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The Need for CMV Prophylaxis in the Transplant Setting

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Roy Chemaly, MD, MPH, MD Anderson Cancer Center; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published: Tuesday, Jan 31, 2017


Transcript:

Harry Erba, MD, PhD:
Let me see if I’m hearing the two of your correctly then. The trouble with the current drugs is that they’re toxic, so you don’t want to have to use them if you don’t need to. So, we’re using this monitoring technique to intervene kind of preemptively, but really early.

Mark Levis, MD, PhD: Actually, yes. When we intervene, there’s a debate as to when should you intervene and what level should you intervene at.

Harry Erba, MD, PhD: Yes. So, you’re intervening when you have some evidence that the disease is there. But if you had a drug available that wasn’t so toxic, it may be a real advantage to give a truly prophylactic drug.

Roy Chemaly, MD, MPH: Absolutely. You don’t want to treat at the first sign of infection. I prefer to prevent the infection because we don’t know, first, how much you have to wait until their viral load goes up and you stop intervening.

Mark Levis, MD, PhD: Prophylaxis is where we’ve gotten in this field thus far; waiting for everything else.

Harry Erba, MD, PhD: Like what we just talked about for fungal infections. So, it makes sense. As we come to the end in this program, let’s talk about that more. But in order to flesh out a little bit of the discussion about this monitoring, when I ask my house staff to order monitoring for CMV (cytomegalovirus), they have a choice of all of these different tests. And usually, you end up getting all of them. Do you need all of them? What do they do? How do we monitor now? What are the various tests available?

Roy Chemaly, MD, MPH: So, for many years, we used to look at the antigen of CMV pp65 in the blood. We know that it wasn’t a really sensitive test.

Harry Erba, MD, PhD: Don’t you need white blood cells?

Roy Chemaly, MD, MPH: Right. This is the thing.

Harry Erba, MD, PhD: It’s in the white blood cells, so you need your white blood cells, and our patients often don’t.

Roy Chemaly, MD, MPH: Absolutely, you’re right. So, that’s why it was an insensitive test. Are we detecting antigenemia when it is almost too late, when the patient already may have an end-organ disease or something like that? Now, with the era of PCR (or viral load), it’s a very sensitive test, so we’re probably catching pretty early reactivation and we’re acting on it in high-risk patients. And is this affecting outcome? Probably, but we had to see the data to know for certain that patients were dying from CMV, and they were very rare. So, the rate of CMV end-organ disease, it went down from 20% to probably 3%, which is great. But the CMV viremia is still occurring. What else can we do?

We were interested to see if someone has already had a good immune system, good T cells, and T-cell response. Are they protected from CMV viremia? This can help us, and I will tell you where. We conducted the study where we looked at all this very low level of reactivation and are we overtreating. Is this patient going to progress or are they going to self-resolution of this viremia? So, we did the CMV-specific T-cell ELISPOT assay and we found out that at a certain level of response of interferon release, these patients are protected from CMV progressing or from even CMV viremia.

This is not validated yet; it’s a small study that we conducted. But in the future, hopefully we’ll see the data from the study in a multi-institution, that we completed enrollment. And this may play a role in the future to help the transplant to determine, is this patient at risk for progressing from CMV or do they need to be treated for low level? Or do they need to be monitored actually if they have good CMV-specific T-cell response?

Mark Levis, MD, PhD: That raises an interesting point, because the PCR assay, first of all, at what level can you or do you need to begin treating? But sometimes we actually have patients that have a negative PCR assay, but have CMV esophagitis or something like that. So, do you think this modality is going to help?

Roy Chemaly, MD, MPH: Absolutely. It may help us to really determine if the patient is protected or not. Because this is what the data are showing: that if you have a good CMV T-cell response, this patient may not need to be monitored all that frequently. But this needs to be validated, and hopefully, we will hear more about it in the future.

Harry Erba, MD, PhD: Explain it to me a little bit more, because I’m not sure I’m quite getting it yet. What is being actually tested? The T cells? And you’re looking to see if they respond to CMV in vitro?

Roy Chemaly, MD, MPH: Yes, in vitro. So, you’re taking the PBMCs (peripheral blood mononuclear cells) within the T cell, exposing them to CMV peptides—pp65 intermediate early antigen—and then you see their interferon release, meaning that these T cells are enough to protect a certain level, a certain threshold, against CMV.

