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Optimal Strategy for CMV Prevention in HCT

CE / CME

Reducing the Burden of Cytomegalovirus in HCT: Optimal Strategy for Prevention

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: July 21, 2023

Expiration: July 20, 2024

Roy F. Chemaly
Roy F. Chemaly, MD, MPH
CME/CE Information

Activity

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Course Completed

Antivirals for CMV Primary Prophylaxis

Historically, antivirals used to suppress CMV were associated with significant toxicity, including severe nephropathy and myelosuppression that increased infection risk. These toxicities made PET a more acceptable option than universal prophylaxis. For example, acyclovir and valacyclovir have poor efficacy. Ganciclovir, valganciclovir, and foscarnet have significant toxicity; and phase III studies of maribavir and brincidofovir for prophylaxis did not meet the primary endpoints.20 However, with better understanding of the risks of CMV viremia and availability of letermovir, which is highly effective and well-tolerated, practice has shifted toward prophylaxis.2,6,9,10,13,20 Letermovir uniquely targets the viral terminase complex, and avoids toxicities associated with other antivirals and limits risk for cross-resistance.21

Letermovir efficacy was established in a phase III study that compared it with placebo for prophylaxis in 565 CMV-seropositive patients undergoing HCT.22 In the study, prophylaxis was initiated a median 9 days after transplantation and continued through Week 14. At Week 24, 37.5% of those receiving letermovir and 60.6% of those receiving placebo had developed csCMVi requiring preemptive treatment. Significant reduction in CMV reactivation was seen in both high-risk and low-risk subgroups.22

Prophylaxis with letermovir improved OS vs placebo following HCT in a prespecified exploratory analysis at 24 weeks of follow-up: 10.2% (95% CI: 6.8-13.6) in the letermovir arm vs 15.9% (95% CI: 10.2-21.6) in the placebo arm (P = .03) (Figure 2).22  At 48 weeks, all-cause mortality in patients who received letermovir prophylaxis was lower than among those who received placebo (20.9% vs 25.5%, respectively, P = .12).22  In another analysis to assess all-cause mortality through Week 48 following letermovir prophylaxis, the hazard ratio was  0.74 (95% CI: 0.49-1.11, P = .14) vs placebo.23 In addition, prophylaxis with letermovir significantly reduced the risk for development of csCMVi after HCT, suggesting that its OS benefit could be related to reduction in CMV reactivation.23 In a meta-analysis of real-world data, letermovir was associated with 27% reduction in risk for all-cause mortality and 35% reduction in risk for nonrelapse mortality beyond 200 days after transplantation.24

Figure 2. All-cause mortality with letermovir CMV prophylaxis after allo-HCT through week 48.22

A single-center retrospective comparative study of 537 consecutive CMV-seropositive HCT recipients found that primary prophylaxis with letermovir was associated with reductions in CMV end-organ disease in the lungs and gastrointestinal tract; reductions in antiviral-resistant or -refractory CMV infections; and lower nonrelapse mortality at Week 48 compared with those not receiving letermovir.25 Subsequently, a meta-analysis of real-world data with letermovir for primary prophylaxis, which included observational studies with 7104 patients who underwent allo-HCT was done. In the analysis, primary prophylaxis with letermovir vs no prophylaxis (with or without PET) was associated with significant reductions in CMV reactivation and reductions in development of csCMVi and CMV disease by Day 100 and Day 200 after transplantation.24 

Expert Insights From Dr Chemaly: A Comparison of Letermovir vs Placebo for Prevention of CMV Reactivation When Used as Primary prophylaxis

In the phase III trial, approximately 10% of all patients and 20% of high-risk patients developed csCMVi after discontinuation of letermovir prophylaxis around Day 100, suggesting longer-duration prophylaxis could be beneficial.7 The optimal duration of letermovir prophylaxis was studied in a phase III trial comparing rates of csCMVi during post-transplant Weeks 14 to 28 (~100-200 days). HCT patients considered at high risk for CMV were randomly assigned to continue letermovir prophylaxis after Day 100 or switch to placebo. Patients who received 200 days of letermovir were less likely to develop csCMVi by Week 28 (2.8% vs 18.9%), and less likely to develop CMV end-organ disease. Treatment failures (csCMVi + discontinuations) occurred in 2.8% with extended letermovir vs 18.9% with placebo (P = .0005).26 

Although highly effective in reducing csCMVi and disease, widespread use of letermovir for primary prophylaxis may raise concerns about antiviral resistance. To address these concerns, some centers have explored a risk-based strategy for primary prophylaxis. Using this approach, 1 single-center study concluded that risk-based letermovir primary prophylaxis effectively protected those at high risk, while allowing most low-risk patients to forego prophylaxis with minimal rates of CMV reactivation, relapse, and development of serious CMV infection.27 

At present, letermovir is approved only for use in adult patients, although it is used in some pediatric centers. A retrospective review of 14 pediatric patients (median age 12 years) who received letermovir prophylaxis concluded that it appears to be well-tolerated and effective.28 A clinical trial in pediatric patients undergoing allo-HCT is ongoing (NCT03948506), and preliminary results in the adolescent age subgroups indicate it is safe and effective.29 Letermovir is not recommended for use in PET strategies given its lower barrier of resistance.7

Only letermovir and ganciclovir are approved specifically for prophylaxis in CMV-seropositive patients undergoing transplantation.14,30 When used as primary prophylaxis, ganciclovir is highly effective against many herpesviruses, but has no survival benefit and the same toxicity issues seen when used in PET, including myelosuppression and secondary bacterial and fungal infections.4 In prophylaxis, it appears that ganciclovir did not improve survival due to the effects of severe neutropenia and secondary fungal infections.6 It was studied in randomized trials as prophylaxis vs placebo in seropositive allo-HCT recipients and significantly reduced rates of CMV infection and CMV disease. In 1 of these studies, ganciclovir-related neutropenia led to treatment interruption in 58% of patients.31 In another study with seronegative recipients, ganciclovir reduced CMV infection and disease, but treatment-associated neutropenia led to higher rates of bacterial infection.32

Neither valganciclovir nor maribavir improved outcomes as prophylaxis. Maribavir was not superior to placebo in a phase III trial, and valganciclovir as prophylaxis did not improve outcomes vs its use in a PET strategy (while still associated with myelosuppression).4,7,13,19,33 The strategy of using prophylactic IV immunoglobulin or CMV-enriched IgG has not demonstrated benefit and its use is not recommended.7

Which of the following is a substantial concern with letermovir?

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