Outcomes of Patients with Chronic Lymphocytic Leukemia Discontinuing Bruton Tyrosine Kinase Inhibitors Due to Adverse Effects

Background: The use of Bruton tyrosine kinase inhibitors (BTKis) has significantly improved the survival of patients with chronic lymphocytic leukemia (CLL). Although BTKis are effective, they are associated with specific toxicities such as gastrointestinal disturbances, bleeding, hypertension, cardiovascular and arthralgias leading to frequent discontinuation of therapy. Previous data from individual trials suggest that prolonged remissions can occur following discontinuation, however, this has not been studied in detail. Therefore, the aim of our study was to further understand the progression free survival (PFS) and the time to next treatment (TTNT) for patients who discontinued BTKis due to adverse events.

Methods: This study is a retrospective analysis of all patients who were initiated on treatment with either ibrutinib or acalabrutinib between 2010 and 2020 at The Ohio State University and discontinued therapy due to adverse effects. The characteristics of patients discontinuing treatment with BTKis were obtained by medical chart review along with PFS, TTNT, and overall survival (OS). We excluded patients who died or who were transitioned to another therapy in the absence of disease progression within 2 weeks of discontinuation. PFS was calculated from the time of BTKi discontinuation to the time of progression or death, censoring patients without events at time of next treatment initiation or last follow-up. Overall survival was calculated at the time from BTKi discontinuation to death of all cause, censoring patients at last follow-up. TTNT was calculated as the time from discontinuation of BTKi to initiation of a subsequent treatment regimen, accounting death without treatment as a competing interest. Time-to-event outcomes PFS and OS were estimated using the method of Kaplan-Meier, while TTNT was estimated using the cumulative incidence function. Univariable and multivariable Cox models were created to identify features associated with PFS after BTKi discontinuation.

Results: Seven hundred and nine patients with CLL began BTKi during this time frame: 559 received ibrutinib and 150 patients received acalabrutinib. Overall, 145 (20.4%) patients discontinued BTKi due to adverse events (22% of the ibrutinib-treated cohort and 14.6% of the acalabrutinib-treated cohort). Of those patients that discontinued BTKi the median age was 67 (range 32-89) and 37% were women. Patients had a median of 2 prior lines of therapies (range: 0-12), and 10.6% of patients received concomitant monoclonal antibody. 64.3% of patients had IGHV unmutated disease,16.2% had del17p by FISH, and 17.7% and 19.1% had complex (≥ 3 abnormalities), or highly complex karyotype (≥ 5 abnormalities), respectively. The median duration of BTKi treatment was 27 months (range 0.1-120.8) and the median follow up after BTKi discontinuation was 19.7 months. The median PFS from the time of BTKi discontinuation was 21.2 months (95% CI: 16.1-28.1), and median OS was 77.6 months (95% CI: 61.8-NR). After discontinuing BTKi, 37.1% and 48.7% of patients started subsequent treatment after 12 and 24 months respectively, with a median TTNT of 24.1 months. In multivariable analysis, after controlling for type of BTKi (HR of acalabrutinib vs ibrutinib 1.15, p=0.69), time on BTKi (HR 0.92 per 3-month increase, p<0.0001), number of lines of therapy (HR 1.27 per line of treatment, p<0.0001), and LDH (HR 1.15 per 50-unit increase, p=0.01) were all associated with PFS. When looking specifically at 2 years as a cut-point for duration of BTKi, we found a median PFS of 28.1 months vs 9.1 months, p=0.0003, for those who had received ≥24 months of therapy vs <24 months.

Conclusions: Here we demonstrate that patients who discontinue BTKi due to toxicity can often enjoy a prolonged remission in the absence of therapy. Those patients with longer duration of BTKi exposure and those who have received less prior therapy have significantly longer PFS following discontinuation of BTKi. This data supports the observation of patients off therapy after BTKi discontinuation for adverse events, rather than immediate initiation of subsequent therapy, particularly in those who received > 2 years of treatment.