ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.
Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.
Of 20 patients with multiple organ involvement, 25 (80%) had responses in at least two organs, and of 9 patients with three or more involved organs, 5 (56%) had responses in at least three organs, he reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation..
“We think that the responses across different organ involvement as well as multiple organ responses speaks to the underlying impact of ibrutinib on the pathogenic pathway and not to masking symptoms or indirect effect,” he said.
The median steroid dose among responders decreased from 0.29 mg/kg daily at baseline to 0.19 mg/kg daily and 0.12 mg/kg daily at weeks 25 and 49, respectively. Overall, 62% of all patients reached steroid doses less than 0.15 mg/kg daily, and five responders discontinued steroid treatment.
“Patients also had clinically meaningful improvement as assessed by the,” he said, noting that scores improved in 61% of responders and 11% of nonresponders.
Study participants had a median age of 56 years and a median of 7.6 months from allogeneic transplant to diagnosis of cGVHD. All had been treated with up to three prior cGVHD regimens (median, two) and had either a rash that exceeded 25% of their body surface area or a National Institutes of Health consensus mouth score greater than 4. They were treated with ibrutinib at a dose of 420 mg/day until cGVHD progression or unacceptable toxicity. The cGVHD response – the primary endpoint of the study – was measured using 2005 NIH response criteria.
Adverse events occurring in at least 20% of patients included fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade 3 or higher adverse events occurring in at least 10% of patients included pneumonia, fatigue, and diarrhea.
Serious adverse events occurred in 52% of patients. Grade 3 or higher serious adverse events occurred in 40% of patients and included pneumonia, septic shock, and pyrexia. Two fatal events were reported and included one case of multilobular pneumonia and one case of bronchopulmonary aspergillosis.
Twelve patients (29%) remained on ibrutinib at 14 months; Of those who discontinued therapy, 5 discontinued because of progressive cGVHD, and 14 because of adverse events.
Patients who have cGVHD and don’t respond to frontline therapy have previously had no effective options. Ibrutinib showed promise in preclinical models; it reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase and interleukin-2–inducible T-cell kinase, Dr. Miklos explained, noting that both B and T cells play a role in the pathophysiology of cGVHD.
The findings from this phase II trial demonstrate that ibrutinib does indeed lead to durable improvement in this patient population, and its safety profile is consistent with that previously reported for B-cell malignancies treated with ibrutinib and for cGVHD patients treated with concomitant steroids, he said.
“We think the efficacy of ibrutinib in this population supports further study in frontline treatment of cGVHD in a randomized, double-blinded study,” he concluded.
A phase III study – the– is now open. The international study will compare ibrutinib and prednisone with placebo and prednisone as a frontline therapy for moderate and severe cGVHD with a primary endpoint of response rate at 24 weeks.
The study was sponsored by Pharmacyclics in collaboration with Janssen Research & Development. Dr. Miklos reported various financial relationships with Pharmacyclics (the maker of ibrutinib [Imbruvica]), Velos, Kite Pharma, Sanofi Oncology, Adaptive Biotechnologies, and Genentech.