Presentation and Manifestation of Acute GVHD

Jaime Shahan

As we are both aware, acute graft-versus-host disease (GVHD) is a potentially serious complication of allogeneic transplant. It occurs when the donor cells recognize the patient’s cells and tissue as foreign. Acute GVHD used to be thought of as something that happened in the first 100 days post-transplant, but it is actually a clinical diagnosis and not limited to a timeframe.¹

Diya, what are some of the indications for allogeneic transplant? And what kinds of patients would we consider for transplant?

Diya Sabnani

So typically with patients who have blood cancers, the cancer originates in the bone marrow, and many of them have diseases either of the myeloid or the lymphoid cell, starting at the origin. Because of that, some of the indications for transplant would be acute myeloid leukemia, acute lymphoid leukemia, some of the myeloproliferative neoplasms like myelofibrosis, as well as high-grade myelodysplastic syndrome. We also offer transplant for bone marrow failure syndromes, like aplastic anemia or Fanconi’s anemia.

Jaime Shahan

Right, we are doing those transplants because the patient has a faulty marrow in the first place. And basically we are doing this because we need to replace the blood production, right?

Diya Sabnani

Yes, we're kind of resetting the patient’s bone marrow so that they can start producing healthy white cells and blood and so that they can live a normal life. Obviously this is not something that we do lightly, due to the potential for complications, like infection, GVHD, or mortality risk, so there are a lot of things that we need to consider as we go into transplant.

Jaime Shahan

One of the first things we’re working on is finding an appropriate donor. We send something called HLA typing, which stands for human leukocyte antigen. As I explain to patients, it’s kind of like sending blood typing, but this is immune system typing. So we want to try to find the best possible match for the patient because GVHD occurs when the donor’s cells attack and damage the patient's healthy cells.

Prior to moving to transplant after HLA typing, we send a large workup that includes a lot of things, such as heart and lung function testing, lab values to evaluate kidney and liver function, and infectious disease markers. We also calculate a hematopoietic cell transplantation comorbidity index, which incorporates other factors such as heart disease, lung disease, mental health factors, obesity, and/or prior cancers, and this helps us decide whether to proceed with transplant.²

Throughout my career, it's been very satisfying to see that most patients have been able to find a donor. We now have a little bit more access to donors, not only because more people are on the registry, but also because we've made some progress with haploidentical donors. These are half-matched donors, and most people have a parent or a child or a sibling that is at least a haploidentical donor. And when we talk about GVHD, I think it's helpful to have the understanding that we want the donor cells to recognize the patient’s cells as foreign. So in the past, identical matched (identical twin) donors were used, but it didn’t work as well because that donor blood was so close to the patient's blood that there were higher relapses in this population.³ So we try to get it as close as possible, but we do actually have some benefit from having that donor cell recognizing the patient's cell as foreign, in the form of GVL, which is graft-versus-leukemia, or graft-versus-lymphoma. But that can obviously cause a problem if there is too much of a mismatch, or if we have such severe GVHD that we need to further immunocompromise the patient.

Diya Sabnani

Can you tell me some of the other risk factors that increase a patient’s chance of experiencing GVHD after transplant?

Jaime Shahan

Beyond a mismatched donor, sometimes we see some additional increases in GVHD with female-to-male transplant: a sex-mismatched transplant. Also, sometimes when our patient is older, or our donor is older, we see an increased risk of GVHD, as well as with our stem cell source; with bone marrow, we have lower rates of GVHD than with our stem cell transplant.⁴ However, despite this, we don't often use bone marrow. For the donor, it is quite uncommon to donate bone marrow, so we are limiting this to very specific situations.

Diya Sabnani

Going back to your point about the balance, Jaime, interestingly you want a little bit of GVHD to provide some GVL, but you don’t want too much GVHD. You want to keep that scale really fine and balanced because unless you have some GVHD, you may not have any GVL, and that’s really important for us to keep in mind. When we talk about GVHD, we are not really going to see it until we start to see the white blood cells engraft after transplant. When a patient is getting a transplant, they come into the hospital, they get chemotherapy, then they get stem cells; the chemotherapy will wipe out their immune system, giving us a blank slate to add stem cells to and start regenerating. So once these stem cells go in, depending on the source, it's going to take 2 to 3 weeks until the white blood cells engraft. Once we see them coming in and coming back, that’s when we may start to see GVHD.

Jaime Shahan

And when we do see acute GVHD in our transplant patients, can you discuss how it manifests in the various organ systems?

Diya Sabnani

In acute GVHD, we can see three main organ systems affected: skin, liver, and the gastrointestinal system, commonly called gut GVHD. In the skin, we usually see an erythematous maculopapular rash. This can affect the soles of the feet and the palmar surface of the hands, but really, in practice, I’ve seen it on the chest and on the back and trunk. We grade this on the Rule of Nines, as we would for burn patients, calculating the body surface area.⁵

When we talk about GI effects, we split it into upper and lower, and for lower, we grade the severity based on quantity of stool. So it's very important that we’re monitoring stool output. Upper GI effects are based on nausea and vomiting, dyspepsia, and whether a patient is able to keep things down, despite the use of antiemetics. With the liver, we’re not grading based on liver function tests, but we are looking solely at the total bilirubin. All of those factors combined help us grade a patient's acute GVHD.⁶

When we're looking at all three of these body systems in this acute phase, and most of the time we’re in the earlier days post-transplant, these patients are on multiple medications, and they’ve been neutropenic, so we have to think, is this medication induced? Is this infectious related? We need to do a good job assessing the patient and getting a good history, and we need to make sure we’re ruling out other causes. Often we need to get a biopsy to make sure we’re dealing with tissue-proven GVHD before we really move forward.

Jaime Shahan

Yes, that's an important point. You work inpatient, I work outpatient, but we're both taking care of these patients typically, and, I would say, in that acute phase, you’re more likely to see the GVHD appear in those first few days after engraftment, while they're still under your inpatient care. Then after that, I’m seeing them in the outpatient clinic when they come for their hospital discharge visit, and then at least twice a week for the first month and then weekly until the 100-day mark. So when we talk to our patients, it's really important to educate them on what kinds of GVHD signs and symptoms they should be looking for at home, and to instruct them to let us know about these things.

When we do see it, it is a clinical diagnosis: The clinical presentation gives us a lot of information that can clue us in on exactly what is going on. If a patient comes in with full-blown multi-organ system GVHD, sometimes it’s a little more obvious. But if they just come with a rash, it may not be as clear. So we need to do our due diligence, rule out other causes, and get that pathologic diagnosis. As you know, even though the gold standard for liver GVHD is biopsy, it's not often that we’re actually doing a liver biopsy, so we need to keep the big picture in mind.

Diya Sabnani

Right. With GI, we often send stool studies and highly consider a colonoscopy with an EGD if we suspect GI GVHD because the treatment of GVHD is immunosuppression, and if there is an infectious source of diarrhea, we will make that infection worse.

Jaime Shahan

As advanced practice providers, we work autonomously within our scope of practice, seeing patients independently and planning treatment adjustments as appropriate. I’ve been blessed to be working with my current supervising physician for over 5.5 years. I confirm my plan with her whenever there is a more severe presentation of GVHD, which may require a change in the level of immunosuppression of the patient.