Real-world data confirm effectiveness of letermovir prophylaxis in reducing CMV manifestations in alloHCT recipients

Cytomegalovirus (CMV) infection is a common complication that surfaces in recipients after allogeneic hematopoietic cell transplantation (alloHCT) and may lead to overall detrimental effects on the transplant outcome.1,2 Antiviral prophylaxis (where antivirals are given to all transplant recipients) or preemptive therapies (where antivirals are prescribed only if CMV is detected) are used to counter the risk of CMV infection in alloHCT recipients.3 The success of preemptive therapy depends on early detection, since the early reactivation of CMV in transplant recipients is associated with significant morbidity and mortality.1,2 This leads to the consideration of antiviral prophylaxis, which can effectively prevent early CMV activation.1,2 The mainstay antiviral drugs like valganciclovir, foscarnet, and cidofovir are often associated with a high incidence of toxicity and adverse drug reactions in these patients, propelling the development of novel antivirals.1,2 Letermovir is a relatively novel antiviral drug that targets the deoxyribonucleic acid terminal transferase of CMV and inhibits its maturation.2,4 This medicine was approved by the United States Food and Drug Administration (FDA)  in 2017 as a prophylactic treatment for alloHCT CMV-seropositive recipients, based on the efficacy results of a phase 3 randomized clinical trial.1,2 Letermovir is safe and efficacious with a favorable tolerability profile, but its clinical performance should be persistently monitored in the real-world setting.1,2,5 In the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) held in March 2022, Raval et al. presented the results of a systematic review and meta-analysis of the real-world observational studies on the impact of letermovir as primary prophylaxis in adult alloHCT recipients in a clinical setting.6

A systematic search for relevant studies via PubMed and Embase till September 2021 and conference presentations since 2019 retrieved 576 citations.6 The inclusion criterion was any single-arm or comparative observational study that has evaluated letermovir as prophylaxis in adult alloHCT recipients.6 Of these, 48 studies (N=7,069 patients) met the inclusion criteria.6 Random effect models were used to get pooled estimates of the absolute and relative effectiveness of the letermovir arm vs. the control arm.6 They evaluated cases of CMV reactivation (CMVr), clinically significant CMV infection (cs-CMVi), CMV disease (CMVd), CMV-related hospitalizations, as well as all-cause and non-relapse mortality.6

The investigators found that a majority of the studies were comparative (N=40), single-center (N=43), and were mostly conducted in the United States (N=28), followed by Italy (N=7).6 The recipients in the study varied: 32 studies included any alloHCT recipients, 4 studies had only cord-blood cell recipients, and 12 studies had either cord-blood or unrelated donor recipients, recipients in post-transplant graft vs. host disease setting, and post T-cell depletion recipients.6 The sample size ranged from 12 to 204 in the letermovir arms and 18 to 638 in the control arms.6 Since the study population was diverse, moderate to high heterogeneity was observed.6

The letermovir arms consistently had better outcomes in all parameters evaluated.6 The pooled absolute rates of endpoints in the letermovir vs. control arms were: CMVr (19% vs. 61%), cs-CMVi (10% vs. 58%), and CMV (1% vs. 5%), respectively.6 The letermovir arms had a reduction in the odds of CMVr, cs-CMVi, and CMVd as compared with the control group at day 100 (with moderate heterogeneity) and day 200 (without heterogeneity).6 Moreover, the letermovir arms had lower odds of all all-cause mortality and non-relapse mortality at day 200 post alloHCT (without any significant heterogeneity).6 The rates of CMV-related hospitalizations and resistant/refractory CMV infection were also lower in the letermovir arms as compared with the control arms, as reported in 5 studies.6

Real-world studies measured the effectiveness of an intervention in routine clinical practice in a population that was more heterogeneous, therefore the results were more generalizable than the ones from randomized clinical trials.5 Thus, real-world evidence was practically applicable and the data were pertinent to healthcare providers and patients for making more well-informed decisions.5

All in all, this study is important as it confirmed that letermovir being used as primary CMV prophylaxis in alloHCT receipts can consistently perform better than the control in all parameters under the real-world conditions, also over and above the tightly controlled framework of the randomized clinical trials.5,6

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