The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice

Abstract

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS‐CoV‐2 Pandemic

“…However, if ibrutinib is discontinued because of an adverse event while CLL is in remission, the disease may continue being under control for a prolonged period of time before an alternative therapy is required. 46 , 50 , 88 – 90 …”

“…This is illustrated by the evidence that temporary ibrutinib dose interruptions associate with shorter progression free survival, suggesting that patients who are able to better adhere to treatment may derive more benefit. 46 , 58 , 90 , 114 – 119 …”

Outcomes of Reduced Frequency Dosing of Ibrutinib in Chronic Lymphocytic Leukemia Patients Following Complete or Partial Remission: A Pilot Study

“…Ibrutinib has been marketed as a safe and simple oral alternative [ 1 , 2 , 4 ]; however, the burden of its distinct and serious SEs in the elderly CLL demographic is generating clinical interest. Dose reduction or interruption to manage toxicities is well documented and shown to not adversely affect disease-related outcomes [ 14 - 17 ]. This study is the first to demonstrate that switchover to a thrice weekly dose regimen following standard daily dose induction could offer a safe and efficacious option in CLL patients that have achieved CR or PR.…”

“…Ibrutinib’s half-life is very short at only 4 h; however, its duration of effect is prolonged and sufficient BTK blockade achieved at lower doses secondary to irreversible binding [ 12 , 13 ]. We know dose reductions to manage ibrutinib toxicities are relatively common in clinical practice [ 14 ] and a number of retrospective reviews have shown equivalent efficacy [ 14 - 17 ]. However, a gap remains in our knowledge and approach toward rationale-based dosing that could significantly reduce drug burden as well as cost to patient and health system.…”

“…This is the first published study to use thrice weekly dosing as opposed to dose reduction or treatment breaks to manage SEs. We hypothesized reduced frequency dosing (RFD) of ibrutinib would limit SEs but preserve efficacy based on drug pharmacokinetics [ 12 , 13 ] and mounting clinical evidence [ 14 - 17 ]. Secondary aims of the study were to examine rates of SEs and outcomes beyond the restrictions of a clinical trial.…”