During a Targeted Oncology™ Case-Based Roundtable™ event, Noah M. Merin, MD, PhD, discussed biologic phases of chronic graft-vs-host disease and which therapies are available for patients who do not respond to steroids.
Targeted OncologyTM: What drugs are available to treat steroid-refractory GVHD?
MERIN: There are 3 [approved] drugs: ibrutinib [Imbruvica], belumosudil [Rezurock], and ruxolitinib [Jakafi].1 We have a long track record with ibrutinib because it was developed to treat chronic lymphocytic leukemia and mantle cell lymphoma, so the safety and toxicity of ibrutinib are established based on its oncologic performance. Ibrutinib was developed as a BTK [Bruton tyrosine kinase] inhibitor, which is downstream from the B-cell receptor. It also inhibits ITK [interleukin-2–inducible T-cell kinase], which is downstream from signaling involving the T-cell receptor. Ibrutinib, even though it's used to treat B-cell malignancies, can treat T-cell–mediated GVHD through its effect on ITK.
Belumosudil is the most recently approved drug. Because it never has been used in any setting other than GVHD, unlike ibrutinib and ruxolitinib, it's a little bit more mysterious how it works, what the adverse event [AE] profile is. The field is still figuring out how to incorporate it, when to incorporate it, and whether it works particularly well in different organs that are involved in GVHD.
Ruxolitinib is a JAK [Janus kinase] inhibitor. It mainly works by inhibiting JAK2, but it also has suppressive effect on signaling through JAK1. [It affects the] surface of a B cell or T cell and it inhibits cytokine-transduced signaling. T cells respond dramatically to IL-2. They proliferate. They become cytotoxic. So inhibiting through JAK1 suppresses T-cell activation and response to the activating cytokine milieu. It has effects on B cells and natural killer cells that are signaling through interferon gamma and then the B-cell–specific interleukins.
The mechanism of action isn't something that comes into the clinic, but it's useful to know. It helps to remember how the drugs work, but you don't need to know it in order to use the drug. I think it is important to understand the AE profile and the types of infections that patients are susceptible to when they're on these drugs for treatment of GVHD.
What distinguishes chronic GVHD from acute GVHD?
When we see a patient when they're on a clinical trial, we have to indicate whether they have acute GVHD or chronic GVHD. Many tools have been developed to try to distinguish chronic from acute GVHD. The easiest way is if it happens prior to 100 days, we call it acute GVHD. If it happens after 100 days, we call it chronic GVHD. That doesn't fit the way we observe patients in the pattern of development of GVHD. Patients can get acute GVHD after 100 days. They can get early-onset chronic GVHD and there can be a smearing of the effect where you could have acute GVHD that's steroid-refractory, that unfortunately just turns into chronic GVHD because you can't control it. It's easier to understand this as a continuum, which [consists of] acute episodes if they are bad or they keep happening, you've educated a large pool of donor immune cells, which are then going to persist and cause persistent problems.
What are the biologic phases of chronic GVHD?
The early inflammatory phase I is acute GVHD, what's happening soon after the transplant.2 You also have strategies for prophylaxis against GVHD: either limiting the T cell dose, killing off all the lymphocytes with any thymocyte globulin, or killing activated T cells after the transplant with post-transplant cyclophosphamide.
There are different drugs that are used to block different components of the immune system. Rituximab [Rituxan] and CD20-targeted monoclonal antibodies destroy B cells. Ibrutinib and belumosudil suppress B-cell activation and ruxolitinib inhibits Tc17 activated T-cells.
If those strategies are not effective, then eventually there is production of alloreactive antibodies, macrophage activation, tissue damage, and production of TGF-β [transforming growth factor-β].
There are strategies to control GVHD during the different phases. During the acute phase, that's when we use tacrolimus, mycophenolate, sirolimus. During the middle phase, the thymic injury, T-cell and B-cell dysregulation phase, that's when we use ibrutinib, belumosudil, and JAK inhibitors. Frankly, there isn't a good treatment for patients that have fibrotic disease with a large amount of alloantibody production, so axatilimab [SNDX-6352] and pirfenidone [Pirespa] are being studied in clinical trials, but they're not in widespread clinical use.
1. Zeiser R, Lee SJ. Three US Food and Drug Administration-approved therapies for chronic GVHD. Blood. 2022;139(11):1642-1645. doi:10.1182/blood.2021014448
2. Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021(1):648-654. doi:10.1182/hematology.2021000301