Ruxolitinib has been shown to be superior to best available therapy in the management of steroid refractory or steroid-dependent chronic graft-versus-host disease (cGVHD).

Professor Robert Zeiser presented the findings of the REACH 3 study in a session on practice-changing clinical trials at the 62nd ASH Annual Meeting.

The open-label, phase 3 study randomised more than 320 patients from 12 years of age to either 10 mg of oral ruxolitinib twice daily or best available therapy (BAT) such as extracorporeal photopheresis, low-dose methotrexate, mycophenolate, everolimus, rituximab, imatinib or ibrutinib.

After the primary endpoint was determined at 24 weeks, patients could cross over from the BAT group to receive ruxolitinib in an extension period.

Professor Zeiser, from Germany’s University Hospital Freiburg, said the patients had a median age of 50 years, and the split of GVHD severity was about 40% moderate and 60% severe.

The study found the overall response rate (ORR) at week 24 was 49.7% with ruxolitinib versus 25.6% in the BAT group (OR, 2.99; 95% CI, 1.86-4.80; p <0.0001).

The median failure-free survival was not reached with ruxolitinib versus 5.7 months with best available therapy (HR, 0.37; 95% CI, 0.268-0.510; p<0.0001).

He said the modified Lee Symptom Scale response showed patients treated with ruxolitinib had a greater improvement in symptoms (≥7-point reduction in total symptom score 24.2% v 11.0%; OR 2.62; p=0.0011) .

The best overall response rate – mostly partial versus complete responses – was also higher in the ruxolitinib group than in the BAT group (76.4% v 60.4%; OR, 2.17; 95% CI, 1.34-3.52).

The median duration of response was not reached in the ruxolitinib group and 6.24 months in the BAT group.

“Safety is an important concern in patients that are very susceptible in particular to infections,” he said.

No significant difference in any-grade adverse events (97.6% v 91.8%) or severe grade ≥3 adverse events (57.0% v 57.6%) were observed.

However adverse events leading to dose modification (37.6% v 16.5%) and discontinuation (16.4% v 7.0%) were higher in the ruxolitinib group.

Anaemia and thrombocytopenia were more commonly observed with ruxolitinib but rates of most other adverse events including infections such as pneumonia were similar in both groups.

Viral and bacterial infections were similar in both groups but there was a trend to more fungal infections with ruxolitinib.

“CMV infection or reactivation is a major concern in patients with cGVHD and there was no significant difference between the groups (5.5% v 8.2%),” he said.

Professor Zeiser said deaths, up to the data cut off, were not significantly different between the groups (18.8% v 16.5%).

He concluded that ruxolitinib was the first agent to demonstrate superior efficacy to BAT in patients with cGVHD and an inadequate response to steroids.

Aussie perspective

Commenting on the study for the limbic, Melbourne haematologist Professor Jeff Szer said the findings were not as dramatic as those from the recent REACH 2 study of ruxolitinib in acute GVHD.

“That really has I think changed practice in places like the US where ruxolitinib is easy to obtain for steroid dependent or refractory aGVHD.”

“cGVHD is a much more difficult target and was a much more difficult study … and from a local point of view, we didn’t see any dramatic responses in the patients we had on the trial.”

“The fact that there has never been a standout candidate for the second line treatment of cGVHD just shows how complicated it is. It’s very difficult although there is no doubt there is a positive outcome here against 10 of the two or three hundred second-line therapies that are being used around the world.”

Professor Szer, president of the World Marrow Donor Association, said it had yet to be shown if the benefit would translate into a survival advantage.

“I doubt very much that our PBS will rapidly approve it in this context but they may depending on data that may emerge on survival and quality of life outcomes later on.”

He said clinicians were familiar with the drug and its toxicities, it was oral and easy to use, and could possibly make a difference to patients in the future.

“If Novartis does their usual good job with approvals we should have it available for aGVHD. The data from the REACH 2 study is dramatic. This is perhaps less so but I think it is going to require longer follow up and survival data.”

“At the moment there is no difference in death rate between the two groups.”

The study was funded by Novartis.