Potential treatment for cGVHD after steroid failure
2016 ASH Annual Meeting
SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.
At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.
The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.
David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.
This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.
“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.
In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.
“So this dose was carried forward into the phase 2 study,” Dr Miklos said.
He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).
Study design
Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.
They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.
Patients with cGVHD had to have failed frontline therapy.
They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.
The primary endpoint was cGVHD response per NIH 2005 response criteria.
Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.
Investigators enrolled 42 patients, the first of whom was dosed in July 2014.
Patient demographics
Patients were a median age of 56 (range, 19–74), and 52% were male.
The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).
Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.
And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.
“This was a heavily treated patient population,” Dr Miklos said.
They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.
Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).
Results
The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.
Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.
