Overall and Subgroup Results from the Third Interim Analysis of FIRE, a Real-World Study of Ibrutinib Treatment for CLL/SLL in France

Background: FIRE is a noninterventional, multicenter, observational study of patients with a confirmed diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treated with ibrutinib in France. Aim: The aim of the study is to collect real-world data to describe ibrutinib treatment patterns and assess its effectiveness and safety in CLL/SLL. Methods: This retrospective (ret) and prospective (pro) study started on May 12, 2016, and is planned to complete after ~6 years. Eligible patients were ≥ 18 years, with a confirmed diagnosis of CLL/SLL, and who initiated ibrutinib therapy on or after November 21, 2014, (date of ibrutinib commercialization) either in previously untreated patients with del17p and/or TP53 mutation, or in patients with relapsed or refractory disease R/R. Pro patients initiated ibrutinib treatment within 30 days of study start. Ret patients initiated ibrutinib treatment more than 30 days before inclusion in the study. Primary outcome measure was progression-free survival (PFS); secondary outcome measures included overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), and safety. Ret-collected adverse events (AEs) included only those considered related to ibrutinib, whereas pro-collected AEs included all treatment-emergent AEs (TEAEs). Therefore, AEs are reported separately for each cohort. Total population effectiveness results were adjusted with left truncation. Patients were treated according to usual local clinical practice. Results: We report results from the third interim analysis for patients with previously untreated and R/R CLL/SLL, with a median follow-up of 47.2 months, and with a focus on subgroup analysis. The effectiveness and safety populations comprised 394 patients (pro, n = 200; ret, n = 194) and 400 patients (pro, n = 202; ret, n = 198), respectively. Median age at ibrutinib initiation was 72 years (range, 39.0-93.0); 66.2% were male; median time from diagnosis to ibrutinib initiation was 7 years (range, 0.0-35.0). Patients received 0 (15.0%), 1 (36.3%), 2 (28.2%), or ≥ 3 (20.6%) prior lines of therapy (LOT). At baseline, complete response (CR; 50.0%) or partial response (PR; 36.2%) were recorded with the last prior therapy. Most patients (87.4%) progressed following last prior therapy, and median time from progression to initiation of ibrutinib was 2.1 months (range, 0.0-100.1). Of reported patients (n = 399), massive or symptomatic lymphadenopathy and/or splenomegaly was the most common reason (42.6%) for initiating ibrutinib treatment. Median PFS was 47.5 months (48.5/51.6 months in pro/ret). LOT and age (≤ 75 vs > 75 years) were statistically significant predictive factors for PFS. In patients with 0, 1, 2, and ≥ 3 prior LOT, median PFS was: not estimable (NE), 53.9 months, 47.5 months, and 33.5 months, respectively (Figure). At 48 months’ follow-up, ORR was 91.4%. Median TTNT was 54.6 months (NE/54.8 months in pro/ret). Median OS was NE overall and in pro/ret cohorts. Main effectiveness outcomes according to prior LOT and age are presented in the Table. Serious TEAEs related to ibrutinib were reported in 25.8% and 28.2/23.2% in pro/ret cohorts, respectively. AEs led to dose interruption (37.6/29.8%), withdrawal (30.2/22.7%), or reduction (26.7/11.1%) in the pro/ret cohorts. TEAEs of interest in the pro/ret cohorts were infection (68.8/57.1%), diarrhea (27.2/15.7%), arthralgia/myalgia (25.2/13.1%), arrhythmia (15.8/13.6% [including atrial fibrillation {9.4%/7.1%}]), hypertension (14.9/14.6%), rash (10.4/8.1%), and major bleeding (7.9/1.5%). Ibrutinib was permanently discontinued in 234 patients (58.5%); reported reasons (n = 212) were mostly due to AEs (36.8%) and disease progression (31.1%). Conclusions: In this longer follow-up of the real-world FIRE study reflecting clinical practice in France, ibrutinib was shown to be an effective treatment for patients with CLL/SLL, and patients who received ibrutinib in earlier LOT achieved better PFS. The effectiveness and adverse event profiles are consistent with observations from clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal