Miguel Perales, MD, discusses the impact of the FDA approval of letermovir for patients with CMV prophylaxis following transplantation.
Miguel Perales, MD
Following allogeneic hematopoietic stem cell transplant (HSCT), the recently FDA-approved regimen letermovir (Prevymis) is highly recommended for high-risk patients with cytomegalovirus (CMV) infection, according to Miguel Perales, MD.
The phase III trial that led to the November 2017 approval randomized 495 patients with baseline undetectable plasma CMV DNA in a 2:1 ratio to receive letermovir once daily versus placebo following HSCT. The results showed that 37.5% of patients treated with letermovir developed CMV by week 24 compared with 60.6% of those treated with placebo (P <.0001). Additionally, letermovir was associated with a lower mortality rate of 12% versus 17% in the placebo arm at 24 weeks.
“This drug is going to be incorporated in many centers as their standard treatment. 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,” Perales said.
In an interview with OncLive, Perales, deputy chief, Adult Bone Marrow Transplant Service, director, Adult Bone Marrow Transplantation Fellowship Program, Memorial Sloan Kettering Cancer Center, discussed the impact of the FDA approval of letermovir for patients with CMV prophylaxis following transplantation.Perales: One of the exciting developments is the approval of letermovir, which is a drug that we use to prevent infection with CMV in patients undergoing stem cell transplant. This is an important regimen in many ways. 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.
CMV remains one of the main complications in terms of infection after transplant. It is associated with significant increase of complications and mortality. A group [of researchers] published data showing that patients who are infected with CMV have a high risk of dying. This is a major issue, making this study critical.
It is a large study that was presented at the 2017 BMT Tandem Meeting and was recently published in the New England Journal of Medicine. This phase III randomized study showed that using letermovir in patients after transplant can decrease the risk of reactivating CMV. The study was designed to stop giving this drug to patients after 100 days to determine the risk of developing CMV infection, not just during the period when the patient is being actively treated but also beyond that period. This is an FDA requirement for administering the drug.
There are some patients who developed infection after stopping the drug, but there were still fewer patients who developed infection overall. There was a difference in the survival between the 2 groups, which speaks to the importance and safety of this drug. In the previous phase II trial that was published, the drug was shown to be safe and this phase III study further confirms that.The study brings up important questions. Patients are treated for 100 days but in some of these high-risk patients, the risk of CMV infection can happen after 100 days. Do I continue the drug, or do I monitor the patient? Many experts feel that the high-risk patients would be better to receive treatment beyond the 100 days, to 200 days or beyond.
The other population that is also critical are patients who develop graft-versus-host disease (GVHD) after transplant. Those patients are often treated with high doses of steroids. However, there is a risk that those patients could reactivate CMV infection. We would like to know if we should be treating those patients with the drug to prevent infection with CMV.
This is a big first step for us. It is a new drug that we are going to be using in these patients. 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.
The final consideration is whether we can use it for treatment. We know that the mechanism of action is different from standard drugs that we have today. We are not sure if we can combine this agent with other drugs. One of the challenges of using it in the treatment setting is that this drug does not interfere with the replication of the virus.
The practical consequence of that is when we measure the virus level in the blood, it takes 2 weeks for us to detect an effect. With standard therapy, we would know in 1 week whether the drug is working. However, with letermovir, it takes 2 weeks to see a change. We do not have a good test to measure its activity. We hope that it is working, since we will not be able to assess it for 2 weeks. 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.
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). In: Proceedings from the 2017 BMT Tandem Meeting; February 23-26, 2017; Orlando, Florida.