RESONATE-2 Trial Confirms Survival Advantage of Ibrutinib in CLL/SLL

In a 10-year follow-up of the RESONATE-2 study, investigators found that ibrutinib provided durable survival and disease control in treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The findings, published in Blood by Jan A. Burger, MD, PhD, and colleagues, suggest that single-agent ibrutinib remains an effective first-line option, particularly for high-risk patients, when compared with traditional chemotherapy such as chlorambucil.

The study enrolled 269 patients with CLL/SLL aged 65 and older. Of these, 136 received once-daily ibrutinib (starting dose of 420 mg per day), and 133 received chlorambucil for up to 12 cycles with doses ranging from 0.5 mg/kg to 0.8 mg/kg, depending on how well they tolerated it. Patients in the chlorambucil arm who experienced disease progression were eligible to try the second-line treatment with ibrutinib. Seventy-eight patients in the chlorambucil arm switched to ibrutinib.

Regarding patient characteristics, in the ibrutinib arm, about 22% of patients had a chromosome 11 deletion, 59% had an unmutated IGHV gene, 8% had a TP53 mutation, and 6% had complex karyotype (CK). In the group that received chlorambucil, only 3% had a TP53 mutation, but the other risk factors were similar between the two groups. These high-risk groups benefited the most from the first-line treatment.

Side effects included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), joint pain (31%), swelling in the arms and legs (31%), and high blood pressure (30%). Thirty-four of 136 in the ibrutinib arm had a dose reduction when side effects became too severe, and the symptoms improved in 30 patients. A few patients experienced more significant health conditions like atrial fibrillation (9 %) and major hemorrhage (2%). By the end of the study, 27% of patients remained on first-line ibrutinib treatment.

The investigators noted that at the final analysis, the median progression-free survival (PFS) with ibrutinib was reached and was 8.9 years (95% CI, 7.0-NE) versus 1.3 years (95% CI, 0.9-1.6) with chlorambucil. Overall survival at 9 years was 68% in the ibrutinib arm.

Ibrutinib as first-line therapy for high-risk patients with CLL/SLL offers nearly a decade-long benefit in survival and disease control, with manageable side effects. This remains an important option for this patient population and remains a key alternative to chemotherapy.