Treating Acute GVHD

Jaime Shahan

Before we start treating a patient with acute GVHD, we need to first understand which organ systems are affected and then grade the disease. Some patients with acute GVHD present with a rash, or some also have elevated LFTs or bilirubin, or some diarrhea. In the Bone Marrow Transplant clinic, the majority of acute GVHD that we see is grade 1 or 2. When it involves the skin, we grade based on the body surface area (BSA) using the rule of nines.¹ Grade 1 is < 25% BSA, and grade 2 is between 25% and 50% skin involvement. For other organ systems, we use the MAGIC criteria for grading,² which involves checking bilirubin levels, stool output, and frequency of nausea/vomiting.

One of the more common times we see acute GVHD is when the immune suppressive medications are tapered. The first planned taper at our institution is at day 35, which is when we discontinue the mycophenolate mofetil. Another common time is when we decrease the posaconazole or other -azole therapy, which decreases the available tacrolimus in the patient’s system. With this decrease in the level of immune suppression, we may see some GVHD involvement.

Diya Sabnani

That early post-transplant time is a very common time to have diarrhea. We do our best to be cautious about any medications that may cause diarrhea, like oral magnesium supplementation, for instance. We try to avoid oral magnesium for any patients who have loose stools because it can cloud the picture about potential gut GVHD.  

Jaime Shahan

That's a good point. So when that patient comes with any symptoms of acute GVHD, after we grade it, we send some blood for a symptomatic onset algorithm panel, which is a lab that sends biomarkers (ST2 and REG3α). This may help foresee how the GVHD may respond to treatment. We favor a pathologic diagnosis, or biopsy of the liver, skin, or GI tract, whenever possible. Then right after that, we typically start treatment.

Importantly, when treating acute GVHD, we try to limit systemic immune suppression wherever possible. At the beginning of a transplant, for most patients, their cancer is in complete remission. But some patients have microscopic disease or minimal residual disease, and when you severely immunocompromise that patient, you increase their risk of relapse and infection. So for those reasons, our treatment of GVHD should be as minimal as possible.

Diya Sabnani

So typically we use topical treatments for those patients with grade 1 or 2 GVHD. For the skin, we favor topical triamcinolone in our practice: 0.1% for the body and 0.025% for the face if needed. We may also continue or restart their original immunosuppressive medication.

With GVHD of the liver, when we see liver enzyme elevation, we typically start the patient on ursodiol. Then for our GI GVHD, we use the topical agent beclomethasone for upper GI involvement. With the lower GI, when we have diarrhea, we use budesonide. We tell our patients it's a little bit like rubbing the inside of their gut with hydrocortisone. Basically we’re trying to calm down that mucosal lining.

Then when we get into the higher grade 3 or 4 GVHD, of course this is a different story.

Jaime Shahan

When the GVHD of whatever organ system gets into the grade 3 or 4 category, we go right to the 1 mg/kg of prednisone as an outpatient, and then if they're inpatient, we use IV methylprednisolone. Depending on the dose, we may split the steroids into about 60% in the morning and about 40% in the afternoon to help give some around-the-clock coverage of their GVHD.³ We are also bringing them back into the clinic very quickly to assess response after just a few days and make sure things are headed the right direction. So if we don’t see someone responding within the first five days, we are going to continue on with our steroids and may dose up to as much as 2 mg/kg to see if we will get a response. But we would start looking at what our second line is going to be because sometimes it takes a few days to get insurance approval and get that medication in hand.

Diya Sabnani

Yes, unfortunately, about 35%-50% of patients with higher-grade acute GVHD who receive first-line high-dose steroids become steroid-refractory.⁴ The next-line treatment options for these patients are limited, and the mortality rates among steroid-refractory patients are high.⁴

When I was a bedside nurse, I had a patient who had an unrelated donor and really all the big risk factors for acute GVHD. At about day 50 post-transplant, she came back to the hospital with really bad hypovolemia and larger volume stool. EGD/colonoscopy showed grade 4 GVHD of the gut. We gave her 1.5 mg/kg steroids, but she had minimal response. She still had ongoing GVHD at 14 days after onset of steroid treatment, and the antidiarrheals and other supportive care, such as GI motility medications like octreotide, weren't helping. And she sadly ended up passing away.

