Standard chemoimmunotherapy regimens are often not tolerated by the majority of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who are typically older patients with considerable comorbidities and disease-related immunosuppression. Treatment options for this patient population are limited; they are commonly treated with alkylating agents such as chlorambucil, underscoring the need for novel and effective therapies. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase that is approved for treatment of patients with CLL who had received >1 prior therapies and for those with deletion 17p cytogenetic abnormality.1 In treatment-naïve patients aged >65 years, ibrutinib treatment resulted in an overall response rate (ORR) of 84%, including complete responses in 23% of patients and a 30-month progression-free survival (PFS) of 96%.2 Based on these encouraging results, a head-to-head comparison of the efficacy and safety of ibrutinib versus chlorambucil was conducted by the randomized, open-label phase 3 RESONATE-2TM trial in treatment-naïve older patients with CLL/SLL; Tedeschi and colleagues reported on these results at the meeting.3
A total of 269 patients were enrolled (median age, 73 years) and treated with ibrutinib (420 mg daily) or chlorambucil (0.5 mg/kg) until progression. At a median follow-up of 18.4 months, ibrutinib significantly prolonged Independent Review Committee (IRC)-assessed PFS compared with chlorambucil (median not reached [NR] vs 18.9 months; hazard ratio [HR], 0.16; P <.0001); ibrutinib decreased the risk of progression or death by 84%. This impressive PFS benefit also extended to patient subgroups, including those aged >70 years, as well as those with high-risk features such as del11q and unmutated IgHV. Importantly, ibrutinib therapy resulted in significant prolongation of overall survival (OS; median OS: NR in both arms; HR, 0.16; P = .0010), and a 24-month OS of 97.8% (vs 85.3%) compared with control. Patients treated with ibrutinib achieved a higher IRC-assessed ORR of 86.0% versus 35.3% with chlorambucil. Moreover, a significantly greater proportion of ibrutinib-treated patients achieved a >50% reduction in lymph node burden (91.2% vs 36.8%; P <.0001); reduction in spleen enlargement (75.7% vs 39.1%; P <.0001); and sustained hematologic improvements, including in patients with baseline anemia (84% vs 45%; P <.0001) or thrombocytopenia (77% vs 43%; P = .0054). Common adverse events (AEs) associated with ibrutinib therapy were diarrhea, fatigue, cough, and nausea. AEs that occurred at higher rates in the ibrutinib cohort included atrial fibrillation (6% vs 1%), hypertension, and hemorrhage (4% vs 2%). However, AEs leading to treatment discontinuation were less frequent with ibrutinib therapy (9% vs 23%). Based on these results, the authors concluded that single-agent ibrutinib therapy was superior to standard chlorambucil in terms of efficacy outcomes, including PFS, OS, and ORR in treatment-naïve older CLL/SLL patients, and was associated with an acceptable safety profile.
