Okay. So let's talk a little bit about refractory and resistant CMV infection in these complicated cases.

Refractory and Resistant CMV: New Definitions

First, we knew that there were no standard definitions for refractory, especially for clinical trials. And when we start—you know, we need to develop new drugs to treat this condition. So how we define refractory, it was all over the place for a long time until we came up with a definition. And we updated recently the definition of refractory, where we put there that it is a CMV DNAemia that increases more than one log increase or it persists less than one log decrease after treatment. So it's not only increase in

[00:49:00]

now viral load but also less than one log decrease.

So the efficacy is not there to reduce viral load after at least two weeks or at least two weeks of treatment with the right drug right route and the right dose at the same time. So I would caution don't jump the gun early. And we see it in our institution. Every institution where someone—depends who you're running with, they could be more anxious than others. They don't want to wait. I sit here smiling and, they call us said, let's wait a little bit. No, but we need to treat right away.

But give it some time, viral load by itself. You see, increased replication with increase in viral, different story. You may start switching therapy earlier, but if it persists at the same level or went up a little bit over the two weeks give it a chance for ganciclovir or even foscarnet.

Now refractory

[00:50:00]

CMV end-organ disease. Same thing. When you have signs and symptoms getting worse, but improving after two weeks of therapy in this patient population, then you may switch therapy and call it refractory.

Now when we talk about resistance, you have to have a genetic assay with mutation conferring resistance to any of these drugs. At least one, or if not more of this antiviral that we use for CMV.

Resistant and Refractory CMVi: Risks in HCT Recipients

So risk factors for resistant and refractory CMV infection usually happen after using antiviral for a couple of weeks, could be three, four, five weeks. It depends. Or you're using suboptimal dose for these antivirals and overall the risk is between zero to 10%. But if you look at refractory per se and as I said before the era of letermovir, it could be up to 30% of

[00:51:00]

all CMV reactivation and resistance usually is around 2%, 5%. So it's not that high when you check for mutations in this patient population.

Now, after the era of letermovir, we're the first one to show that even resistant/refractory went down, resistant from 11% down to 3% in one of the studies that we conducted. When you prevent CMV, you have less chance for the virus to replicate and less chance for becoming refractory or resistant.

So prior antiviral drug exposure is very important risk factor, prolonged antiviral therapy, what we used to call maintenance also or lower the dose to keep patient to control CMV can put them at risk for resistant as well and recurrent CMV infection. Many others that you see listed here.

So refractory is much more common than resistant when you identify a mutation.

Identifying Resistant CMVi

And how we identify mutation? We talked about genotypic assays. It is available.

[00:52:00]

You send it to a central lab, either Eurofins Viracor or probably Mayo and others.

And they look for mutation on either UL97, 54, 56, depends which drug you're suspecting resistance. If using ganciclovir, you go to UL97, foscarnet 54, and cidofovir as well. And letermovir, you have to ask for UL56 mutations. Be careful with the false positive to mix population with low viral load. When you have very low viral load, you can have some subpopulation with resistant some or not, but also false negative because of the sensitivity of the test to detect the subpopulation with resistance.

So you treat where they got better and then all of a sudden the viral load goes up because you selected for this mutant and you have now resistant virus as one.

Mutations Associated With Resistance

So we talked about UL97 mutations conferring resistance to ganciclovir. But now with maribavir also

[00:53:00]

the mechanism of action, which I'm going to go over it, you have mutations on UL97 conferring resistance to maribavir. But two specific mutations keep in mind, C480F or F342Y. This mutation confers resistance to both, ganciclovir and maribavir, something that you keep in mind where you can't switch to maribavir if you have a C480F and patient on ganciclovir and vice versa.

UL54 for the three drugs listed here and 56 as we talked about, letermovir. And no cross-resistance between letermovir and the other drug that you see listed here.

Refractory CMV: Higher Risk for CMV Disease and Non-relapse Mortality

So why refractory is so important? Look at the burden of this infection. You have higher incidence of CMV disease but also increase in non-relapse mortality when you compare refractory to non-refractory CMV infection. And we did the same

[00:54:00]

study that we hopefully will submit it for publication, we found the same thing. Impact on CMV disease, which is higher incidence, and also on non-relapse mortality in this patient population.

