Perspective

Letermovir effective as prophylaxis for cytomegalovirus in high-risk hematopoietic cell transplant patients

Letermovir was highly effective in a phase 3 trial at preventing infection with cytomegalovirus, or CMV, in patients who underwent allogeneic hematopoietic cell transplantation who were CMV–seropositive at the time of transplant. Additionally, the drug was well-tolerated overall, with most side effects comparable to placebo.

CMV is a common complication of hematopoietic cell transplantation (HCT) and has been the focus of a decades-long search for an effective prophylaxis, explained Francisco Marty, MD, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

Francisco Marty
Francisco Marty

“People who are CMV–seropositive do worse than people who are CMV–seronegative at the time of transplant,” Marty told Infectious Disease News. “So, the question has been, ‘Can these patients do better if we can provide a safe and effective primary antiviral prophylaxis?’ That has been the quest for the last 10 years with maribavir [ViroPharma/Shire], brincidofovir [Chimerix] and letermovir [AiCuris/Merck].”

Marty and colleagues compared letermovir with placebo for the prevention of clinically significant CMV (CS-CMV) infection in CMV–seropositive HCT patients aged 18 years or older who had undetectable plasma CMV DNA within 5 days of randomization.

From June 2014 to March 2016, patients were randomly assigned 2:1 to receive either 480 mg per day of letermovir — or 240 mg per day if on cyclosporine — or placebo orally or intravenously for 14 weeks after HCT. Marty and colleagues assessed the participants each week for the first 14 weeks, biweekly through week 24 and then every other month through week 48. Those who developed CS-CMV were discontinued from the study and treated for their infection. 

Among 565 participants, 31% were at high risk for CMV disease, 50% received myeloablative conditioning and 35% received rabbit anti-thymocyte globulin (ATG), Marty and colleagues said. The donors included 14% mismatched unrelated, 13% haploidentical and 4% cord blood. The subjects began the study a median of 9 days after transplant, and only 37% had engrafted prior to the start of treatment.

Among 495 treated subjects with undetectable CMV DNA at randomization (the primary efficacy study population), 38% of the patients treated with letermovir developed clinically significant CMV or were considered failures by week 24 compared with 61% of patients in the placebo arm (stratum adjusted treatment difference, –23.5% (95% CI, –32.5 to –14.6; P < .0001).

The most common adverse events in each arm were graft-versus-host disease, diarrhea and nausea. The all-cause mortality was 10% in patients who received letermovir and 15% in the placebo arm.

Marty said 71% of the patients completed 100 days of treatment, a very high proportion in this population.

Marty will be presenting detailed results of the trial on Sunday, Feb. 26, in Orlando, Florida, during the late-breaking abstract session of the Tandem BMT meetings organized by the American Society of Blood and Marrow Transplantation and the Center of International Blood and Marrow Transplantation Research.

“At the clinician level, the important thing is that it was highly effective at preventing CMV reactivation or CMV disease during treatment, and that benefit persisted at week 24,” Marty said. “Not only did we prevent CMV reactivation and CMV disease, we also noticed a lower mortality in the people who received letermovir compared with those who received placebo.”

According to Merck, letermovir has been granted orphan drug status in Europe, Japan and the United States for the prevention of CMV infection and disease in at-risk populations, and the FDA has given the drug a fast-track designation in the United States.

Marty said the researchers are just finishing up some of the 48-week analyses and will probably submit to the FDA later this year. – by Gerard Gallagher

Reference:

Marty FM, 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; Feb. 22-26, 2017; Orlando, Florida.

Disclosure: Marty reports receiving research grants from Astellas, Chimerix, Merck and Shire. He has also received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.

Letermovir was highly effective in a phase 3 trial at preventing infection with cytomegalovirus, or CMV, in patients who underwent allogeneic hematopoietic cell transplantation who were CMV–seropositive at the time of transplant. Additionally, the drug was well-tolerated overall, with most side effects comparable to placebo.

CMV is a common complication of hematopoietic cell transplantation (HCT) and has been the focus of a decades-long search for an effective prophylaxis, explained Francisco Marty, MD, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

Francisco Marty
Francisco Marty

“People who are CMV–seropositive do worse than people who are CMV–seronegative at the time of transplant,” Marty told Infectious Disease News. “So, the question has been, ‘Can these patients do better if we can provide a safe and effective primary antiviral prophylaxis?’ That has been the quest for the last 10 years with maribavir [ViroPharma/Shire], brincidofovir [Chimerix] and letermovir [AiCuris/Merck].”

