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Second-Line Management of Acute Graft-Versus-Host Disease

Insights From: Joseph Antin, MD, Dana-Farber Cancer Institute; Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute
Published: Tuesday, Sep 10, 2019



Transcript: 

Corey S. Cutler, MD, MPH, FRCPC: So you did touch on the fact that some of our patients have graft-versus-host disease (GVHD) that is refractory to steroids as first-line therapy. It’s important to recognize that probably up to 50% of our GVHD patients at some time are going to require a second-line agent. Probably a quarter of our patients have GVHD that is primarily resistant such that the steroids don’t work at all. And then another quarter of the patients will have a recurrence of their acute GVHD as the steroids are being tapered, or perhaps after a complete response. So it’s at that point that we reach to our tool bag for second-line drugs. We do know offhand that the response to steroids is very important in determining long-term outcome, as would be the response to second- and even third-line agents, if we actually have to go there.

In the setting in which a second agent is required, what are the factors that you use to decide what drug you’re going to use, and what are the common agents you typically reach for?

Joseph Antin, MD: So this is an area that I spent the bulk of my career on. And over the course of the last 30 plus years, I’ve learned a few things. The first is that because GVHD and the immunological response to infection are essentially the same thing, you have to be very cautious about adding on immunosuppressants. It’s easy enough to add immunosuppressant after immunosuppressant or go up to 5 mg/kg or 10 mg/kg of steroids. What you have to realize is that the more you do that, the more you paralyze the patient’s ability to fight infection. And if you look through the literature, in the not so early days of transplantation, even up until relatively recently, what you can find is that many drugs will increase the response rate but fail to improve survival because the infection rate goes up very substantially.

This is a situation where it’s very difficult to have your cake and eat it too. If the same T cells are responsible for controlling viruses and fungi, etcetera, and you completely paralyze them or eliminate them, you are by definition going to get an infection. So what we need to do is focus our attention on therapies that are less immunosuppressant and more anti-inflammatory or that take advantage of the body’s intrinsic immunoregulatory mechanisms to prevent GVHD. So one component of the immune system that we like to foster is regulatory T cells, or Tregs. And we’ve done some studies on that that you might want to comment on.

Corey S. Cutler, MD, MPH, FRCPC: We’ve done a number of trials at our center on regulatory T cells. Most of those have focused on the chronic GVHD setting, but there are others that focus on the role of fostering regulatory T cells in the acute setting. Most of the current research is on the administration of regulatory T cells early after transplantation to try to set up a calmer inflammatory milieu, if you will, to prevent GVHD. No one’s really looked terribly deeply at the role of regulatory T cells administered during flares of acute GVHD at this time. We’ve had to focus on pharmacologic agents because you do need to act when there is acute GVHD, and so taking the time to culture and grow and isolate regulatory T cells is tricky. So we’ve tended to focus on the use of pharmacologic agents in this setting.

Joseph Antin, MD: So what we’d like to use are pharmacologic agents that either are nonimmunosuppressive or in which the level of immunosuppression is administered through regulatory T cells, and there are a number of drugs that can do that type of thing. A number of years ago a group in Minnesota actually did what Dr Cutler was referring to, which is to isolate, expand, and infuse regulatory T cells. It actually worked, although it’s very labor intensive, very expensive, and only transiently effective.

So getting back to the original question, what we’re looking at now are ways to reduce the inflammatory aspects of GVHD, without completely paralyzing the immune system. And one approach to that would be through JAK inhibition, for instance. JAK inhibitors like ruxolitinib or itacitinib will downregulate the body’s response to inflammatory cytokines without completely paralyzing the immune response. As many hematology/oncology people are aware, you can use drugs like ruxolitinib in myeloproliferative disorders without making the patient immunocompromised, but if you abruptly stop them, the patient will get a rebound of inflammation that can be quite unpleasant. Therefore, by using that type of drug, we can suppress the inflammatory manifestations—some of the diarrhea, some of the rash—and hopefully allow the immune system to recover more naturally.

