected >3 weeks after subjects 2 and 3, respectively, had discontinued LET prophylaxis and received preemptive therapy with ganciclovir.ConclusionsThe detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low. The LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture.
| S-EPMC7075417 | biostudies-literature
Project description:BackgroundQuantitative cytomegalovirus (CMV) DNA-specific polymerase chain reaction (PCR) analysis is widely used as a surveillance method for hematopoietic stem cell transplant (HCT) recipients. However, no CMV DNA threshold exists in bronchoalveolar lavage (BAL) to differentiate pneumonia from pulmonary shedding.MethodsWe tested archived BAL fluid samples from 132 HCT recipients with CMV pneumonia and 139 controls (100 patients with non-CMV pneumonia, 18 with idiopathic pneumonia syndrome [IPS], and 21 who were asymptomatic) by quantitative CMV and β-globin DNA-specific PCR.ResultsPatients with CMV pneumonia had higher median viral loads (3.9 log10 IU/mL; interquartile range [IQR], 2.6-6.0 log10 IU/mL) than controls (0 log10 IU/mL [IQR, 0-1.6 log10 IU/mL] for patients with non-CMV pneumonia, 0 log10 IU/mL [IQR, 0-1.6 log10 IU/mL] for patients with IPS, and 1.63 log10 IU/mL [IQR, 0-2.5 log10 IU/mL] for patients who were asymptomatic; P < .001 for all comparisons to patients with CMV pneumonia). Receiver operating characteristic curve analyses and predictive models identified a cutoff CMV DNA level of 500 IU/mL to differentiate between CMV pneumonia and pulmonary shedding, using current CMV pneumonia prevalence figures. However, different levels may be appropriate in settings of very high or low CMV pneumonia prevalence. The presence of pulmonary copathogens, radiographic presentation, or pulmonary hemorrhage did not alter predictive values.ConclusionCMV DNA load in BAL can be used to differentiate CMV pneumonia from pulmonary shedding.
| S-EPMC5461426 | biostudies-literature
Project description:ObjectivesTo date no definitive cut-off value for cytomegalovirus (CMV) DNA load in bronchoalveolar lavage (BAL) fluid specimens has been established to discriminate between CMV pneumonia and pulmonary CMV DNA shedding in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients.MethodsThe current retrospective study is aimed at assessing the range of CMV DNA loads quantified in BAL fluid specimens from allo-HSCT patients with pneumonia in which different microorganisms were causally involved.ResultsA total of 144 BAL specimens from 123 patients were included. CMV DNA was detected in 56 out of 144 BAL fluid specimens and the median CMV DNA load from patients in whom CMV pneumonia was unlikely or could be tentatively ruled out was 1210 (31-68, 920) IU/ml. The frequency of CMV DNA detection and median CMV DNA loads were comparable, irrespective of the attributable cause of pneumonia. Detection of CMV DNA loads in BAL fluid specimens >500 IU/ml was independently associated with pneumonia-attributable mortality.ConclusionsThe current study highlights the difficulty in establishing universal CMV DNA load thresholds in BAL fluid specimens for distinguishing between CMV pneumonia and pulmonary CMV DNA shedding, and suggests that the presence of CMV DNA in BAL fluid specimens beyond a certain level may have a deleterious impact on patient outcome.
| S-EPMC7126576 | biostudies-literature
Project description:Cytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients have a high incidence of CMV-associated complications. There are limited data regarding the efficacy of letermovir for preventing clinically significant CMV infection (CS-CMVi), and the impact of letermovir prophylaxis on delayed-onset CMV reactivation after letermovir discontinuation, in CBT recipients. We compared the cumulative incidence of CS-CMVi and CMV detection in 21 CMV-seropositive CBT recipients receiving letermovir prophylaxis with a historical cohort of 40 CBT recipients receiving high-dose valacyclovir prophylaxis. Letermovir was administered on day +1 up to day +98. The cumulative incidence of CS-CMVi was significantly lower by day 98 in the letermovir cohort (19% vs 65%). This difference was lost by 1 year due to a higher incidence of delayed-onset CMV reactivation in the letermovir cohort. No patients developed CMV disease in the letermovir cohort within the first 98 days compared with 2 cases (2.4%) in the high-dose valacyclovir cohort; 2 patients developed CMV enteritis after discontinuing letermovir. Median viral loads were similar in both cohorts. Thus, letermovir is effective at preventing CS-CMVi after CBT, but frequent delayed-onset infections after letermovir discontinuation mandate close monitoring and consideration for extended prophylaxis.
