Letermovir as CMV Prophylaxis in HSCT Patients

Robert J. Soiffer, MD: The ideal approach would be to be able to prevent CMV reactivation. To use a drug prophylactically, of course there are limitations. You want to make sure that those drugs are safe, nontoxic, don’t have significant interactions with medications that are being used for the transplant because there’s calcineurin inhibitors, and don’t cause the kind of cytopenias that you described. There has been a drug recently approved, letermovir, and I know you’ve had some experience with it. Can you describe letermovir, its mechanism of action, and how it has been used?

Genovefa Papanicolaou, MD: It’s been an exciting time in the field of CMV and transplant. The letermovir approval culminates a 10-year quest to find an agent that is suitable for prevention in the stem cell transplant space. We know that in solid organ transplants, ganciclovir, or valganciclovir, is used routinely for CMV prevention. However, valganciclovir is not an option for stem cell transplants due to cytopenia.

Letermovir is a very potent CMV-specific antiviral that has a novel mechanism of action. It inhibits the terminase. It’s an enzyme of CMV that cuts the DNA at the appropriate place as the CMV DNA is produced. It stops CMV packaging and, eventually, the completion of the CMV particles. Recently, a phase III trial was concluded with very strong results showing that letermovir was very effective in preventing a CMV infection when given for 14 weeks after transplant.

Robert J. Soiffer, MD: I know that patients can still be at risk for CMV after those 14 weeks. It’s still important to monitor them after completion of letermovir.

Genovefa Papanicolaou, MD: Right. A very important manuscript showed that letermovir was extremely effective in the first 14 weeks of which it was given. The patients were followed, subsequently, through 24 weeks after transplant (about 6 months after transplant), and we saw that a number of patients that had not developed CMV infection in the first 14 weeks went on to develop infection from 3 months to 6 months after transplant. So, all of these patients are routinely monitored and they start preemptive therapy later on.

Robert J. Soiffer, MD: In CMV infection, it’s not just viremia that we’re trying to prevent. We’re obviously trying to prevent CMV disease. I don’t think, in this particular manuscript, there was a difference in CMV disease. But as I recall, there was a difference in mortality after transplant. Could you talk about that?

Genovefa Papanicolaou, MD: Right. Yes. CMV disease is pretty well prevented nowadays. We have seen that in a previous randomized trial and in this trial. CMV disease at 6 months was less than 2% in the letermovir arm and in placebo arm, showing that preemptive therapy is very effective in preventing CMV disease.

Now, always in clinical trials, patients are monitored extremely well. So, in the real world, perhaps the CMV disease rate at 6 months may be a little higher than 2%. But again, the rates are low, in general.

What’s very exciting about the letermovir trial is that there was a difference in mortality at 24 weeks, and a trend for lower mortality with letermovir at 48 weeks. This is the first time, in a randomized controlled setting, that we see that an agent for the prevention of CMV infection has an impact on mortality.

Transcript edited for clarity.