Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) occur mainly in older patients, who are likely to have several comorbidities and who often are unable to receive aggressive drug therapies, such as alkylating drugs, which are typically used for patients with CLL or SLL. Ibrutinib is the first FDA-approved once-daily inhibitor of Bruton’s tyrosine kinase indicated for the treatment of patients with CLL/SLL, thereby allowing this patient population to receive treatment without chemotherapy.
The phase 3 RESONATE-2 clinical trial compared the efficacy and safety of ibrutinib and chlorambucil in patients (aged ≥65 years) with treatment-naïve CLL or SLL; at a median of 18.4 months of follow-up, ibrutinib showed significant reduction in the risk for disease progression or death by 84%.
Updated results for the RESONATE-2 study at a follow-up of 29 months were reported by Barr and colleagues for treatment-naïve patients with CLL or SLL. A total of 269 patients (median age, 73 years) with treatment-naïve CLL or SLL were randomized to receive ibrutinib 420 mg daily until disease progression or chlorambucil 0.5 mg/kg (maximum 0.8 mg/kg) on days 1 and 15 of a 28-day cycle, for a total of up to 12 cycles. Patients with deletion (del)17p were excluded from this extension study. Patients who received chlorambucil whose disease progressed were allowed to cross over to the ibrutinib arm. The primary end point was progression-free survival (PFS); the secondary end point was overall survival (OS).
At a median of 29 months of follow-up, the increased duration of PFS was sustained, at 89%, with ibrutinib versus 34% with chlorambucil at 24 months. The PFS improved significantly with ibrutinib versus chlorambucil at all the high-risk subgroups, including those with del11q and those without IGHV mutation. Ibrutinib demonstrated a 99% reduction in the risk for disease progression or death, and a 92% reduction in the subgroup of patients with del11q.
Overall, 41% of patients switched from chlorambucil to ibrutinib; the 2-year OS rates based on the OS analysis in the intent-to-treat population resulted in estimated rates of 95% in the ibrutinib arm and 84% in the chlorambucil arm. Similarly, the investigator-assessed overall response rate was 92% with ibrutinib and 36% with chlorambucil.
Ibrutinib showed higher sustained hematologic improvements from baseline versus chlorambucil in patients with anemia (90% vs 45% improvement in hemoglobin) and thrombocytopenia (80% vs 46% improvement in platelet counts). Grade ≥3 adverse events (AEs) in ≥5% of patients included neutropenia, pneumonia, anemia, and hypertension; AEs of any grade leading to dose reductions were reported in 13% of patients. The incidence of the common grade ≥3 AEs in the ibrutinib-treated patients typically decreased over time. Overall, important AEs decreased in frequency with longer follow-up.
At a median of 29 months, ibrutinib continued to demonstrate significant efficacy, with an 88% reduction in the risk for disease progression or death versus chlorambucil.