Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients

Abstract

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukemia patients. The UK Chronic Lymphocytic Leukaemia Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year "discontinuation-free survival" and 1 year overall survival. With a median of 16 months follow up, data on 315 patients demonstrated a 1 year discontinuation-free survival of 73.7% and a 1 year overall survival of 83.8%. Patients with better pre-treatment performance status (0/1 vs. 2+) had superior discontinuation-free survival (77.5% vs. 61.3%; P<0.0001) and overall survival (86.3% vs. 76.0%; P=0.0001). In univariable analysis, overall survival and discontinuation-free survival were not associated with the number of prior lines of therapy or 17p deletion. However, multivariable analysis identified an interaction between prior lines of therapy, age and 17p deletion, suggesting that older patients with 17p deletion did worse when treated with ibrutinib beyond the second line. Overall, 55.6% of patients had no first year dose reductions or treatment breaks of >14 days and had an overall survival rate of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks of >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year overall survival: 91.7%), but patients who had first year treatment breaks of >14 days, particularly permanent cessation of ibrutinib had both reduced 1 year overall survival (68.5%), and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year overall survival; 90%: progression-free survival; 84%), this may partly reflect the inclusion of performance status 2+ patients, and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression.

Figure 1.

Kaplan-Meier plots of (A) discontinuation-free survival (DFS) and (B) overall survival (OS) for the whole cohort of 315 patients. Patient outcomes as per pre-ibrutinib performance status showing (C) DFS and (D) OS. PS: performance status.

Figure 2.

Kaplan-Meier plots of (A) overall survival (OS) of patients older than median age and median age or younger, (B) OS with or without 17p deletion (*P-value for the comparion of patients with and without 17p deletion) (C) OS of patients by number of prior lines of therapy and (D) OS of patients classified by local clinician as ‘responder’ or ‘non-responder’ to ibrutinib therapy. FISH: fluorescence in situ hybridization.

Figure 3.

Kaplan-Meier plots of overall survival (OS) for (A) patients equal to or younger than the median age and (B) patients older than the median age and (C) patients without 17p deletion and (D) patients with 17p deletion stratified by the number of prior lines of therapy.

Figure 4.

Kaplan-Meier plots of discontinuation-free survival (DFS) (A) and overall survival (OS) (B) of patients divided into group A, B or C as per definition in the text.

Figure 5.

Kaplan-meir plots of discontinuation-free survival (DFS) (A) and overall survival (OS) (B) for groups A, B, C1 and C2 showing survival beyond one year.