New Antiviral Agent May Prevent Posttransplant Cytomegalovirus Infections

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Patients receiving the antiviral letermovir (MK-8228, AIC246), as compared to placebo, were almost twice as likely to avoid infection with cytomegalovirus or fail for other reasons in a randomized phase III international trial presented at the 2017 BMT Tandem Meetings, the joint meeting of the American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant ­Research.

Letermovir was overall well tolerated and provides a new approach to cytomegalovirus prevention.
— Francisco M. Marty, MD

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“At the end of treatment, the overall failure rate was 50% in the placebo arm and 19% in the letermovir arm. This kind of success in a phase III trial is awesome,” commented lead investigator Francisco M. Marty, MD, Associate Professor of Medicine at Harvard Medical School and attending physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, who presented the late-breaking abstract.1

Transplant-Related Cytomegalovirus

Dr. Marty explained that other antiviral agents have been studied in this setting but have not evolved past phase II trials or have failed in phase III trials due to lack of efficacy or have been associated with excessive toxicity.

Because of effective surveillance and preemptive therapy for cytomegalovirus, the risk of developing cytomegalovirus disease—which can involve pneumonitis, colitis, retinitis, hepatitis, and other complications—has dropped to less than 5% at 1 year and 2.5% at 6 months posttransplant. “Despite this, patients who go into hematopoietic cell transplantation and are cytomegalovirus-seropositive fare worse than those who are not, even today,” he said, emphasizing the need for effective prevention.

As yet, no antiviral drug has been established as suitable for prophylaxis. Letermovir is a first-in-class drug that inhibits the cytomegalovirus terminase complex. A dose-escalation phase II trial showed that letermovir prophylaxis for up to 12 weeks following hematopoietic cell transplant was effective, and its safety profile was similar to that of placebo.2

In the current phase III trial, Dr. Marty and colleagues compared prophylaxis with letermovir to placebo for the prevention of clinically significant cytomegalovirus infection, defined as cytomegalovirus disease or cytomegalovirus viremia leading to preemptive treatment. The population included 565 adult cytomegalovirus-seropositive allogeneic hematopoietic cell transplant recipients with undetectable plasma cytomegalovirus DNA, who started treatment by day 28 posttransplant. Subjects were enrolled from 67 centers in 20 countries.

Study Protocol and Findings

Patients were randomized 2:1 to receive letermovir or placebo through week 14 (day 100) posttransplant. Letermovir was dosed at 480 mg/d (or 240 mg/d if given with cyclosporine, due to drug-drug interaction); letermovir was available as oral tablets or intravenous infusion. Those who developed clinically significant cytomegalovirus discontinued the study drug and received anticytomegalovirus treatment.

Posttransplant Letermovir

  • The antiviral letermovir prevented infection with cytomegalovirus in patients after hematopoietic cell transplant, in an international phase III study of 565 patients.
  • By week 24, fewer patients developed clinically significant cytomegalovirus in the letermovir arm (38%) compared to placebo (61%, P < .0001).
  • Through day 100, the failure rate was 19% in the letermovir arm and 50% in the placebo arm (P < .0001).

The primary endpoint was the proportion of subjects with clinically significant cytomegalovirus through week 24 posttransplant among subjects with undetectable cytomegalovirus DNA at randomization; those who discontinued the study for any reason or had missing data at week 24 were considered failures, making this a “very conservative” endpoint, he said. The analysis was also performed at the end of treatment, ie, day 100.

Of the 565 patients who received study treatment, 31% were considered at high risk for cytomegalovirus, 50% received myeloablative conditioning, 35% received antithymocyte globulin, and 60% had donors who were cytomegalovirus-seropositive. Patients underwent peripheral blood or bone marrow transplant for a variety of conditions, the most common of which was acute myeloid leukemia (38%). Patients began the study drug a median of 9 days posttransplant; 37% had engrafted prior to the start of the drug.

Protection Against Cytomegalovirus

The analysis of the primary endpoint was based on 495 subjects with undetectable cytomegalovirus DNA at randomization. By week 24, fewer patients developed clinically significant cytomegalovirus in the letermovir arm (38%), compared to the placebo arm (61%, P < .0001), Dr. Marty reported.

Clinically significant cytomegalovirus infection was defined as the onset of cytomegalovirus disease, initiation of anticytomegalovirus preemptive therapy based on confirmation of cytomegalovirus viremia and cytomegalovirus disease risk, or early discontinuation of therapy for any reason.

Importantly, through day 100, the failure rate was 19% in the letermovir arm and 50% in the placebo arm (P < .0001). Clinically significant cytomegalovirus was documented in only 8% of the letermovir arm vs 39% in the placebo arm at this time. Positive findings on preemptive therapy were seen in 38% and 7%, respectively. Results were similar for patients at high risk (P < .0001) and at low risk (P < .0001) for cytomegalovirus at baseline.

“Letermovir was also associated with lower all-cause mortality,” he reported. At week 24, this rate was 10% in the letermovir arm and 16% in the placebo arm, and non–relapse-related mortality was 7% and 11%, respectively. These differences were statistically significant (P = .0317).

Letermovir Well Tolerated

The most common adverse events of any severity, for letermovir vs placebo, respectively, were graft-vs-host disease (39% vs 38%), diarrhea (26% vs 25%), nausea (27% vs 23%), dyspnea (8% vs 3%), myalgia (5% vs 2%), ear and labyrinth disorders (5% vs 1%), hyperkalemia (7% vs 2%), alanine aminotransferase elevations (4% vs 2%), vomiting (19% vs 14%), edema (15% vs 9%), cough (14% vs 10%), and peripheral edema (14% vs 9%). Serious adverse events in general were not higher in the letermovir arm (44% vs 47%), and some occurred more frequently in the placebo arm (eg, diarrhea, acute kidney injury).

“Atrial arrhythmia was numerically higher on letermovir (10% vs 5%), but this arm had a higher frequency of patients with cardiac conditions. The arrhythmia was rarely serious and did not lead to discontinuation,” Dr. Marty said.

“Letermovir prophylaxis beginning after hematopoietic cell transplant, through day 100, significantly reduced cytomegalovirus infection requiring preemptive antiviral therapy through week 24 posttransplant,” Dr. Marty concluded. “Letermovir was overall well tolerated and provides a new approach to cytomegalovirus prevention.” ■

Disclosure: Dr. Marty has been a consultant for and received honoraria from Alexion, Chimerix, LFB, Merck, Roche, and Shire and has received research funding from Astellas, Chimerix, Merck, and Shire.


1. Marty FM, Ljungman PT, Chemaly RF, et al: A phase III randomized, double-blind, placebo-controlled trial of letermovir for prevention of cytomegalovirus infection in adult CMV-seropositive recipients of allogeneic hematopoietic call transplantation. 2017 BMT Tandem Meetings. Abstract LBA2. Presented February 26, 2017.

2. Chemaly RF, Ullmann AJ, Stoelben S, et al: Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med 370:1781-1789, 2014.

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Expert Point of View: Partow Kebriaei, MD

The benefit in the reduction of clinically significant cytomegalovirus through day 100 posttransplant was most notable in the haploidentical group…. This is an important finding as we increase our use of haploidentical hematopoietic cell transplants.
— Partow Kebriaei, MD