Ibrutinib as Second-Line Therapy for Steroid-Refractory Chronic GVHD


Catherine Lee reviews data on use of ibrutinib for steroid-refractory chronic graft versus host disease.


Catherine J. Lee, MD, MS: To be fair, as we’re going onto this next slide, ibrutinib [Imbruvica] is an option, you know, in this situation, particularly for patients who have more of the inflammatory features of chronic GVHD [graft-versus-host disease]. But as we’re speaking about this trial now, the ibrutinib trial, which was a phase 1b 2 single-arm registration trial, or which led to the FDA approval, there were patients who did have some form of sclerotic chronic GVHD. And patients, 11 out of 18 patients, who did have sclerosis responded to ibrutinib. I think one of the kind of issues with ibrutinib that many providers are facing is that there are intolerable side effects as well for ibrutinib, such as muscle cramping, face changes, things like that. I think ibrutinib overall has kind of fallen out of favor in most institutions. [I’m] sorry. I just took over. But going back to the ibrutinib trial, this was a trial that initiated from Dr David Miklos from Stanford, where ibrutinib, which is a BTK [Bruton tyrosine kinase] inhibitor and thought to exert its action by the irreversible and selective inhibitor of the Bruton tyrosine kinase as well, it does have effects on T cells.

Ultimately, [it] blocks B-cell activation and function, as well as T-cell activation and function, which is thought to be important mediators in chronic GVHD. So that is sort of the biologic rationale of why ibrutinib was tested to help kind of block these crucial cell players in chronic GVHD. And so, in this trial, which only had 42 patients, and again, with a single-arm trial, there was no control arm, about 85% of patients had 2 or more organ involvement at baseline. And again, most of these patients had to have inflammatory features—a skin involvement of BSA [body surface area] of more than 25% or having an oral score of 4 or higher to be enrolled in this trial. As you can see here, more than 80% of patients had mouth involvement, skin involvement, and about 40% of patients had some form of GI [gastrointestinal] involvement. And in this trial, patients, to be eligible, had to have failed at least 1 prior regimen. The median number of failed lines here was 1. In terms of the primary end point, which was overall response rate at 24 weeks. The best overall chronic GVHD response came out at 69% at a median of 26 months follow-up. Approximately 70% of patients had a sustained response for 20 weeks or more. A good proportion, almost a little over 60%, of patients were able to taper their prednisone to less than 0.15 mg per kg per day during the study. So there definitely were responses patients responding in this trial. Again, I don’t have probably as much real-world experience as you do or Dr Cutler does. So maybe the both of you can comment about your real-world experience of using ibrutinib. But overall, I do feel that ruxolitinib [Jakafi] has been the preferred choice over ibrutinib.

Yi-Bin Chen, MD:I think the most impressive part of this study that there was a highly selective population and a small-ish study was the 31% CR [complete response]. That’s not what you see in a chronic GVHD, in any chronic GVHD study. Corey, your group’s published some real-world data, if you want to briefly tell us about it.

Corey S. Cutler, MD, MPH, FRCPC: Sure. So what we’ve published is a little bit at odds with what you see in the graphic here. And it’s largely because of patient selection. So, as you heard these were patients who had inflammatory manifestations of chronic GVHD and earlier chronic GVHD, which probably is the reason why they were able to attain CRs. We looked at all the patients at our institute who received ibrutinib after its FDA approval, so patients who received commercial supply, and unfortunately for those patients at our center, there was somewhat over larger number than this, it was over 50 patients. The median time to failure, which was defined as either starting another systemic drug, relapse, or death, was only 4 months. And what that tells us is that the response rate for this compound in the real world might not be as high as we saw in the selected patients in the clinical trial. And the failures here were almost all exclusively related to starting another agent, be it from toxicity, be it from lack of response. A very small minority of patients remained on ibrutinib for more than 6 or 8 months.

Transcript edited for clarity.

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Yi-Bin Chen, MD, an expert on GVHD
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