Characteristics and Outcomes of Patients Receiving Sequential Bruton's Tyrosine Kinase Inhibitor (BTKi)/B-Cell Lymphoma 2 Inhibitor (BCL2i) for Treatment of Chronic Lymphocytic Leukemia (CLL) in the Real-World (rw) Practice Setting
Authors: Davids Matthew S. , Ambrose Jacob , De Nigris Enrico , Prescott Jennifer , Leng Siyang , Farooqui Mohammed Z.H. , Gandra Shravanthi R. , Zettler Christina M. , Fernandes Laura L. , Wang Ching-Kun , Shadman Mazyar 
Published: December 2023

Introduction: Bruton's Tyrosine Kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is) are targeted agents that have proven to be particularly effective in treating chronic lymphocytic leukemia (CLL). It is critical to understand the current utilization patterns and outcomes of patients receiving these therapies in a sequential manner in the real-world (rw). This study explored patient characteristics and treatment outcomes for patients who were exposed to and discontinued treatment with BTKis and BCL2is in two consecutive lines of therapy (LOTs) for CLL.
Methods: Patients were identified in the COTA rw database, a Health Insurance Portability and Accountability Act-compliant database comprised of longitudinal data abstracted from the electronic health records of healthcare provider sites in the United States. Eligible patients met the following study criteria: Aged ≥ 18 years at diagnosis with a confirmed CLL/ small lymphocytic lymphoma (SLL) diagnosis who initiated second line (2L) therapy between January 1, 2014 - June 30, 2021 and discontinued two consecutive LOTs for the analysis in question. The treatment groups assessed were (1) patients who were exposed to and discontinued treatment with BTKi and BCL2i therapies in sequential LOTs, regardless of which agent(s) was initiated first (“BTKi/BCL2i treatment” group) and (2) patients who completed treatment in the same two LOTs, but who did not receive BTKi and BCL2i therapies in both LOTs (“other” group). Other non-BTKi/BCL2i therapies received included bendamustine+rituximab, rituximab monotherapy, investigational regimens, chlorambucil+obinutuzumab, and other regimens. Patients were considered to have discontinued a given LOT if the patient had a documented end date for the LOT for any reason, including treatment completion as indicated or premature discontinuation for any reason (i.e., toxicity, progression, etc.). Patients were ineligible if they had a documented diagnosis of a concurrent primary malignancy or histologic transformation at the time of CLL/SLL diagnosis or a history of other primary malignancies, excluding benign skin cancers, within 3 years prior to CLL/SLL diagnosis. The index date for the study was the initiation of the second LOT in the sequence. The observation period was defined as the duration of time from index date to the date of patient death or last visit date (if date of death was not available). Time to next treatment (TTNT) and rw progression-free survival (rwPFS) were evaluated using the Kaplan-Meier method. Rw overall response rate (rwORR) was the proportion of patients who had a clinician-documented PR or CR as the best response to a LOT.
Results: A total of 67 patients were identified to have been exposed to and discontinued a BTKi/BCL2i treatment sequence (1L→2L: N=21, 2L→3L: N=23, 3L+: N=23). The median age at diagnosis was 63 years (IQR: 55, 70), and patients were predominantly White (76%), male (67%), and treated in the community setting (81%). 67.2% of patients who completed two consecutive BTKi/BCL2i therapies were diagnosed in 2014 or earlier. Median follow up time from diagnosis was 112.6 months (IQR: 72.4, 149.4).
Outcomes analysis was conducted for patients who received a BTKi/BCL2i treatment sequence in 1L→2L relative to patients in the other treatment group in the same LOTs. Patients in the BTKi/BCL2i treatment group in 1L→2L (N=21) had more favorable rwPFS (41.8 months, HR 0.46, 95% CI: 0.23-0.93) relative to patients in the other treatment group in 1L→2L (N=833, 23.4 months). Median TTNT and rwORR for patients in the BTKi/BCL2i treatment group were not reached (NR) and 81.0%, respectively. Patients in the other treatment group experienced median TTNT of 21.4 months and rwORR of 78.3%.
Conclusions: Our findings indicate that patients treated with BTKi/BCL2i sequences in 1L and 2L may have experienced improved outcomes relative to patients who received other sequences in the same LOTs. While research is beginning to investigate characteristics and outcomes for patients who received these therapies consecutively (Lew et al., Blood Adv 2021), future research should further examine these outcomes in a larger patient population and in patients who have already discontinued and relapsed on both BTKis and BCL2is.