Real World Evidence
Real World Evidence
Disclaimer: The information presented are from on real-world evidence, which may be subject to certain limitations and biases. Real-world studies can lack randomisation and may include selection bias, reporting bias, and variability in data completeness and accuracy. Additionally, the use of historical or non-randomised control groups can introduce confounding factors that may affect the validity of the results. Therefore, while real-world evidence provides valuable insights into clinical use of interventions in diverse patient populations and settings, the results should be interpreted with caution. No definitive conclusions can be drawn without considering these potential biases and limitations.
RWE: Systematic review and meta-analysis
Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies.1
A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients.
A systematic search of MEDLINE/PubMed, Embase, and conferences (from database inception to October 2021) was conducted to identify the studies for inclusion. Forty-eight studies included adults who had an allogeneic HSCT and received PREVYMIS as primary prophylaxis, irrespective of serostatus (N=7104). Prospective or retrospective observational studies utilizing case control or cohort design were included. Studies had either a single arm (no comparator) or a comparator arm (with or without PET).The analysis utilized random-effect models to derive pooled estimates on the relative effectiveness of PREVYMIS primary prophylaxis in comparison to the control arm. Presented below is data for studies that enrolled R+ patients only.
Forty-eight unique studies (n = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P <.05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively.
Outcome
(D+100)a
# of
studies/N
Pooled OR
(95% CI)
P-value
I2b
| CMV reactivation | 9/1670 | 0.11 (0.04-0.29) | <0.01 | 85% | |
| csCMV infection | 10/2127 | 0.11 (0.05-0.25) | <0.01 | 81% | |
| CMV disease | 5/675 | 0.49 (0.13-1.34) | >0.05 | 0% |
aDuration: D+100, follow-up of 100 days or 14 weeks post-HSCT.
bHeterogeneity was examined as I2 statistic along with other parameter as per the Cochrane Handbook for systematic reviews: 30%–60% may represent moderate heterogeneity; 50%–90%, substantial heterogeneity; 75%–100%, considerable heterogeneity. CMV reactivation indicates any CMV DNAemia or viremia; clinically significant CMV infection indicates CMV DNAemia or viremia requiring preemptive therapy.
RWE from Japan: Efficacy2
Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: A single-center retrospective analysis.
Objective was to investigate whether the positive effects of LET for clinically significant CMV infection (csCMVi) in the phase 3 study can be confirmed, and evaluate the influence of LET prophylaxis on transplant outcomes in real-world situations.
A retrospective study. 111 consecutive patients who underwent allogeneic HSCT (allo-HSCT), retrospectively, to evaluate the efficacy of LET prophylaxis for clinically significant CMV infection (csCMVi) in real-world situations were analysed. In addition, the influence of LET on transplant outcomes was analysed. Thirty-eight patients who were administered LET prophylactically were compared with 73 patients without LET prophylaxis after allo-HSCT.
On day 180, the cumulative incidence of csCMVi in patients who received LET prophylaxis was significantly lower than that in patients without LET prophylaxis (29.7% vs. 56.2%, P < 0.001). Among the patients who developed csCMVi, the interval from allo-HSCT to the initiation of preemptive therapy was significantly longer in patients who received LET prophylaxis than in those who did not (129.5 days vs. 42 days, P < 0.001).
Letermovir prophylaxis was effective in preventing csCMVi in allo-HSCT recipients in a real world setting.
RWE from Germany: Efficacy3
Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data.
The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease.
The study cohort consisted of the first seropositive 80 patients who received LET prophylaxis as standard of care and were transplanted at the Heidelberg University Hospital between March 2018 and March 2019. These were compared retrospectively with the last 80 seropositive patients transplanted prior to the implementation of LET in the institutional routine (January 2017–March 2018, control cohort). Primary endpoint was the cumulative incidence of CS-CMVi (CMV reactivation demanding PET, and/or CMV disease) at day +100 post allo-HSCT. All data were obtained by electronic chart review.
Cumulative incidence of CMVi at day +100 (11 events) was 14% in letermovir group, and 41% (33 events) in the control groups (HR 0.29; p < 0.001).
The clinical benefit of letermovir prophylaxis suggested by the approval phase 3 trial could be reproduced in a real-world setting.
References:
- Vyas A, Raval AD, Kamat S, LaPlante K, Tang Y, Chemaly RF. Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies. Open Forum Infect Dis. 2022 Dec 22;10(1):ofac687. doi: 10.1093/ofid/ofac687. PMID: 36726548; PMCID: PMC9879759.
- Yoshimura H et al., Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: A single-center retrospective analysis. J Infect Chemother. 2022 Sep;28(9):1317-1323.
- Derigs P et al., Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann Hematol. 2021 Aug;100(8):2087-2093.
Prevymis (letermovir) 240 mg og 480mg, tabletter og konsentrat til infusjonsvæske, oppløsning.