Transcript Edited for Clarity
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Transcript: 

Corey S. Cutler, MD, MPH, FRCPC: So you did touch on the fact that some of our patients have graft-versus-host disease (GVHD) that is refractory to steroids as first-line therapy. It’s important to recognize that probably up to 50% of our GVHD patients at some time are going to require a second-line agent. Probably a quarter of our patients have GVHD that is primarily resistant such that the steroids don’t work at all. And then another quarter of the patients will have a recurrence of their acute GVHD as the steroids are being tapered, or perhaps after a complete response. So it’s at that point that we reach to our tool bag for second-line drugs. We do know offhand that the response to steroids is very important in determining long-term outcome, as would be the response to second- and even third-line agents, if we actually have to go there.

In the setting in which a second agent is required, what are the factors that you use to decide what drug you’re going to use, and what are the common agents you typically reach for?

Joseph Antin, MD: So this is an area that I spent the bulk of my career on. And over the course of the last 30 plus years, I’ve learned a few things. The first is that because GVHD and the immunological response to infection are essentially the same thing, you have to be very cautious about adding on immunosuppressants. It’s easy enough to add immunosuppressant after immunosuppressant or go up to 5 mg/kg or 10 mg/kg of steroids. What you have to realize is that the more you do that, the more you paralyze the patient’s ability to fight infection. And if you look through the literature, in the not so early days of transplantation, even up until relatively recently, what you can find is that many drugs will increase the response rate but fail to improve survival because the infection rate goes up very substantially.

This is a situation where it’s very difficult to have your cake and eat it too. If the same T cells are responsible for controlling viruses and fungi, etcetera, and you completely paralyze them or eliminate them, you are by definition going to get an infection. So what we need to do is focus our attention on therapies that are less immunosuppressant and more anti-inflammatory or that take advantage of the body’s intrinsic immunoregulatory mechanisms to prevent GVHD. So one component of the immune system that we like to foster is regulatory T cells, or Tregs. And we’ve done some studies on that that you might want to comment on.

Corey S. Cutler, MD, MPH, FRCPC: We’ve done a number of trials at our center on regulatory T cells. Most of those have focused on the chronic GVHD setting, but there are others that focus on the role of fostering regulatory T cells in the acute setting. Most of the current research is on the administration of regulatory T cells early after transplantation to try to set up a calmer inflammatory milieu, if you will, to prevent GVHD. No one’s really looked terribly deeply at the role of regulatory T cells administered during flares of acute GVHD at this time. We’ve had to focus on pharmacologic agents because you do need to act when there is acute GVHD, and so taking the time to culture and grow and isolate regulatory T cells is tricky. So we’ve tended to focus on the use of pharmacologic agents in this setting.

Joseph Antin, MD: So what we’d like to use are pharmacologic agents that either are nonimmunosuppressive or in which the level of immunosuppression is administered through regulatory T cells, and there are a number of drugs that can do that type of thing. A number of years ago a group in Minnesota actually did what Dr Cutler was referring to, which is to isolate, expand, and infuse regulatory T cells. It actually worked, although it’s very labor intensive, very expensive, and only transiently effective.

So getting back to the original question, what we’re looking at now are ways to reduce the inflammatory aspects of GVHD, without completely paralyzing the immune system. And one approach to that would be through JAK inhibition, for instance. JAK inhibitors like ruxolitinib or itacitinib will downregulate the body’s response to inflammatory cytokines without completely paralyzing the immune response. As many hematology/oncology people are aware, you can use drugs like ruxolitinib in myeloproliferative disorders without making the patient immunocompromised, but if you abruptly stop them, the patient will get a rebound of inflammation that can be quite unpleasant. Therefore, by using that type of drug, we can suppress the inflammatory manifestations—some of the diarrhea, some of the rash—and hopefully allow the immune system to recover more naturally.

Transcript Edited for Clarity
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