Real-world evidence study of treatment patterns and outcomes following covalent BTKi discontinuation in a contemporary cohort of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients.
Authors: Lin Kevin H. , Huynh Lynn , Yang Xiaoqin , Zanardo Enrico , Lema Neema , Matay Lisa , Balasubramanian Sobana , Liborski Daria , McDonough Mikaela , Foreman Jillian , Farooqui Mohammed Z.H. , De Nigris Enrico , Gandra Shravanthi R. , Sarpong Eric M. , Duh Mei Sheng , Brown Jennifer R. , Davids Matthew Steven 
Published: June 2023

e19510 Background: In the past decade, covalent Bruton Tyrosine Kinase inhibitors (BTKi) have transformed the treatment landscape for patients with CLL/SLL. Previous research described BTKi discontinuation in CLL/SLL cohorts where most patients received the BTKi after multiple prior lines of therapy. Information on outcomes of patients who received BTKi in first or second line (1L or 2L) and subsequently discontinued is limited. We examine a cohort of contemporary CLL/SLL patients who discontinued the BTKi, a majority of whom initially received BTKi in 1L or 2L. Methods: A retrospective chart review study of adult CLL/SLL patients who were treated with a covalent BTKi at Dana-Farber Cancer Institute and who were resistant/refractory or intolerant to BTKi was conducted. Abstraction took place 12/2021-12/2022. Data abstracted included demographics, clinical characteristics, treatment patterns, reasons for treatment discontinuation, and cause of death. Results: A total of 104 patients were included with median time from CLL/SLL diagnosis to first BTKi initiation (index date) of 7 years, median age of 67 years at index date, and median follow-up of 6 years. Prognostic marker testing revealed the following: del(13q): 58%, del(11q): 28%, del(17p): 26%, trisomy 12: 20%, complex karyotype: 16%; IGHV unmutated: 59%, TP53 mutation: 66%. The most common index BTKi was ibrutinib (92%: 59% as monotherapy and 12% in combination with anti-CD20 mAb). 27% of patients were treated with BTKi in 1L, 32% in 2L, and 41% in later lines of therapy. 102 (98%) patients discontinued index BTKi. The median duration of index BTKi treatment was 2 years. 53% of patients discontinued index BTKi due to adverse events, most commonly atrial fibrillation (26%) and bleeding events (13%); 40% discontinued due to disease progression; and 3% due to Richter’s transformation. Subsequent treatments were observed for 74% of patients who discontinued due to adverse events and all patients who discontinued due to progression. Following last BTKi treatment, 60% received subsequent therapies; among these, 86% received regimens with venetoclax from index BTKi initiation to data cutoff. 34% of patients died with the most frequent causes of death being disease progression (62%), infection (17%), and secondary malignancy (7%). Conclusions: In this retrospective chart review study of adult CLL/SLL patients, adverse events and disease progression were key drivers for BTKi discontinuation, as found in earlier studies in more heavily pre-treated patients. Following BTKi discontinuation, a high percentage of patients received venetoclax-based regimens, yet with a median follow-up of 6 years, 34% died. This suggests that novel treatment approaches are sorely needed for less heavily pre-treated CLL/SLL patients who discontinue covalent BTKi.