Ongoing Monitoring and Assessment for Chronic GVHD

Jaime Shahan

When it comes to chronic graft-versus-host disease (GVHD), there are several different special considerations we need to factor in for these patients. They are very complex, vulnerable patients; they're immunocompromised, and we need to closely monitor them for a lot of different things. One thing that we should always have in the back of our minds is that the majority of these patients had a bone marrow transplant because they had underlying malignant disease. So we are monitoring them for recurrence of their disease in the background, and we're also checking for their donor chimerism. But one of the most important things we're monitoring them for and trying to prevent is infection.

Diya Sabnani

Yes, and patients with chronic GVHD can be on several different treatments, for example, sirolimus, tacrolimus, ruxolitinib, prednisone, belumosudil—the options are endless. Sometimes they're on dual agents or maybe even five different drugs. We need to consider that we're pushing down their immune system to get their GVHD under control, which, in turn, is going to increase their risk of infection. So we should be continuing to monitor for things like EBV (Epstein-Barr virus), cytomegalovirus, HSV (herpes simplex virus), encapsulated bacteria, hepatitis B, bacterial infections, and fungal infections, and making sure our patients are on prophylactic medications to prevent these potential infections.

Jaime Shahan

In terms of the prophylactic agents, we're typically using acyclovir or valacyclovir for antiviral. When a patient needs mold coverage, we use posaconazole or isavuconazonium. Patients have to be on penicillin VK because patients with chronic GVHD are considered asplenic. This means that the patient's spleen is unable to help clear out encapsulated bacteria from the blood, so we have to have them on a medication that will help with this. We also need PJP prophylaxis—that's pneumocystis jirovecii.

Diya Sabnani

That's right, and the type of PJP prophylaxis we use depends on the patient's blood counts. In the early phase after transplant, when neutropenia and thrombocytopenia are common, we often use pentamidine, which is an inhaled monthly medication given in combination with albuterol. It's usually tolerated pretty well. It would be challenging to give an inhaled medication to a patient with chronic GVHD of the lungs because they're already having lung issues. If your patient's renal function and neutrophils are good, you can use Bactrim. Other options include dapsone or atovaquone. Patients don't love the taste of atovaquone, and it can sometimes be pricey. So each medication has its pros and cons, but these are the mainstays that we use for PJP prevention.

Jaime Shahan

Absolutely. And then we’re also taking the patient's immunity into consideration. Post-transplant, patients lose immunity to the vaccines they received as a child. Therefore, we have to consider whether it's appropriate to restart them. For patients with active chronic GVHD, we don't recommend that they move forward with vaccination because most of the time their CD4 count is low, and they may not actually mount a response to the vaccines. We've also had to recently consider whether certain chronic GVHD patients with some immune system presence should receive the COVID-19 vaccine. We’ve unfortunately had a couple of patients experience GVHD flares after receiving the COVID-19 vaccination. So we definitely want to be cautious and considerate of each of those patients’ particular situations.

Diya Sabnani

As well as, like we mentioned, checking T-cell subsets and monitoring CD4 counts for immune reconstitution.

Jaime Shahan

Definitely. We check those counts at the 100-day mark post-transplant and then again at the 180-day mark, and then at the annual mark. But if we have a patient that has an inadequate T-cell recovery, meaning their CD4 count is still less than 200, then we may consider repeating these count checks prior to the 1-year mark. So if we're at day 180 and their CD4 count is, say, in the 100s, then we may check it again in 8 weeks to see whether it's improved at all.

Diya Sabnani

Switching gears a bit, let's talk about hormone considerations in patients with chronic GVHD. Many patients have impaired hormone function post-transplant. We typically are monitoring and replacing testosterone or considering female hormone replacement as appropriate, if patients are in premature menopause. Sometimes even when you're talking to your patients, getting your review of systems, they'll tell you that their energy is really low and they are just not really feeling motivated. And sometimes their libido is low. It's key to ask our patients about these types of things, but we should also be checking hormone levels annually even if they're not giving us this information.

Jaime Shahan

Similarly, when patients have chronic GVHD in the vaginal area, they may experience sexual dysfunction related to either the GVHD or their treatment. We should be asking our patients about their sexual health and considering whether to intervene or offer medication based on those situations.

Also, many of our patients who are on chronic or intermittent steroids sometimes do develop impairment of their glucose clearance, so they may have hyperglycemia. Some of them do actually develop type 2 diabetes or steroid-induced diabetes. We should also be monitoring their hemoglobin A1C, even if their fasting sugars are not elevated.

