The indication for letermovir represents a significant milestone, since CMV infection remains the most common complication of stem cell transplantation for patients with cancer.
Miguel Perales, MD
Letermovir (Prevymis, Merck) became the first new treatment in over a decade for the prevention of cytomegalovirus (CMV) infection for patients undergoing a stem cell transplantation, following approval from the US Food and Drug Administration (FDA) in November 2017.
The indication for letermovir represents a significant milestone, since CMV infection remains the most common complication of stem cell transplantation for patients with cancer. Furthermore, the importance of the new medication is further enhanced by the paucity of effective options, with existing treatments for CMV causing severe adverse events, according to bone marrow transplantation expert Miguel Perales, MD.
"This is an important regimen in many ways," Perales, from the Memorial Sloan Kettering Cancer Center in New York, said in an interview with MD Magazine's sister publication OncLive. "The current management involves monitoring the patients after transplant for CMV. If CMV infection is detected, then we would treat them with drugs that can be quite toxic, either affecting the bone marrow or the kidneys. We need to juggle the ability to treat these patients and mitigate the side effects."
The FDA granted approval to letermovir based on findings from a phase III study that was published in the New England Journal of Medicine. In this pivotal study, 37.5% of patients treated with letermovir developed CMV by week 24 post-HSCT compared with 60.6% of those in the placebo arm (P <.0001). Moreover, letermovir was associated with lower all-cause mortality versus placebo after 48 weeks (20.9% vs 25.5%).
Adverse events were similar between the letermovir and placebo groups. Overall, vomiting was reported for 18.5% of patients in the investigational arm compared with 13.5% of those receiving placebo. Other events between the letermovir and placebo arms, respectively, included edema (14.5% vs 9.4%) and atrial fibrillation or flutter (4.6% vs 1.0%).
“This drug is going to be incorporated in many centers as their standard treatment," Perales said. "In high-risk patients, I believe that every patient is going to receive this drug after transplant. Some centers are going to decide if they should use this drug in low-risk patients or continue to observe them.”
The FDA approved tablet and injection formulations of letermovir. The recommended dose of letermovir was set at 480 mg. The drug can be continued until day 100 post-transplantation. It is also available as 240 mg, to be used with co-administered cyclosporine.
However, one of the lingering questions, Perales noted, was whether treatment should be continued longer than 100 days, particularly for those at high risk of CMV infection. In these patients, infection can occur as far out as 200 days, potentially warranting longer treatment.
"This is a big first step for us. It is a new drug that we are going to be using in these patients," said Perales. "We want to understand how long we will treat the patients and whether the high-risk patients on steroids would benefit from the drug. These are things that we are going to study. We are looking at some of these options, but the field is discussing some potential studies to better understand the best use of this drug."
Right now, letermovir is a prophylactic option prior to CMV infection. It remains unclear whether the medication might be a potential treatment once CMV infection occurs, with research potentially addressing this in the future. This approach is faced with distinct challenges, Perales noted.
"We are not sure if we can combine this agent with other drugs," he said. "One of the challenges of using it in the treatment setting is that this drug does not interfere with the replication of the virus." He also added that “…We do not have a good test to measure its activity.”
These limitations stress the need for early use of prophylaxis with letermovir, as treatment may not be effective once an infection occurs. "There are some practical aspects in terms of using it in the treatment setting; however, nevertheless, it is an important breakthrough. The drug has been released and we are going to start using it," Perales concluded.
Related Coverage >>>