Ibrutinib shows promise for children with chronic graft-versus-host disease
Click Here to Manage Email Alerts
SALT LAKE CITY — Ibrutinib appeared safe and effective for children with previously untreated or relapsed/refractory chronic graft-versus-host disease, according to study results.
Paul A. Carpenter, MD, professor at Fred Hutchinson Cancer Research Center, presented the results at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
Rationale and methods
“Chronic GVHD is a potentially debilitating life-threatening complication of allogeneic [hematopoietic stem cell transplantation],” Carpenter said during a presentation. “There are limited treatment options for children, with most studies of potential therapies in children having small sample sizes. Current treatments have suboptimal efficacy and use is often based on adult data only.”
Ibrutinib (Imbruvica; Pharmacyclics, Janssen) — a once-daily oral Bruton tyrosine kinase inhibitor — is the first approved therapy in the United States for adults with chronic GVHD after failure of prior systemic therapy.
The open-label, multicenter, phase 1/2 iMAGINE study included 59 patients (median age, 13 years; 71% male) with previously untreated or relapsed or refractory, moderate or severe, chronic GVHD.
The study had two parts conducted in parallel. During part A, a dose-finding and safety study, investigators evaluated pharmacokinetics of ibrutinib for children aged 1 year to 12 years with a starting dose of 120 mg/m². If no treatment-related grade 3 or higher toxicities occurred after 14 days, investigators escalated the dose to 240 mg/m² — which is equivalent to 420 mg starting dose for adults.
“The ultimate goal of part A was to determine the recommended pediatric-equivalent dose. Once that was determined, those aged 1 to 12 years could be enrolled on part B at the recommended pediatric-equivalent dose,” Carpenter said.
Part B included patients aged 12 years or older who received once-daily ibrutinib dosed at 420 mg.
Treatment continued until no longer required, initiation of new systemic chronic GVHD therapy, chronic GVHD progression, underlying disease recurrence or unacceptable toxicity.
Forty-seven pretreated patients had received a median two to 12 lines of prior therapy, and 12 patients had received no prior treatment. Nearly two-thirds (64%) had underlying malignant disease and an indication for transplant.
Pharmacokinetics and safety served as primary endpoints. Secondary endpoints included duration of response, overall response rate defined by 2014 NIH criteria, OS and patient-reported outcomes.
Patients received ibrutinib treatment for a median 8 months.
Key findings
Results showed plasma-concentration profiles with 240 mg/m² ibrutinib comparable to those of adults with chronic GVHD treated with 420 mg daily ibrutinib.
Researchers reported an ORR of 78%, with 83% of treatment-naive patients and 77% of those with relapsed or refractory chronic GVHD achieving response.
The percentage of patients who had at least 1-year duration of response appeared comparable between treatment-naive patients and those with relapsed or refractory chronic GHVD (60% vs. 58%).
Median time to response was 4 weeks and median time to best response was 6 weeks.
Researchers observed sustained treatment response for 20 weeks or more among 70% of treatment-naive patients and 58% of those with relapsed or refractory disease.
Moreover, 44% of patients aged 12 years or older experienced improvements in Lee Symptom Scale scores on two or more consecutive visits.
Two-thirds (64%) of patients experienced grade 3 or higher treatment-associated adverse events, and 24% of patients experienced adverse events that led to treatment discontinuation.
“The most frequent adverse events that occurred in 10% of patients or more included stomatitis in 17%, which is higher than what we see in adults,” Carpenter said.
Implications
“Ibrutinib, given at the recommended pediatric dose of 240 mg/m² in those younger than 12 years, achieved plasma concentration-time profiles consistent with what we would expect in a full adult dose in those aged 12 years and older,” Carpenter said. “The bottom line is that ibrutinib has shown clinically meaningful activity in children with moderate to severe chronic GVHD, with comparable efficacy and safety outcomes to those reported in adults.”
Collapse
Carpenter PA, et al. Abstract 126. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
Click Here to Manage Email Alerts