Ruxolitinib Beats Standard Therapy at Tamping Down Resistant Graft-Versus-Host Disease

By Gene Emery

April 24, 2020

NEW YORK (Reuters Health) - When graft-versus-host disease (GVHD) is resistant to standard glucocorticoid therapy in patients who have received an allogeneic stem-cell transplant, ruxolitinib performs better than other treatment options, according to results of the REACH2 trial.

The control group in the open-label phase-3 trial included 155 patients who received any of nine conventional therapies to fight the deadly inflammatory response. The choice of control therapy was based on the judgment of an investigator at the time of randomization.

The 28-day response rate was 39% in the control group and 62% for the 154 volunteers assigned to receive 10 mg of ruxolitinib twice daily (P<0.001).

At day 56, the durable-response rate was 22% with conventional therapy and 40% with ruxolitinib (P<0.001). Response rates by grade were 53% for grade IV GVHD (versus 23% in the control group), 56% for grade III (38% with control) and 75% for grade II (51% with control).

Median overall survival was 6.5 months in the control group versus 11.1 months with the drug, a non-significant difference.

"Overall survival data at this point . . . are not sufficiently mature to allow conclusions to be drawn regarding survival benefit," the researchers note.

But failure-free survival, which was five months with ruxolitinib versus one month in the control group, "was considerably longer with ruxolitinib than with control," offering new hope for patients, chief author Dr. Robert Zeiser of University Medical Center Freiburg in Germany told Reuters Health by email.

Thrombocytopenia was significantly more common in the ruxolitinib group (33%) than in the control group (18%).

The rates of anemia, cytomegalovirus infection and other infections were "modestly" higher in the treatment group, the researchers report in the New England Journal of Medicine.

Ultimately 72% in the ruxolitinib group and 85% in the control group discontinued their assigned treatment.

All of the volunteers, treated at 105 centers in 22 countries, were allowed to have standard supportive therapy such as transfusion support, growth factors, calcineurin inhibitors and glucocorticoids.

The drug costs about 3,000 Euros ($3,250) per month, Dr. Zeiser said. "The advantage is that once GVHD is gone, you do not have to treat the patient anymore - so all patients with a complete response don't need treatment anymore."

Ruxolitinib's brand name is Jakafi in the U.S. and Jakavi elsewhere. The drug is being developed and sold in the United States by Delaware-based Incyte. Novartis, which designed and financed the study and also analyzed the results, owns licensing rights outside the U.S.

GVHD appears in roughly 60% of patients who receive an allogeneic stem-cell transplant. Standard glucocorticoid treatment fails half the time, Dr. Zeiser said.

"With the exception of ruxolitinib, no new drugs have been approved either as first-line or second-line treatment for GVHD in the past 30 years," he and his colleagues write.

Ruxolitinib was previously approved by the U.S. Food and Drug Administration (FDA) for certain myeloproliferative neoplasms including myelofibrosis and polycythemia vera.

Based on earlier findings, the FDA approved it for steroid-refractory acute graft-versus-host disease last May. It's the only therapy approved for this indication. Other options for doctors include everolimus, mycophenolate mofetil, tacrolimus and etanercept.

Dr. Zeiser said a subsequent study "where we compare ruxolitinib with cortisone will tell us if it is better than current first-line therapy."

Another phase 3 study, REACH3, is exploring the use of ruxolitinib in patients with steroid-refractory chronic GVHD. "This is a different disease that progresses very slowly and incurs a lower risk for death," said Dr. Zeiser. Results are expected by year's end, according to Incyte.

Research released just over a year ago at the Endocrine Society's annual meeting by researchers at the Icahn School of Medicine at Mount Sinai, in New York City, found that about half the people who take the drug over the long term gain a "substantial" amount of weight and may see an increase systolic blood pressure.

Hypertension was reported as a side effect in 11% of REACH2 patients.

Ruxolitinib is also being tested in North America and Europe in trials with COVID-19 patients to treat the "cytokine storm" immune response seen in some cases of severe disease.

SOURCE: The New England Journal of Medicine, online April 22, 2020