Treatment Options for Refractory/Resistant CMV

So what are the treatment options now these days? For UL97 mutation with high level resistance to ganciclovir, you have to switch. Don't go with high dose ganciclovir. You're going to cause more toxicities than success in treating this patient.

We switched to either foscarnet or maribavir. This based on the recent guidelines we have the two choices depend on your situation. The patient can tolerate foscarnet or you can go to maribavir if you have good access to it.

Now, when you have low level resistant mutation for ganciclovir on the UL97, also either maribavir or foscarnet, but at the same time high-dose ganciclovir. I'm not sure how many will go to high-dose ganciclovir now these days, especially when we

[00:55:00]

know myelosuppression is going to be pretty common in this patient population.

UL54 mutation, you cannot use foscarnet, especially the specific mutation for foscarnet. Then you go to ganciclovir or maribavir. But there is some mutations in the UL54 DNA polymerase conferring to either foscarnet and ganciclovir, or the three drugs as well, like cidofovir, not only foscarnet, ganciclovir, cidofovir, some mutations. At that point you have to go to maribavir and/or investigational agent, which is brinci, which hopefully, it will be continue to be studied and investigated for CMV in the future, but stay tuned.

Actually, there will be a presentation by Dr. Khawaja on Saturday late breaker on IV brincidofovir for CMV reactivation and some patients had refractory or resistant CMV infection as well. So if you would like to attend

[00:56:00]

Are full to learn a little bit about this drug. But it's still pretty early under development for CMV.

Now some UL97 mutations conferring resistance to maribavir you see listed here. Then you have to switch to other drug.

MD Anderson R/R CMV Infection Management Approach

What we do at our institution, a patient being on valganciclovir, we switch—you know, so we have the algorithm. You go to either foscarnet or maribavir. And if patient has been on foscarnet, then you switch to either ganciclovir or maribavir. But keep in mind, for maribavir at least you have to have prophylaxis for herpes simplex and VZV separately. Same thing for letermovir as well.

Combination therapy. What we used to do for a long time when we didn't have much of choices and we stock patient where are having worsening infection with CMV, we used to go with foscarnet and ganciclovir either full dose

[00:57:00]

or foscarnet full dose, ganciclovir-reduced dose, foscarnet-reduced dose versus ganciclovir full dose. But can you imagine the toxicities and what happened to the patient.

So it is kind of a discussion and lead to more resistance probably when you go to the reduced dose.

Now with maribavir what we are suggesting or proposing and it went to the guideline to do combination foscarnet but when you have high viral load or hard to treat infection with tissue invasive disease, very short course of foscarnet with maribavir, then you can stop foscarnet and then move on with maribavir. So this is one of the new proposition or recommendation, I would say, in the new guidelines.

Assessing Other Treatment Strategies

Other alternative therapy for this kind of infection. Would you change your calcineurin inhibitor to mTOR, immunosuppression, which has some antiviral in vitro effect.

[00:58:00]

Some centers may do that. We don't in our institution.

What about CMV IVIG also? I know they use it quite a bit in the pediatric patient population after allo transplant, but we don't. I don't think it has a role to treat refractory CMV infection or resistant CMV infection.

We used to use quite a bit of leflunomide in the past. I remember when we published our experience on that a long time ago. We don't use as monotherapy, of course, in combination, but try to control a little bit CMV by itself, not going to get rid of your viral load. And secondary prophylaxis is recommended. It's very important.

And CMV T-cell therapy, we have some institutional protocols access to CMV specific T-cell where you can use it and we know it is safe and could be effective.

Maribavir: Mechanism of Action

So maribavir is an option to treat this infection that we talked about. This is the mechanism of action where it inhibits UL97, where it has multiple impact on

[00:59:00]

viral encapsidation nuclear egress and does not affect UL54. Of course, no cross-resistance, as you see, but ganciclovir need UL97 to be phosphorylated before they go to cellular kinase and exert their action on DNA polymerase.

