Steroid-Refractory GvHD: Treatment With JAK Inhibitors

Corey S. Cutler, MD, MPH, FRCPC: We’ll talk a little bit about the JAK [Janus kinase] inhibitors for treatment of steroid-refractory GvHD [graft-versus-host disease]. Currently, the only JAK inhibitor that is being used in graft-versus-host disease on a large scale is ruxolitinib, which does carry an FDA approval for therapy of steroid-refractory acute graft-versus-host disease based on the REACH1 and REACH2 trials. In chronic GvHD, it remains an experimental agent and is being tested in a very large randomized REACH3 trial. REACH3 is randomizing individuals with steroid-refractory chronic GvHD to either ruxolitinib or best available care at the discretion of the treating investigators.

JAK inhibitors are an exciting class of compounds. They inhibit signal transduction through the JAK-STAT [signal transducer and activator of transcription] pathway. Multiple cytokines signal through that pathway, IL-6 [interleukin-6] and others, so they do represent an interesting way to treat graft-versus-host disease. In general, we start ruxolitinib at a dose of 5 mg twice daily and escalate up to 10 mg twice daily if the patient doesn’t have dose-limiting cytopenias. There are other drugs that have been tried in chronic graft-versus-host disease, such as itacitinib, which was the subject of the GRAVITAS trials. Unfortunately, that compound does not appear to be promising at this time in the management of chronic GvHD, although there certainly needs to be further study on that.

We generally combine drugs like ruxolitinib or other second-line agents with corticosteroids for the management of steroid-refractory disease. Often the point of adding these second-line agents is to allow us to reduce the dose of corticosteroids when a patient does have a symptomatic response. Some investigators will taper steroids much earlier, even in the absence of a response, because it will reduce steroid-related adverse effects and comorbidity. There are lots of ways to do this. We could either use an additive approach or a substitution-type approach, but there is no correct answer here. We certainly do all agree that if patients are having adverse effects from a drug, then that drug should be eliminated as quickly as possible. But caution has to be taken when eliminating ruxolitinib as there can be a withdrawal reaction to rapid stopping of the drug. So we do recommend that this drug be weaned or tapered, even if it has to be done rapidly.

Transcript edited for clarity.

Case: A 49-Year-Old Man With Steroid-Refractory Chronic Graft Versus Host Disease

Initial presentation

• A 49-year-old man complains of “color and texture” changes to his skin, nails and the inside of his mouth; he also complains of shoulder and elbow joint discomfort limiting his normal daily activity
• PMH: he underwent matched related allogenic transplant from his brother for treatment of AML
• PE: depigmentation and lichen planus-like features noted on his chin, nose, cheeks and forearms bilaterally, and in the oral mucosa (~40% BSA); longitudinal ridging of the fingernails; joint stiffness and decreased range of motion
  
  

Clinical workup

• Labs: plt 70 x 109/L, total bilirubin 7.6 mg/dl, AST 150 U/L, ALT 165 U/L, ALP 430 U/L
  • Negative for HBV, HBV, CMV, EBV, HHV-6
• NIH Global Severity of cGvHD moderate cGvHD; P-ROM score 4
• ECOG 1
  
  

Treatment

• Tacrolimus + dexamethasone oral rinse
  • No treatment response after 4 weeks
• He was started on ruxolitinib 5 mg PO BID which was tolerated well; increased to 10 mg PO BID on day 6