SAN DIEGO ― Patients with chronic graft-vs-host-disease (cGVHD), a serious complication of allogeneic stem cell transplantation, may soon have another treatment option.
Results from a small clinical trial show that the novel agent ibrutinib (Imbruvica, Janssen/Pharmacyclics) was beneficial for patients who had stopped responding to corticosteroids. The new findings were reported here at the American Society of Hematology (ASH) 2016 Annual Meeting (abstract LBA-3).
"Ibrutinib resulted in a meaningful and sustained clinical response in patients who have failed at least one prior treatment for chronic GVHD," said lead author David Miklos, MD, PhD, an associate professor of medicine at Stanford University, in California.
At a median follow-up of 14 months, the overall response rate was 67%, and 21% of patients achieved a complete response. In addition, 48% of responders showed a sustained response, with some responses lasting more than 6 months.
"Patients with multiple organ involvement generally showed responses to two or more organs," said Dr Miklos during his presentation. "They also experienced reductions in corticosteroid doses, and biomarker changes support the clinical effect chronic GVHD immune cell subsets."
Ibrutinib is a first-in-class oral, covalent inhibitor of Bruton's tyrosine kinase (BTK). It was first approved in 2013 for treatment of patients with mantle cell lymphoma. It has since been approved for use in patients with pretreated chronic lymphocytic leukemia (CLL), and in CLL patients with the del17p mutation (including use as initial treatment), and more recently, for first-line use in CLL.
It has also been granted breakthrough therapy designation for cGVHD on the basis of a preliminary phase 1 trial. The drug has also shown promise in preclinical models, which suggest that it reduces the severity of GVHD through the blockade of BTK and the IL-2 inducible T-cell kinase
Targeting Underlying Pathology
The new findings reported at the meeting come from a phase 2 trial conducted in 42 patients using the recommended dose of 420 mg that was identified in the earlier phase 1 trial.
"The study was initiated in patients who were steroid dependent and steroid refractory who had failed three or fewer prior therapies, and if they were on other immunosuppressants, they were allowed to continue them," explained Dr Miklos.
The median age of the cohort was 56 years, and the median duration of cGVHD before entry into the study was 13.7 months (range, 1.1 - 63.2). Patients had received a median number of two prior regimens.
Patients taking ibrutinib were able to receive smaller doses of corticosteroids. At a median follow-up of 13.9 months, two thirds of the cohort showed a response, and for 21 responders (75%), corticosteroid doses were less than 0.15 mg/kg/day during the study period.
In addition, five responders were able to discontinue corticosteroid therapy.
The median overall clinician-assessed severity of cGVHD decreased from a score of 7 at baseline (n = 41) to 4 at week 25 (n = 20) and decreased further to a score of 3 by week 49 (n = 15). There was a corresponding decrease in median patient-assessed overall cGVHD score, from 7 at baseline (n = 42) to 5 at week 25 (n = 18) and 4 at week 49 (n = 14).
Dr Miklos noted that there was also an improvement in the Lee cGVHD symptom score for 12 (43%) responders by month 6, and 17 (61%) overall, vs 1 (11%) of 9 nonresponders for both periods.
Of 36 patients with two or more involved organs, 20 (56%) showed a response in two or more organs; of 12 patients with three or more involved organs, five (42%) showed a response in three or more organs.
"These responses seen across all organs and multiple organs suggest that ibrutinib is actually targeting the underlying process of cGVHD and not simply masking the symptoms of cGVHD," said Dr Miklos.
The most common adverse events reported were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Serious adverse events of grade ≥3 were reported in 17 patients (40%) and included pneumonia (n = 5), septic shock (n = 2), and pyrexia (n = 2).
There were also two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis).
These adverse events are consistent with those previously reported for ibrutinib and those observed in patients with cGVHD, explained Dr Miklos.
Twelve patients have continued to receive ibrutinib; for those patients, treatment duration ranges from 5.6 to 24.9 months.
"We believe these findings support further study of ibrutinib in the frontline setting in a randomized, double-blinded study that is already underway, Dr Miklos concluded.
Approached by Medscape Medical News for an independent comment, Yi-Bin Albert Chen, MD, director of clinical research, Bone Marrow Transplant Program at Massachusetts General Hospital in Boston, noted that the rationale for using ibrutinib is based on the T-cell immunomodulating and B-cell inhibitory activities of ibrutinib and that safety has been established in multiple trials involving patients with B-cell malignancies.
"The overall response rate of 67% is quite compelling and certainly merits further study for this agent," said Dr Chen. "A large phase 3 randomized study combining ibrutinib with corticosteroids for the initial therapy of chronic GVHD is planned."