Ibrutinib sustains efficacy in CLL at 4-year follow-up
NEW YORK, NY—The 4-year follow-up of the RESONATE trial suggests ibrutinib may provide long-term efficacy in previously treated patients with chronic lymphocytic leukemia (CLL).
The median progression-free survival (PFS) has not yet been reached in this trial, regardless of high-risk cytogenetics, according to Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
She presented the update at Lymphoma & Myeloma 2017. The follow-up study was awarded the best clinical CLL abstract of the meeting.
In the phase 3 RESONATE study, investigators compared ibrutinib—the first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase—to ofatumumab in previously treated CLL/small lymphocytic lymphoma (SLL).
The primary analysis showed ibrutinib significantly improved survival, with a 78% reduction in the risk of progression and a 57% reduction in the risk of death.
The phase 3 trial randomized 195 CLL/SLL patients to oral ibrutinib at 420 mg once daily and 196 patients to intravenous ofatumumab at an initial dose of 300 mg followed by 2000 mg for 11 doses over 24 weeks.
One hundred thirty-three patients progressed on ofatumumab and crossed over to receive once-daily ibrutinib.
Patient characteristics
In each arm, the median patient age was 67, more than half of patients had an ECOG status of 1, and more than half had advanced-stage disease.
High-risk genetic abnormalities were common, Dr Brown said, with deletion 11q in a third of patients in the ibrutinib arm and 31% in the ofatumumab arm. Another third in each arm had deletion 17p, while 51% in the ibrutinib arm and 46% in the ofatumumab arm had TP53 mutation.
About a quarter of the patients in each arm had complex karyotype, and 73% and 63% in the ibrutinib and ofatumumab arms, respectively, were IGHV-unmutated.
Survival
Ibrutinib significantly extended PFS compared with ofatumumab. At a median follow-up for ibrutinib of 44 months (range, 0.33 – 53), ibrutinib led to an 87% reduction in the risk of progression or death. The 3-year PFS rate was 59% with ibrutinib and 3% with ofatumumab.
Ibrutinib conferred a benefit in PFS across all baseline patient characteristics.
Among ibrutinib-treated patients, the 3-year PFS was 53% for patients with deletion 17p, 66% for those with deletion 11q but not deletion 17p, and 58% for those with neither abnormality.
Dr Brown noted how closely complex karyotype associates with high-risk cytogenetics. Forty-two percent of patients with 17p deletion had a complex karyotype, as did 23% of patients with 11q deletion and 15% of patients with neither 17p nor 11q deletion.
For IGHV-mutation status, Dr Brown said there is no difference in PFS with this degree of follow-up.
In terms of TP53 mutation status, Dr Brown pointed out a trend toward a worse PFS in those patients with the mutation.
“We actually looked by individual p53 mutation versus 17p deletion, versus both, versus neither, in the 2-year follow-up paper and found that p53 with 17p, both abnormalities, did have worse PFS than neither,” she said.
“This may require further follow-up because we do know that most 17p patients also have a p53 mutation, particularly in the relapsed setting.”
As expected, Dr Brown said, those patients with more than 2 prior therapies had a worse PFS compared to patients with 2 or fewer prior therapies.
Multivariate analysis demonstrated that more than 2 prior lines of therapy or an elevated ß2 microglobulin were associated with decreased PFS with ibrutinib.
When the investigators adjusted the overall survival data for cross-over, ibrutinib was projected to continue the overall survival benefit compared with ofatumumab, with a hazard ratio of 0.37.
