Treatment Options for Steroid-Refractory cGVHD

Video

A focused discussion on available treatment options for patients with steroid-refractory cGVHD.

Case: A 58-Year-Old Man With Moderate Steroid-Refractory Chronic Graft-Versus-Host Disease

Initial Presentation

  • A 58-year-old man previously underwent myeloablative conditioning and an allogeneic PBSC transplant for acute lymphocytic leukemia
  • Received tacrolimus and methotrexate for GVHD prophylaxis
  • At 10 months post-transplant, patient developed moderate muscle and joint pain with decreased range of motion, mild erythematous rash on cheeks

First-line Treatment

  • Patient received topical steroid cream for rash, and was started on oral prednisone at 1 mg/kg/day
  • After 4 weeks of treatment, the patient’s rash resolved but muscle/joint pain continued

Second-line Treatment

  • Patient is now receiving ruxolitinib 10 mg orally twice daily, alongside 1 mg/kg/day steroids

Pashna Munshi, MD: The 3 main approved drugs for chronic GVHD [graft-vs-host disease] are ibrutinib [Imbruvica], belumosudil [Rezurock], and ruxolitinib [Jakafi]. Ibrutinib was the first to be approved for chronic GVHD. It’s a Bruton tyrosine kinase inhibitor as well as interleukin 2 T-cell kinase inhibitor, an ITK as well. What that means is it targets both the B lymphocytes and the T lymphocytes. It’s a very attractive option if there are manifestations that involve an auto antibody production. But it does have some adverse effects. It does cause patients to have fatigue, some degree of diarrhea, muscle spasms, nausea, and bruising because it does affect the platelet function, and it’s not ideal in those patients who have diarrhea already or have low platelet counts. And the approved dose is easy to give. It’s an oral drug. It’s given once a day—420 mg was the approved dose in the multicenter open label trial published in 2017. However, you must remember that because it suppresses the B and T cells, that there is a risk of opportunistic infections, and that people need to be covered for anti-therapy. In terms of the other drugs like belumosudil, which was recently approved for steroid-refractory or dependent chronic GVHD, this is a ROCK2 inhibitor, or Rho-kinase inhibitor. The pivotal trial that led to its approval was called the ROCKstar study. This was a phase 2, dose-finding, randomized registration study that evaluated the belumosudil dose of 200 mg daily vs 200 mg twice daily. And it showed efficacy in steroid-refractory chronic GVHD in response to all organs, particularly in those patients also who had previously received treatment with ibrutinib or ruxolitinib. The mechanism of action is different. It reduces the Th17 cells and the follicular T helper cells via downregulation of STAT3 pathway. And in doing so, it also enhances the regulatory T cells, which are the good players, and you want more regulatory T cells in patients who have GVHD in upregulating of the STAT5 pathway. That’s one mechanism through the STAT pathway, but then it also plays an interesting role in the anti-fibrotic pathways. It prevents differentiation of fibroblasts into myofibroblasts, and therefore inhibits laying down of collagen. And it does have this nice anti-fibrotic mechanism of action as well, which is exciting to use in somebody who does have skin sclerosis, or maybe potentially lung involvement. For example, in bronchiolitis obliterans. And based on the trial, they saw that there were no statistical differences between the 2 doses, even though some organ systems had better response with the higher twice a day frequency dose, and the FDA [Food and Drug Administration] approved belumosudil 200 mg once a day dose. Now, in terms of some of the adverse effects because it acts on the liver pathway, it may increase transaminitis or cause transaminitis; it may increase GGT [gamma-glutamyl transferase] levels; it does cause hypertension; hyperglycemia; there is some risk of pneumonia. But otherwise, overall, it’s well tolerated. If your patients have liver dysfunction, probably this isn’t the ideal drug to use, or if they have diabetes that’s not very well controlled, or blood pressure problems. This drug may cause a bit of challenge to use. And then the third approved drug is ruxolitinib. This is a JAK [Janus kinase] 1 and 2 inhibitor. It targets many signaling pathways that are overall involved in the pathophysiology of chronic GVHD. The main pivotal trial that led to approval for chronic GVHD was the phase 3 REACH3 trial. And ruxolitinib, again, is an oral drug. It’s given twice a day. The formulation is 10 mg twice a day based on the trial approval, FDA approval. It does have some adverse effects of cytopenias, namely anemia and thrombocytopenia. If your patients have low blood counts, it might be challenging to use this drug as well if you’re not familiar with how to manage patients through their cytopenias. Other therapies that are available that have been used for many years in chronic GHVD patients, one of them is called extracorporeal photopheresis, or ECP. And phase 2 data has shown excellent responses of use in people with sclerotic skin changes and mucosal changes on GVHD. It does work well if people have it skin only or any sclerosis of the skin. It requires patients to come in frequently. It’s a very long chronic therapy. Oftentimes, there is an induction phase where patients must come twice a week for several weeks for the first month or 2 months until there is some response to the treatments that they’re getting. And then slowly they’re weaned off to once alternate week visits, etc. It is a bit cumbersome to the patients, but it is highly effective therapy if it’s done right, and it’s otherwise well-tolerated and steroid-sparing. And then there are other drugs that are used in combination with steroids like the typical calcineurin inhibitor or the low-dose methotrexate, which is also an oral drug that’s given. There are many differences and nuances to a lot of these drugs that have been out there and been used frequently.

Transcript edited for clarity.

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