IBRUTINIB FOR RELAPSED / REFRACTORY CLL: AN UPDATE OF THE UK AND IRELAND ANALYSIS OF OUTCOMES IN 315 PATIENTS

Abstract

Introduction: The UK CLL Forum recently published the largest realworld data set of patients treated with ibrutinib for relapsed/refractory CLL (Haematologica, 2016). We have now updated our database with an additional 14 months median follow-up. Methods: Data were collected retrospectively from 62 centres, and discontinuation free survival (DFS) and overall survival (OS) were analysed and stratified by baseline and treatment-related characteristics. Results: of the original 315 patients, 103 have now died, 37 are alive but have stopped ibrutinib, and 175 continue to take the drug. With a median 30 months follow-up, 54.4% (95% CI: 48.5-60.0) of patients are still taking ibrutinib and 66.1% (60.4-71.3) are still alive. Despite the additional follow-up, with univariable analysis, we could still not show any deleterious effect of 17p deletion or number of prior lines of therapy on discontinuation-free survival or overall survival (OS) (OS for 17p deleted vs 17p wildtype: 68.6% vs 67.8%; OS for number of prior lines 1 vs 2 vs 3+: 66.0% vs 64.9% vs 66.6%). However, increased age and poorer pre-treatment performance status remain associated with ibrutinib discontinuation and earlier death. With our original publication, we were unable to demonstrate any survival detriment for dosereduced patients, although patients who had treatment breaks >14 days, had inferior outcomes. of the 48 patients who had dose-reduced ibrutinib without treatment breaks in the first year, 17 have now stopped the drug, 10 have died, 25 continue on dose-reduced ibrutinib and 6 are back to standard dose. To analyse on-going potential effects of first year dose reductions and treatment breaks, we classified all patients who were alive at 1 year into one of 4 different groups depending on first year treatment, namely, A: standard dosing with no breaks >14 days; B: dose reductions but no breaks >14 days; C1: temporary treatment breaks >14 days (but re-taking ibrutinib by 1 year); C2: permanent discontinuation of ibrutinib within the first year. Figure 1 plots DFS and OS with 18 months median follow-up for these patients beyond one year. There is no statistical difference in DFS and OS between groups A and B (DFS; 76.7% (68.3-83.1) vs 71.1% (53.3-83.1), p = 0.23: OS; 88.1% (81.6-92.5) vs 83.7% (66.8-92.5), p = 0.75). However, patients who had temporary breaks >14 days (C1) or permanently stopped ibrutinib (C2) within the first year have impaired survival over the next 18 months compared with groups A and B (OS C1: 63% (41.4-78.5); OS C2: 40.6% (22.7-57.8).This represents a 3.1-fold and 7.7-fold respective increase risk of death for groups C1 and C2 compared with standard dosed patients. Conclusions: Over half of patients are still taking ibrutinib and two thirds of patients are alive with 30 months median follow-up. Although temporary or permanent cessation of therapy within the first year strongly associates with earlier death, a direct causal (Figure Presented) relationship between these factors is not proven by this association, as there are multiple additional confounding medical factors which can influence OS.