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The effectiveness of ibrutinib in chronic lymphocytic leukaemia: a nationwide, population‐based study in the Netherlands

At present, in the Netherlands, the application in daily practice of ibrutinib in patients with chronic lymphocytic leukaemia (CLL) is, as yet, restricted to CLL patients with del(17p) or a TP53 mutation across all treatment lines, and in particular to patient subsets with previously treated CLL (Kersting et al., 2018). Efficacy data derived from the RESONATE trial (Byrd et al., 2014) — which led to the approval of ibrutinib for the abovementioned indications — cannot always be readily extrapolated into “real-world” effectiveness. This issue relates to the restricted patient selection criteria in clinical trials (Meyer, 2010). Most population-based information on the effectiveness of ibrutinib in CLL currently derives from compassionate-use programmes (CUPs) and series in which patients were primarily managed in academic centres (Winqvist et al., 2016; Ysebaert et al., 2017; Hillmen et al., 2018). Such series might also suffer from patient selection, as in clinical trials. Therefore, this nationwide, populationbased study aimed to assess the effectiveness of ibrutinib among CLL patients in a post-approval setting in the Netherlands. All CLL patients who initiated treatment with commercially available ibrutinib between 2015 and 2016 in the Netherlands were identified and queried via the Nationwide Registry of Hospital Discharges (i.e. inpatient and outpatient discharges) and the nationwide Netherlands Cancer Registry. Details about the registries are provided in the Supporting information. The primary endpoint was progression-free survival (PFS). The secondary endpoints included assessment of the application of ibrutinib according to the Dutch guidelines by HOVON, duration and toxicity of ibrutinib treatment, overall survival (OS), and event-free survival (EFS). Survival distributions were constructed using the Kaplan-Meier method and compared using the log-rank test. Regression analyses were performed to assess various covariates associated with ibrutinib discontinuation and survival outcomes. Details about the endpoints (Table SI) and statistical methods are described in the Supporting information. All 155 ibrutinib-treated CLL patients [median age 70 years (range: 48–91 years), 74% males; 67% Rai stage III–IV; 68% managed in non-university hospitals; 6% with small lymphocytic lymphoma] were included in the study. Patient characteristics are presented in Table SII. At a median follow-up of 14 2 months (range 0 9–31 9), 75 (48%) patients were still receiving ibrutinib and 45 (29%) patients had died. Reasons for ibrutinib discontinuation and the best response rate are described in the Supporting information. Overall, the median time on ibrutinib was 11 6 months (range 0 1–30 9). Multivariable logistic regression showed that Rai stage III–IV — especially anaemia — was the sole covariate associated with ibrutinib discontinuation (Table SIII). The median PFS (95% CI: 22 9, median not reached) and OS (95% CI: median not reached) were not reached (Fig 1). Oneyear PFS and OS were 73% (95% CI, 65–79%) and 77% (95% CI, 69–83%) respectively (Fig 1). Multivariable Cox regression analyses revealed that Rai stage III-IV (HR for PFS, 2 56; 95% CI: 1 26–5 19 and HR for OS, 2 54; 95% CI: 1 17– 5 55) (Table IA) — particularly anaemia (HR for PFS, 4 09; 95% CI 2 02–8 28 and HR for OS, 3 61; 95% CI 1 69–7 70) (Table IB) — and the number of previous therapies per one treatment line increase (HR for PFS, 1 27; 95% CI: 1 04–1 55 and HR for OS, 1 29; 95%CI: 1 04–1 60) were associated with inferior PFS and OS, respectively. Besides, haepatoand/or splenomegaly (HR for OS, 3 16; 95% CI: 1 12–8 92) was only associated with inferior OS (Table IB). The median EFS and one-year EFS were 18 2 months (95% CI, 11 6, median not reached) and 58% (95% CI, 50– 66%), respectively (Fig 1). Multivariable Cox regression