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

Abstract

I n 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.

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

“…The present analyses focus on patients with early incomplete adherence and possibly represents a group that is at greater risk of poor adherence and subsequent poor outcomes. Despite our results and those obtained within the context of a clinical trial 3 demonstrating transient disease progression related to temporary dose holds, this appears to be reversible with re-initation of therapy 16 .…”

“…This would suggest that the ideal treatment strategy would be to recommend initiation of therapy at standard dosing and interruption as needed as directed in the FDA label. Two studies have reported no negative impact for patients requiring dose reductions 16, 17 , however differences may be attributable to population differences and timing of reductions. The present analyses focus on patients with early incomplete adherence and possibly represents a group that is at greater risk of poor adherence and subsequent poor outcomes.…”

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…In a real‐world study of ibrutinib‐treated patients enrolled in a compassionate‐use programme, the estimated 10‐month PFS and OS rates were 71% and 78%, respectively, for 50 patients with del(17p) (Winqvist et al , 2016). In a real‐world study of ibrutinib‐treated patients in a named patient scheme, the estimated 12‐month discontinuation‐free progression and OS rates were 71% and 84%, respectively for 90 patients with del(17p) (UK CLL Forum 2016). Together, the results of these clinical trials and real‐world analyses support the conclusion that ibrutinib is among the most active agents yet developed for the treatment of del(17p) CLL.…”

“…Since the initial study, many more patients with del(17p) CLL have been treated with ibrutinib, including in real‐world settings (Mato et al , 2016, UK CLL Forum 2016; Winqvist et al , 2016). To provide a more robust description of outcomes in the prospective trials in this important high‐risk patient population, we conducted a combined analysis of 243 patients with R/R del(17p) CLL who received treatment with single‐agent ibrutinib (420 mg) in 1 of 3 prospective clinical studies (Byrd et al , 2013, 2014, 2015; O'Brien et al , 2014, 2016a).…”

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…Despite, the well characterized toxicity profile of the drug, analysis of clinical trials and real-world data revealed that in particular patient cohorts, up to approximately 30% patients discontinue ibrutinib therapy due to toxicity [57,61,62,[73][74][75][76]].…”