| S-EPMC8405185 | biostudies-literature
Project description:ObjectivesCytomegalovirus (CMV) infections in liver transplant recipients are common and result in significant morbidity and mortality. Intravenous ganciclovir or oral valganciclovir are the standard treatment for CMV infection. The present study investigates the efficacy of oral valganciclovir in CMV infection as a preemptive treatment after liver transplantation.MethodsBetween 2012 and 2013, 161 patients underwent liver transplantation at Samsung Medical Center. All patients received tacrolimus, steroids, and mycophenolate mofetil. Patients with CMV infection were administered oral valganciclovir (VGCV) 900mg/day daily or intravenous ganciclovir (GCV) 5mg/kg twice daily as preemptive treatment. Stable liver transplant recipients received VGCV.ResultsEighty-three patients (51.6%) received antiviral therapy as a preemptive treatment because of CMV infection. The model for end-stage liver disease (MELD) score and the proportions of Child-Pugh class C, hepatorenal syndrome, and deceased donor liver transplantation in the CMV infection group were higher than in the no CMV infection group. Sixty-one patients received GCV and 22 patients received VGCV. The MELD scores in the GCV group were higher than in the VGCV group, but there were no statistical differences in the pretransplant variables between the two groups. AST, ALT, and total bilirubin levels in the GCV group were higher than in the VGCV group when CMV infection occurred. The incidences of recurrent CMV infection in the GCV and VGCV groups were 14.8% and 4.5%, respectively (P=0.277).ConclusionOral valganciclovir is feasible as a preemptive treatment for CMV infection in liver transplant recipients with stable graft function.
| S-EPMC4420490 | biostudies-literature
Project description:Real-life data on the administration of letermovir as cytomegalovirus (CMV) primary prophylaxis after allogeneic hematopoietic cell transplantation (HCT) remain limited. We conducted a retrospective single-center matched cohort study, comparing consecutive high-risk allogeneic HCT recipients (cases) receiving primary prophylaxis with letermovir and untreated matched historical controls, during a study period of 180 days. The primary outcome was the incidence of clinically significant (cs) CMV infection. Secondary outcomes included duration and costs of CMV-antiviral treatments, hospital resource utilization, hematology and laboratory parameters. Letermovir prophylaxis decreased csCMV infection incidence from 82.7% (controls) to 34.5% (cases; p-value < 0.0001). Controls were more likely to have >1 episode of csCMV infection (59.6%) compared to cases (11.5%; p-value < 0.0001). Letermovir was associated with: shorter overall CMV-associated treatment duration (49 days vs. 77.8 days; p-value: 0.02) and a trend for lower costs of CMV-associated treatments ($4096 vs. $9736; p-value: 0.07) and reduced length of stay (44.8 days vs. 59.8 days; p-value: 0.16). Letermovir administration was associated with significantly shorter duration (27.3 days vs. 57.1 days; p-value: 0.008) and lower costs ($1089 vs. $2281; p-value: 0.008) of valganciclovir treatment. Compared to controls, higher platelet counts were observed in cases (138 G/L vs. 92 G/L; p-value: 0.03) and renal function was improved (94 mL/min/1.73 m2 vs. 74 mL/min/1.73 m2; p-value: 0.006). Primary anti-CMV letermovir prophylaxis decreased the incidence of csCMV infection and the administration of CMV-associated treatments and costs, particularly those associated with valganciclovir. An effect of letermovir on platelet reconstitution and renal function of csCMV post-HCT was observed and needs further investigation.
| S-EPMC8069238 | biostudies-literature
Project description:BACKGROUND:Cytomegalovirus (CMV) viremia after CD34+ -selected hematopoietic stem cell transplant (HCT) often requires prolonged antiviral therapy. We report rates and outcomes of resistant CMV in a contemporary cohort of CD34+ -selected HCT recipients managed preemptively. METHODS:We retrospectively reviewed 220 consecutive, CMV-seropositive recipients (R+), who received CD34+ -selected HCT at Memorial Sloan Kettering Cancer Center between June 2010 and December 2014. Patients were monitored by quantitative CMV PCR and were treated preemptively. CMV resistance was tested by a genotypic assay. RESULTS:One hundred and sixty-one (73%) patients developed CMV viremia and 47 (29% of viremic and 21% of total patients) had CMV resistance testing by one-year from HCT. CMV resistance was confirmed in 19 (12% of viremic and 9% of total) patients and was identified >3 months from HCT in 90% of patients. Twelve patients had mutations in UL97 only; the remaining 7 patients had mutations in UL54 only or UL54 and UL97. By 1 year from HCT, 11 of 19 (58%) patients with mutations had CMV end-organ disease. CMV-related mortality in patients with resistance was 42%. CONCLUSIONS:Nine percent of CMV R+, CD34+ -selected HCT recipients had resistant CMV by 1 year from HCT. Of 19 patients with resistant CMV, 58% had CMV end-organ disease and 42% died of CMV. Effective strategies for CMV prevention and restoration of CMV immunity are needed for CD34+ -selected HCT.
| S-EPMC5988949 | biostudies-literature