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Managing CMV Risk in HCT Recipients: Optimizing Transplant Outcomes Through Contemporary CMV Management
Released: March 09, 2026
Activity
So we'll start with the introduction. My name is Roy Chemaly.
I'm the Professor of Medicine and the Chair of the Infectious Disease Department at MD Anderson Cancer Center in Houston, Texas. And I have with me Dr. Marcus Pereira, who's an Associate Professor of Medicine and the Director of the Clinical Services in the Division of Infectious Disease. And also, he is running the Transplant Infectious Disease program at Columbia University Irving Medical Center from New York.
And now I will give the microphone to Dr. Pereira, who is going to go over the burden of CMV.
Dr. Marcus Pereira (Columbia University Irving Medical Center): Thank you so much, Dr. Chemaly. It's an honor to be here. I'm Dr. Pereira -Marcus Pereira from infectious disease at Columbia.
The Burden of CMV on HCT Recipients
So let's start this session talking a little bit about CMV. So as many of you will be aware, you know, the burden of CMV on HCT recipients, it's quite extensive. So - and it's one of the most significant infections complications after HCT. And in fact, actually in the first six months after allogeneic HCT in CMV recipient-positive - or antibody positive recipients without prophylaxis, CMV tends to reactivate quite early and quite extensively, up to 41%.
And comparing placebo with letermovir, the patients on placebo, they reactivated at a high rate and early on up to 41% in this population.
Now different types of HCT carry different risks of CMV reactivation. So for example, in cord blood transplant, you have actually even higher rates of CMV reactivation up to 64% in this particular case series.
Now for those of you who take care of pediatric patients, that rate is somewhere in between about 40% incidence rate of reactivation of CMV. So quite common and certainly an important complication.
CMV Reactivation Associated With Poor Outcomes in HCT Recipients
So the reason why we talked about CMV and - and focus so much on it is because it is associated with poor outcomes after HCT in our recipient - recipients. And that sort of poor impact or - or impact, it comes in different ways. Certainly all-cause mortality has been associated with CMV reactivation, and some of it depends at the timing of reactivation.
Early reactivation, meaning less than 60 days post-HCT certainly carries a very high risk of mortality - all-cause mortality. But even late reactivation, meaning maybe the - the patient is already engrafted and - and may not even be on GVHD prophylaxis. That risk is still sustained.
And here, in this particular study looking at all-cause mortality from CMV, that in the early days, sort of less than 60. That impact certainly is sort of directly proportional to the viral load. So meaning the higher the viremia or the DNAemia, you know, the higher the risk up to sort of an adjusted hazard ratio of 26.5. But even post day 60, the risk is quite extensive as well as you can see, it's also across the board.
So that's for all-cause mortality. How about GVHD? So we know that the relationship between CMV and GVHD is quite complicated. And in general, it's a bidirectional relationship, meaning CMV can lead to GVHD, but GVHD can certainly lead to CMV reactivation as well. But in the case where CMV is a risk factor for acute GVHD, certainly there's been an association. And that association, the impact is certainly across different spectra of GVHD, whether it's skin, gut or liver or even the grade or the severity of GVHD. All of those are associated with CMV reactivation.
Now, in addition to these two, certainly costs and hospitalizations, in terms of the increase and - and - and sort of more length of stay for our patients that those are all associated with CMV reactivation as well. So all in all, it's a pretty serious complication, as many of you will be aware.
Clinical Impact of CMV After HCT: Direct Effects
Now, that - that the impact of CMV comes in two ways, right. So we generally think of CMV causing direct impacts and indirect impacts. So in the direct spectrum, that's when we think about patients actually getting sick from CMV. Like any viral infection, it can cause symptoms and make patients sick.
And an tissue invasive disease is the one that we fear the most from CMV. Many of you may have seen a patient with direct impact in tissue invasive disease. So the ones that we generally think or worry the most are GI and pulmonary CMV disease. And certainly those are the most impactful. Thinking about GI CMV, the cumulative incidence rate can be about 2% by year two post-transplant. So not a lot. But for those patients who do get it, they can get quite sick.
