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Ibrutinib yields durable responses in chronic GVHD
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SAN DIEGO — Ibrutinib conferred clinically meaningful and durable responses in a cohort of patients with chronic graft-versus-host disease who had failed after corticosteroids, according to findings presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
Based on these data, ibrutinib (Imbruvica; Janssen, Pharmacyclics) has received FDA breakthrough therapy designation for this indication.
Graft-versus-hosts disease (GVHD) is the most common cause of morbidity after allogeneic stem cell transplantation, but there no approved therapies for patients who fail corticosteroids, David Miklos, MD, PhD, associate professor of medicine at Stanford University Medical Center, said during his presentation.
“These results are encouraging as they suggest ibrutinib has clinically meaningful potential in patients with steroid-refractory chronic GVHD,” Miklos said in a company-issued press release. “Chronic GVHD patients face a challenging treatment journey with the majority of patients being prescribed steroids, with which long-term use can lead to serious health complications. With no FDA-approved therapies available specifically for cGVHD, new treatment options are critically needed.”
Miklos presented final results of a trial that evaluated a 420-mg dose of ibrutinib in 42 patients (median age, 56 years; range, 19–74) with chronic GVHD who had received three or fewer previous regimens treated until progression or unacceptable toxicity. Median duration of chronic GVHD before study entry was 13.7 months (range, 1.1–63.2), and patients had received a median of two (range, 1-3) prior regimens.
Chronic GVHD response served as the primary outcome measure. Rate of sustained response, change in Lee chronic GVHD symptom scale, changes in corticosteroid requirement over time and safety served as secondary endpoints. The researchers also evaluated the impact of ibrutinib on myeloid cell signaling pathways.
Median follow-up was 13.9 months. Twelve patients remained on treatment at the time of the analysis, with median duration of treatment ranging from 5.6 months to 24.9 months.
Results indicated an overall response rate of 67% — which included a 21% complete response rate and 45% partial response rate. Further, 7% of patients had stable disease and 2% had progressive disease.
Among 28 responders, 71% had a sustained chronic GVHD response for at least 5 months, according to Miklos.
When responses were broken down by organ, researchers observed responses in the skin, mouth and gastrointestinal system in more than 88% of patients. Liver response occurred in 67% of the cohort.
“Eighty percent of patients with two or more involved organs at baseline responded in two organs,” Miklos said.
A greater proportion of responders demonstrated improvement in Lee chronic GVHD symptom score a 6 months (43% vs. 11%) and overall (61% vs. 11%).
“We also observed improvement in proinflammatory and fibrotic factors with ibrutinib,” Miklos said.
Twenty-six responding patients received a corticosteroid dose of less than 0.15 mgs/kg, including five patients who discontinued corticosteroids, according to Miklos.
The most common adverse events were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%) and bruising (24%).
Serious adverse events occurred in 52% of patients, which included pneumonia in six patients, and septic shock and pyrexia each in two patients.
Laboratory analysis indicated that ibrutinib was associated with direct inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase, according to Miklos.
“Ibrutinib resulted in clinically meaningful and sustained response in patients who failed at least one prior treatment,” he concluded. “Patients experienced reductions in corticosteroid doses while on ibrutinib. Biomarker changes support a clinical benefit of ibrutinib. We believe this supports further study in frontline treatment of ibrutinib in chronic GVHD. This study is already underway.” – by Rob Volansky
For more information:
Miklos D, et al. Abstract LBA-3. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Miklos reports consultant roles with and travel expenses and research funding from Kite Pharma, Pharmacyclics, Novartis, Roche and Sanofi Oncology. Please see the abstract for a list of all other researchers’ relevant financial disclosures.