Clinical Outcomes and Adverse Events Among Patients with Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma (CLL/SLL) Initiating First-Line (1L) Ibrutinib: Analysis of Subgroups Receiving Subsequent Second Generation (2G) Bruton Tyrosine Kinase Inhibitors, Non-Bruton Tyrosine Kinase Inhibitor Therapy, or Ibrutinib Retreatment in the US Community Oncology Setting
Authors: Burke John M. , Zackon Ira , Wayne Brittani , Wang Yunfei , Murphy John , Prescott Jennifer , Gandra Shravanthi , Leng Siyang , De Nigris Enrico 
Published: December 2024

Ibrutinib and 2G Bruton tyrosine kinase inhibitors (BTKis) have transformed the CLL/SLL treatment landscape and are widely used in the 1L setting. Patients who discontinue ibrutinib due to adverse events (AEs) may be retreated with ibrutinib or switch to an alternate therapy such as a 2G BTKi or non-BTKi therapy. Yet, outcomes associated with these various sequencing strategies are not well understood. This study evaluated the outcomes and AEs of patients who initiated ibrutinib, focusing on patients who had ibrutinib held and resumed, received a 2G BTKi or non-BTKi therapy.

This retrospective observational study included CLL/SLL patients initiating a 1L ibrutinib-based regimen from 11/21/2019 - 7/31/2023 in The US Oncology Network. Data were captured from the iKnowMed electronic health record. Patients were sorted into subsets based on their treatment sequence: 1) second line (2L) non-BTKi therapy, 2) ibrutinib retreatment, 3) 2L 2G BTKi, and 4) no subsequent new treatment (ongoing ibrutinib or discontinuation without subsequent 2L). Clinical outcomes assessed after starting ibrutinib (index) included time to treatment discontinuation (TTD), time to next treatment/death (TTNT-D), real-world progression-free survival (rwPFS) and overall survival (OS), using Kaplan Meier methods.

In the overall population (n=384), the median age at index was 74 years (interquartile range [IQR] 66, 80). The median time from diagnosis to index was 23.9 months (IQR 4.1, 60.6) and the median follow-up duration was 25.6 months (IQR 16.2, 35.2). During ibrutinib treatment, the following AEs were documented for the overall population: fatigue (172 of 384; 44.8%), diarrhea (87 of 384; 22.7%), rash (60 of 384; 15.6%) and atrial fibrillation (AFib) (35 of 384; 9.1%).

Median rwPFS and OS were not reached (NR) for the overall population. At 24 months, rwPFS probability was 72.5% (95% confidence interval [CI] 67.3, 76.9) and OS rate was 81.8% (95% CI 77.2, 85.5). Of the 352 patients who discontinued 1L ibrutinib (91.7%), the median TTD was 14.5 months (95% CI 12.6, 17.2) and median TTNT-D was 39.1 months (95% CI 15.2, NR). By the end of the study period, only 32 out of 384 patients (8.3%) sustained ongoing ibrutinib treatment.

Of the total population (384), 34 (8.9%) initiated 2L non-BTKi therapy, 55 (14.3%) were retreated with ibrutinib, and 47 (12.2%) started 2L 2G BTKi therapy. Lastly, 23 (9.3%) continued ibrutinib treatment and 225 discontinued without starting 2L therapy.

Of the 34 patients receiving 2L non-BTKi therapy, 9 (26.5%) discontinued ibrutinib due to PD and 21 (61.8%) due to AEs. The median TTD was 3.3 months (95% CI 1.6, 6.2), and the median follow-up duration was 26.5 months (IQR 15.7, 35.8). The median rwPFS was 14.8 months (95% CI 10.5, 29.0), with a 24-month rwPFS of 38.3% (95% CI 21.1, 55.3). The 24-month OS rate was 73.1% (95% CI 53.1, 85.6).

Of the 55 patients who were retreated with ibrutinib, the median TTD was 24.8 months (95% CI 18.3, 30.1). The median follow-up duration was 26.3 months (IQR 18.5, 37.5). The median rwPFS was 38 months (95% CI 23.6, NR), with a 24-month rwPFS of 62.9% (95% CI 48.1, 74.6). The 24-month OS rate was 76.2% (95% CI 61.8, 85.8).

Among the 47 patients treated with 2L 2G BTKis, 3 (6.4%) discontinued ibrutinib due to PD, and 41 (87.2%) due to AEs. The median TTD was 6.9 months (95% CI 3.4, 11.3). The median follow-up duration was 28.6 months (IQR 17.8, 39.2). The median rwPFS was 39 months (95% CI 26.7, NR), with a 24-month rwPFS of 73.5% (95% CI 56.9, 84.5). The 24-month OS rate was 95.7% (95% CI 84.0, 98.9).

This study analyzed CLL/SLL patients treated with 1L ibrutinib in The US Oncology Network. Around 20% of patients discontinued ibrutinib for 2L therapies, mostly due to AEs rather than PD. The observed AEs, such as AFib at 9.1%, were consistent with existing data. Patients who interrupted and resumed ibrutinib had similar rwPFS as those who switched to a 2G BTKi. However, patients who switched to non-BTKis had lower rwPFS, suggesting a less favorable subset. The 24-month overall OS rate was around 80%, lower than reported in prospective clinical trials of 1L ibrutinib. Patients who interrupted and resumed ibrutinib or switched to non-BTKis had similar OS, while those who switched to 2G BTKis had better OS, indicating the need for further investigation.

This study highlights the importance of optimizing supportive care and sequencing strategies to enhance outcomes for CLL/SLL patients in real-world community settings.