Combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone, and is recognized as a standard of care for younger patients with treatment-naïve chronic lymphocytic leukemia (CLL). In recent years, the Bruton’s tyrosine kinase inhibitor ibrutinib has had a major impact on clinical practice. However, the efficacy of ibrutinib as a first-line treatment for younger CLL patients relative to FCR was unknown.
Eligible patients were previously untreated, aged ≤70 years with Eastern Cooperative Oncology Group status ≤2; patients with the del(17p) chromosomal mutation were excluded. Participants were randomized 2:1 to receive 420 mg of ibrutinib daily and rituximab escalating to 500 mg/m2 on day 1 of cycles 3 to 7 of treatment, or 6 courses of intravenous fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 with rituximab escalating to 500 mg/m2 on day 1 of cycles 2 to 6 every 28 days. The primary end point was PFS, with a secondary end point of OS.
In the intent-to-treat population, a total of 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. With a median follow-up of 33.6 months, researchers observed 37 PFS events in the IR arm and 40 PFS events in the FCR arm. The hazard ratio (HR) for PFS and OS both favored IR over FCR, as follows:
- PFS: HR = 0.352; 95% confidence interval (CI), 0.223-0.558; P <.0001
- OS: HR = 0.168; 95% CI, 0.053-0.538; P = .0003.
Likewise, a subgroup analysis of PFS data showed that IR was superior to FCR independent of age, sex, performance status, disease stage, or the presence or absence of del(11q22). In addition, IR was also superior to FCR for IGHV-unmutated patients (HR, 0.262; 95% CI, 0.137-0.498; P <.0001) but not IGHV-mutated patients (HR, 0.435; 95% CI, 0.140-0.1350; P = .07).
Grade 3 and 4 treatment-related adverse events were observed in 58.5% of IR- and 72.1% of FCR-treated patients (P = .004), and FCR was associated with a higher rate of grade 3 and 4 neutropenia and infectious complications. There were 14 deaths during active treatment +30 days (4 in the IR arm and 10 in the FCR arm), representing a greater than 5-fold difference given the 2:1 randomization.
In summary, the combination of ibrutinib and rituximab provided superior PFS and OS relative to FCR for younger patients with previously untreated CLL in this randomized phase 3 trial. These findings add to the evidence base supporting ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL.
Shanafelt TD, et al. ASH 2018. Abstract LBA4.