Mark Levis, MD, PhD: That’s an active area in a bone marrow transplant research. When do the T cells protect you from CMV? First of all, did you kill them with your preferred regimen? Or if you did, or lowered them, when do they come back? Roy Chemaly, MD, MPH: Right. Harry Erba, MD, PhD: Is that similar to the QuantiFERON-TB test?

Roy Chemaly, MD, MPH: It’s similar to T-SPOT.TB, or ELISPOT, it’s kind of the same. But the T-SPOT.TB test tells you that if a patient has already been exposed to tuberculosis, then they would be at risk for infection. The CMV T-SPOT assay, or ELISPOT assay, will tell you that if the patient has enough CMV T cells, they are protected against reactivation.

Harry Erba, MD, PhD: So, what’s the CMV QuantiFERON test?

Roy Chemaly, MD, MPH: QuantiFERON is like the ELISA test. It’s a different platform to test for. It’s the same kind of concept, looking at interferon release from this T cell, but a different platform from the ELISA test. I would say probably it’s not as robust as the ELISPOT testing that is done for CMV.

Harry Erba, MD, PhD: But right now, are those being used in clinical practice? Maybe I didn’t get that yet.

Roy Chemaly, MD, MPH: I would say not yet, but more to come hopefully, yes.

Harry Erba, MD, PhD: Okay, so for our listeners then, it’s still the CMV viral load by PCR?

Mark Levis, MD, PhD: We made a lot of progress, but that’s our current status.

Harry Erba, MD, PhD: And you trigger therapy at what level? I know no one agrees, but you guys are the experts.

Roy Chemaly, MD, MPH: It depends. I think, depending on the institution—and I talked to many institutions here and in Europe also—it’s a different threshold. This is the problem with the viral load. For us, probably for cord and haplo high-risk patients, it is any positive triggered treatment. Now, for low-risk, we’ll wait until 1000 IU/mL (international unit per mL). But other institutions, they have low thresholds or higher.

Mark Levis, MD, PhD: I think we’re still debating with that issue.

Harry Erba, MD, PhD: So, again, it comes to—I assume you get your whole team together, Mark—it’s a risk benefit. The idea is in there, and they’re saying, “I think we should treat,” and you’re saying, “Wait a second. This patient has no counts, and I don’t want to kill the graft.”

Mark Levis, MD, PhD: Well, no. At our institution, our whole group gets together to set guidelines, but each patient is individualized.

Harry Erba, MD, PhD: In different positions.

Transcript Edited for Clarity
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Transcript:

Harry Erba, MD, PhD:
Let me see if I’m hearing the two of your correctly then. The trouble with the current drugs is that they’re toxic, so you don’t want to have to use them if you don’t need to. So, we’re using this monitoring technique to intervene kind of preemptively, but really early.

Mark Levis, MD, PhD: Actually, yes. When we intervene, there’s a debate as to when should you intervene and what level should you intervene at.

Harry Erba, MD, PhD: Yes. So, you’re intervening when you have some evidence that the disease is there. But if you had a drug available that wasn’t so toxic, it may be a real advantage to give a truly prophylactic drug.

Roy Chemaly, MD, MPH: Absolutely. You don’t want to treat at the first sign of infection. I prefer to prevent the infection because we don’t know, first, how much you have to wait until their viral load goes up and you stop intervening.

Mark Levis, MD, PhD: Prophylaxis is where we’ve gotten in this field thus far; waiting for everything else.

Harry Erba, MD, PhD: Like what we just talked about for fungal infections. So, it makes sense. As we come to the end in this program, let’s talk about that more. But in order to flesh out a little bit of the discussion about this monitoring, when I ask my house staff to order monitoring for CMV (cytomegalovirus), they have a choice of all of these different tests. And usually, you end up getting all of them. Do you need all of them? What do they do? How do we monitor now? What are the various tests available?

Roy Chemaly, MD, MPH: So, for many years, we used to look at the antigen of CMV pp65 in the blood. We know that it wasn’t a really sensitive test.

Harry Erba, MD, PhD: Don’t you need white blood cells?

Roy Chemaly, MD, MPH: Right. This is the thing.

Harry Erba, MD, PhD: It’s in the white blood cells, so you need your white blood cells, and our patients often don’t.

Roy Chemaly, MD, MPH: Absolutely, you’re right. So, that’s why it was an insensitive test. Are we detecting antigenemia when it is almost too late, when the patient already may have an end-organ disease or something like that? Now, with the era of PCR (or viral load), it’s a very sensitive test, so we’re probably catching pretty early reactivation and we’re acting on it in high-risk patients. And is this affecting outcome? Probably, but we had to see the data to know for certain that patients were dying from CMV, and they were very rare. So, the rate of CMV end-organ disease, it went down from 20% to probably 3%, which is great. But the CMV viremia is still occurring. What else can we do?