When you inhibit UL97, then you cannot use ganciclovir in combination with maribavir. So something to keep in mind. Combination is antagonistic between maribavir, ganciclovir or valganciclovir. Okay, but not with foscarnet. That's why recommendation a short course of foscarnet with maribavir in some specific situation, of course.

Maribavir: Indications and Characteristics

So what are the indications and characteristics for maribavir approved for the treatment of post-transplant CMV infection? Of course, it’s refractory with or without genotypic resistance and resistant to—with when they refractory this drug listed its oral route, bioavailability is important, not

[01:00:00]

myelosuppressive or nephrotoxicity, pretty safe. The only main side effect which is did not lead to discontinuation of the drug during the trial is the dysgeusia or taste disturbance as well.

SOLSTICE: Maribavir for Resistant or Refractory CMV

And this is the study. I'm not going to go over it. Hopefully, you are all familiar with the SOLSTICE study, where it led to the indication of refractory and resistant CMV infection for maribavir compared to the investigator-assigned therapy that we had. And looking at the primary endpoint, which is confirmed CMV clearance at the end of week eight.

SOLSTICE: Symptom Control and Confirmed CMV Viremia Clearance

And this is the result of the study that maribavir worked much better in clearing CMV viremia at week eight, 56% versus 24% on the IAT, and the effect continue up to week 20 as well.

Treatment-Emergent Adverse Events Reported by >10% of Patients

And this is the dysgeusia from maribavir versus myelosuppression on ganciclovir or valganciclovir or neutropenia and acute kidney injury, of course,

[01:01:00]

from foscarnet. It was not surprising. So it's an oral, effective and safer drug that now we have it and it made it to the new guidelines.

European and US CMV Treatment Guidelines

Our guidelines from the American Society of Transplant Cellular Therapy, as well as the EASL guidelines that was also published this year. Both of them were published this year for update, the recommendation for CMV infection.

Updated Topics for ASTCT CMV Guidelines Are in the Form of FAQs

And mainly update the CMV screening, prophylaxis and letermovir.

ASTCT Guidelines: Maribavir for Resistant/Refractory CMV Infections

But also we added maribavir recommendation for resistant/refractory CMV infection. And for the first time, the guideline where we make it optional to test for CMV cellular-mediated immunity in specific situation as well, which is interesting. It was kind of better for me. I've been a proponent of it for many years and it made it because we start seeing the value of it in specific situation as well.

So for maribavir, as I mentioned, to the guidance

[01:02:00]

to treat refractory CMV infection but what you remember at antagonistic effect was valgan or ganciclovir. Poor CNS penetration as well. Okay. You don't use it for CMV retinitis or encephalitis, although it is rare in our patient population. And you have to use an anti-HSV or VZV drug as well.

Now for preemptive therapy, we said in specific situation where the patient cannot tolerate foscarnet or ganciclovir, you may use it. Although the study done at AURORA study was negative, they didn't reach the primary endpoint but was very tight confidence interval. And we still think if it works for resistant refractory, why not for preemptive. So it made it to the guideline that it's an option in some situation where you cannot use the other drug.

You can—maribavir could be an option as well, but it's not indicated for preemptive therapy as well.

ASTCT Recommendations: Managing Resistant/Refractory CMV Infections

Genotypic assay, do it right away. Don't wait. Some people have no access to it. In Europe mainly,

[01:03:00]

or other parts of the world, they may not have access to it, but here we have. So send for genotypic assay but modify your treatment as well.

We talked about short course of combination foscarnet with maribavir. When you have high viral load, we know maribavir may not be the perfect drug, but with short course of foscarnet together with maribavir, it may reduce the viral load and you continue with maribavir.

Patient Case 2

So let's go over the final case. A 42-year-old man with AML had MUD, and this is a conditioning regimen. He had early—this is obviously the anemia, got foscarnet, got skin GVHD, high dose steroid, and then developed viremia later on, at 1,100 - 11,200 IU/mL started on ganciclovir. Viral load increased to 17,800 IU/mL.