CMV pneumonia can have even a greater impact with mortalities up to 50%. Certainly, maybe some of this data are historical, because the good news is that we don't see many of these patients anymore in terms of tissue invasive disease, and certainly that's welcome news.
Retinitis and CNS disease, generally, we think about those for patients with HIV and other immunocompromising conditions, but luckily not so much with stem cell transplant.
Clinical Impact of CMV After HCT: Indirect Effects
So we talked about direct impact. How about the indirect impact? And in some ways this is sort of the more import - important aspect of CMV. Luckily, we don't see as many patients directly sick. But this impact of indirect - indirect is certainly more extensive.
So the first one to talk about are opportunistic infections. It turns out that CMV is an immunomodulating virus, meaning that if it reactivates, it can actually further immunosuppress our patients. And - and the manifestation of that will be with a greater number of opportunistic infections.
So for example, invasive fungal disease, which obviously is a quite important type of infection in our patients directly related with rates of CMV reactivation, perhaps not early on. So this was a study looking at CMV and its correlation with invasive fungal disease, perhaps not early on. You see any kind of separation. But in those patients, after 200 days with CMV reactivation, you see a much greater rate of invasive fungal disease, whether that's aspergillus, rhizopus, you name it. Those are all correlated with CMV reactivation.
And - and obviously we know that well, and we see a lot of patients with invasive fungal disease. But you also have a relationship, perhaps with less common types of infections. So non-tuberculous mycobacteria, whether it's MAC, M. abscessus, chelonae. There are dozens of different types of NTMs, and many of them can be correlated with CMV reactivation in the setting of post-HCT.
Key Takeaways
So the key takeaways on the burden of CMV is that there are significant direct impacts. Certainly tissue invasive disease is an important and for clinicians is critical to be aware of. GI, pulmonary are the main ones. Luckily, they're not that common.
But the most clinically significant CMV infections are not really associated with tissue invasive disease, like I said. It's really the indirect effects that we worry most in terms of the burden of CMV.
Managing Risk of CMV in HCT Recipients
All right. So how do we manage this risk?
Risk Factors for CMV Infection
As you can imagine, we have spent over the decades a lot of time and thinking about how to mitigate that risk of CMV. And many of you are aware of the strategies. But going over the risk factors, you know, the main - the main takeaway is that this is a dynamic sort of relationship between the risk factors and time after post-HCT.
So you have here sort of the first 30 days, days 30 to 100 and then after 100 days. And those risk factors change over this sort of timeline.
So in the beginning, as you can imagine, general risk factors for CMV and end-organ disease will include a CMV seropositive recipient, right. The CMV is
in their bodies and has the potential for reactivating. But other factors like advanced age, the type of transfer we talked about, core transplant being a higher risk, and the conditioning regimen. So certainly between the different agents that can be used. Post-transplant cyclophosphamide has been highly implicated with CMV reactivation.
The CM - the presentation of CMV in the initial period. People may have asymptomatic DNAemia or viremia. End-organ disease is quite rare in the first 30 days because they're being monitored so closely, they're usually still in the hospital. And we have, you know - and they might even be in prophylaxis.
All right. So what happens after day 30 and up to day 100? So they maintain - the - the risk factors that were early on are still quite significant. Obviously, being seropositive for CMV will remain a significant risk factor. But then you add a few additional risk factors, like the presence of GVHD and the treatment for GVHD. Those are going to increase the risk of CMV reactivation, and delayed T-cell recovery will also increase the risk for CMV reactivation. Those can be pretty straightforward, at least in understanding those risk factors.
CMV infection is common during this period, particularly in the high-risk patients who are not on prophylaxis. And CMV pneumonia, although rare, will be - if it's going to happen, it might happen during this particular period. Okay. Intense immunosuppression and the potential for CMV to reactivate and cause disease.
All right, so what happens after 100 days? So you still have all of these risk factors. But now sort of you add more chronic risk factors such as steroid use perhaps for chronic GVHD. Again, delay in T-cell recovery. Now nonmyeloablative conditioning, right, because it can delay T-cell recovery will be a risk factor here. I had already pointed that out, but it's really important to include that here as well.
