Francisco M. Marty, MD
Prophylactic treatment with letermovir lowered the rates of cytomegalovirus (CMV) infection and all-cause mortality compared with placebo for CMV-seropositive patients following an allogeneic hematopoietic stem cell transplant (HSCT), according to findings from a phase III study presented at the 2017 BMT Tandem Meetings.
In the study, 37.5% of patients developed CMV by week 24 post-HSCT in the letermovir arm compared with 60.6% of those in the placebo arm, representing a meaningful improvement between the two groups (P
<.0001). Moreover, letermovir was associated with lower all-cause mortality versus placebo at 24 weeks (9.8% vs 15.9%; P
= .0317). Based on these findings, Merck, the developer of letermovir, plans to submit a new drug application to the FDA and European Medicines agency for approval of the agent.
"In the trial, we showed that letermovir was very effective at preventing cytomegalovirus infection when used early after transplant through day 100 post-transplant. The benefit persisted to week 24," said Francisco M. Marty, MD, attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute, in an interview with OncLive
. "The other thing that was very compelling and interesting to us was that there was lower morality in the letermovir group."
The study randomized 495 patients with baseline undetectable plasma CMV DNA in a 2:1 ratio to receive once-daily letermovir (n = 325) or placebo (n = 170) following HSCT. Letermovir was administered for 100 days at 480 mg/day or 240 mg/day for those on cyclosporine. Treatment was started on the day of transplant or up to day 28 post-transplant (median, day 9).
Of those enrolled, 31% were at high-risk of CMV. Treatment included myeloablative conditioning for 50% of patients and 35% received ATG. In addition to related donors, HSCT also consisted of mismatched unrelated donors (14%), haploidentical donors (13%), and cord blood (4%).
The primary endpoint of the study was clinically significant CMV infection through week 24 post-HSCT, which was defined as the onset of CMV, initiation of anti-CMV preemptive therapy, or treatment discontinuation and initiation of anti-CMV preemptive therapy. Developed of CMV was labeled as a treatment failure. Secondary endpoints focused CMV infection at various time points and mortality.
At the 24-week assessment, there were 122 failures in the letermovir arm (37.5%), which consisted of clinically significant CMV (n = 57; 17.5%), PET for CMV (n = 52; 16%), and CMV disease (n = 5; 1.5%). In the placebo arm, failures consisted of clinically significant CMV (n = 71; 41.8%), PET for CMV (n = 68; 37.6%), CMV disease (n = 3; 1.8%), although there was some overlap in these figures. Reduction in the risk of clinically significant CMV was observed for letermovir in those at high risk (P
<.0001) and low risk for CMV stratum (P
At week 14, the all-cause mortality rate was 5.2% in the letermovir arm versus 7.1% in the placebo group. Non-relapse mortality was 4.0% versus 5.3%, respectively. Failure rates at this point were 19.1% in the letermovir group and 50% for placebo. At week 24, all-cause mortality was 9.8% versus 15.9% and non-relapse mortality was 6.5% versus 10.6%, for letermovir and placebo, respectively.
“These results showed that letermovir prophylaxis beginning after HSCT and continuing through day 100 post-transplant significantly reduced CMV infection requiring preemptive antiviral therapy through week 24 post-transplant,” said Marty.
There were 56 early discontinuations in the letermovir arm (17.2%) versus 27 in the placebo group (15.9%). Discontinuation events in the letermovir and placebo arms, respectively, were related to adverse events (1.8% vs 0.6%), death without CMV (6.8% vs 7.1%), other reasons (6.8% vs 8.2%), and missing outcomes (2.8% vs 2.9%).
"Treatment benefit decreased after discontinuation of letermovir but persisted through week 24 post-HSCT," said Marty. "Post-prophylaxis events likely reflect ongoing or new risk periods for CMV reactivation, such as GVHD."
The most common adverse events in the letermovir and placebo arms, respectively, were GVHD (39.1% vs 38.5%), diarrhea (26.0% vs 24.5%), and nausea (26.5% vs 23.4%). Additionally, patients experienced vomiting (18.5% vs 13.5%), peripheral edema (14.5% vs 9.4%), and cough (14.2% vs 10.4%). The most common serious adverse events were infection (20.6% vs 18.8%), GVHD (9.9% vs 10.4%), and acute kidney injury (1.3% vs 4.7%).
"Letermovir was well-tolerated overall, with minimal attributable toxicity," said Marty. "Letermovir primary prophylaxis of CMV infection may represent a new strategy for the prevention of CMV in allogeneic HSCT in CMV seropositive recipients."
Letermovir is a non-nucleoside CMV inhibitor that targets the viral terminase complex to prevent replication. The agent has received orphan designation and a fast track designation from the FDA. Merck hopes to complete the applications for the medication within 2017.
Marty FM, Ljungman PT, Chemaly RF, et al. A Phase III Randomized, Double-Blind, Placebo-Controlled Trial of Letermovir (LET) for Prevention of Cytomegalovirus (CMV) Infection in Adult CMV-Seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation (HCT). Presented at: BMT Tandem Meetings; February 23-26, 2017; Orlando, Florida.
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