Identifying When Additional Treatment Is Needed for cGVHD

Carrie L. Kitko, MD (Moderator)

Associate Professor of Pediatrics

Medical Director, Pediatric Stem Cell Transplantation Program

Ingram Professor of Pediatric Oncology

Monroe Carell Jr. Children’s Hospital at Vanderbilt

Nashville, TN

DISCUSSION QUESTION

• How do you define steroid-refractory, steroid-dependent, and steroid-intolerant patients with chronic graft-vs-host disease (cGVHD)?

CARRIE L. KITKO, MD: In the clinical trial setting, a steroid-refractory or resistant patient is someone who is actively progressing on steroids, typically a high dose after 1 to 2 weeks.¹ Or if they’re not responding on the lower dose, you were worried about comorbidities and you started at 0.5 mg/kg or 1 mg/kg every other day and you haven’t seen any improvement after 1 to 2 months, then that’s someone who in the textbook or on a clinical trial would be considered a steroid-refractory or resistant patient.

The steroid-dependent patients are the ones who initially tolerated the steroids and had improvement. But, every time you go below a certain threshold…0.25 mg/kg per day or 0.5 mg/kg every other day after at least twice, then that would be somebody who you should be thinking is…more dependent on the steroids and maybe adding something else would help get them off the steroids potentially. Then we all have patients who just have too many comorbidities and [have] steroid intolerance. Even though they might respond to steroids, the toxicity is such that you want to get them off, [such as] bad infections and diabetes.

DISCUSSION QUESTIONS

• Do you ever re-evaluate histopathology for patients with suspected cGVHD who are not responding to systemic steroids? For which types of patients?​

KITKO: What is your practice for biopsying these patients? If you had a biopsy potentially at some point or you diagnosed with them chronically at some point if they’re not responding, would you think about going back and getting another pathology to confirm that you’re still treating cGVHD?

SHERIF FARAG, MD: The organ that’s often most difficult in terms of chronic GVHD is the liver because so many other things can contribute to abnormal liver enzymes and so forth. If it’s going to change my management, based on everything else that’s going on, that’s the organ that I tend to biopsy the most.

KITKO: Yes, the liver can be definitely frustrating to figure out what’s happening.

JAIME SUAREZ-LONDONO, MD: I agree. The liver and lung would be the ones I would be more inclined to biopsy.

KITKO: The challenge with the lung is that you can get some of the pulmonary [specialists] to do a transbronchial biopsy, but then you get so little tissue, if you get a negative biopsy, do you believe it? Doing a wedge biopsy is much more morbid, [so] it’s more challenging.

WILLIAM TSE, MD: I have a high threshold to biopsy the patient in cGVHD because you’re running a risk of non-healing process because those patients sometimes can be a challenge. [It] will affect my management and carrying that morbidity for the patients sometimes could be [harmful].

KITKO: Especially if they have sclerotic skin, it’s hard to heal that as well. [I] just keep in mind as some of these patients have bad oral involvement, what started off as lichenoid changes [has become patients] getting hyperkeratotic plaques or severe ulcers that aren’t healing. They have increased risk for oral cancers. If you’re going down that path, thinking about [if] we need a biopsy to make sure this hasn’t become something else is important.

Our patients with skin GVHD can sometimes be confusing, especially the ones who have a lot of ulcers that have healed and become more thickened, almost like lumps of skin that also then create risk for skin cancer as well. I always send my patients to dermatology at least once a year to make sure that somebody besides me is looking over head to toe and making sure that I’m not missing a spot that the dermatologist is more concerned it might become a squamous cell carcinoma, for example. Those are the patients for whom I’m definitely actively thinking about making sure I’m not missing something besides their GVHD.

DISCUSSION QUESTIONS

• What treatment options are you most likely to recommend for a patient with steroid-dependent GVHD?
• Would you continue steroid?​
• Would you switch to another therapy? If so, which therapy?​

KITKO: What about treatment options for those patients? When you’re seeing these patients who have become either steroid dependent or steroid refractory, what is your go-to agent to try and help?

JOANNE WEINER, MD: For skin I like ECP [extracorporeal photopheresis]. I think it works well. For…overall skin changes, I’ve seen good results.

KITKO: Do you ever have difficulty getting patients to decide on that, especially now if they’re savvy and reading that there are pills they can take instead of doing ECP?

WEINER: Absolutely. Patients have become more savvy and less savvy as we move on in treatment.

KITKO: I think ECP is great. I used a lot of it for many years and when it was the clinical practice and I explained to a patient why I thought this was important and why it was a good treatment, I could get most patients to agree to do it. Then I was shocked with the BMT CTN 0801 study [NCT01106833] that initially was randomly assigning patients to sirolimus [Rapamune] vs ECP. When patients heard they could get randomly assigned to a pill vs this treatment…we could get almost nobody to do [ECP]. I would imagine that as patients are getting more savvy and know that there are these pills that are out there, they’re probably going to want to fail 1 or 2 of those options before agreeing to ECP.

WEINER: I probably would, too. I [understand]. Sometimes you have to see it through, and sometimes it works, sometimes it doesn’t.

KITKO: Absolutely. Anybody else? What is your go-to agent for somebody who needs to move beyond steroids?

TSE: I like ruxolitinib [Jakafi]. I like ibrutinib [Imbruvica]. I sometimes also like bortezomib [Velcade]. Sometimes it’s a little harder to get insurance approval, but I have good luck with bortezomib.

KITKO: The guidelines from the National Comprehensive Cancer Network list many of the different drugs…we do have ruxolitinib, belumosudil [Rezurock], and ibrutinib.¹ Ruxolitinib and belumosudil are approved for patients aged 12 and up. Just this past year or so, ibrutinib was approved all the way down to age 1, which…is nice for pediatric [oncologists] to have at least an option for younger kids.² It’s forced them to make a liquid formulation. But…there’s lots of other potential treatments that we have available.

References:

1. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplant, version 1.2023. Accessed August 14, 2023. https://tinyurl.com/bp9v7a45

2. U.S. FDA approves IMBRUVICA® (ibrutinib) as first and only BTKi treatment for pediatric patients with chronic graft-versus-host disease. Johnson & Johnson. News release. August 24, 2022. Accessed August 14, 2023. https://tinyurl.com/mr23pc9n