Diya Sabnani

Another consideration for patients with chronic GVHD who are receiving steroids is bone health and associated complications, such as fractures, osteopenia, osteoporosis, and avascular necrosis of the bone. If a patient complains of bone pain, like jarring hip pain, we may need an MRI or x-ray. We also check vitamin D levels at 30, 100, and 180 days post-transplant and then annually, and have them get bone density scans annually if the results come back abnormal or every other year if normal.

Jaime Shahan

Speaking of vitamin D, patients who have chronic GVHD are instructed to avoid sun exposure, which can cause them to become vitamin D deficient. We've learned that vitamin D is really important for healing and obviously bone health as well. But even with COVID-19, we've learned that vitamin D levels can be important, with vitamin D deficiency being associated with a higher rate of hospitalization among patients with the virus.¹ So we definitely want to make sure we're replacing vitamin D adequately for our GVHD patients. We put them on vitamin D supplementation any time their level is lower than the goal, which is 30 ng/mL.

Diya Sabnani

Moving on to the eyes…when patients are on chemotherapy and steroids, they have a high risk of experiencing cataracts.² We refer chronic GVHD patients to an ophthalmologist and optometrist for at least yearly visits before they even start reporting ocular symptoms to make sure that we catch those signs and symptoms early.

Jaime Shahan

We are also monitoring heart health and cholesterol levels for our chronic GVHD patients. So many patients on pharmacologic treatment for their chronic GVHD are having impaired fasting lipid panels, especially patients on ruxolitinib who can experience increased cholesterol. So we need to monitor those laboratory studies regularly and treat those patients as appropriate if they have high triglycerides or hyperlipidemia.

Diya Sabnani

We should also have them get an echocardiogram at least a year after transplant to reassess their cardiac function and look for any major changes that we need to address.

Jaime Shahan

When it comes to the lungs, chronic GVHD patients can have impairment without being symptomatic. So we recommend that transplant patients undergo a regular pulmonary function test. My team does it at day 100 post-transplant, but also at day 180, and then at the 1-year and 2-year marks. Then if we need to treat them, we may repeat the test more often.

For those patients with chronic GVHD of the lungs, we monitor them more frequently and often involve a pulmonologist as well.

Diya Sabnani

We also have to monitor our patients' renal function. Usually we check their chemistry panels at each visit, but at least yearly, looking at serum creatinine and BUN, and making sure there's no major changes. We also check intermittent urinalysis, looking for high proteins in the urine and making sure we're not missing any renal issues.

Jaime Shahan

Agreed. Sometimes we can miss microangiopathy or something similar in these patients if we're not checking urinalysis for protein.

Diya Sabnani

As many patients receive multiple transfusions throughout their treatment and post-transplant course, another consideration for our chronic GVHD patients is iron overload. We may have to consider whether to send them for phlebotomy, or, if their blood counts are not adequate for phlebotomy, we may consider iron chelation to remove the excess iron from their body.

Jaime Shahan

We're also monitoring chronic GVHD patients for secondary cancers because they're very immunocompromised, and it's typically the immune system that first catches small things that may be changing toward cancer. So when a patient is immunocompromised or on multiple immune suppressants, the risk of cancer increases significantly.³ We need to monitor these patients regularly across the board for secondary malignancies, including colonoscopy, PSA (prostate-specific antigen), mammography, and also sending patients for high-risk dermatology consultations at least once a year, among other monitoring measures based on each individual patient. We recommend they see their dentist one or two times a year as well to screen for secondary malignancies in the mouth. And we are very up front with our patients about smoking cessation, the risks, and getting them help if they need it, and even the risks of being around secondhand smoke.

Diya Sabnani

Having a malignancy is a big deal. It's very hard on patients. Then going through transplant and potentially having chronic GVHD is even more stressful, not to mention undergoing all of these monitoring measures we've mentioned. It’s critical that we also check in on their psychosocial well-being. Depression and anxiety are all common among patients with chronic GVHD,⁴ and I think sometimes they're afraid to express it. So it's important that we as providers bring up these topics with our patients and refer them to a psychologist, social worker, or cancer psychology, if your center has that service available.

Jaime Shahan

Yes, that’s a very important consideration. We definitely need to be looking at the whole patient. It's not just, "Are we treating their GVHD?" but also, "Are we considering all of those factors that can keep them safe and healthy overall?" They've gone through such a big treatment for their cancer, and with chronic GVHD, they're trading their cancer for a new, sometimes lifelong, battle. So we definitely need to consider all these aspects whenever we are treating chronic GVHD in the clinic.