Marty and colleagues compared letermovir with placebo for the prevention of clinically significant CMV (CS-CMV) infection in CMV–seropositive HCT patients aged 18 years or older who had undetectable plasma CMV DNA within 5 days of randomization.

From June 2014 to March 2016, patients were randomly assigned 2:1 to receive either 480 mg per day of letermovir — or 240 mg per day if on cyclosporine — or placebo orally or intravenously for 14 weeks after HCT. Marty and colleagues assessed the participants each week for the first 14 weeks, biweekly through week 24 and then every other month through week 48. Those who developed CS-CMV were discontinued from the study and treated for their infection. 

Among 565 participants, 31% were at high risk for CMV disease, 50% received myeloablative conditioning and 35% received rabbit anti-thymocyte globulin (ATG), Marty and colleagues said. The donors included 14% mismatched unrelated, 13% haploidentical and 4% cord blood. The subjects began the study a median of 9 days after transplant, and only 37% had engrafted prior to the start of treatment.

Among 495 treated subjects with undetectable CMV DNA at randomization (the primary efficacy study population), 38% of the patients treated with letermovir developed clinically significant CMV or were considered failures by week 24 compared with 61% of patients in the placebo arm (stratum adjusted treatment difference, –23.5% (95% CI, –32.5 to –14.6; P < .0001).

The most common adverse events in each arm were graft-versus-host disease, diarrhea and nausea. The all-cause mortality was 10% in patients who received letermovir and 15% in the placebo arm.

Marty said 71% of the patients completed 100 days of treatment, a very high proportion in this population.

Marty will be presenting detailed results of the trial on Sunday, Feb. 26, in Orlando, Florida, during the late-breaking abstract session of the Tandem BMT meetings organized by the American Society of Blood and Marrow Transplantation and the Center of International Blood and Marrow Transplantation Research.

“At the clinician level, the important thing is that it was highly effective at preventing CMV reactivation or CMV disease during treatment, and that benefit persisted at week 24,” Marty said. “Not only did we prevent CMV reactivation and CMV disease, we also noticed a lower mortality in the people who received letermovir compared with those who received placebo.”

According to Merck, letermovir has been granted orphan drug status in Europe, Japan and the United States for the prevention of CMV infection and disease in at-risk populations, and the FDA has given the drug a fast-track designation in the United States.

Marty said the researchers are just finishing up some of the 48-week analyses and will probably submit to the FDA later this year. – by Gerard Gallagher

Reference:

Marty FM, 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; Feb. 22-26, 2017; Orlando, Florida.

Disclosure: Marty reports receiving research grants from Astellas, Chimerix, Merck and Shire. He has also received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.

    Perspective
    Gerhard Carl Hildebrandt

    Gerhard Carl Hildebrandt

    Marty and colleagues in their randomized, phase 3, placebo-controlled clinical trial related to the preventive use of letermovir demonstrated an impressive reduction of clinically significant CMV infection incidence from 61% to 38% by 24 weeks after transplant, thereby providing a promising new approach in the prevention of a long-standing problem in allogeneic hematopoietic cell transplant recipients.

    Close monitoring of CMV viral load after transplant is standard of care with the goal of early initiation of pre-emptive treatment at time of CMV reactivation/infection and before the development of potentially fatal CMV disease. Pre-emptive treatment using currently available drugs is associated with significant side effects and toxicities, and accordingly, CMV reactivation and its treatment significantly contribute to morbidity and mortality, mandating the need for better preventive strategies instead.

    Letermovir in the presented study was given preventively until day 100 after transplant, leading to a significant reduction in significant CMV infection by 37.7%. Based on the reported adverse event profile in both groups, toxicity seemed to be acceptable. More frequently observed adverse events include edema, atrial arrhythmia, vomiting and alanine aminotransferase elevation, with the latter two requiring more attention in the clinical setting due to their potential overlap with presentation of GVHD. Interestingly, although CMV reactivation has been associated in some reports with increased risk to develop GVHD, in the presented trial no difference in GVHD was observed between groups, nor was a strong difference in overall survival by the end of the observation period found. Further analyses are needed to explore whether certain subgroups of patients may benefit more from receiving preventive letermovir than others (eg, Anti–thymocyte globulin-treated patients).

    Considering the currently lacking options in efficaciously addressing this critical challenge of CMV prevention in allogeneic HCT, the results of this study are promising, and whether letermovir presents a real breakthrough warrants further evaluation.

    • Gerhard Carl Hildebrandt, MD, FACP
    • Professor of medicine Chief, division of hematology and blood and marrow transplantation University of Kentucky Markey Cancer Center

    Disclosures: Hildebrandt reports no relevant financial disclosures.