Treating Chronic GVHD

Jaime Shahan

It's important to remember that the treatment of chronic graft-versus-host disease (GVHD) is not a cookbook recipe or an algorithm. Treatment of chronic GVHD is very patient-specific and very practice-specific. In our conversation today we’ll talk about how we typically treat chronic GVHD at our institutions, but readers should understand that this may differ from how another patient may be treated at another practice.

Diya Sabnani

When we talk about severity of chronic GVHD, we're using the 2014 NIH Consensus document.¹ Using that, we treat based on severity of symptoms, features, or diagnostic tests, depending on the organ system.

Jaime Shahan

Starting with mild overall global severity, the typical treatment for mild chronic GVHD is topical therapy rather than systemic treatment most often.

Diya Sabnani

Definitely. So for ocular GVHD, symptoms are usually dry eyes, grittiness, photophobia, or ocular pain. When we're talking about chronic GVHD, we want to try to alleviate the symptoms that patients are presenting with. We're going to go with our topical agents, as you mentioned, which are lubricating eyedrops such as artificial tears that are preservative-free. If they have really dry eyes, we can use moisturizing eye ointment, which is a little bit of a thicker solution that patients can put on their eyes at night to help alleviate the symptoms. We definitely would want an ophthalmology consult and evaluation frequently and to have the patients checked for keratoconjunctivitis and inflammation. Occasionally we would also use a limited course of steroid eye drops, but this is usually prescribed by an ophthalmologist. Depending on the severity of symptoms, we can also consider using punctal plugs, which are plugs that are placed into the tear ducts to help prevent moisture loss and help keep the eyes more lubricated.

Jaime Shahan

We do also have patients who get scleral lenses as well, or if they have persistent eye dryness after all of these conservative measures, they may get a special contact that actually covers the eye to help with some of the symptoms, called scleral lenses.

Moving on next to oral chronic GVHD. We are typically seeing these patients come in with specific changes in their oral or their buccal mucosa. Sometimes they have redness or irritation, lichenoid changes, mucoceles, and even ulceration. For these patients, we use a couple of different versions of topical steroids. One is a dexamethasone solution that patients hold in their mouth, swish, and then spit. It's very challenging to hold it in your mouth as long as it's recommended, but it's only working when it's actively in their mouth. We have them do it up to five minutes and encourage them to keep it in there, but many patients struggle with that. The other stronger oral steroid is clobetasol. Sometimes we use Kenalog in Orabase, which is a thicker topical paste that patients can actually put on their cheek and keep it there. So that is an option if they're having a hard time with the mouth rinse and still only requiring topical agents, or if we want to avoid systemic treatment.

Diya Sabnani

Whenever I had patients who had oral GVHD and they were using the dexamethasone rinse, they would always complain of severe burning in their mouth. So I always try and tell patients that's totally normal, do it as long as you can, but usually they're not able to tolerate that full 5 minutes.

Jaime Shahan

We have had some success with premedicating with a miracle mouthwash or a viscous lidocaine solution if they're having pain with the treatment. If treatment is causing the same symptoms as the problem, then obviously we try to alleviate those issues as best we can.

Switching gears to the skin, we really are not seeing active erythema in our chronic GVHD patients, unless they do have some overlapping symptoms from acute GVHD. But for those patients who do have reddening of the skin, we give them the option to use a topical triamcinolone steroid cream. We do also have ointments that we can use, like tacrolimus ointment. And then of course, if they do have any scaly lesions on their skin that are itchy, they can also use the topical steroids for that.

Diya Sabnani

For patients experiencing vaginal GVHD, this can be burning with urination or dryness of the vagina with intercourse. This requires close monitoring because it's something that's frequently missed or not talked about between providers and patients. So early and aggressive treatment is imperative. We can use topical clobetasol cream and estradiol cream. And then depending on the severity of the symptoms, how much atrophy, tightness, or pain that they're having, they can use dilators, but this should be done under the care of a gynecologist.

Jaime Shahan

Absolutely. And then when we talk about topicals with regard to the GI tract, we do split this up based on upper and lower GI. So for our upper GI GVHD, patients are primarily experiencing nausea, persistent difficulty with eating, weight loss, inability to hold food down, or even esophageal strictures or webbing. The topical treatment for these issues is called beclomethasone; it's a solution that's actually compounded at a pharmacy, so it's a special order. I know it's sometimes mixed in oil, so it's not a great-tasting thing, but if patients are able to swallow it, it helps to coat their upper GI tract and reduce the inflammation there.

