Tedeschi A, et al. - In this phase 3 RESONATE-2 study, researchers compared the effectiveness and safety of first-line ibrutinib (ibr) vs chlorambucil (chl) in older patients with CLL/small lymphocytic lymphoma (SLL), as well as analyzed long-term effectiveness and safety data for ibr, which is given as continuous therapy. For this investigation, 269 patients with previously untreated CLL/SLL without 17p deletion and ≥65 y old were randomized 1:1 to continuous ibr 420 mg once daily or chl 0.5–0.8 mg/kg for up to 12 cycles. Common grade ≥3 adverse events involved neutropenia, pneumonia, hypertension, anemia, hyponatremia, atrial fibrillation, and cataract, with rates of most events declining over time. In the longest follow-up to date from a phase 3 study of first-line BTK-directed therapy, single-agent ibr sustained superior progression-free survival and overall survival vs chl, including for patients with high-risk genomic characteristics. Responses to ibr improved over time with almost three-fold more patients achieving CR/CRi with long-term follow-up after up to 66 mo follow-up. More than half of the patients remain in continuous long-term ibr treatment, and no new safety signals have emerged.