SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).
Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).
“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.
In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.
He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).
The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).
IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m2 on day 1 of cycle 2, at 325 mg/m2 on day 2 of cycle 2, and at 500 mg/m2 on day 1 for cycles 3 to 7.
From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.
Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.
He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.
In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).
In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).
In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.
PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).
In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).
In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).
Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.
Safety and cost
Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).
Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).
AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).
Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.
“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.
The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.
*Data in the abstract differ from the presentation.