JAK Inhibition as Treatment for GVHD

Claudio Anasetti, MD:There have been a number of preclinical studies using human cells in the test tube and using experimental animal models that have indicated that JAK1 and JAK2 are potential targets for intervention in prevention and treatment of graft-versus-host disease [GVHD].

Based on the preclinical and clinical studies, the REACH1 trial was designed, recently concluded, and reported in the literature, and the use of ruxolitinib was approved by the FDA. Forty-nine patients with acute GVHD that were steroid-refractory or steroid-dependent were treated. The response rate at day 28 was 54.9%. Many of these patients survived, among those that we never thought could. Their graft-versus-host disease was so advanced and so life-threatening.

Because there are no other drugs that are FDA approved for treatment of steroid-refractory or steroid-dependent GVHD, the REACH1 data is practice-changing. We have all started to use ruxolitinib for the treatment of patients who are steroid-refractory or steroid-dependent.

The starting dose of ruxolitinib is 5 mg by mouth twice a day. If after 3 days we don’t see toxicity, we can increase the dose to 10 mg twice a day. The toxicity of ruxolitinib is primarily hematopoietic, and we observed neutropenia, thrombocytopenia, and anemia. We have to be careful about escalating the dose in patients who have any evidence of hematopoietic compromise. In addition, if patients are on a stable dose and develop new onset of hematopoietic compromise—neutropenia or thrombocytopenia—we have to either decrease the dose or hold the dose until the toxicity is reversed.

I have used ruxolitinib for the treatment of steroid-refractory patients, and the effect of ruxolitinib is over and above what we have seen with any other agents available to us. I have had patients beyond the point of expected return who have actually begun to improve. The median improvement time in the study was 7 days and that matches my observation. The responses are usually long-lasting, but, upon taper of glucocorticoids or taper of the ruxolitinib, the flares may still occur. And responses, especially in patients with severe disease, are not invariable.

The next question in the development of clinical ruxolitinib for the treatment of steroid-refractory or steroid-dependent acute GVHD is to show that the treatment is actually better than an alternative standard of care. There is no single standard of care, but the available best drugs as chosen by individual centers will constitute the control arm on the REACH2 trial. We will be able to compare results of ruxolitinib to available best therapy. This is a worldwide trial that will be enrolling patients—up to a little more than 300 of them—and the results, as I understand, will be available later in 2019.

The REACH3 trial is actually a randomized worldwide trial that compares ruxolitinib against best available therapy for chronic graft-versus-host disease. Since many patients with acute graft-versus-host disease develop chronic disease, this is definitely looking at meeting an unmet need.

Transcript edited for clarity.