Mechanism of Action of Ruxolitinib

EP: 1.Background on Graft-vs-Host Disease: Risk Factors and Prevention

EP: 2.Acute vs Chronic GVHD: Identification and Stratification

EP: 3.Frontline Treatment Options for Chronic GVHD

EP: 4.Defining Steroid-Refractory and Steroid-Dependent GVHD

EP: 5.Identifying and Managing Steroid-Refractory Chronic GVHD

EP: 6.Ibrutinib’s Approval and Use in Chronic Graft-Versus-Host Disease

EP: 7.Belumosudil’s Approval and Use in Chronic Graft-Vs-Host Disease

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EP: 8.Mechanism of Action of Ruxolitinib

EP: 9.REACH3 Trial: Approval of Ruxolitinib in Chronic GVHD

EP: 10.Chronic GVHD: Real-World Use of Ruxolitinib

EP: 11.Selecting Second-Line Therapy for Chronic GVHD

EP: 12.Chronic GVHD: Novel Treatment Approaches With Approved Agents

EP: 13.Novel Targeted Agents in GVHD: The FLIGHT and AGAVE-201 Trials

EP: 14.HSCT Approaches to Retain GVL While Preventing GVHD

EP: 15.Emerging Treatment Strategies for Chronic GVHD

Transcript:

Yi-Bin Chen, MD: Ruxolitinib has been a huge advance in graft-vs-host disease. As many of you know, it’s now FDA approved for the treatment of not only steroid-refractory acute graft-vs-host disease, but recently in 2021, for steroid-refractory chronic graft-vs-host disease. I don’t think we can truly state 1 mechanism of action, it’s complicated, and I think the pathways that we draw are our best guesses of what happens in the body. All of us have had experience of using ruxolitinib for its initial approval, which was in myeloproliferative neoplasms, and we found that in those diseases it wasn’t biologically disease changing, but better as an anti-inflammatory agent. Specifically if patients had systemic symptoms of the disease, which were driven by systemic inflammation, ruxolitinib was excellent at relieving those symptoms.

Ruxolitinib is an oral JAK1, JAK2 inhibitor. The JAK signaling cascade is like a bottleneck where a lot of inflammation or inflammatory pathways signal through, which is why it works so well for symptoms in myeloproliferative neoplasms. That’s part of the reason why it works for the therapy of both acute and chronic graft-vs-host disease, it’s a powerful anti-inflammatory agent. The inflammatory pathways set up an environment that’s ripe to develop an immune response, and even when that immune response develops, the systemic inflammation is propagated through signaling through the JAK1 and JAK2 systems that allow graft-vs-host disease to continue. The inflammation that’s present can also start the whole cascade. Exploring how we could use JAK inhibitors, either for prevention or much earlier in therapy, is a huge avenue that we must explore.

The signaling through the JAKs also appears essential for the dendritic cell and TMV [tobacco mosaic virus] cell interactions. From an adaptive immune system perspective, when T cells and B cells recognize their specific antigen on dendritic cells or other antigen-presenting cells, the signaling to activate those cells involves both JAK1 and JAK2 systems, so blocking that activation is part of this. Once T cells and B cells are activated, there is lymphocyte trafficking or migration to certain organs, be it secondary lymphoid tissue, or the effector tissue itself. The JAKs have a role in directing this lymphocyte trafficking as well. Modulation of lymphocyte trafficking that influences the immune response is certainly there as well. For chronic graft-vs-host disease, if you biopsy any tissue that’s affected, the hallmark is fibrosis, or the scar that’s laid down in tissues; that’s manifested in things like scleroderma of the skin. The process of fibrosis is complex, but a big cellular mediator is thought to be activated macrophages signaling through TGF [transforming growth factor]-beta, and this signaling cascade goes through the JAK1 cascade as well.

There are a lot of mouse models, a series of elegant experiments done by colleagues, that have elucidated all these certain pathways where ruxolitinib might have an effect. My guess is it does all of these to a certain extent, but the proof is in how much it’s improved the lives of our patients.

Transcript edited for clarity.