Using NCCN Guidelines for Chronic GVHD Therapy in Clinical Practice

Noah M. Merin, MD, PhD

Assistant Professor of Medicine

Medical Director, Hematology and Cellular Therapy Disease Research Group

Cedars-Sinai Samuel Oschin Cancer Center

Los Angeles, CA

Targeted Oncology^TM: What do the National Comprehensive Cancer Network (NCCN) guidelines advise for first-line for chronic graft-vs-host disease (GVHD)?

MERIN: The NCCN is attempting to cover GVHD. Unfortunately, they list all the therapies without a hierarchal schema that would allow you to choose between the different therapies.¹ The NCCN guidelines are an acknowledgement that treatment is largely empiric. That is, you give a drug at a high dose if it's working. If not, you switch to a different drug.

The first-line therapies are often steroids. There is not a benefit to going beyond 1 mg/kg per day. We always use topical steroids if there is skin involvement, inhaled steroid with or without azithromycin for lung involvement [such as] FAM [fluticasone, azithromycin, montelukast] therapy. Have caution that the azithromycin, when it's used for prophylaxis, increases the rate of relapse.²

If that works well, the patient doesn't have GVHD anymore. You taper off steroids. Patients don't develop chronic GVHD if they responded to steroids. If they don't respond or if they have multiple episodes or if they have recurrence of GVHD during the steroid taper, then you should add another agent. I'd also say that pretty much any patient who has…beyond just 1 episode or 2 episodes of easy-to-treat liver GVHD, if they have other sites [as well as] visceral involvement, then you should be thinking about starting second-line therapy during your initial steroid taper.

Which options are suggested in steroid-refractory chronic GVHD?

Ruxolitinib [Jakafi] is approved and has a label indication for treating acute GVHD to steroid-refractory resistance, as well as for chronic GVHD.³ Ibrutinib [Imbruvica] and belumosudil [Rezurock] are only labeled for chronic GVHD, but can be used off-label for acute GVHD, particularly ibrutinib.^4,5 For everything else [listed on the NCCN guidelines], I wouldn't try it. [I would] refer the patient back to whichever transplant center treated them or see if the patient will go on a clinical trial, because there are so many choices [on the guidelines] and they have such different effects on patients based on what type of transplant they have, what the donor source is, and what the GVHD prophylaxis was.

The GVHD prophylaxis has impact on the pattern of the appearance of GVHD and the severity of the GVHD. But one of the things for physicians who are involved in a practice where you're seeing a lot of GVHD, you have to know your regimens. You have to get familiar with the typical time of onset of GVHD and its typical manifestation in patients who are being treated using the regimens that are common in your [local treatment center] because that helps you to distinguish GVHD from non-GVHD extra-organ involvement.

Infliximab [Remicade] is a tumor necrosis factor alpha [TNF-α] inhibitor that is used in inflammatory bowel disease. It is one of the drugs that is affected in colon GVHD and gastrointestinal GVHD, just like an inflammatory bowel disease in patients who are steroid refractory. Similar to when we treat inflammatory bowel disease, you can use C-reactive protein levels to tell if infliximab is working. That's one trick for managing severe colon GVHD.

What are your thoughts on the available therapies for steroid-refractory chronic GVHD?

Only ruxolitinib, belumosudil, and ibrutinib are approved [for chronic GVHD]. The other ones are all used off-label and frankly, very rarely. The only one I called out on the list was infliximab. What you don't want to do is just randomly choose drugs. You want to have a rationale.

I generally don't reintroduce calcineurin inhibitors. I don’t think imatinib [Gleevec] works. Some centers use low-dose IL-2. [I would] absolutely not use low-dose methotrexate. mTOR inhibitors are like calcineurin inhibitors. They're very immunosuppressive. They cause wasting and cytopenias, so generally [I would not use them].

Mycophenolate is particularly good in liver GVHD. If a patient has a late flare of GVHD, sometimes I will put them on several months of mycophenolate. If it's strictly elevated liver function tests and alkaline phosphatase elevated, sometimes I will use mycophenolate at 1000 mg twice a day with a 3- or 4-month taper before I would commit to doing ruxolitinib or ibrutinib. Sometimes it works temporarily and then you have to add the other drugs anyway, but at least it allows the patient to get off the steroids.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplant, version 3.2022. Accessed February 22, 2023. https://bit.ly/3m0dGPh}

_{2. Vallet N, Le Grand S, Bondeelle L, et al. Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation. Blood. 2022;140(23):2500-2513. doi:10.1182/blood.2022016926}

_{3. Jakafi. Prescribing information. Incyte; 2021. Accessed February 22, 2023. https://bit.ly/3EtbfLi}

_{4. Imbruvica. Prescribing information. Pharmacyclics LLC; 2022. Accessed February 22, 2023. https://bit.ly/3SoE5lL}

_{5. Rezurock. Prescribing information. Kadmon Pharmaceuticals, LLC; 2021. Accessed February 22, 2023. https://bit.ly/3Ex8R6p}