We were interested to see if someone has already had a good immune system, good T cells, and T-cell response. Are they protected from CMV viremia? This can help us, and I will tell you where. We conducted the study where we looked at all this very low level of reactivation and are we overtreating. Is this patient going to progress or are they going to self-resolution of this viremia? So, we did the CMV-specific T-cell ELISPOT assay and we found out that at a certain level of response of interferon release, these patients are protected from CMV progressing or from even CMV viremia.

This is not validated yet; it’s a small study that we conducted. But in the future, hopefully we’ll see the data from the study in a multi-institution, that we completed enrollment. And this may play a role in the future to help the transplant to determine, is this patient at risk for progressing from CMV or do they need to be treated for low level? Or do they need to be monitored actually if they have good CMV-specific T-cell response?

Mark Levis, MD, PhD: That raises an interesting point, because the PCR assay, first of all, at what level can you or do you need to begin treating? But sometimes we actually have patients that have a negative PCR assay, but have CMV esophagitis or something like that. So, do you think this modality is going to help?

Roy Chemaly, MD, MPH: Absolutely. It may help us to really determine if the patient is protected or not. Because this is what the data are showing: that if you have a good CMV T-cell response, this patient may not need to be monitored all that frequently. But this needs to be validated, and hopefully, we will hear more about it in the future.

Harry Erba, MD, PhD: Explain it to me a little bit more, because I’m not sure I’m quite getting it yet. What is being actually tested? The T cells? And you’re looking to see if they respond to CMV in vitro?

Roy Chemaly, MD, MPH: Yes, in vitro. So, you’re taking the PBMCs (peripheral blood mononuclear cells) within the T cell, exposing them to CMV peptides—pp65 intermediate early antigen—and then you see their interferon release, meaning that these T cells are enough to protect a certain level, a certain threshold, against CMV.

Mark Levis, MD, PhD: That’s an active area in a bone marrow transplant research. When do the T cells protect you from CMV? First of all, did you kill them with your preferred regimen? Or if you did, or lowered them, when do they come back? Roy Chemaly, MD, MPH: Right. Harry Erba, MD, PhD: Is that similar to the QuantiFERON-TB test?

Roy Chemaly, MD, MPH: It’s similar to T-SPOT.TB, or ELISPOT, it’s kind of the same. But the T-SPOT.TB test tells you that if a patient has already been exposed to tuberculosis, then they would be at risk for infection. The CMV T-SPOT assay, or ELISPOT assay, will tell you that if the patient has enough CMV T cells, they are protected against reactivation.

Harry Erba, MD, PhD: So, what’s the CMV QuantiFERON test?

Roy Chemaly, MD, MPH: QuantiFERON is like the ELISA test. It’s a different platform to test for. It’s the same kind of concept, looking at interferon release from this T cell, but a different platform from the ELISA test. I would say probably it’s not as robust as the ELISPOT testing that is done for CMV.

Harry Erba, MD, PhD: But right now, are those being used in clinical practice? Maybe I didn’t get that yet.

Roy Chemaly, MD, MPH: I would say not yet, but more to come hopefully, yes.

Harry Erba, MD, PhD: Okay, so for our listeners then, it’s still the CMV viral load by PCR?

Mark Levis, MD, PhD: We made a lot of progress, but that’s our current status.

Harry Erba, MD, PhD: And you trigger therapy at what level? I know no one agrees, but you guys are the experts.

Roy Chemaly, MD, MPH: It depends. I think, depending on the institution—and I talked to many institutions here and in Europe also—it’s a different threshold. This is the problem with the viral load. For us, probably for cord and haplo high-risk patients, it is any positive triggered treatment. Now, for low-risk, we’ll wait until 1000 IU/mL (international unit per mL). But other institutions, they have low thresholds or higher.

Mark Levis, MD, PhD: I think we’re still debating with that issue.

Harry Erba, MD, PhD: So, again, it comes to—I assume you get your whole team together, Mark—it’s a risk benefit. The idea is in there, and they’re saying, “I think we should treat,” and you’re saying, “Wait a second. This patient has no counts, and I don’t want to kill the graft.”

Mark Levis, MD, PhD: Well, no. At our institution, our whole group gets together to set guidelines, but each patient is individualized.

Harry Erba, MD, PhD: In different positions.

Transcript Edited for Clarity
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