And - and as it comes with CMV, you know, past CMV reactivation is a risk factor for future reactivation. And that's an important concept. Your patients who have had CMV before, they will - there's something about them that will keep their risk elevated.
Comparison of Strategies for Prevention of CMVi
All right. So what do we do to prevent CMV? I think many of you will be aware of our two main strategies: monitoring with preemptive therapy and antiviral prophylaxis. Right?
So let's talk about antiviral prophylaxis, meaning giving an antiviral to prevent CMV from reactivation during a certain period of time. It's highly effective and it actually prevents those indirect effects from CMV that we talked about, whether it's GVHD, opportunistic infections and so on.
But there are some drawbacks. Certainly it delays CMV immunity to the degree that your patient can create some sort of CMV immunity that's going to be pushed down the line because there's no CMV reactivating to trigger that response. And there will - there will be a risk for post-prophylaxis, clinically significant CMV as well.
Now, the drug that we're talking about is letermovir, as many of you will be aware. It does have some drug interactions that are important to be aware of. So tacrolimus, cyclosporin, sirolimus, the azoles for sort of antifungal prophylaxis and many others. So this is a drug that you always want to check in with your pharmacist to make sure that the dosing and other interactions are taking into account.
Now also important to note that letermovir does not have HSV and VZV activity, right? So if you think your patient is at risk and most of them are, you need to add an additional antiviral for prophylaxis because letermovir is not going to provide it.
All right. So how about monitoring with preemptive therapy? That's basically weekly CM - weekly CMV QNAT monitoring. It does allow for brief, low level - low-level viral replication and potentially immune priming, right. So there's potential some benefit there.
In the SOT world, we have shown that that might be beneficial. That's a little bit less clear in the HCT sort of types of patients. But certainly that's - the thought is there.
There is always the low risk of late onset clinically significant CMV. Obviously that risk will stay there. And there are obviously some drawbacks, right. So significant logistical requirements of having your patient coming every week for lab monitoring and then somebody to track that lab, you know, and make a decision if it's - if it's detecting CMV whether to start preemptive treatment or not. So those are sort of, you know, a lot of logistical drawbacks for services that are always stretched in.
And the - the last one is that, you know, monitoring with preemptive therapy, there is some relationship with increased all-cause mortality. So that's obviously a problem.
Letermovir for Antiviral Prophylaxis: Efficacy and Safety
Let's talk about letermovir. This, many of you will be familiar with the double blind phase III clinical trial that sort of was the pivotal study for letermovir approval. It included 565 CMV sero-positive HCT transplant recipients. This is now many years ago.
And letermovir was given for 100 days and compared to placebo. The primary outcome was clinically significant CMV infection. And by all measures, this was a statistically significant result in that letermovir effectively prevented CMV from reactivating, whereas placebo did not. So this was a really significant result if directly led to letermovir being approved for HCT Patients.
Now, what was intriguing about that study, and this was sort of a secondary outcome looking at all-cause mortality, at week 14 and week 24, there was a signal that perhaps letermovir was also reducing all-cause mortality. That disappeared by week 48. And - but certainly there was a trend towards reducing all-cause mortality with letermovir. And that obviously was important to the researchers and to most programs adopting letermovir for prophylaxis.
Letermovir for Antiviral Prophylaxis: Efficacy and Safety of Extended Treatment
Now, that initial study was for 100 days. There was an extension study to include patients up to 200 days on letermovir thinking about perhaps there would be added benefits of - of preventing CMV from reactivating up to 200 days post-HCT. And by and large, you know, although the study was smaller, it did show that, you know, prophylaxis with letermovir was highly effective in preventing CMV from reactivating up to 200 days or - or past 200 days.
Interestingly, we looked again at all-cause mortality. And in this particular study, for various reasons about patient selection, there was - there was no - no trend towards reduced mortality with letermovir. But the question remains because some studies have shown that letermovir can reduce all-cause mortality, but the data are not as striking as at least reducing CMV from reactivation.