December 9, 2023
By Catlin Nalley
Long-term outcome data from a Phase II study demonstrated the durable benefit of single-agent ibrutinib among patients with chronic lymphocytic leukemia (CLL), according to findings presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9-12 in San Diego (Abstract 201).
“Ibrutinib, the first-in-class BTK inhibitor was FDA-approved for CLL in 2014. BTK inhibitors improved survival of CLL patients over chemoimmunotherapy,” said study author Adrian Wiestner, MD, leader of the lymphoid malignancies section of the Hematology Branch at the National Cancer Institute, while noting that single-agent BTK inhibitors are typically dosed continuously until disease progression or toxicity.
“While the reported overall response rates to BTK inhibitors are high, undetectable, minimal residual disease is uncommon,” he added. “Long-term outcomes in the era of targeted agents remain to be fully defined.”
With a median follow-up of nearly 10 years, Wiestner and colleagues assessed efficacy, safety, and depth of response among CLL patients who were treated with long-term ibrutinib therapy. Eligible patients included those with high-risk CLL, which was defined by TP53 alterations or age ≥65 years old, who received ibrutinib 420 mg orally once daily until disease progression or intolerable side effects, according to the study authors.
Response assessments were performed annually with CT scans up to 5 years and subsequently with physical exams. After year 5, the researchers switched to only clinical and laboratory assessments every 3-6 months and a CT to confirm progression.
“Minimal residual disease (MRD) was performed annually with peripheral blood flow cytometry,” Wiestner and team stated. “Undetectable MRD (uMRD) was defined as <1 CLL cell per 10,000 leukocytes.”
Eighty-four patients were enrolled in this single-center, Phase II, investigator-initiated study (NCT01500733) between January 2012 and January 2014. In the TP53 cohort (n=50), the median age was 62 years and the majority were male (60%). Sixty-eight percent were treatment-naïve. Among patients in the elderly cohort (≥65 years), the median age was 69 years and 53 percent were male. Fifty-three percent of patients were treatment-naïve.
With a median follow-up of 113 months, Wiestner reported a median progression-free survival of 85.9 months for all patients. Data showed that the median progression-free survival was significantly shorter among patients with TP53 alterations (67.3 months). It was not reached in patients without TP53 alterations. Treatment-naïve patients had a median PFS 108 months compared to 49 months in those with relapsed disease.
With a median follow-up of 117 months (estimated from reverse Kaplan-Meier), the median overall survival was not reached and was 61.6 percent at 117 months, according to Wiestner. Patients with TP53 alterations had an overall survival of 54.1 percent. OS at 117 months was 73.8 percent for treatment-naïve patients.
Study authors observed uMRD in 15.4 percent (13/84) of all patients. The median time to uMRD was 5 years. Of 13 patients with uMRD, 10 achieved CR, seven patients sustained uMRD for 1-6 years, and one patient has persistent uMRD more than 3 years off all therapy.
Summarizing his presentation, Wiestner highlighted the durable benefit of single-agent ibrutinib in this patient population with a median PFS over 7 years (85.9 months) and median overall survival not yet reached, including for TP53 altered CLL treated in the first-line.
“Prior treatment status, TP53 alterations, and IGHV unmutated status impact prognosis,” he said. “With almost 10 years of follow-up, 44 percent of patients discontinued therapy due to progressive disease and 32 percent for adverse events.
“Patients with persistently high MRD even at 10 years into treatment also had long-term disease control. With increasing treatment duration, however, we do see uMRD becomes more common and appears to be sustained,” Wiestner concluded. “These data suggest that a subset of patients could safely discontinue BTK inhibitor therapy.”
Catlin Nalley is a contributing writer.