By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A Phase III, randomized, double-blind, placebo-controlled superiority trial that included patients 18 years of age or older undergoing allogeneic hematopoietic stem cell transplantation found that prophylaxis with letermovir resulted in significantly lower risk for cytomegalovirus infection in the first 24 weeks than placebo. Safety and adverse events were similar between letermovir and placebo.

SOURCE: Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:2433-2444.

Reactivation of cytomegalovirus (CMV) is a major complication following hematopoietic stem cell transplantation (HSCT), especially in CMV-seropositive recipients. Prophylaxis options after HSCT are limited due to the myelosuppression that occurs with available antiviral agents (i.e., ganciclovir and valganciclovir). Marty and colleagues evaluated the safety and efficacy of letermovir, a recently FDA-approved inhibitor of the CMV-terminase complex, for CMV prophylaxis after HSCT in CMV-seropositive recipients.

The study was a Phase III, randomized, double-blind, placebo-controlled superiority trial that included patients 18 years of age or older undergoing allogeneic HSCT at 67 centers in 20 countries. Patients were eligible for inclusion if they were CMV-seropositive, had an undetectable CMV plasma DNA level within five days of randomization, and could start taking the trial drug by day 28 post-transplantation.

Exclusion criteria included severe liver or renal disease and current or recent receipt of a drug with anti-CMV activity. Asian patients were excluded briefly due to concerns related to pharmacokinetic issues, but the concerns were resolved, and these patients were included in the analysis.

The patients were randomized in a 2:1 ratio to receive letermovir or placebo through week 14 after transplantation. Letermovir was prescribed at 480 mg daily except for those patients receiving cyclosporine, whose dose of letermovir was decreased to 240 mg daily due to a drug-drug interaction. Patients were evaluated weekly through week 14 after transplantation, then every two weeks through week 24, then every other month through week 48. Plasma CMV DNA was measured at every visit.

Those who developed clinically significant CMV infection discontinued the trial regimen and began anti-CMV therapy according to local practice. The primary endpoint was the proportion of patients with clinically significant CMV infection through week 24 after transplantation among patients without detectable CMV DNA at randomization. The secondary endpoints were the proportion of patients with clinically significant CMV infection through week 14 and the time to clinically significant CMV infection.

Of the 570 patients who underwent randomization, 295 of those assigned to receive letermovir and 136 of those assigned to receive placebo completed the trial to week 24. Patients began either letermovir or placebo a median of nine days (range, 0 to 28 days) following HSCT. Fewer patients in the letermovir group compared to the placebo group developed a clinically significant CMV infection in the first 24 weeks after transplantation (37.5% vs. 60.6%, respectively; P < 0.001). Regarding the secondary endpoints, significantly fewer patients developed a CMV infection by week 14 in the letermovir group compared to the placebo group (19.1% vs. 50.0%, respectively; P < 0.001).

Starting around week 18, the incidence of CMV infection began to increase in the patients receiving letermovir, likely as a result of graft vs. host disease (GVHD) and/or steroid use. All-cause mortality at 24 weeks after transplantation was lower in the letermovir recipients compared to the placebo group (10.2% [95% confidence interval {CI}, 6.8-13.6] vs. 15.9% [95% CI, 10.2-21.6]; P = 0.03). At 48 weeks, all-cause mortality was 20.9% (95% CI, 16.2-25.6) in the letermovir group and 25.5% (95% CI, 18.6-32.5) in the placebo group (P = 0.12).

Adverse reactions were similar between the letermovir and placebo groups, with vomiting (18.5% vs. 13.5%, respectively), edema (14.5% vs. 9.4%, respectively), dyspnea (8.0% vs. 3.1%, respectively), myalgias (5.1% vs. 1.6%, respectively), atrial fibrillation (4.6% vs. 1.0%, respectively), and acute kidney injury (9.7% vs. 13.0%, respectively) being the most common. One patient who received letermovir had breakthrough viremia. Genotyping revealed the UL56 V236M mutation, which is known to confer letermovir resistance. Finally, the mortality benefit from letermovir was more pronounced for high-risk patients, which included those with GVHD, mismatched donor HLA gene loci, use of umbilical cord blood as the stem cell source, and the use of ex vivo T-cell-depleted grafts.

COMMENTARY

Because of the unacceptably high rate of myelosuppression with antiviral prophylaxis, clinicians instead employ a preemptive strategy following HSCT in which there is active surveillance for CMV in the blood. When the virus is detected, antiviral therapy is begun. The study by Marty et al is important because it reopens the possibility of using an antiviral agent for CMV prophylaxis after HSCT. Only one patient developed breakthrough viremia while on letermovir, which was due to a UL56 mutation. Previous studies have shown that these CMV mutants remain susceptible to other antivirals, including ganciclovir.

Overall, letermovir appears to be safe, and the absence of myelotoxic effects allows for the initiation of prophylaxis before engraftment. The lack of nephrotoxicity with letermovir also was a welcome finding, given the complex medication regimens HSCT recipients receive, which carry the potential for a multitude of drug-drug interactions. Data on the use of letermovir to treat active CMV disease currently are limited to case reports and one small trial. This is an area that needs further investigation.

The impressive study by Marty et al represents the culmination of a decade-long effort to produce a safe and effective drug that prevents CMV infection after HSCT. Importantly, future pharmacoeconomic studies are needed to determine the cost vs. benefit ratio between prophylaxis with letermovir and our current preemptive strategy. Ongoing surveillance for letermovir-resistant strains, particularly those with the UL56 mutation, will be needed as the drug becomes more widely used in clinical practice.