Indikasjoner: Profylakse mot cytomegalovirus (CMV)-reaktivering og -sykdom hos voksne og pediatriske pasienter som veier minst 15 kg (dersom gitt som tablett) eller minst 5 kg (dersom gitt som infusjonsvæske), som er CMV-seropositive mottagere [R+] i forbindelse med allogen hematopoetisk stamcelletransplantasjon (HSCT). Profylakse mot CMV-sykdom hos CMV-seronegative voksne og pediatriske pasienter som veier minst 40 kg (uavhengig av formulering), som har mottatt et nyretransplantat fra en CMV-seropositiv donor [D+/R-]. Det bør tas hensyn til offisielle retningslinjer for riktig bruk av antivirale midler.
Dosering: Bør initieres av en lege med erfaring i behandling av pasienter som har hatt en allogen hematopoetisk stamcelletransplantasjon eller nyretransplantasjon. Tabletter og konsentrat til infusjonsvæske, oppløsning kan brukes om hverandre etter legens vurdering. Anbefalt dose er 480 mg daglig. Ved samtidig bruk av ciklosporin, skal dosen reduseres til 240 mg en gang daglig. Sikkerhet og effekt hos pasienter under 18 år har ikke blitt fastslått. For oppstart og dosejustering se pkt. 4.2 i SPC. HSCT: Bør startes på transplantasjonsdagen og ikke senere enn 28 dager etter HSCT. Profylakse bør fortsettes i 100 dager etter HSCT. Forlenget behandling utover 100 dager kan være fordelaktig hos noen pasienter med høy risiko. Sikkerhet og effekt ved bruk i mer enn 200 dager ikke undersøkt. Nyretransplantasjon: Bør startes på transplantasjonsdagen og ikke senere enn 7 dager etter nyretransplantasjonen, og fortsettes i 200 dager etter transplantasjonen.
Pakninger og priser (AUP): Tabletter 28 stk.: kr 55506.70. Konsentrat til infusjonsvæske (hettegl. 12ml) 1 stk.: kr 2252.40. Reseptgruppe C. Tabletter: H-resept. HSCT besluttet innført av Beslutningsforum 25.02.2019.
Utvalgt sikkerhetsinformasjon:
Kontraindikasjoner: Samtidig administrering med pimozid, ergotalkaloider eller johannesurt (prikkperikum). Når letermovir kombineres med ciklosporin er samtidig bruk av dabigatran, atorvastatin, simvastatin, rosuvastatin eller pitavastatin kontraindisert.
Forsiktighetsregler:
- Anbefales ikke ved alvorlig (Child-Pugh klasse C) nedsatt leverfunksjon, eller ved moderat nedsatt leverfunksjon kombinert med moderat eller alvorlig nedsatt nyrefunksjon. Effekt og sikkerhet ikke vist ved terminal nyresykdom.
- Overvåkning av CMV-DNA: Sikkerhet og effekt er fastslått ved negativ CMV-DNA-test i forkant av oppstart av profylakse. I tilfeller med klinisk signifikant CMV-DNAemi eller sykdom, bør profylakse med letermovir stoppes, og standard forebyggende behandling mot CMV («pre-emptive therapy» (PET)) eller behandling bør startes opp. Hos pasienter der letermovirprofylakse startes opp og CMV-DNA-test ved baseline senere blir funnet å være positiv, kan profylakse fortsettes dersom PET-kriteriene ikke er oppfylt.
- Risiko for bivirkninger eller redusert terapeutisk effekt som følge av legemiddelinteraksjoner.
Interaksjoner: Se tabell 1 pkt. 4.5 i SPC for interaksjoner og doseringsanbefalinger for andre legemidler. Interaksjonspotensial og kliniske konsekvenser kan være forskjellige avhengig av hvilket letermovir-regime som brukes og om ciklosporin gis samtidig. Når administreringsvei endres, eller dersom immunsuppressivt middel endres, bør man igjen sjekke anbefalinger som gjelder samtidig administrering med andre legemidler (se tabell pkt. 4.5 i SPC). Økt overvåking av ciklosporin, takrolimus, sirolimus anbefales de første to ukene etter å ha startet eller avsluttet letermovir i tillegg til ved endring av administreringsvei for letermovir.
Graviditet, amming, fertilitet: Anbefales ikke under graviditet og hos fertile kvinner som ikke bruker prevensjon. Overgang i morsmelk er ukjent. Det må tas en beslutning om amming skal opphøre eller behandling avstås fra, basert på nytte-/risikovurdering for barnet og for moren.
Bivirkninger: De mest vanlige bivirkningene er kvalme (7,2 %), diaré (2,4 %) og oppkast (1,9 %).
Konsulter PREVYMIS SPC 04/2025 før forskrivning eller bruk for komplett informasjon om dosering, kontraindikasjoner, advarsler og forsiktighetsregler, interaksjoner og bivirkninger.
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