Corey S. Cutler, MD, MPH, FRCPC

 In terms of future directions and unmet needs in chronic graft-versus-host disease [GvHD], unfortunately there are several. First, we need to find better ways of preventing the disease. Probably the most promising way of preventing chronic graft-versus-host disease is using an approach around the time of transplant that will prevent it entirely. For example, the use of post-transplantation cyclophosphamide has been associated with lower rates of chronic graft-versus-host disease, and there are some interesting and novel strategies around T-cell manipulation or T-cell depletion that might also be very promising for preventing chronic graft-versus-host disease. There are some clinical trials testing interventions using B-cell–depleting approaches or B-cell therapeutics to try to prevent graft-versus-host disease, but we have not yet seen the readout of those trials.

I think another factor in chronic GvHD that’s often overlooked is the supportive care of the individual organs. For that, I would point the viewers toward a comprehensive set of guidelines from the American Society for Transplantation and Cellular Therapy [ASTCT]. We have an NIH [National Institutes of Health] consensus document that is published on the ASTCT website. The most recent version is from 2014 and discusses all the supportive care measures that can be delivered to each individual organ, both topically and systemic supportive care for individual organs.

Finally, there are issues related to the long-term use of corticosteroids and prevention of corticosteroid-related toxicity. These include preventing osteoporosis, managing glucose intolerance, hypertension, managing weight and weight changes associated with chronic steroid use, and the psychological support of being on chronic corticosteroids. All of these are really important things that one has to consider when starting corticosteroids for chronic graft-versus-host disease and especially in the general care of the chronic GvHD patient.

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

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



Labs: plt 70 x 109/L, total bilirubin 7.6 mg/dl, AST 150 U/L, ALT 165 U/L, ALP 430 U/L

NIH Global Severity of cGvHD moderate cGvHD; P-ROM score 4

He was started on ruxolitinib 5 mg PO BID which was tolerated well; increased to 10 mg PO BID on day 6

Videos

Future Directions and Unmet Needs in Chronic GvHD

 There are a lot of other drugs being tested in graft-versus-host disease and a lot of other approaches. We’re targeting multiple cytokines and multiple pathways. People are very interested in both the B-cell and T-cell side of things, as well as directly inhibiting cytokines. There remains some interest in the use of extracorporeal phototherapy.

One of the more promising drugs that’s being developed is the ROCK2 inhibitor KD025. This drug has been tested in an open-label phase 2 dose escalation study and then more recently in a randomized phase 2 trial where 2 different doses were tested. In this study, which was presented at the last meeting of the Transplantation & Cellular Therapy Meetings, the drug was noted to have a response rate of approximately 65%. This was in patients who were heavily pretreated, between 2 and 5 lines of prior therapy. It turned out that individuals who had received prior ibrutinib or ruxolitinib had very good responses, and individuals with both moderate and severe graft-versus-host disease responded very nicely to it. We wait to see the long-term results of that study. The results I just presented were the results of an interim planned analysis, and the final analysis will occur after all patients have been followed for 12 months on the study.

There are other compounds that are being tested along the lines of the ROCK inhibitors, and we’re anxiously waiting for those compounds to complete their clinical trials because quite frankly, chronic graft-versus-host disease still is suboptimally treated, and we don’t have enough tools in the tool kit to treat it today.

Emerging Agents for the Treatment of Chronic GvHD

 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.

Steroid-Refractory GvHD: Treatment With JAK Inhibitors

 What are the treatment options for this patient? This case is de novo chronic graft-versus-host disease [GvHD], and the standard of care is to treat with corticosteroids. Steroids are generally given at a dose of 0.5 to 1 mg/kg of body weight, usually 0.5 mg/kg per day or 1 mg/kg every other day. However, some clinicians will start at a dose of 1 mg/kg per day. In general, doses higher than that are not recommended in chronic graft-versus-host disease. There is some evidence that adding a calcineurin inhibitor at the onset of chronic GvHD might decrease steroid burden over time, although it does not increase response rates. Some of us clinicians will add drugs like tacrolimus or cyclosporine at the time of initial therapy for chronic graft-versus-host disease.

For chronic GvHD, most of us will treat at a minimum for 4 weeks at a single steroid dose, and up to 3 months has been often the classic teaching in this disease. We generally wouldn’t consider someone steroid-refractory unless they were progressing after several weeks of therapy or really had no response after a good trial of 2 to 3 months of therapy. There are certain clinical scenarios, particularly those that are involving scleroderma or progressive lung disease that merit earlier switch to a second-line agent.

In terms of the drugs that we use for the second-line setting, there’s only 1 drug that is approved at this point and that is ibrutinib. Ibrutinib is approved based on a 42-patient study done, an open-label phase 2 trial that demonstrated a response rate of about two-thirds in patients with steroid-refractory chronic graft-versus-host disease. So ibrutinib is the de facto second-line agent. We also recommend participation in clinical trials whenever possible, and there are a number of exciting compounds that are being tested these days for second-line therapy and beyond for chronic graft-versus-host disease.

Corey S. Cutler, MD, MPH, FRCPC | Authors

Articles

Future Directions and Unmet Needs in Chronic GvHD

Emerging Agents for the Treatment of Chronic GvHD

Steroid-Refractory GvHD: Treatment With JAK Inhibitors

Treatment Options for Chronic GvHD