Treatment of cGVHD Requires a Patient-Centered Approach

Chronic graft-vs-host disease (cGVHD) is a complication of allogeneic stem cell transplantation that affects the organs; as many as 40% of transplant patients can develop cGVHD, explained Zahra Mahmoudjafari, PharmD, BCOP, MBA, FHOPA, a clinical pharmacy manager of hematology/blood and marrow transplant/cellular therapeutics at the University of Kansas Cancer Center, in Kansas City, Missouri, during a Pharmacy Times Clinical Forum. For patients with cGVHD, the pharmacist can create a systemic treatment regimen to manage the patient’s condition, according to Mahmoudjafari.

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“It’s kind of a wild, wild West scenario when a patient presents with cGVHD,” Mahmoudjafari said during the Clinical Forum.

The National Institutes of Health grades cGVHD with scores between 0 and 3; it is considered mild, moderate, or severe based on the number of organs that are affected and severity. cGVHD usually develops more than 100 days after transplant—unlike acute GVHD, which will develop within 100 days and present different symptoms—and it may be associated with varying survival outcomes, according to Mahmoudjafari. However, patients can have symptoms of acute and chronic conditions, which is termed overlap syndrome.¹

There are distinctive clinical features of cGVHD that may be present on the skin (vitiligo and papulosquamous lesions), hair (new scalp scarring or premature graying, thinning, brittleness), nails (longitudinal ridging or nail splitting), mouth (lichen planus–like changes, xerostomia, and mucosal atrophy), and eyes (new onset of “gritty,” painful eyes; keratoconjunctivitis sicca; and photophobia).

“[However,] the thing with cGVHD, and any type of transplant patient, is that it’s never the only story. There’s always a lot of other things going on, whether they have iron overload because we’ve given them a blood transfusion [or] hypothyroidism because we’ve jacked that entire system in general adrenal insufficiency,” Mahmoudjafari said. “There’s a lot to be aware of and a lot to manage.”

Treatment of cGVHD

Steroids are usually indicated as a first-line treatment for cGVHD, but creating a standard of care or algorithm for treatments following the first line can be difficult, as the disease can manifest differently from patient to patient, explained Laura Henshaw, PharmD, BCOP, BCPS, a clinical pharmacy specialist of hematology/oncology/cell therapy at Franciscan Health in Indianapolis, Indiana. Moreover, approximately 50% of patients with cGVHD will need a second line of therapy.

“There have been a hundred occasions where we’ve written an algorithm, [but] it is not black and white,” Henshaw said. “[With cGVHD,] you’re trying to do a black-and-white algorithm when you are dealing with a gray population.”

In 2017, ibrutinib (Imbruvica; Janssen) was approved for patients with cGVHD whose disease did not respond to 1 or more lines of systemic therapy. In 2021, belumosudil (Rezurock; Kadmon [a Sanofi Company]), an inhibitor of kinases ROCK1 and ROCK2, and ruxolitinib (Jakafi; Incyte), an inhibitor of Janus kinases 1 and 2 (JAK1 and JAK2), were approved to treat patients who have failed prior lines of systemic therapy.

Ruxolitinib has an overall response rate (ORR) of 70% and appears fairly “organ agnostic” in its treatment of cGVHD symptoms, and belumosudil has a high ORR of 75% at 6 months and targets inflammation and fibrosis associated with the disease, Mahmoudjafari explained. However, there are significant adverse events (AEs) associated with both therapies.

Belumosudil has been shown to cause pneumonia, hypertension, and severe hyperglycemia, according to Mahmoudjafari. Patients are also at risk of hepatotoxicity, which pharmacists can help to manage. Ruxolitinib is associated with low platelet counts, low absolute neutrophil count, and increased total bilirubin. In regard to both drugs, pharmacists can manage patient AEs by reducing or holding doses until patient recovery or treatment if AEs get too severe.

Other treatments for cGVHD include interleukin 2 and have different mechanisms of action and can elicit different patient responses. “The pharmacist really plays an important role in helping providers decide within that long list of options what would be the next best option [in the second line],” Mahmoudjafari said.

“It really is the kitchen sink when it comes to the second, third, fourth, fifth, and 17th line of therapy,” Mahmoudjafari added. “There’s a variety of different options that we have.”

Similarly, there have been certain instances when patients have received combination second-line therapies of belumosudil and ruxolitinib under pharmacist supervision, said Lauren Ooka, PharmD, BCOP, a clinical pharmacy specialist of hematology/cellular therapy at Franciscan Health.

But in this instance, it can be difficult to know which one is more effective (and knowing which one to stop) when the patient shows signs of improvement. For the pharmacist, “there’s a lot of opportunity to better understand how this works,” Ooka said.

Patient Management

The pharmacist can be an important resource for managing patients with this disease, especially if the patient presents complications, explained Job Bruner, PharmD, BCOP, senior pharmacist of clinical oncology at Purdue University and Ball Memorial Cancer Center and Indiana University Health in Muncie, Indiana. As the pharmacist, Bruner learns a lot about the patient’s background and barriers to treatment, such as distance to care, and can help where possible.

Delaney Wolfe, PharmD, BCOP, a clinical pharmacy specialist in hematology and cellular therapy at Community Health Network in Indianapolis, Indiana, gets patients in touch with pharmacies that offer home deliveries and does other initiatives to improve community access, such as checking in with patients to discuss medication adherence or schedule accessible telehealth appointments using virtual resources.

Pharmacists are also a unique source for educating patients about treatment protocols and medications, said Ooka. Additionally, Ooka noted that without pharmacist intervention, she has observed instances where doctors did not provide enough direction to patients on how to use the medication properly. As the pharmacist, she often tells patients “[the] things that no one had really told [them] before.”

Henshaw adds that the pharmacist can improve patient care by simply updating their medication list. “One of the biggest pieces of feedback we get as pharmacists is just how great these medication lists are that we update, because the doctors don’t always tell the patients about changes,” Henshaw said during the forum.

For instance, Henshaw will identify patients who could have errors on their medication lists, and, as the pharmacist, creates a visual of their medication. This visual will include the medication name, dose, times at which the medication is taken, and the number of times per day the medication is taken.

Taking the time to look over the patient’s medication list and schedule can also be an effective strategy to reduce AEs associated with medications, according to Henshaw. Similarly, the pharmacists can consolidate medications or remove unnecessary medications that might cause patient burden, Wolfe explained.

The pharmacist is even equipped to advocate for patients in various ways, which can include helping them to get a necessary referral or listening to needs patients may have been hesitant to share with their physician, according to Ooka.

Ultimately, the management of cGVHD may require the pharmacist and the care team to personalize treatment and care for each patient. “There are a lot of other therapies…that might be good for these niche patients,” said Ooka. There is also a myriad of ways that the pharmacist can serve the patient and improve the level of care that they are given, the panelists noted.

Ultimately, treating patients with cGVHD might simply be “an art over a science,” according to Wolfe. It is crucial to account for various drug interactions, patient response to medications, comorbidities, and “reapproach [the patient] differently every single time they come in because it is a journey and not a destination,” Wolfe said.

Reference

1. Wolff D, Lawitschka A. Chronic graft-versus-host disease. In: Carreras E, Dufour C, Mohty M, Kröger N, eds. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. 7th ed. Springer; 2019:331-345.