But this was before we started using post-transplant cyclophosphamide (PTCy) prophylaxis for acute GVHD. In the 3 years that I’ve been practicing since PTCy has come about, it's not as common that we’re seeing this awful GVHD because we’ve gotten so much better with treatment and getting it under control. PTCy, which helps reduce the risk of acute GVHD by targeting allo-reactive T cells that cause the disease, is given twice after the stem cell infusion, usually days 3 and 4.⁵

Jaime Shahan

I know what you’re saying. When I first started in transplant 12 years ago, I remember my attending telling me that when he was in training, everyone knew that patients with grade 4 GVHD of the gut were going to die. It used to be almost 100% fatal. I don’t know whether that is attributable to PTCy, or some of the newer agents we have, or just that we have better ways to manage between our infectious disease providers and better antibiotics, antifungals, and better supportive care options, but we don’t see these bad outcomes that often anymore.

When we do have that steroid-refractory patient, we are typically pulling out our second line, which would be ruxolitinib.³ And in those patients where ruxolitinib may be not appropriate, like those with severe transfusion dependent cytopenias, we may be starting another agent, like ibrutinib, or putting back another agent that the patient may have previously been on, like mycophenolate mofetil, or tacrolimus or sirolimus, to add more immune suppression.

I’ve been really pleased with acute GVHD outcomes since the FDA approvals of those newer agents because it was a difficult situation before. Most of the older agents had lower success rates, whereas our newer agents have higher response rates.^6,7 That way we are better able to limit steroids and taper them faster. Because I’m sure you’ve seen, Diya, and I’ve seen in the outpatient setting, that people get a lot of steroid toxicity. Steroids can make people feel great at the very beginning, but then they also make their muscles waste, they make them weak, they make their blood glucose high, and they can cause eye issues and healing issues. I had a patient who couldn’t even keep his head up because his muscles had wasted so much. So steroids have a lot of toxicity, and we have to be very cautious and very sparing, as much as possible. I have seen a lot of improvement in patients who fail steroids; most of the time they do respond to the second-line agents we mentioned.  

Diya Sabnani

Yes, steroid toxicity can also be an issue, and we really should monitor patients closely for that. One other thing I'd like to touch on: So far, we've talked about a couple of the differences and similarities between inpatient and outpatient care for acute GVHD. Earlier, you mentioned how it can be difficult to get insurance approval for some second-line drugs. I remember working outpatient and how sometimes there was a bit of a lag there. Now that I work in inpatient care, I definitely find this less of an issue. If a patient is in inpatient care, they're pretty sick, they’ve already been on the topical medications, and they’ve already been on some steroids or we don’t think the prednisone is going to be enough. So we’ll go ahead and as you said start the methylprednisolone IV in divided doses. But when we are not seeing that improvement in a few days, it's a little bit easier to get some of the other medications approved quicker, especially those drugs that are on formulary at the hospital for steroid-refractory GVHD, and I think that is a benefit.

Another difference I notice is that often patients are in inpatient care because they need a lot of supportive care. It's important to remember that if they’re having a lot of volume loss—through diarrhea/vomiting or possibly malabsorption—we need to consider whether they need IV hydration and whether to start total parenteral nutrition. These are things that we need to think about as providers, because we don’t want them to go too long without nutrition. Similarly, if a patient has severely elevated bilirubin, we think about clotting issues and bleeding issues, things that come along with liver dysfunction, and medication clearance. So if they're in the hospital for GVHD, then there’s a reason.

Jaime Shahan

Absolutely, if the patient needs to be admitted to the hospital, they need additional support medically beyond just what is available in the outpatient clinic or at home. Thank you for that insight, Diya. I appreciate that we both have such different perspectives even as we take care of the same patient populations in different settings and different acuity levels.