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Long-term Outcomes for Ibrutinib-Rituximab and Chemoimmunotherapy in CLL: Updated Results of the E1912 Trial

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients with CLL age <70 years. Patients were randomly assigned (2:1 ratio) to receive ibrutinib and rituximab (IR) or six cycles of FCR. With a median follow-up of 5.8 years, median PFS is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in both IGHV mutated (HR: 0.27; P < 0.001) and IGHV unmutated patients (HR: 0.27; P < 0.001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events/complication, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. Median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in OS was observed for patients on the IR arm (HR=0.47; p=0.018). In conclusion, Ibrutinib-rituximab therapy offers superior PFS relative to FCR in both IGHV mutated and unmutated CLL patients as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients.

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