This is a study that was sponsored by the pharmaceutical company Pharmacyclics and in follow up to the FDA approval of ibrutinib for the treatment of therapy, non-therapy-naïve, chronic GvHD, and then asking the question to this randomized 180 patient placebo-controlled blinded study. Would ibrutinib plus corticosteroids dosed at one milligram per kilogram of prednisone be superior to prednisone alone?
This is an international study, 31 sites, many investigators, and it was my privilege to lead this...
This is a study that was sponsored by the pharmaceutical company Pharmacyclics and in follow up to the FDA approval of ibrutinib for the treatment of therapy, non-therapy-naïve, chronic GvHD, and then asking the question to this randomized 180 patient placebo-controlled blinded study. Would ibrutinib plus corticosteroids dosed at one milligram per kilogram of prednisone be superior to prednisone alone?
This is an international study, 31 sites, many investigators, and it was my privilege to lead this. The expectation of patients who enrolled, eligibility required moderate or severe chronic GvHD by the NIH 2014 consensus criteria and then the goal was to start patients on the standard 420 milligrams of ibrutinib in combination with, as I said, one milligram per kilogram of prednisone dosing, and that was a recommended way to taper the prednisone over the six-month period. Patients were then monitored for event-free and overall survivals, durability of responses, quality of life, and the ability to get off all immune suppression.
The primary endpoint for this study was the ability to have chronic GvHD response benefits at 12 months after initiation of the study in comparison to the placebo arm. It’s important to make it very clear that the overall ability to get off of- to have this response rate was 41% in the patients who had the ibrutinib, and 37% in the patients with placebo. So, there was no difference, no statistical difference, in the primary end points, that is response rate at 48 weeks. The patients were followed for a minimum of two years, median duration of two and a half years and the bond was maintained.
What was observed over the next two years were no increased risks or side effects or toxicities in the patients receiving the ibrutinib compared to the placebo arm. I’ll say that again, no increased risks of infections, toxicities, arrhythmias, cardiac deaths, or other concerns or fungal deaths in the patients receiving the ibrutinib.
This is very reassuring when you consider that there was, there has been much discussion about whether the drug is not well-tolerated, and nothing like a placebo controlled study makes it more clear the benefits to a patient and the absence of toxicities when using the therapeutic arm.
The second issue was that there were benefits to the patients. Probably, again I’m going to highlight the event-free survival as being one of the more exciting ways to consider this, an event-free survival is death, malignancy from relapse, chronic GvHD progression or the initiation of subsequent therapies. And in the study the median ibrutinib arm was 14.98 in comparison to 8.25 for the median event-free survival and that was approaching statistical significance with a nominal p-value of 0.96. Likewise, there were benefits showing ability to get off of the immune suppressions themselves and there were benefits in duration of response. There were benefits in patients with improved quality of life by Stephanie Lee scale.
So, all of these analyses together do not change what is a negative study, the primary endpoint of 12 months, duration, overall response rates, chronic GVHD benefit, was no different in the placebo versus prednisone arm, but I find it fairly comforting and reassuring that these trends observed in the important clinical end points, along with the unexpected safety concerns, suggest that ibrutinib is something that I will continue to consider for my patients with chronic GvHD, not only in those patients who have relapsed chronic GvHD in second-line therapy, but also early as possible to help manage them.