We also are referring these patients to gastroenterology typically for the diagnosis, but also for treatment. When we have a patient who has symptoms of getting pills or food stuck their throat, we can refer them over to our GI colleagues who perform an EGD and actually dilate the esophagus or rid the patient of the stricture, so to speak.

Diya Sabnani

For lower GI, we see more diarrhea, GI upset, and symptoms like that. For these issues, we would use oral budesonide, which comes in pill form. The dose is 3 mg, and we can dose it two to three times a day. It's the same thought process as the other topicals: We're not using it as systemic; it's absorbed in the GI tract to help reduce the inflammation.

Jaime Shahan

Absolutely. And then for chronic lung GVHD, for many years we were using a triple combination called FAM therapy, which is fluticasone together with azithromycin and montelukast. But in recent years, we've actually moved away from the regular use of azithromycin because data published in early 2020 showed that regular azithromycin use can increase cancer risk in patients with bronchiolitis obliterans.² Since that time, we've omitted the regular use of azithromycin from our treatment of chronic lung GVHD, but we are still using fluticasone and the montelukast for patients who are having symptoms. This includes shortness of breath, reduced FEV1 or reduced diffusion capacity, or difficulty walking distances or upstairs—those types of things.

For treatment, we are using inhaled topical steroids. Even for chronic GVHD patients who don't necessarily have lung GVHD, we are using inhaled topical steroids to treat upper respiratory infections. In those patients that have a new respiratory infection, like an acute viral infection, we will recommend that they be on at least 2 weeks of a combined inhaler, like a long-acting twice-a-day inhaler. And typically we're using a combined long-acting inhaled steroid for at least 2 weeks because those patients—and those with GVHD in other systems—can develop a flare or inflammation in their lungs that can lead to lung GVHD if they don't already have symptoms.

Diya Sabnani

Moving on to the joints, we really try to prevent chronic GvHD of the joints by having patients focus mainly on daily stretching and deep tissue massages. We also look for early indicators of joint GVHD and refer those patients to physical therapy right away.

Jaime Shahan

And lastly, for mild GVHD in the liver, we can use ursodiol for LFT elevation, but when we get into the moderate or severe symptoms, we have to talk about systemic treatment, which leads to the other part of our discussion. For any patient who has a moderate or severe global severity score, we are recommending that they receive systemic therapy. Many of these patients may have had some acute GVHD or may still be on their prophylactic GVHD medication. At our institution, we're using mostly tacrolimus or sometimes sirolimus. And we may increase their dose to make them therapeutic because often we're tapering them after the 100-day mark. So we may start to check levels again and adjust their dosing until we see therapeutic levels.

Diya Sabnani

For these patients with moderate and severe chronic GVHD, we're also going to be talking about adding systemic steroids. As we've talked about, we use topicals for mild GVHD to try and decrease inflammation in each of those organ systems to avoid using systemic steroids. But when we hit moderate and severe chronic GvHD, patients need systemic steroids. We use prednisone, starting anywhere from 0.5 to 1 mg/kg, and it depends on the symptom severity. We typically monitor patients frequently and reassess their symptoms depending on their presentation. We look at how they're responding within 2 weeks, at 2 to 4 weeks, and we consider adding a second-line therapy if we're not seeing a reduction or improvement in their symptoms.

Jaime Shahan

Absolutely. And typically, when we're not seeing a response or we feel like we're going to have to continue steroids for a longer period of time, we're pulling out our second-line therapy. At our institution, we use ruxolitinib for second-line therapy. We typically start at about 10 mg twice a day, depending upon the patient and their blood counts. And then we monitor blood counts regularly and hope to be able to reduce the steroids over time so that we can reduce the overall toxicity. When we start to titrate the steroids down, and still have the patient on ruxolitinib, we monitor blood counts to see if it's tolerable. Sometimes we do get a drop in blood counts when a patient is on ruxolitinib, so we may have to dose adjust based on their cytopenia.

Diya Sabnani

Some other systemic therapies that can be used are tacrolimus, which is dosed based on trough levels; sirolimus, again, based on trough levels; and mycophenolate mofetil usually started at 1,000 mg three times a day and then tapered down based on institution guidelines. There's also ECP, or extracorporeal photopheresis, which is where a patient is hooked up to a machine and their blood is circulated through, almost like an apheresis machine. Light helps deactivate overactive T cells, which is the cause of the GVHD.³ These patients also receive rituximab typically monthly for 4 months.

Jaime Shahan

Also, if patients are not able to tolerate ruxolitinib or if we don't see a good enough response, we do often try ibrutinib, unless there's a contraindication. Ibrutinib has an increased bleeding risk, so if a patient requires blood thinners, for instance, or has a history of cardiac issues, or is on ECP, we may not want to use it.