Pretest 6

The first question for you, has borderline kidney dysfunction in this patient 1.4 creatinine and ANC 980. So what's the next step? Do you:

[01:04:00]

1. Switch to foscarnet at 60 mg per kg adjusted renal dysfunction; Or
2. Switch to maribavir 400; or
3. Continue ganciclovir at higher dose;
4. What about IV letermovir.

Okay. Let's see. Okay. So switch to 400. Around 51%, 52%, if I see here. Excellent. And actually for the—so now I need to close the voting. Okay, so no mutation was found, so patient had refractory and was switched to combination short course foscarnet and long course of maribavir as we talked about it early and he did fine, but at one point his viral went up again. And this is when he had GI GVHD. So he was

[01:05:00]

suspecting malabsorption.

I'm not going to go over this question for the sake of time. But what would you recommend? Would you:

1. Order genotype and switch foscarnet; or
2. Order genotype and continue maribavir, especially may respond; or
3. Switch to ganciclovir.

Here we know that probably patient has resistance to maribavir because of bioavailability from GI GVHD. And it was actually C480F, ganciclovir and maribavir, so foscarnet at the time. But at this end, patient died from GI bleed. So it was bad news. And actually it was a published cases. We published our experience with maribavir around 11 cases recently.

Clinical Tools for Antiviral Selection

So this is my last slide. We're going to go over the post-test question quickly. But keep in mind we have—ASTCT have a app where the guidelines are uploaded in the format of question and answers. So it's very easy to navigate and to get your answer, any question

[01:06:00]

about CMV that you would like to be answered there.

Key Takeaways

So this is the key takeaway that prevention of CMV improve outcome. We know that. Resistant and refractory infection associated with bad outcome, we know that. And at least we have some option to treat or alternative therapy compared to the toxic drug that we used to use for long period of time.

Posttest 1

So to go to the post-test questions. Following HCT, most clinically significant infections are—if you remember this question from earlier. These are:

1. Associated with retinitis;
2. Associated with GI disease;
3. Pulmonary disease; or
4. Not associated with tissue invasive disease.

So please vote.

Okay. Excellent. It looks like most of you. You see it. You see the result. Get the right answer.

Posttest 1: Rationale

And yeah. And this is the rationale.

[01:07:00]

Posttest 2

And the next question. Which of these transplant factors associated with increased risk of early CMV reactivation after transplant? And you can see here:

1. MRD;
2. Non-myelo;
3. Younger age; and

Start voting. Probably hopefully most of you got this question. And this is—yeah, excellent, 100% post. You've been listening.

Posttest 2: Rationale

And this is the rationale.

Posttest 3

My third question is, patient with CML, if you remember, was on foscarnet for viral load, high viral load, creatinine went up and ANC down. What would you recommend at this point?

Okay.

[01:08:00]

Most of you switched and some switched to ganciclovir even with ANC. But we worry about the graft. But yeah, now at least we have some options safer than what we have. But that's what we used to do before the era of maribavir.

Posttest 4

And the last question about patients with recurrent CMV infection. High viral load after three weeks of valganciclovir, creatinine is pretty high, and UL97 mutation to ganciclovir. What would you do? And start voting. Here would try to get this kind of new concept in place based on not much of data. I will tell you, based on some of our experience in this patient with high viral load or tissue invasive disease. And ID people love combination like you guys also treatment. So that's why we came up with this concept maribavir and short course of foscarnet. But as I said, it's

[01:09:00]

not really based on good data or clinical trial data.

Poll 3

How many of you plan to change your practice based on what you learned?

1. Yes; or
2. No.

Especially if there's something new that you learned. And I would encourage you to go over the guidelines, which was published recently from our society here. Very nice and clear.

Excellent. All right. And I’ll close voting.

Go Online for More Coverage of CMV in HCT!

And please enter—scan this QR code. What's that? No. Okay. Done. Okay. Here what you need to do, please to get your CME, go online for more coverage of CMV, and you will see the slide will be available.

And I forgot to mention earlier, this program was provided by Clinical Care Options and supported by a grant from

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Takeda as well.

And it could be my last slide. Thank you. We went five minutes after the hour. Lots to cover. But thank you for staying and thank you for being here this morning.